Note: Descriptions are shown in the official language in which they were submitted.
- 1 1336905
RAN 4440/163
The present invention relates to novel tricyclic
compounds, more particularly to pyridot3,2,1-ij]-1,3,4-
-benzoxadiazine derivatives, to a process for their manufac-
ture, to pharmaceutical preparations containing them and to
intermediates useful in said process.
- More particularly, the present invention relates to
novel pyridot3,2,1-ij]-1,3,4-benzoxadiazine derivatives
represented by the general formula
R6- N ~ COOR
R ~ (I)
wherein R is a hydrogen atom or a carboxy-protecting
radical; R2 is a hydrogen atom or a lower alkyl
radical which may be substituted with a halogen atom;
R3 and R4 independently are a hydrogen atom or a
lower alkyl radical which may be sub6tituted with a hydroxy
radical or with a ~ubstituted or unsubstituted amino
radical; X is a halogen atom: and R5 and R6 are
independently a hydrogen atom or a lower alkyl radical
which may be substituted with a hydroxy radical, a lower
alkoxy radical or a substituted or unsubstituted amino
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
- 2 _ 1 3 3 6 9 0 5
more substituents at the carbon atom(s), and the hetero-
cyclic ring may further contain -NR -, -0-, -S-, -S0-,
-S02- or -NR -C0-, [R is a hydrogen atom, a lower
alkenyl radical, a lower alkyl or aralkyl radical which
may be substituted, or a radical represented by the
general formula
~(CH2)nCR (II)
L0 (in which n is 0 to 4 and R is a hydrogen atom, a
lower alkoxy radical, or an amino, lower alkyl or aryl
radical which may be substituted)],
as well as pharmaceutically acceptable salts thereof, and
hydrates or solvates of the compounds of the formula I or
their salts, which are useful as effective ingredients in
antibacterial agents.
The respective radicals of the formula I which are
defined above are explained in more detail as follows;
reference to the term ''lowerl' is intended to mean a carbon
chain preferably containing up to and including 7 carbon
atoms, unless otherwise indicated.
~xplanation of R :
R 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 (e.g.
acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and
l-pivaloyloxyethyl); lower alkoxycarbonyloxyalkyl (e.g.
methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and
l-isopropoxycarbonyloxyethyl); lactonyl (e.g. phthalidyl and
thiophthalidyl); lower alkoxymethyl (e.g. methoxymethyl);
benzyloxymethyl; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; or
~ - 3 - 1 336905
lower alkanoylaminomethyl (e.g. acetamidomethyl). Other
ester groups e.g. benzyl, cyanomethyl, phenacyl, phenyl and
the like can also be used.
Explanation of R :
R is a hydrogen atom or a lower alkyl radical which
may be substituted with a halogen atom.
In the above, the lower alkyl radical preferably
contains l 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 R :
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 l to 4 carbon atoms, especially methyl, ethyl,
n-propyl, iso-propyl, n-butyl, and the like. The substitu-
ted amino radicals can be di-lower alkylamino such as
dimethylamino, diethylamino: lower alkylamino such as
methylamino, ethylamino, lower cycloalkylamino such as cyclo-
propylamino, and the like.
Explanation of R and R :
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-
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 -NR7-, -0-, -S-, -SO-, -S0z- or
1 336905
-- 4
-NR -C0- [wherein R is a hydrogen atom, a lower alkenyl
radical, a lower alkyl or aralkyl radical which may be sub-
stituted, or a radical represented by the general formula
S ~tCH2)ncOR (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)].
L0
The above defined radicals will be further illustrated
in more detail as follows:
The lower alkyl radical preferably contains 1 to 4
~5 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl,
n-butyl, and the like. The lower alkoxy radical preferably
contains 1 to 4 carbon atoms such as methoxy, ethoxy, n-pro-
poxy, iso-propoxy, n-butoxy, and the like. The substituted
amino radical can be di-lower alkylamino such as dimethyl-
amino, diethylamino, ethylmethylamino: lower alkylamino suchas methylamino, ethylamino, n-propylamino, iso-propylamino;
lower cycloalkylamino such as cyclopropylamino and the like.
The 5 to 7 membered heterocyclic ring formed by R and
R6 can be piperazinyl, morpholinyl, thiomorpholinyl,
piperidyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, imidazolyl, triazolyl and the like. Examples of
the substituents at the carbon atom(s) of the heterocyclic
ring are hydroxy, lower alkoxy such as methoxy, ethoxy,
n-propoxy: amino: lower alkylamino such as methylamino,
ethylamino, n-propylamino, iso-propylamino: lower cyclo-
alkylamino such as cyclopropylamino: di-lower alkylamino
such as dimethylamino, diethylamino, ethylmethylamino: lower
alkanoylamino such as acetylamino: benzylamino optionally
substituted by nitro, amino, halogen, hydroxy and/or lower
alkoxy, e.g. t4-aminobenzyl)amino: a group of the general
formula
_ ~ 5 ~ 1 336905
R50
N-CH=N-
R5 ~
where R and R are lower alkyl or together with the
nitrogen atom represent a 5 to 8 membered saturated
N-heterocycle such as (dimethylamino)methyleneamino, (hexa-
hydro-lH-azepin-l-yl)methyleneamino; 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: amino-
methyl, (methylamino)methyl, (ethylamino)methyl, (n-propyl-
amino)methyl, (iso-propylamino~methyl, (cyclopropylamino)-
L5 methyl, (dimethylamino)methyl, (diethylamino)methyl, (ethyl-
methylamino)methyl, acetylaminomethyl, 2-aminoethyl, 2-
-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(diethylamino)-
ethyl, 2-(dimethylamino)ethyl, 2-(ethylmethylamino)ethyl;
hydroxy-(lower alkyl) such as hydroxymethyl, 2-hydroxy-
ethyl: phenyl, optionally substituted by amino, halogen,
hydroxy and/or lower alkoxy such as 4-aminophenyl,
4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 4-methoxy-
phenyl; a heterocyclic ring such as pyrrolyl, 4-methyl-1-
-piperazinyl and the like.
The lower alkenyl radical represented by R is e.g.
allyl, 3-methyl-2-butenyl, 2-butenyl, 1-methyl-2-propenyl,
3-butenyl and the like.
The substituted alkyl radical represented by R is
e.g. hydroxy-(lower alkyl) such as 2-hydroxyethyl,
3-hydroxybutyl; lower alkoxy-lower alkyl such as 2-methoxy-
ethyl, 2-ethoxyethyl; amino-lower alkyl such as 2-amino-
ethyl, 3-aminobutyl; lower alkylamino-lower alkyl such as
2-(methylamino)ethyl, 2-(ethylamino)ethyl, 3-(methylamino)-
butyl, 3-(ethylamino)butyl; di-lower alkylamino-lower alkyl
such as 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl,
_ 6 - l 33690~
3-(dimethylamino)butyl, 3-(diethylamino)butyl; halogen-lower
alkyl such as 2-fluoroethyl, 3-fluoro-n-butyl; carboxy-lower
alkyl such as carboxymethyl, 2-carboxyethyl; sulfo-lower
alkyl such as sulfomethyl, 2-sulfoethyl and the like.
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.
The amino radical R may be unsubstituted or substitu-
ted 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
R is e.g. carrying a carboxy or lower alkoxycarbonyl
radical such as in 2-carboxyethyl, 3-carboxy-n-propyl,
2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycar-
bonyl-n-propyl and the like.
The aryl radical represented by R is preferably
phenyl; substituted aryl is preferably carrying one or more
halogen, lower alkoxy, hydroxy, nitro and/or amino group(s)
such as in 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,
4-methoxyphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-nitro-
phenyl, 4-aminophenyl and the like.
Especially preferable radicals represented by R are
hydrogen, methyl, ethyl, n-propyl, iso-propyl, 2-hydroxy-
ethyl, 2-methoxyethyl, 2-aminoethyl, 3-amino-n-butyl,
2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-fluoroethyl,
carboxymethyl, sulfomethyl, allyl, 4-aminobenzyl, 4-fluoro-
benzyl, formyl, acetyl, propionyl, benzoyl, 4-aminobenzoyl,
1 336905
-- 7 --
2-oxo-n-propyl, 2-oxo-n-butyl, 3-oxo-n-butyl, 3-oxo-n-
-pentyl, 3-carboxypropionyl, 3-ethoxycarbonylpropionyl,
4-carboxy-n-butyryl, phenacyl, 4'-aminophenacyl, ethoxycar-
bonyl, methoxycarbonyl, carbamoyl and the like.
Especially preferable radicals represented by
R R N- in the formula (I) are l-piperazinyl, 4-methyl-l-
-piperazinyl, 3-methyl-l-piperazinyl, 3-phenyl-l-pipera-
zinyl, 3,4-dimethyl-l-piperazinyl, 4-ethyl-l-piperazinyl,
3-(4-aminophenyl)-l-piperazinyl, 4-n-propyl-l-piperazinyl,
4-(2-fluoroethyl)-l-piperazinyl, 4-allyl-l-piperazinyl,
4-(2-oxo-n-propyl)-l-piperazinyl, 4-(carboxymethyl)-l-
-piperazinyl, 4-(3-oxo-n-butyl)-l-piperazinyl, 4-(sulfo-
methyl)-l-piperazinyl, 4-(4-aminobenzyl)-l-piperazinyl,
4-(2-hydroxyethyl)-l-piperazinyl, 3-oxo-l-piperazinyl,
4-phenacyl-l-piperazinyl, 4-(3-carboxypropionyl)-l-pipera-
zinyl, 4-acetyl-l-piperazinyl, 4-(4-nitrobenzyl)-l-pipera-
zinyl, morpholino, 2-methyl-4-morpholinyl, 2,6-dimethyl-4-
-morpholinyl, 4-thiomorpholinyl, l-oxide-4-thiomorpholinyl,
l,l-dioxide-4-thiomorpholinyl, 4-(aminomethyl)-l-piperidyl,
4-[(methylamino)methyl]-l-piperidyl, 4-methoxy-l-piperidyl,
4-hydroxy-l-piperidyl, 4-(l-pyrrolyl)-l-piperidyl, 4-amino-
-l-piperidyl, 4-(methylamino)-l-piperidyl, 4-(ethylamino)-l-
-piperidyl, l-homopiperazinyl, 4-methyl-l-homopiperazinyl,
3-amino-l-pyrrolidinyl, 3-(methylamino)-l-pyrrolidinyl,
3-(ethylamino)-l-pyrrolidinyl, 3-(benzyloxycarbonylamino)-l-
-pyrrolidinyl, 3-(aminomethyl)-l-pyrrolidinyl, 3-amino-4-
-phenyl-l-pyrrolidinyl, 3-amino-3-methyl-l-pyrrolidinyl,
3-amino-4-methyl-l-pyrrolidinyl, 3-(4-aminobenzylamino)-l-
-pyrrolidinyl, 3-(4-methyl-l-piperazinyl)-l-pyrrolidinyl.
3-[(dimethylamino)methyleneamino]-l-pyrrolidinyl,
3-[(methylamino)methyl]-l-pyrrolidinyl, 3-[(methylamino)-
methyl]-4-phenyl-l-pyrrolidinyl, 3-methyl-3-[(methylamino)-
methyl]-l-pyrrolidinyl, 3-[(ethylamino)methyl]-l-pyrroli-
dinyl, 3-(acetylaminomethyl)-l-pyrrolidinyl, 3-[(dimethyl-
amino)methyl]-l-pyrrolidinyl, 3-[(ethylmethylamino)-
methyl]-l-pyrrolidinyl, 3-amino-4-methoxy-l-pyrrolidinyl,
_ - 8 - ~ 3 3 6 9 0 5
3-methoxy-4-(methylamino)-l-pyrrolidinyl,
3-(ethylamino)-4-methoxy-l-pyrrolidinyl, 3-amino-4-chloro-l-
-pyrrolidinyl, 3-chloro-4-(methylamino)-l-pyrrolidinyl,
3-chloro-4-(ethylamino)-l-pyrrolidinyl, 3-amino-4-fluoro-l-
-pyrrolidinyl, 3-fluoro-4-(methylamino)-l-pyrrolidinyl,
3-(ethylamino)-4-fluoro-l-pyrrolidinyl, 3-(aminomethyl)-4-
-chloro-l-pyrrolidinyl, 3-chloro-4-[(methylamino)methyl]-l-
-pyrrolidinyl, 3-chloro-4-[(ethylamino)methyl]-l-pyrroli-
dinyl, 3-(aminomethyl)-4-fluoro-l-pyrrolidinyl, 3-fluoro-4-
-[(methylamino)methyl]-l-pyrrolidinyl, 3-[(ethylamino)-
methyl]-4-fluoro-l-pyrrolidinyl, 3-(aminomethyl)-4-methyl-l-
-pyrrolidinyl, 3-methyl-4-[(methylamino)methyl]-l-pyrroli-
dinyl, 3-[(ethylamino)methyl]-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, l-imidazolyl, 4-methyl-l-imi-
dazolyl, 3-amino-4-hydroxy-l-pyrrolidinyl, 3-(methylamino)-
-4-hydroxy-l-pyrrolidinyl, 3-(ethylamino)-4-hydroxy-l-
-pyrrolidinyl, 3-(dimethylamino)-4-hydroxy-l-pyrrolidinyl,
zo [Z-(dimethylamino)ethyl]methylamino, and the like.
Explanation of X:
X is a halogen atom such as fluorine, chlorine or
bromine, preferably fluorine or chlorine.
The novel pyrido[3,2,l-ij]-l,3,4-benzoxadiazine deriva-
tives of the formula (I) and their pharmaceutically accep-
table salts and hydrates or solvates thereof and of these
salts are manufactured in accordance with the present
invention by a process which comprises
(a) reacting a compound represented by the general formula
-
- g - I 336905
X~OOR (III)
R ~h3
wherein Rl R2 R3 R4 d X th
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 - R5 (IV)
I
R
wherein R and R are the same as defined above,
followed, if necessary by removal of a protecting radical, or
(b) reacting a compound represented by the general formula
X ~ (V)
R
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
lO - 1 3 3 6 9 0 5
C=0 (VI)
R4 /
s wherein R 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
(c) 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
(d) 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 and/or R are hydrogen
or contain an amino, lower alkylamino or hydroxy group, or
(e) for the manufacture of a compound of formula I in which
R R N- is a 5 to 7 membered heterocyclic ring with -S0-
or -S02- subjecting a corresponding compound wherein the
heterocyclic ring contains -S- to oxidation, or
(f) for the manufacture of a compound of formula I having a
free amino, hydroxy and/or carboxy group splitting off the
protecting group(s) from a corresponding compound of formula
I having (a) protected amino, hydroxy and/or carboxy
group(s), or
.(g) for the manufacture of a compound of formula I
containing a halogen atom halogenating a correspondingly
hydroxy-substituted compound of foemula I in which Rl is a
carboxy-protecting radical and, if desired, splitting off
said protecting radical R , or
(h) for the manufacture of a compound of formula I
containing an amino group reducing the nitro group of a
11 - 1 3 3 6 9 0 5
correspondingly nitro-substituted compound of formula I, or
(i) for the manufacture of a compound of formula I
containing a group of the formula R ~
- N-CH=N-,
R ~
where RS and R are lower alkyl or together with the
nitrogen atom represent a S 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
RSO
N-CH0 (VII)
R ~
wherein R and R are as above,
or
(j) for the manufacture of a compound of formula I in which
Rl is a carboxy-protecting radical subjecting a carboxylic
acid of formula I to a corresponding esterification, or
(k) 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.
Process A:
As stated above, the desired compounds can be obtained
by reacting a compound represented by the general formula
~ - 12 -
1 336905
X ~ OOR (III)
, ~ ~R,2
wherein R , R , R , R and X are the same as
defined above, and Xl 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)
R6
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
to the following reaction scheme a) or b).
a) 1 336905
X ~reduction~ X~ ~ H2 H5C20CH=C(cooc2Hs)2
H . OH
(A) (B)
H5C200C H5C200C
X ~ ~ C2H5 X ~ ~ COOC2H5
X' ~ ~ OH-protection ~ N~ cyclization
H R'
(C) (D)
O,H O
X~COOC2H5 X~:OOC2H5
X~ ~ ~ amination ~ J N-protection
R' OR' NH2
(E) (F)
O O
X~COOC2H5 X~COOC2H5
X' ~ N~ al~ylation X' ~ NY deprotection
(G) (H)
X ~ cycliza~on ~ ~ OOR"'
OH NHR O
R4~<RN~2
(Va) (IIIa)
- 14 -
b) 1 3369~5
H5C2C\ C0C2H5 qH
~IL JJ x ,,COOC2H5
OH cyclization X' ~ N~ OH-protection
OH
(C) (J)
OH O
~,COOC2H5 X~C2H5
amination X' ~ 1~ N-protectio~
~E) (F)
X~f OOC2H5 X COOC2H5
X' ~ N alkylation ~ deprotection
OR' NHR" I a
OR' N-R
R"
(G) (H)
O O
X ~ COOR"' X~ ~ COOR"'
X~ ~ cyclization X~ ~ N
OH NHR; R4 ~R~
(Va) (IIIa)
1S - I 336905
wherein R , R , R , X and X' are the same as
defined above; R' is a protecting radical, such as
benzyl, methoxybenzyl, methoxymethyl, methoxyethoxy-
methyl, tetrahydropyranyl, allyl, t-butyl, t-butyldi-
methylsilyl, acetyl, benzoyl and the like; R~ is a
protecting radical, such as formyl, acetyl, trifluoro-
acetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxy-
carbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxy-
carbonyl and the like and R"' 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, benzyloxy-
carbonyl, 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
30C to about 200C, preferably from 80C to 150C in order
to obtain sufficiently fast reaction rate.
The reaction is preferably carried out in the presence
of an acid acceptor such as triethylamine, pyridine,
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. Alter-
natively an excess of the amine of the formula (IV) may be
utilized as the acid acceptor.
The convenient solvents for this reaction are non-reac-
tive solvents such as acetonitrile, alcohols, dimethylsul-
foxide, dimethylformamide, dimethylacetamide, pyridine,
- 16 ~ 1 3 3 6 9 0 5
picoline, lutidine, N,N'-dlmethylpropyleneurea, and the like
Mixtures of two or more solvents may also be used.
The protecting radical may, if desired, be removed after
s 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:
9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridot3,2,1-ij]-
1,3,4-benzoxadiazine-6-carboxylic acid,
~5
9,10-dichloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-
1,3,4-benzoxadiazine-6-carboxylic acid,
9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-
t3.2,1-ii]-1,3,4-benzoxadiazine-6-carboxylic acid,
ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-
t3.2.1-ii]-1.3.4-benzoxadiazine-6-carboxylate,
benzyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-
t3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylate,
9,10-difluoro-3-(2-fluoroethyl)-7-oxo-2,3-dihydro-7H-pyrido-
t3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid,
9,10-difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido-
t3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid,
9,10-difluoro-2-(hydroxymethyl)-3-methyl-7-oxo-2,3-dihydro-
7H-pyridot3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid,
-- - 17 - 1 336905
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,
9,10-difluoro-2,2,3-trimethyl-7-oxo-2,3-dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, and the
like.
The amine of the formula (I~) used in the above reaction
is, for instance, piperazine, 4-methylpiperazine,
3-methylpiperazine, 3-phenylpiperazine, 3-(4-aminophenyl)-
piperazine, 3-(4-nitrophenyl)piperazine, 4-(2-hydroxyethyl)-
piperazine, morpholine, 2-methylmorpholine, 2,6-dimethylmor-
pholine, thiomorpholine, 4-(aminomethyl)piperidine,
4-[(methylamino)methyl]piperidine, 4-[(ethylamino)methyl]-
piperidine, 4-aminopiperidine, 4-(methylamino)piperidine,
4-(ethylamino)piperidine, 4-(benzyloxycarbonylamino)piperi-
dine, 4-(benzyloxycarbonylmethylamino)piperidine, 4-(benzyl-
oxycarbonylethylamino)piperidine, 4-hydroxypiperidine,
4-methoxypiperidine, 4-(1-pyrrolyl)piperidine, homopipera-
zine, 3-[(methylamino)methyl]pyrrolidine, 3-[(ethylamino)-
methyl]pyrrolidine, 3-(acetylaminomethyl)pyrrolidine,
3-hydroxypyrrolidine, 3-methoxypyrrolidine, 3-aminopyrroli-
dine, 3-(benzyloxycarbonylamino)pyrrolidine, 3-(methyl-
amino)pyrrolidine, 3-(benzyloxycarbonylmethylamino)pyrroli-
dine, 3-amino-4-phenylpyrrolidine, 3-amino-3-methylpyrroli-
dine, 3-amino-4-methylpyrrolidine, 3-(4-aminobenzylamino)-
pyrrolidine, 3-(4-methyl-1-piperazinyl)pyrrolidine,
3-[(dimethylamino)methyleneamino]pyrrolidine, 3-[(methyl-
amino)methyl]-4-phenylpyrrolidine, 3-methyl-3-[(methyl-
amino)methyl]pyrrolidine, 3-(ethylamino)pyrrolidine,
3-(benzyloxycarbonylethylamino)pyrrolidine, 3-[(dimethyl-
amino)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-hydroxy-
pyrrolidine-, 3-amino-4-hydroxypyrrolidine, 3-(methylamino)-
- - 18 - ~ 3369~5
-4-hydroxypyrrolidine, 3-(ethylamino)-4-hydroxypyrrolidine,
3-(aminomethyl)-4-methylpyrrolidine, 3-methyl-4-[(methyl-
amino)methyl]pyrrolidine, 3-[(ethylamino)methyl]-4-methyl-
pyrrolidine, 3-hydroxy-4-methoxypyrrolidine, 3-(acetylamino-
methyl)-4-hydroxypyrrolidine, imidazole, 4-methylimidazole,
N,N,N'-trimethylethylenediamine and the like.
Process B:
The desired compound can be obtained by reacting a
L0 compound represented by the formula
~5 6 ~ OORl (V)
R---N I 2
OH ~H~
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
Z5 R
C=O (VI)
R4 /
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
b), or reacting a compound (H) or(Va~with an amine of the
19 - I 3 3 6 9 0 5
formula (IV).
If the carbonyl compound of formula (VI) or its polymer,
acetal, ketal or enol ether contains an amino or monoalkyl-
amino substituent, 6aid substituent may, if desired, be
protected by a radical ~uch as described above under R~ in
formulas (G) and (H).
The reaction may, if desired, be carried out in a
solvent, such as dioxane, tetrahydrofuran, acetonitrile,
chloroform, dimethylformamide, dimethylsulfoxide, N,N'-
dimethylpropyleneurea, acetic acid and the like. Mixtures
of two or more solvents may also be used.
The reaction may, if necessary, be carried out in the
L5 presence of an acid catalyst such as acetic acid, hydro-
chloric acid, 6ulfuric 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
like.
The reaction temperature may be varied within a relati-
vely wide range. In qeneral, the reaction is carried out ata temperature between 20C and 150C.
In a preferred embodiment of the process provided
according to the present invention, about 1 mole or excess
moles of the carbonyl compound of the formula (VI), or its
polymer, acetal, ketal or enol ether per mole of the
compound of the formula (V) is employed.
The amino or 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
radical may be removed by acid or base hydrolysis preferably
* Trade Marks
_ 20 - 1336905
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-l-(methylamino)-4-oxo-1,4-dihydro-
3-quinolinecarboxylic acid,
ethyl 6,7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-l,4-
dihydro-3-quinolinecarboxylate,
benzyl 6,7-difluoro-8-hydroxy-l-(methylamino)-4-oxo-l,4-
dihydro-3-quinolinecarboxylate,
6,7-dichloro-8-hydroxy-l-(methylamino)-4-oxo-l,4-dihydro-
3-quinolinecarboxylic acid,
6-chloro-7-fluoro-8-hydroxy-l-(methylamino)-4-oxo-1,4-
dihydro-3-quinolinecarboxylic acid,
6,7-difluoro-l-[(2-fluoroethyl)amino]-8-hydroxy-4-oxo-l,4-
dihydro-3-quinolinecarboxylic acid,
6-fluoro-8-hydroxy-7-(l-imidazolyl)-l-(methylamino)-4
l,4-dihydro-3-quinolinecarboxylic acid,
ethyl 6-fluoro-8-hydroxy-7-(l-imidazolyl)-1-(methylamino)-4-
oxo-l,4-dihydro-3-quinolinecarboxylate,
benzyl 6-fluoro-8-hydroxy-7-(l-imidazolyl)-l-(methylamino)-
4-oxo-l,4-dihydro-3-quinolinecarboxylate,
6-fluoro-l-[(2-fluoroethyl)amino]-8-hydroxy-7-(l-imidazolyl)-
4-oxo-l,4-dihydro-3-quinolinecarboxylic acid,
1 33690~
6-chloro-8-hydroxy-7-(1-imidazolyl)-1-(methylamino)-4-oxo-
1,4-dihydro-3-quinolinecarboxylic acid,
6-fluoro-8-hydroxy-1-(methylamino)-7-(4-methyl-1-pipera-
zinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid,
7-(3,4-dimethyl-1-piperazinyl)-6-fluoro-8-hydroxy-1-(methyl-
amino )-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid,
7-[3-[(benzyloxycarbonylethylamino)methyl]-1-pyrrolidinyl]-6-
fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinoline
carboxylic acid,
7-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-6-fluoro-8-
hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecar-
boxylic acid,
7-[3-[(benzyloxycarbonylmethylamino)methyl]-4-methyl-1-
pyrrolidinyl]-6-fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-
dihydro-3-quinolinecarboxylic acid,
7-[3-~(benzyloxycarbonylamino)methyl]-4-chloro-1-pyrroli-
dinyl]-6-fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-
3-quinolinecarboxylic acid, and the like.
Examples of compounds which can be reacted with a com-
pound of the formula (V) are carbonyl compounds of formula
(VI) such as formaldehyde, acetaldehyde, acetone, methyl
ethyl ketone, and the like ; their polymers such as para-
formaldehyde, paracetaldehyde, trioxane, and the like ;their acetals such as dimethoxymethane, l,l-dimethoxyethane,
1,3-dioxolane, glycolaldehyde dimethylacetal, dimethylamino-
acetaldehyde 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.
- - 22 - 1 336~5
Process C:
When it is desired to manufacture compounds of formula I
wherein the radical R R N- is a 5 to 7 membered
heterocyclic ring containing a group -NR - where R is
5 other than hydrogen, such as in
/~~~
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)nCR (II)
L5
(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
of formula I in which R is hydrogen with an agent
yielding the group R70. This reaction, an N-alkylation (or
an N-acylation), can be accomplished e.g. as follows:
N-alkylation:
A compound of the general formula
CO~l
~ ~ (IX)
HN ~ 0 ~ N~R~
~- 3
- - 23 - 1 336905
wherein Rl R2 R3 R4 d X th
defined above, the piperazinyl radical may be substitu-
ted at carbon atom(s), and amino, hydroxy and/or carboxy
groups present may be protected,
can be reacted
(i) with a compound represented by the general formula
R70 y (X)
wherein Y is a leaving group and R is the same as
defined above,
or (for obtaining compounds where R is the group
2 2 )
~5
(ii) with a Michael acceptor of the general formula
R -C0-CH=CH2 (XI)
wherein R is a lower alkyl radical or a lower alkoxy
radical,
or (for obtaining compounds where R is methyl or sulfo-
methyl)
(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
~ C0 \ (XII)
Z O
~ C0 /
~ 336905
_ - 24 -
wherein Z is an optionally ~ubstituted alkylene chain
having 2 or 3 carbon atoms, or arylene radical,
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 (I~) with a compound
represented by the formula (X). As leaving group Y there may
be mentioned e.g. halogen atoms such as chloro, bromo, iodo,
acyloxy radicals such as acetoxy, lower alkanesulfonyloxy
radicals such a~ methanesulfonyloxy, arylsulfonyloxy radi-
cals such as p-toluenesulfonyloxy; optionally nitrated
phenoxy radicals such as phenoxy, 4-nitrophenoxy; or
succinimidooxy or phthalimidooxy.
If the compound of the formula (X) contains an amino or
monoalkylamino substituent, said substituent may, if
desired, be protected by a radical such as described above
under R~' in formulas (G) and (H).
The reaction may, if necessary, be carried out in a
Z5 solvent such as dimethylformamide, dimethylacetamide,
dimethylsulfoxide,` N,N'-dimethylpropyleneurea, dioxane,
tetrahydrofuran, pyridine and the like. Mixtures of two
or more solvents may also be used.
The reaction is preferably carried out in the presence
of an acid acceptor such as triethylamine, pyridine,
N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydride, alkali
metal hydroxides, alkali metal carbonates and the like.
The reaction temperature may be varied within a relati-
vely wide range. In general, the reaction is carried out at
a temperature between about 0C and 180C, preferably bet-
- - 25 - 1 336905
ween 0C and 110C. In carrying out the process provided
according to the present invention, 1 to 4 moles, preferably
1 to 2 moles of the compound of the formula (X) is employed,
based on one mole of the compound of the formula (IX).
The compound of the formula (X) used in the present
invention can be iodomethane, iodoethane, bromoethane,
l-iodobutane, l-bromobutane, l-iodopropane, 2-iodopropane,
l-fluoro-2-iodoethane, 1-iodo-2-methoxyethane, N-(2-iodo-
L0 ethyl)acetamide, N-(2-iodoethyl)-N-methylacetamide, bromo-
acetic acid, allyl bromide, 4-fluorobenzyl bromide, acetic
formic anhydride, acetic anhydride, acetyl chloride, pro-
pionic anhydride, propionyl chloride, benzoic anhydride,
benzoyl chloride, 4-[(trifluoroacetyl)amino]benzoic
~5 anhydride, chloroacetone, 1-chloro-2-butanone, phenacyl
chloride, 4-acetylaminophenyl chloromethyl ketone, ethyl
chloroformate, methyl chloroformate, chloromethyl 4-nitro-
phenyl ketone, 4-nitrobenzyl bromide, dimethylcarbamoyl
chloride and the like.
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 relati-
vely wide range. In general, the reaction is carried out at
a temperature between about 30C and about 170C, preferably
between 50C and 140C.
- 26 - 1 3 3 6 9 0 ~
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 is methyl or sulfomethyl are
obtained) is normally carried out at slightly elevated
temperature, e.g. at about +50C to +100C.
Moreover, the desired compound can be produced by
reacting a compound of the formula (IX) with an anhydride of
the formula (XII).
The reaction may, if necessary, be carried out in a
solvent such as pyridine, dimethylformamide, dioxane, tetra-
hydrofuran and the like. Mixtures of two or more solvents
may also be used.
The reaction is preferably carried out in the presence
f an acid acceptor such as triethylamine, pyridine,
N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, alkali
metal hydroxides, alkali metal carbonates and the like.
The reaction temperature may be varied within a relati-
vely wide range. In general, the reaction is carried out ata temperature between about 0C and 120C, preferably bet-
ween 0C and 100C.
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.
~ - 27 - 1 336905
The anhydride used in the present invention is e.g.
succinic anhydride, glutaric anhydride, N-benzyloxycarbonyl-
aspartic 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.
Process D:
When it is desired to manufacture a compound of formula
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
R5 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
RlOY (XIII)
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 (X). Also, the reaction can be
carried out in the same manner as the alkylation reaction of
the compounds (IX) with (X) described above. The 0-alkyla-
tion is effected as the N-alkylation; however, expediently a
proton acceptor such as an alkali metal hydride e.g. sodium
hydride is added.
- 28 -
1 3369~5
Process E:
When it is desired to manufacture a compound of formula
I in which R R N- is a 5 to 7 membered heterocyclic ring
with an -S0- or -S02- member these compounds can be manu-
factured by oxidizing the corresponding desoxy-compounds of
formula I viz. with an -S- member in the heterocycle.
The oxidation is carried out by treatment with an
organic or inorganic oxidizing agent. Various compounds
which readily yield oxygen can be used as the oxidizing
agent; for example, organic peroxides such as monosubstitu-
ted organic peroxides (e.g. Cl-C4-alkyl- or alkanoyl-
hydroperoxides such as t-butylhydroperoxide), performic acid
and peracetic acid, as well as phenyl-substituted deriva-
tives of these hydroperoxides such as cumenehydroperoxide
and perbenzoic acid. The phenyl substituent can, if desired,
carry a further lower group (e.g. a Cl-C4 alkyl or
alkoxy group), a halogen atom or a carboxy group (e.g.
4-methylperbenzoic acid, 4-methoxy-perbenzoic, 3-chloroper-
benzoic acid and monoperphthalic acid). Various inorganic
oxidizing agents can also be used as the oxidizing agent:
for example, hydrogen peroxide, ozone, permanganates such as
potassium or sodium permanganate, hypochlorites such as
sodium, potassium or ammonium hypochlorite, peroxymonosul-
phuric and peroxydisulphuric acid. The use of 3-chloroper-
benzoic acid is preferred. The oxidation is advantageously
carried out in an inert solvent, for example, in an aprotic
inert solvent such as tetrahydrofuran, dioxan, methylene
chloride, chloroform or ethyl acetate. The oxidation is
generally carried out at a temperature in the range of -20C
to +50C.
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 sulfoxide, i.e. a
compound of formula I in which the heterocycle contains an
~ - 29 - 1 336905
-S0- 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 -SO2-
member. It is also possible to obtain the sulfone from thecorresponding sulfoxide by treatment with an equimolar or
greater amount of the oxidizing agent.
Process F:
~0
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,
L5 hydroxy and carboxy groups present in protected form.
Amino-protecting groups are e.g. lower alkanoyl such as
acetyl; benzoyl; an alkoxycarbonyl group, e.g., t-butoxycar-
bonyl or ethoxycarbonyl; a substituted alkoxycarbonyl group,
e.g. trichloroethoxycarbonyl: phenoxycarbonyl; benzyloxy-
carbonyl; 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 (e.g. the t-butoxycarbonyl or trityl group) or by
basic hydrolysis (e.g. the trifluoroacetyl group). Benzyl-
oxycarbonyl and p-nitrobenzyloxycarbonyl are removed by
hydrogenolysis.
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 parti-
cular, formic acid or trifluoroacetic acid is used. The acid
hydrolysis is generally carried out at room temperature,
_ 1 3 3 6 9 0 5
- 30 -
although it can be carried out at a slightly higher or
slightly lower temperature (e.g. a temperature in the range
of about 0C to +40C). Protecting groups which are
cleavable under basic conditions are generally hydrolyzed
with dilute aqueous caustic alkali at 0C to 30C.
Carboxy-protecting groups are e.g. the carboxy-protec-
ting radicals discussed under R above.
The removal of these protecting grou~s 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
0C and room temperature. Specific methods are also useful
e.g: p-nitrobenzyl removed by hydrolysis in the presence of
sodium sulfide at about or below 0C 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 0C to room temperature with or
without a co-solvent, such as methylene chloride; or allyl
removed by a palladium ~0) catalyzed transallylation reac-
tion in the presence of sodium or potassium salt of 2-ethyl
hexanoic acid, see for example J. Org. Chem. 1982, 47, 587.
Process G:
When it i8 desired to manufacture a compound of formula
~ containing a halogen atom, such as a compound where
R5R6N- is Cl- C N-, this compound can be manufactured by
halogenating a correspondin~ly hydroxy-substituted compound
(e.g. where RSR N- is HO ~ N-). The halogenating agent
is preferably a thionyl halide, especially thionyl chloride:
or phosphorous trichloride, phosphorous oxychloride or
phosphorous pentachloride. The reaction temperature is
. . .
- 31 - ~336905
preferably between about 0C and 80C. Carboxy groups
present are preferably protected, e.g. benzylated, and
subsequently, if desired, again set free e.g. by hydrogena-
tion (removal of benzyl).
Process H:
When it is desired to manufacture a compound of formula
I containing an amino group such as a compound where
R R N- is H2N ~ -CH2-N ~ -, this compound can be
manufactured by reducing the nitro groups of a
correspondingly nitro-substituted compound of formula I. The
reduction can be effected by hydrogenation in the presence
of a noble metal catalyst such as palladium on charcoal. The
reaction is suitably effected in water or a lower alkanol
e.g. methanol or ethanol, if desired in admixture with other
solvents soluble therein. The reaction temperature normally
lies between about 10C and about 40C, preferably at about
room temperature.
Process I:
When it is desired to manufacture a compound of formula
I containing a group of the formula
R50
~ N-CH=N-
R51/
(wherein R50 and R51 are as above) such as a compound
where R R N- is (CH3)2N-CH=N ~ -, this compound
can be manufactured by reacting the amino group of a
correspondingly amino substituted compound of formula I
(e.g. where R5R6N- is H2 ~ -) with a reactive
derivative of a formamide derivative of the general formula
_ - 32 - 1 33690~
R50
~ N-CH0 (VII)
R5 ~
5wherein 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 0C and 100C.
Process J:
~5
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 0C-40C.
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
- 33 - 1336905
as water or an organic solvent (e.g. ethanol, methanol,
acetone and the like). The temperature at which the salt
formation is carried out is not critical. The salt formation
is generally carried out at room temperature, but it can be
carried out at a temperature slightly above or below room
temperature, for example in the range of 0C to +50C.
Examples of pharmaceutically acceptable 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, hydroxyethane-
~5 fiulfonic, benzenesulfonic, p-toluenesulfonic, gluconic,
glucuronic, galacturonic, aspartic and glutamic acid :
methionine, tryptophan, lysine, arginine, and the like.
The acid addition salts can be converted into a free
form by treatment with a base, such as a metal hydroxide,
ammonia and the like.
The base salts of the compounds of the formula (I) can
be prepared by reacting a compound of the formula (I) with a
metal base or amine such as an alkali or alkaline earth
metal hydroxide, or an organic amine. Examples of the
metals used as cations are sodium, potassium, magnesium,
calcium and the like. Examples of amines are diethanol-
amine, N,N '-dibenzylethylenediamine, choline, ethylenediamine
and the like.
The acid addition salts or base salts of the compounds
of the formula (I) differ from the corresponding free form
in certain physical properties such as solubility in water.
The compounds of the formula (I) and their pharmaceuti-
cally acceptable salts can exist in unsolvated as well as
_ 34 _ 1 3~ 690~
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 (e.g. at about +10C to +40C). 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.
~5
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
The in vitro antibacterial activities of the represen-
tative 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 ~g/ml) are
shown in Table 1 and Table 2. The compounds used here were
produced by respective Examples as mentioned below.
TABLE 1 f
Antlbacterial ape~ MIC I ~g/_l
~ ,~ ' IExample No. )
Aerobic microorganism_ 5 6 7 8 9 12 13 15 16 17 18 19 21
Gram-positive bacteria
Baclllus subtill_ PCI 219 0.05 0.100.10 0.025 <0.0008 0.10 <0.00080.05 0.20 0.0130.0130.05 0.05
Staphylococc~c aureus FDA 209P JC-l 0.39 0.39 0.390.39 0.20 0.10 0.10 0.78 0.390.05 0.05 0.39 0.39
Staphylococcus aureus NR 2855 0.20 3.13 1.56 0,39 0.00650.78 0,05 0.78 6.25 0.200.10 0.39 0.20
Staphylococc~q aureu_ Smlth 0.20 0.39 0.20 0.20 0.00330.10 0.025 0.39 0.39 0.0250.0250.20 0.39
Staphylococcus ~ri~rmi~is IFO i2993 0.39 1.56 0.780.39 0.20 0.39 0.10 0.78 ' 1.56 0.20 0.10 0.39 0.39
Staphylococc~q epid~rmi~is NR 2942 0.39 1.56 0.780.39 0.00650.39 0.05 0.78 1.560.10 0.10 0.39 0.39
Enterococcus faecalls NR 2943 3.1312.5 12.5 6.2512.5 3.13 3.13 6.25 25 1.561.56 6.25 3.13
Gram-negative bacteria
Alcaligenes faecalis IFO 13111 0.39 3.13 6.25 0.78 6.25 50 3.13 3.13 50 6.256.25 6.25 0.78
Cltrobacter freundii IFO 12681 0.013 0.013 0.05 0.025 0.390.78 0.39 0.05 0.10 0.200.10 1.56 0.78
Enterobacter aerogenes NR 2945 0.013 0.013 0.05 0.025 0.0065 0.20 0.20 0.05 0.050.05 0.05 1.56 0.20
Enterobacter cloacae NR 2946 0.025 0.025 0.10 0,05 0.0130.78 0.39 0.10 0.10 0.100.05 1.56 0.78
Escherichia coli NIHJ JC-2 0.025 0.025 0.10 0,05 0.10 0.20 0.39 0.10 0.20 0.100.05 1.56 0.39
Escherichia coli NR 2630 0.013 0.025 0.025 0.013<0.0008 0.10 - - _ 0.025 0.013 0,39 0.20
Klebsiella pneumoniae FDA PCI 602 0.10 0.10 0.390.20 3.13 3.13 0.78 0.39 1.560.78 0.39 6.25 0.78
Bordetella bron~his~rtica ATCC 4617 0.2~ 6.25 3.130.39 1.56 6.25 0.78 0.78 25 6.25 3.13 6.25 0.78
Proteus rettgeri ATCC 14505 0.20 0.10 0.78 0.39 1.56 12.5 0.78 0.78 1.56 1.560.39 3.13 0.78
Proteus vulgaris OX19 ATCC 6898 0.013 0.013 0.025 0.025<0.0008 0.10 0.05 0.025 0.10 0.025 0.025 0.39 0.05
Ps~ ' -s aeruginosa A3 0.20 0.100.20 0.39 6.250.78 1.56 0.78 0,39 0,39 0.786.25 1.56
Pse ' -s aeruginosa NR 2950 0.78 0.783.13 3.13 12.512.5 6.25 3.13 6.25 6.25 6.25 25 3.13
Pse~ s stutzeri IFO 12695 0.025 0.025 0.05 0.025<0.0008 - 0.10 0.05 0.050.025 0.025 0.39 0.20
Serratia marcescens IFO 12648 0.10 0.10 0.20 0.10 0.78 3.13 0.39 0.39 0.39 0.780.39 3.13 0.39
Salmonella typhimurium IFO 12529 0.025 0.013 o.o5 0.025 0.00330.'0 0.10 o,o50.10 0.05 0.025 1.56 0.39
1 336905
-- 36
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TABLE 1 - continued
Antlbacterial spectrum MIC (~g/ml)
m - n~ ~ Example No.)
Aerobic microorganisms37 38 39 40 41 4243 44 4546 48 49
Gram-positive bacteria
Bacillus subtilis PCI 219 ~0.0008 <0.0008 0.025 0.10 3.130.05 0.10 0.05 0.39 0.05 0.05 3.13
Staphylococcuc aureus FDA 209P JC-1 0.0016 0.39 0.39 1.56 6.250,39 0.78 0.78 1.56 0.78 0.39 6.25
Staphylococcus aureus NR 2855 <0.0008 0.20 0.78 0.78 6.250.39 0.78 0.39 3.13 0.39 0.39 12.5
Staphylococc~c aureus Smith <0.0008 0.10 0.39 0.78 6.250.39 0.39 0.39 0.78 0.39 0.20 6.25
Staphylococcus epidermidis IFO 12993 0.025 0.39 0-39 1.56 6.25 0.39 0.39 0.78 3.13 0.78 0,39 12.5
Staphylococcus epidermidis NR 2942 <0.0008 0.39 0.39 0.78 12.50.39 0.39 0.39 3.13 0.39 0.78 12.5
Enterococcus faecalis NR 2943 3.13 12.512.5 12,5 100 6.25 6.25 12.5 50 6.25 6.25 100
Gram-negative bacteria
Alcaligenes faecalis IFO 13111 12.5 6.25 6.25 6.25 50 1.56 0.78 1.56 12.5 1.56 3.13 100
Citrobacter freundii IFO 12681 0.78 6.25 0.78 0.20 0.390.05 0.10 0.20 0.10 0.10 0.39 0.39
Enterobacter aerogenes NR 2945 0.10 3.13 0.05 0.10 0.100.025 0.10 0.10 0.05 0.10 0.39 0,39
Enterobacter cloacae NR 2946 0.20 6.25 0.78 0.39 0.78 0.05 0.10 0.20 0.20 0.20 0.39 0.78
Escherichia coli NIHJ JC-2 0.10 6.25 0.78 0.39 0.78 0.05 0.10 0.20 0.20 0.10 0.39 1.56
Escherichia coli NR 2630 <0.0008 0.39 0.025 0.20 0.390.025 0.05 0.05 0.10 0.05 0.10 0.39
Klebsiella pneumoniae FDA PCI 602 3.13 25 1.56 1.56 3.13 0.39 0.39 0.39 0.39 0.78 1.56 1.56 (~
aordetella bronchiseptica ATCC 4617 1.56 6.25 0.78 1.56 25 0.39 0.39 0.39 12.5 0.39 6.25 50 ~O
Proteus rettgeri ATCC 14505 6.25 25 3.13 3.13 3.13 0.39 0.78 1.56 0.78 1.56 3.13 3.13 0
Proteus vulgaris OX19 ATCC 6898 <0.0008 3.13 0.05 0.20 1.560.025 0.10 0.10 0.10 0.05 0.39 0.78
Ps ' -s aeruginosa A3 6.25 25 3.13 1.56 3.13 0.39 0.78 0.78 0.78 1.56 3.13 3.13
Fs ~ - -s aeruginosa NR 2950 25 50 12.512.5 12.5 3.13 6.25 6.25 6.25 6.25 50 50
P_ ' -s stutzeri IFO 12695 0.013 6.25 - - _ 0.10 - 0.20 0.05 - 1.56
Serratia 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 typhimurium IFO 12529 0.20 6.25 0.20 0.39 0.780.025 0.10 0.20 0~10 0.10 0.39 0.39
TABLE 1 - contlnued
'
- Antlbacterial a~ect~l MIC (~g/ml)
~ , nd (Example No.~
Aeroblc microorg~ni~ - 50 51 52 53 54 56 S9 63 69
Gram-positive bacteria
Bacillus subtilis PCI 219 0.0065 0.10 0.20 0.025 0.025 0.20 0.0065 0.78 0.20
Staphylococcus aureus FDA 209P JC-1 0.39 0.20 0.39 0.10 0.013 0.39 0.39 0.78 1.56
Staphylococcus aureus NR 2855 0.39 1.56 3.13 0.10 0.20 0.78 0.10 3.13 1.56
Staphylococct~q aureus Smlth 0.10 0.39 0.39 0.05 0.025 0.39 0.05 0.39 0.78
Staphylococcus epidermidls IFO 12993 0.39 0.78 1.56 0.10 0.10 0.39 0.39 1.56 1.56
Staphylococcus epidermidis NR 2942 0.20 0.78 1.56 0.10 0.10 0.39 0.20 0.78 1.56
Enterococcus faecalis NR 2943 3.13 12.5 25 1.56 1.56 1Z.S 3.13 25 12.5
Gram-negative bacteria
Alcaligenes faecalls IFO 13111 12.5 3.13 12.5 3.13 6.25 3.13 6.25 100 3.13
Citrobacter freundii IFO 12681 3.13 0.025 0.025 0.10 0.10 0.10 1.56 0.78 0.10
Enterobacter aerogenes NR 2945 0.78 0.025 0.025 0.10 0.025 0.10 0.78 0.39 0.10
Enterobacter cloacae NR 2946 1.56 0.05 0.05 0.20 0.10 0.05 0.78 1.56 0.20
Escherichia coli NIBJ JC-2 1.56 0.10 0,05 0.20 0.10 0.10 1.56 1.56 0.20
Escherichia coli NR 2630 0.20 0.025 0.025 0.05 0.025 0.0065 0.39 O.78 0.10
~lebsiella pnel iae FDA PCI 602 6.25 0.20 0.20 0.39 0.78 0.39 3.13 6.25 0.39 ~J~
Bordetella bronchiseptica ATCC 4617 3.13 1.56 6.25 0.78 3.133.13 3.13 50 0.78
Proteus rettgeri ATCC 14505 6.25 0.20 0.20 1.56 0.78 1.56 3.13 6.25 0.78
Proteus vulgaris OX19 ATCC 6898 0.39 0.025 0.025 0.10 0.013 0.013 0.20 0.39 0.05
pS~ f -s aeruginosa A3 6.25 0.10 0.20 0.78 0.20 3.13 3.13 3.130.78F5 ~ - -q aeruginosa NR 2950 25 1.56 1.56 12.5 1.56 6.25 25 25 6.25pSr ' -s stutzeri IFO 12695 - 0.05 0.05 0.20 0.013 0.0033 1.56 0.39 0.20
Serratia marcescens IFO 12648 3.13 0.10 0.20 0.78 0.39 0.78 3.13 3.13 0.20
Salmonella typhimurium IFO 12529 0.78 0.025 0.025 0.10 0.025 0.05 1.56 0.78 0.10
_ 39 _ 1 3 3 6 ~ 0 5
TABLE 2
Antibacterial spectrum MIC (~g/ml)
Compound (Example No.
Anaerobic microorganisms 5 30
Bacteroides fragilis ATCC Z3745 0.78 0.20
Bacteroides fragilis NR 2579 3.13 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 29520.10 0.10
- _ 40 _ 1 336905
2. In vivo therapeutic ~fficacy
The in vivo antibacterial activities of
pyrido[3,2,1-ij]-1,3,4-benzoxadiazine derivatives prepared
by Example 5, Example 30, Example 65 and Example 66 as
mentioned below were tested against lethal infection of
Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 and
Streptococcus pneumoniae 6-001. ICR mice weighing about 20
g were infected by intraperitoneal injection of a correspon-
ding bacterial suspension. The test compounds were admini-
stered orally or subcutaneously at the time of injection.The mortality was observed for 5 days. The respective 50%
effective dose (ED50, mg/kg) which protects 50% of the
animals from death caused by infection, is shown in Table 3.
L5 Table 3
In vivo Antibacterial Activities Against Systemic Infection
in Mice (ED50, mg/kg)
Bacterium
Escherichia Pseudomonas Streptococcus
Compoundcoli 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
30 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.
~ - 41 - 1 336~05
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, aminogly-
cosides, 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 anti-
bacterial agents which are commercially available. There-
fore, the compounds of the present invention can be effecti-
vely utilized for the prevention or treatment of diseasescaused by gram-positive and gram-negative bacteria, and
bacterioid microorganisms in human beings or animals.
For example, diseases caused by the following micro-
organisms, or by mixtures of the following microorganismscan be treated and/or prevented: Staphylococcus, Strepto-
coccus, Aerococcus, Enterococcus, Micrococcus, Lacto-
bacillus, Bifidobacterium, Clostridium, Eubacterium, Pepto-
coccus, Peptostreptococcus, Propionibacterium, Escherichia,
Citrobacter, Campylobacter, Enterobacter, Klebsiella,
Proteus, Pseudomonas, Serratia, Salmonella, Shigella,
Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter,
Alcaligenes, Bordetella, Bacteroides, Fusobacterium, Myco-
plasma and other microorganisms.
The present invention further relates to the pharma-
ceutical compositions containing one or more compounds of
the present invention.
The compounds of the present invention can be admini-
strated orally or non-orally to human beings or animals by
various conventional administration methods.
1 336905
- 42 -
Moreover, the compounds according to the present
invention are used singly or formulated with auxiliaries,
liquid diluents, binders, lubricants, humectants, etc., for
example, in the form of general medicinal compositions such
as tablets, granulars, sugar coating tablets, powder,
capsules, gels, dry syrup, syrup, ampules, suspension,
liquid, emulsion, ointments, paste, cream, suppositories,
and the like.
Furthermore, dissolution delaying agents, absorption
accelerating agents, surface active agents, and the like can
be used as other additives for formulation, i.e., any forms
which are pharmaceutically acceptable can be employed.
The compounds according to the present invention can be
used as alone or mixture of two or more different kinds of
compounds and the amount of the compounds is about O.l to
99.5 %, preferably 0.5 to 95% based on the weight of the all
medicinal composition.
The medical composition according to the present
invention may be formulated in a combination of the compound
of the present invention or the mixture thereof with other
conventional compounds which are pharmaceutically active.
A dosage per day to a patient of the novel compound
according to the present invention may be varied depending
upon an individual man, kinds of animals, weights thereof
and a state to be remedied, but generally is in the range of
0.5 to 500 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
36 invention.
1 336905
- 43 -
Preparation of startinq materials
Reference example
Preparation of diethYl N-(3,4-difluoro-2-hydroxy-
phenYl)aminomethylenemalonate
(a) 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
0 stream and the filtrate was evaporated under reduced
pressure to give 414 mg of crude 2-amino-5,6-difluorophenol.
(b) A mixture of the above amine (414 mg) and diethyl
ethoxymethylenemalonate (618 mg) was heated at 130C under
nitrogen atomosphere for 5 minutes. The resulting crystal-
line residue was triturated with ethanol and filtered to
give 590 mg of diethyl N-(3,4-difluoro-2-hydroxyphenyl)-
aminomethylenemalonate, mp 178-180C; MS m/z 315 (M ).
Additional 59 mg of the crystals were obtained after silica
gel column chromatography of the mother liquid using
CHC13/acetone (20:1) as the eluent.
Preparation of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-
quinolinecarboxylate (Route 1)
(c) To a mixture of diethyl N-(3,4-difluoro-2-hydroxy-
phenyl)aminomethylenemalonate (80 mg) and anhydrous
potassium carbonate (70 mg) in dry dimethylformamide (1.5
ml) was added benzyl bromide (30 ~1). The mixture was
stirred at room temperature for 2 hours. After removal of
the solvent under reduced pressure, the residue was dissol-
ved 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 87C; MS m/z 405 (M ).
_ ~ 44 ~ 1 336905
(d) A solution of the above malonate (280 mg) in diphenyl
ether (2.8 ml) was heated at Z50C 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
(30:1). 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 200-201C; MS m/z 359 (M ), was prepared by
recrystallization from methanol.
PreParation of ethYl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-
quinolinecarboxYlate (Route 2)
To a stirred solution of ethyl 6,7-difluoro-4,8-
-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethyl-
formamide (6 ml), was added anhydrous potassium carbonate
(308 mg) and then benzyl chloride (145 ~1). The mixture
was stirred at 55-65C for 11 hours. The reaction mixture
was diluted with water (30 ml) and extracted with chloro-
form. The extract was dried over anhydrous sodium sulfateand 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 200-201C: MS
m/z 359 (M ), after recrystallization from methanol.
Preparation of ethyl 8-benzyloxy-6,7-difluoro-1-(formyl-
methylamino)-4-oxo-1,4-dihYdro-3-quinolinecarboxylate
(e) After a mixture of ethyl 8-benzyloxy-6,7-difluoro-4-
-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous
potassium carbonate (315 mg) in dry dimethylformamide (10
I 336~05
_ - 45 -
ml) was stirred at room temperature for 3 hours, 0-(2,4-di-
nitrophenyl)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
prepared by recrystallization from methanol.
(f) 98% Formic acid (0.60 ml) was added to acetic anhydride
(1.51 ml) at 0C. The mixture was stirred at 0C for 15
L5 minutes, at 50C for 15 minutes, and then cooled to 0C. To
this solution was added dropwise a solution of the above
amine (400 mg) in 98~ formic acid (2.1 ml). The mixture was
stirred at room temperature for 2 days. The reaction
mixture was evaporated under reduced pressure to give the
crystalline residue, which was recrystallized from ethanol
to give 410 mg of ethyl 8-benzyloxy-6,7-difluoro-1-(formyl-
amino)-4-oxo -1,4-dihydro-3-quinolinecarboxylate, mp
188-190C; MS m/z 402 (M ).
(g) A mixture of the above formamide (400 mg), anhydrous
potassium carbonate (275 mg) and anhydrous dimethylformamide
(17 ml) was stirred at room temperature for 1.5 hours.
Methyl iodide (0.19 ml) was added to the mixture and
stirring was continued for 2.5 hours. The solvent was
removed under reduced pressure and the cesidue was parti-
tioned between chloroform and water. The organic layer was
dried over anhydrous sodium sulfate and concentrated to
dryness under reduced pressure. The residue was recrystal-
lized from ethanol to give 335 mg of ethyl 8-benzyloxy-6,7-
-difluoro-1-(formylmethylamino)-4-oxo-1,4 -dihydro-3-quino-
linecarboxylate, mp 180-181C; MS m/z 416 (M ).
- 46 - 1 3 3 6 9 0 5
Preparation of 6~7-difluoro-8-hYdroxy-l-(methylamino)-4
oxo-1,4-dihYdro-3-quinolinecarboxylic acid
(h) Ethyl 8-benzyloxy-6,7-difluoro-1-(formylmethylamino)-4-
-oxo-1,4 -dihydro-3-quinolinecarboxylate (330 mg) was hydro-
genated over 5~ Pd/C (50 mg) in chloroform (14 ml) for 4
hours. The reaction mixture was diluted with methanol (14
ml) and filtered. The filtered cake was washed with chloro-
form/methanol (1:1). The combined filtrate was evaporated
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 Z21-225 C
(dec.): MS m/z 326 (M ).
(i) A mixture of the above ester (210 mg) and O.SN sodium
hydroxide (5.2 ml) was heated at 100C 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
pressure to give 168 mg of 6,7-difluoro-8-hydroxy-1-(methyl-
amino)-4-oxo-1,4-dihydro -3-quinolinecarboxylic acid. An
analytical sample, mp 248-250C (dec.); MS m/z 270 (M ),
was prepared by recrystallization from ethanol.
Example 1
PreParation of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-
pyrido[3,2,1-ii]-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 (i), paraformaldehyde (150 mg)
and dry dioxane (5 ml) was heated at 100C 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 ~ 1 336905
formamide and the combined filtrate was evaporated underreduced 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-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-
-carboxylic acid. An analytical sample, mp 290-292C
(dec.); MS m/z 282 (M ) was prepared by recrystallization
from dimethylformamide.
Example 2
PreParation of 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-
dihYdro-7H-pyrido[3~2~l-ij]-l~3~4-benzoxadiazine-6-carboxylic
acid
A mixture of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-
-oxo-1,4-dihydro -3-quinolinecarboxylic acid (50 mg)
obtained in Reference example (i), 90% acetaldehyde (1 ml)
and dioxane (5 ml) was heated at 100C for 3 hours under
nitrogen atmosphere. The reaction mixture was evaporated
under reduced pressure to give 52 mg of 9,10-difluoro-2,3-
-dimethyl-7-oxo-2,3-dihydro -7H-pyrido[3,2,1-ij]-1,3,4-
-benzoxadiazine-6-carboxylic acid, mp 285-289C; MS m/z 296
(M )O
Example 3
Preparation of 9~10-difluoro-2-(hydroxYmethyl)-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ii]-1,3,4-benzoxadiazine-6-
carboxYlic acid
A suspension of 6,7-difluoro-8-hydroxy-1-(methylamino)-
-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg)
obtained in Reference example (i), glycolaldehyde diethyl-
acetal (45 ~1) and pyridinium p-toluenesufonate (7 mg) in
dry dioxane (2 ml) was heated at 110C for 5 hours under
nitrogen atmosphere. After the solvent was removed under
reduced pressure, the crystalline residue was washed with
- 48 - 1 336905
water and methanol to give 52 mg of 9,10-difluoro-2-
-(hydroxymethyl)- 3-methyl-7-oxo-Z,3-dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4- benzoxadiazine-6-carboxylic acid, mp
254-258C (dec.): MS m/z 312 (M ).
Example 4
Preparation of 9~10-difluoro-2-[(dimethylamino)methyl]-
3-methYl-7-oxo-2~3-dihydro-7H-pyrido[3~2~ 3~4-benzoxa
diazine-6-carboxylic acid P-toluenesulfonate
A suspension of 6,7-difluoro-8-hydroxy-1-(methylamino)-
-4-oxo-1,4-dihydro -3-quinolinecarboxylic acid (50 mg)
obtained in Reference example (i), dimethylaminoacetaldehyde
L5 dimethylacetal (37 mg) and p-toluenesulfonic acid mono-
hydrate (53 mg) in dry dioxane (2 ml) was heated at 110C
for 17 hours under nitrogen atmosphere. After the solvent
was removed under reduced pressure, the residue was
recrystallized from methanol to give 61 mg of 9,10-difluoro-
-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 232-236C (dec.); FAB-MS m/z 340
(MH ).
Example 5
Preparation of 9-fluoro-3-methYl-lo-(4-methyl-l-pipera-
zinyl)-7-oxo-2,3-dihydro-7H-pyrido r 3,2,1-ii]-1,3,4-benzoxa-
diazine-6-carboxYlic acid
A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro
-7H-pyrido~3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid
(30 mg) obtained in Example 1, N-methylpiperazine (47 ~1)
and dry pyridine (3 ml) was heated at 100-110C for 9 hours
under nitrogen atmosphere. Pyridine was removed under
reduced pressure and the residue was recrystallized from
methanol to give 23 mg of 9-fluoro-3-methyl-10-(4-methyl-1-
~ 49 ~ 1 3 3 6 9 G 5
-piperazinyl)-7-oxo -2,3-dihydro-7H-pyrido[3,2,l-ij]-l,3,4-
-benzoxadiazine -6-carboxylic acid, mp 268-269C (dec.); MS
m/z 362 (M ).
The following compounds were obtained according to a
manner analogous to that of Example 5:
- 50 - 1 336905
F~C02H
R R N ~ N,U
~_,N~CH3
Example R5R6~1 Melting point solvent
6 H ~ - 240~245 (dec.) MeOH 349 (MH+)*
7 H ~ - 237~239 (dec.) MeOH/CHC13 362 (M+)
CH3
8 H ~ - 256~259 (dec.) DMF 425 (MH+)*
9 ~ - ~300 EtOH/CHC13 349 (M+)
CH3
~ _ >300 DMF 377 (M+)
CH3
11 ~ _ >300 (dec.) DMF 365 (M+)
12 H2N ~ - 238~242 (dec.) MeOH 377 (MH+)*
13 H ~ - 256~258 MeOH/CHC13 363 (M+)
14 ~ ~ - 272~274 (dec . ) EtOH 413 (MH+)*
`~ N- 270~275 H20 393 (MH+)*
16 H ~ - 243~246 MeOH/C~C13 362 (M+)
CH3N ~ - 242~244 (dec.) DMF 377 (MH+)*
18 H r N- 251~252 (dec.) EtOH 391 (MH+)*
C2H5N~/
19 H r~ 239~241 (dec.) EtOH 405 (MH+)*
AcN ~
* FAB-MS
- 51 -
1 33690~
continued
Example R5R6N_ Melting point RecrystalliZation MS m/z
H
20CH3jN ~ ~ 3 266~268 (dec.) EtOH 365 (MH+)*
CH3
21 ~ - 284~286 (dec.) DMF 350 (MH+)*
HO
22 CH3 ~ _ 280~284 (dec-) MeOH/CHC13/Et20 345 ~MH+)*
N
23 CH3 ~ _ 220~222 (dec.) EtOH 391 (MH+)~
CH3~
* FAB-MS
~xample 24
Preparation of 9-fluoro-3-methyl-7-oxo-10-(3-oxo-1-pipera-
zinyl)-2,3-dihydro-7H-pYrido[3,2,1-ii]-1,3,4-benzoxadiazine-
6-carboxylic acid
A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro
-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid
(40 mg) obtained in Example 1, 2-piperazinone (31.1 mg),
1,4-diazabicyclo[2.2.2]octane (31.8 mg) and dry dimethylsul-
foxide (1 ml) was heated at 130C for 28.5 hours under
nitrogen atmosphere. The solvent was removed under reduced
pressure. The residue was purified by preparative TLC
(Silica gel: CHC13/MeOH, 10:1.5) and recrystallized from
a mixture of dichlo~omethane and methanol to give 6.3 mg of
9-fluoro-3-methyl-7-oxo-10-(3-oxo-1-piperazinyl)-2,3-dihydro
-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid,
mp >300C; FAB-MS m/z 363 (MH ).
_ - 52 - 1 336~
The following compounds were prepared from the compounds
described in Example 2, 3 and 4 according to a manner
analogous to that of Example 5:
o
R5R6N ~C02H
R3
Example R5R6~- Meltjng point Recrystall;_
No. R3 C zation MS m/z
solvent
H ~ - CH3 240~242 (dec.)MeOH 362 (M+)
26 CH3 ~ - CH3 203~Z06 EtOH 376 (M~)
27 CHB ~ N CH20H 229~231 (dec.)MeOH 393 (MH+)*
28 CH3 ~ N- cH2N(cH3)2 210~212 MeOH 420 (MH+)*
* FAB-MS
ExamPle 29
PreParation of 10-[3-(benzYloxycarbonylamino)-l-pyrroli
dinyl]-9-fluoro-3-methYl-7-oxo-2~3-dihYdro-7H-Pyrido-
[3,2,1-ii]-1,3,4-benzoxadiazine-6-carboxylic acid
A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
-7H-pyrido[3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid
(28 mg) obtained in Example 1, 3-(benzyloxycarbonylamino)-
pyrrolidine (94 mg) and dry pyridine (3 ml) was heated at
100C for 3 hours under nitrogen atmosphere. Pyridine was
removed under reduced pressure and the residue was
- 1 336905
- 53 -
recrystallized from methanol to give 36 mg of 10-[3-(benzyl-
oxycarbonylamino)-l-pyrrolidinyl]-9-fluoro -3-methyl-7-oxo-
-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4 -benzoxadiazine-6-
-carboxylic acid, mp 227-230C: MS m/z 482 (M ).
ExamPle 30
Preparation of lO-(3-amino-l-Pyrrolidinyl)-9-fluoro-3
methYl-7-oxo-2~3-dihydro-7H-pyrido[3~2~ ]-l~3~4-benzoxa
L0 diazine-6-carboxylic acid
10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro
-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4
-benzoxadiazine-6-carboxylic acid (30 mg) obtained in
Exa-mple 29 was hydrogenated over 5% Pd/C (lO mg) in
dimethylformamide (2 ml) for 4.5 hours. After removal of
the catalyst by filtration the filtrate was concentrated
under reduced pressure. The residue was recrystallized from
methanol to give 16 mg of 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-carboxylic acid, mp 230-234C
(dec.); MS m/z 348 (M ).
The following compounds were obtained according to a
manner analogous to that of Examples 29 and 30:
1 336905
R R ~ C02H
O~N~CH3
Example R5R6N_ Melting point Recrystall1zation MS m/z
No. C solvent
31 ~ - Z86~288 (dec.) H20 363 (MH+)*
CH3HN--
32 ~ N- 269~273 (dec.) MeOH 377 (MH+)*
C2H5H
33 H2N ~ ~ 240~245 (dec.) MeOH 363 (MH+)*
34 CH3N ~ - 262~265 (dec.) MeOH 37i (MH+)*
H
C2H5N ~ N- 252~256 (dec. ) EtOH 390 (M+)
* FAB-MS
ExamPle 36
Preparation of 10-(3,4-dimethyl-1-piperazinyl)-9-fluoro-3-
methyl-7-oxo-2,3-dihYdro-7H-pyrido[3,Z,l-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid
A mixture of 9-fluoro-3-methyl-10-(3-methyl-1-pipera-
_ _ 55 - 1 336905
zinyl)-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid (60 mg) obtained in Example 7, 98%
formic acid (1 ml) and 35% formalin (1 ml) was stirred at
100-110C. After heating for 2 hours, the mixture was
s evaporated under reduced pressure. The residue was dissol-
ved in water, neutralized with lN 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-1-piperazinyl)-9-fluoro-3-methyl-7-oxo
-2,3-dihydro-7H-pyrido~3,2,1-ij]-1,3,4-benzoxadiazine
-6-carboxylic acid, mp 257-259C; FAB-MS m/z 377 (MH ).
L5 Example 37
Preparation of 9-fluoro-10-(3-methoxy-1-pyrrolidinyl)-
3-methYl-7-oxo-2~3-dihydro-7H-pyrido[3~2~ ]-l~3~4-benzoxa
diazine-6-carboxylic acid
To a suspension of 9-fluoro-10-(3-hydroxy-1-pyrroli-
dinyl)-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 60%
sodium hydride in oil (30 mg) and methyl iodide (40 ~1).
After stirring the mixture at room temperature for 2 hours,
additional 60% sodium hydride (30 mg) and methyl iodide (40
~1) were added, and the mixture was stirred at 45C for 3
hours. The solvent was then removed under reduced
pressure. To the residue was added cold water (2 ml) and
0.5N sodium hydroxide (2.3 ml) and the resulting suspension
was heated at 100C 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 ~educed
pressure to give the crystalline residue, which was chroma-
~ - 56 - 1 336905
tographed on silica gel using acetone/chloroform (1:9) as an
eluent. 42 mg of 9-fluoro-10-(3-methoxy-1-pyrrolidinyl)-3-
-methyl-7-oxo -2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-
-benzoxadiazine -6-carboxylic acid, mp 233-234C; FAB-MS m/z
364 (MH ), was obtained after recrystallization from
methanol.
- Example 38
PreParation of 9-fluoro-10-(4-methoxy-1-piperidyl)-3-methyl-
7-oxo-2~3-dihydro-7H-pyrido[3~2~1-ii]-1,3~4-benzoxadiazine-6-
carboxylic acid
9-Fluoro-10-(4-methoxy-1-piperidyl)-3-methyl-7-oxo
-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-
carboxylic acid was prepared from 9-fluoro-10-(4-hydroxy-1-
-piperidyl)-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-
-1,3,4-benzoxadiazine-6-carboxylic acid obtained in Example
13 analogously to Example 37, and was obtained as crystals,
mp. 229-233C (dec.): MS m/z 377 (M ), after recrystalli-
zation from chloroform/n-hexane.
Example 39
Preparation of 10-(1,1-dioxide-4-thiomorpholinyl)-9-fluoro-3-
methyl-7-oxo-2~3-dihydro-7H-pyrido[3~2~1-ii]-1~3~4-benzoxa-
diazine-6-carboxylic acid
To a suspension of 9-fluoro-3-methyl-7-oxo-10-(4-thio-
morpholinyl)-2,3-dihydro -7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid (50 mg) obtained in ~xample 11 in
dichloromethane (5 ml) was added m-chloroperbenzoic acid
(70% purity, 74 mg). The mixture was stirred at room
temperature for 18 hours. The solvent was then removed
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
1 336~oS
10-(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, mp >300C: MS m/z 397 (M ).
ExamPle 40
PreParation of 9-fluoro-3-methYl-7-oxo-lo-[4-(2-oxo-n
Propyl)-l-piperazinyl]-2~3-dihydro-7H-pyrido[3~2~l-ii]-l~3~4
benzoxadiazine-6-carboxylic acid
A mixture of 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 (50 mg) obtained in Example 6, chloro-
acetone (17 ~1), triethylamine (40 ~1) and dry dimethyl-
~5 formamide (1 ml) was heated at 80C for 3.5 hours. Thevolatile components were then removed under reduced pressure
and the residue was suspended in water. The precipitate was
collected by filtration and recrystallized from a mixture of
dichloromethane and methanol to give 32 mg of 9-fluoro-3-
-methyl-7-oxo-10-[4-(2-oxo-n-propyl)-1-piperazinyl]
-2,3-dihydro-7H-pyrido[3,2,1-ij]-~,3,4-benzoxadiazine
-6-carboxylic acid, mp 225-229C (dec.), FAB-MS m/z 405
(MH ).
The following compounds were obtained according to a
manner analogous to that of Example 40.
-
- 58 - I 3 3 6 9 0 5
o
F ~ C02H
R7o~ ~ O~ `C~
s
Example R70 Melting point Recrystalli-
No. C zation FAB-MS m/z
- solvent
41 ~ COCH2-l 223~226 (dec.) DMF 467 (MH+)
42 CH3CH2- 273~275 (dec.) EtOH 377 (MH+)
43 CH3CH2CH2-255~257 (dec.) EtOH 391 (MH+)
44 FCH2CH2- 257~259 (dec.) EtOH 395 (MH+)
H02CCH2- 256~259 (dec.) H20 407 (MH+)
46 CH2=CHCH2-236~238 (dec. ) MeOH 389 (MH+)
47 02N ~ CH2_27S~276 (dec.) EtOH 484 (MH+)
Example 48
Preparation of 10-r3-[(ethylmethylamino)methyll-1-pyrroli-
dinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-
~3,2,1-ii]-1,3,4-benzoxadiazine-6-carboxylic acid
10-[3-[(ethylmethylamino)methyl]-1-pyrrolidinyl]
-9-fluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido[3,2,1-ij]-
-1,3,4-benzoxadiazine-6-carboxylic acid was prepared from
9-fluoro-3-methyl-10-[3-[(methylamino)methyl] -l-pyrroli-
dinyl]-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4 -benzoxa-
diazine-6-carboxylic acid obtained in Example 17 and ethyl
iodide analogously to Example 40, and was obtained as
crystals, mp 210-225C (dec.): FAB-MS m/z 405 (MH ) after
1 336905
_ - 59 -
recrystallization from a mixture of chloroform, methanol and
n-hexane.
Example 49
s
PreParation of 10-[4-(3-carboxYpropionyl)-l-piperazinyl]
fluoro-3-methYl-7-oxo-2~3-dihydro-7H-pyrido[3~2~ 3~4
benzoxadiazine-6-carboxylic acid
A mixture of 9-fluoro-3-methyl-7-oxo-10-(1-pipera-
zinyl)-2,3-dihydro -7H-pyrido[3,2,1-ij]-1,3,4-benzoxadia-
zine-6-carboxylic acid (50 mg) obtained in Example 6,
succinic anhydride (21.6 mg), triethylamine (40 ~1) and
dry dimethylformamide (4 ml) was heated at 80C 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 10-[4-(3-car-
boxypropionyl)-l-piperazinyl]-9-fluoro-3-methyl -7-oxo-2,3-
-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-car-
boxylic acid, mp 257-259C (dec.); FAB-MS m/z 449 (MH ).
Example 50
Preparation of 10-(4-acetYl-l-piperazinyl)-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ii]-1,3,4-benzoxa-
diazine-6-carboxylic acid
10-(4-Acetyl-l-piperazinyl)-9-fluoro-3-methyl-7-oxo
-2,3-dihydro-7H-pyrido[3,2,1-ij]-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 294-296C (dec.); FAB-MS m/z 391
(MH ), after recrystallization from dichloromethane/
methanol.
_ 60 - : 1 3369~5
Example 51
PreParation of 9-fluoro-3-methYl-7-oxo-lo-[4-(3-oxo-n-butyl)
- l-Piperazinyl]-2~3-dihydro-7H-pyrido[3~2~ ]-l~3~4-benzoxa
diazine-6-carboxylic acid
A mixture of 9-fluoro-3-methyl-7-oxo-10-(1-pipera-
zinyl)-2,3-dihydro -7H-pyridot3~2~ 3~4-benzoxadia-
zine-6-carboxylic acid (30 mg) obtained in Example 6, methyl
L0 vinyl ketone (36 ~1) and ethanol (1 ml) was refluxed for
12 hours, and then cooled to room temeerature. The preci-
pitate 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)-1-piperazinyl]
~5 -2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine
-6-carboxylic acid, mp 187-189C (dec.); FAB-MS m/z 419
(MH ).
Example 52
Preparation of disodium 9-fluoro-3-methyl-7-oxo-10-[4-
(sulfonatomethyl)-l-piPerazinyl]-2~3-dihydro-7H-pyrido-
[3~2~1-ii]-1,3~4-benzoxadiazine-6-carboxYlate
A mixture of 35% formalin (26 mg), sodium hydrogen
sulfite (32 mg) and water (0.5 ml) was heated at 75C for 30
minutes and then cooled to room temperature. To this
solution was added 9-fluoro-3-methyl-7-oxo-10-(1-pipera-
zinyl)-2,3-dihydro -7H-eyrido[3,2,1-ij]-1,3,4-benzoxadia-
zine-6-carboxylic acid (100 mg) obtained in Example 6 and
sodium hydroxide (15 mg). After the mixture was heated at
75C 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
3s from water/ethanol (1:2) to give disodium 9-fluoro-3-methyl-
-7-oxo-10-[4-(sulfonatomethyl)-1-pieerazinyl] -2,3-dihydro-
-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylate, mp
_ - 61 - 133690~
260-263C (dec.); H NMR (D20) ~: 2.98 (3H,S), 3.05
(4H,m), 3.39 (4H,m), 3.84 (2H,S), 5.18 (2H,S), 7.55
(lH,d,J=13.4 Hz), 8.34 (lH,S).
Example 53
Preparation of 10-[4-(4-aminobenzyl)-1-piperazinyl]-9-
fluoro-3-methYl-7-oxo-2~3-dihYdro-7H-pyridor3~2~l-ii]-l~3~4
benzoxadiazine-6-carboxylic acid
9-Fluoro-3-methyl-10-[4-(4-nitrobenzyl)-1-piperazinyl]
-7-oxo-2,3-dihydro-7H-pyrido~3,2,1-ij]-1,3,4-benzoxadiazine
-6-carboxylic acid (100 mg) obtained in Example 47 was
hydrogenated over 5% Pd/C (10 mg) in dichloromethane/metha-
nol (1:1) for 2 hours. After removal of the catalyst byfiltration, the filtrate was concentrated to dryness under
reduced pressure. The residue was recrystallized from
ethanol to give 69 mg of 10-[4-(4-aminobenzyl)-1-pipera-
zinyl]-9-fluoro-3-methyl-7-oxo -2,3-dihydro-7H-pyrido-
~3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp
237-238C (dec.): FAB-MS m/z 454 (MH+).
Example 54
PreParation of 10-[3-(aminomethYl)-l-pyrrolidinyl]-9-fluoro-
3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid
The mixture of 10-[3-(acetylaminomethyl)-1-pyrroli-
dinyl]-9-fluoro-3-methyl -7-oxo-2,3-dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid (40 mg)
obtained in Example 19 and lN sodium hydroxide (2.5 ml) was
heated at 100C for 3 hours. After cooling to room tempera-
ture, 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
10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo
1 336905
- 62 -
-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine
-6-carboxylic acid, mp 177-180C (dec.); FAB-MS m/z 363
(MH ).
Example 55
PreParation of 6-fluoro-8-hYdroxy-7-(l-imidazolyl)-l-
(methYlamino)-4-oxo-l~4-dihydro-3-quinolinecarboxylic acid
Carbonyldiimidazole (32 mg) was added to a stirred
solution of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-
-1,4-dihydro -3-quinolinecarboxylic acid (50 mg) obtained in
Reference example (i) in dry dimethylformamide (2 ml).
Stirring was continued at room temperature for 2 hours and
then at 80C 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 precipi-
tate which separated out was filtered and washed with
methanol to give 35 mg of 6-fluoro-8-hydroxy-7-(1-imida-
zolyl)-1-(methylamino)-4-oxo -1,4-dihydro-3-quinolinecar-
boxylic acid as pale yellow powder, FAB-MS m/z 319 (MH );
lH-NMR (d6-DMSO) ~: 2.82 (3H,s), 7.10 (lH, d, J=10.7
Hz), 7.61 (lH, d), 7.75 (lH, d), 8.62 (lH,s), 8.92 (lH,s),
15033 (lH, br.s)
ExamPle 56
Preparation of 9-fluoro-10-(1-imidazolyl)-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido[3,2,1-ii]-1,3,4-benzoxadiazine-6-
carboxylic acid
A suspension of 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-
-(methylamino)-4-oxo-1,4 -dihydro-3-quinolinecarboxylic acid
(15 mg) obtained in Example 55 in a mixture of 35% formalin
(1 ml) and dioxane (1 ml) was heated at 100-110C for 1.5
hours under nitrogen atmosphere. The solvent was removed
under reduced pressure and the crystalline residue was
~ - 63 1 336905
washed with methanol to give 15 mg of 9-fluoro-10-(1-imida-
zolyl)-3-methyl-7-oxo-2,3-dihydro -7H-pyrido[3,2,1-ij]-
-1,3,4-benzoxadiazine-6-carboxylic acid as pale pink
powder. An analytical sample, mp >300C; FAB-MS m/z 331
(MH ) was prepared by recrystallization from dimethyl-
formamide and ether.
9-Fluoro-10-(1-imidazolyl)-3-methyl-7-oxo-2,3-dihydro
-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid
was also prepared from 9,10-difluoro-3-methyl-7-oxo-2,3-
-dihydro-7H-pyrido[3,2,1-ij] -1,3,4-benzoxadiazine-6-car-
boxylic acid and imidazole in dimethylsulfoxide analogously
to Example 5.
Example 57
Preparation of benzyl 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-
3-methyl-7-oxo-2~3-dihydro-7H-Pyrido[3~2~ 3~4-benzoxa
diazine-6-carboxylate
A mixture of 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-
-methyl-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-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 triturated with ether to
give 11 mg of benzyl 9-fluoro-10-(3-hydroxy-1-pyrroli-
dinyl)-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-
-1,3,4-benzoxadiazine -6-carboxylate, mp 196-198C (dec.);
FAB-MS m/z 440 (MH ).
- 64 _ 1 33 6 905
Example 58
Preparation of benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-
3-methYl-7-oxo-2~3-dihydro-7H-pyrido[3~2~ ]-l~3~4-benzoxa
diazine-6-carboxylate
Benzyl 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-
-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine
-6-carboxylate (8 mg) obtained in Example 57 was dissolved
in 0.2 ml of thionyl chloride and stirred at 60C for 15
minutes. The reaction mixture was diluted with water and
extracted with chloroform.
The extract was concentrated under reduced pressure.
The residue was chromatographed on silica gel (2 g) with
chloroform to give 2.8 mg of benzyl 10-(3-chloro-1-pyrroli-
dinyl)-9-fluoro-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylate, mp >300C;
FAB-MS m/z 458 (MH ), 460 (MH+2) .
Example 59
Preparation of 10-(3-chloro-l-Pyrrolidinyl)-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid
Benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-methyl-7-
-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine
-6-carboxylate (2.5 mg) obtained in Example 58 was hydro-
genated over 5% Pd/C (1 mg) in chloroform.
After removal of the catalyst by filtration, thefiltrate was concentrated to dryness under reduced
pressure. The residue was recrystallized from ethanol to
give 1.0 mg of 10-(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, mp 269-272C (dec.);
- - 65 - 1 336905
FAB-MS m/z 368 (MH ), 370 (MH+2) .
Example 60
PreParation of 9-fluoro-3-methYl-lo-(4-methyl-l-piperazinyl)
7-oxo-2,3-dihYdro-7H-Pyrido[3~2~ ]-l~3~4-benzoxadiazine-6
carboxylic acid via the fluoroborane intermediate
(a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
-7H-pyrido[3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid
(100 mg) obtained in Example 1 and 60% aqueous fluoboric
acid (1 ml) was heated at 90C for 12 hours. After the
reaction mixture was cooled to room temperature the precipi-
tate was collected by filtration, washed with methanol and
dried under reduced pressure to give 110 mg of crude
9,10-difluoro-6-~[(difluoroboryl)oxy]carbonyl]-3-methyl-2,3
-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazin-7-one;
FAB-MS m/z 331 (MH ).
(b) To a stirred solution of the above borane intermediate
(33 mg) in dimethylsulfoxide (1 ml) were added N-methyl-
piperazine (15 ~1) and triethylamine (20 ~1). 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-10 -(4-methyl-1-piperazinyl)-2,3-dihydro-
-7H-pyrido[3,2,1-ij] -1,3,4-benzoxadiazin-7-one as yellow
crystals, mp 228-230C (dec.); FAB-MS m/z 411 (MH ).
(c) To a solution of the above borane intermediate (5 mg) in
95% ethanol (1 ml) was added triethylamine (3 ~1). 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-1-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4-benzoxadiazine-6 -carboxylic acid, mp
268-269C (dec.).
- 66 - 1 3 3 6 9 0 5
Example 61
PreParation of 9-fluoro-3-methYl-lo-(4-methyl-l-pipera
zinyl)-7-oxo-2,3-dihYdro-7H-pyrido[3~2~l-ii]-l~3~4-benzoxa-
diazine-6-carboxYlic acid via the acetoxyborane intermediate
(a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
-7H-pyrido[3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid
(100 mg) obtained in Example 1, acetic anhydride (1 ml) and
L0 triacetoxyborane (100 mg) was heated at 140C for 15
minutes. The reaction mixture was evaporated under reduced
pressure. The residue was triturated with acetone and
filtered to give 138 mg of 6-[[(diacetoxyboryl)oxy]car-
bonyl]-9,10-difluoro-3-methyl-2,3 -dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4-benzoxadiazin-7-one; FAB-MS m/z 411 (MH ).
(b) To a solution of the above borane intermediate (41 mg)
in dimethylsulfoxide (1 ml) were added N-methylpiperazine
(15 ~1) and triethylamine (20 ~1). 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]car-
bonyl]-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 156-157C (dec.); FAB-MS m/z 491 (MH ).
(c) The above borane intermediate (5 mg) was suspended in
acetone (0.1 ml) and added conc. HCl (2.5 ~1). The
reaction mixture was stirred at room temperature for 30
minutes and cooled in ice bath. The precipitate which
separated out was collected by filtration and the precipi-
tate was dissolved in 95% ethanol (0.1 ml). To the solution
was added triethylamine (2 ~1) 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-l-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido-
- 67 - 1 3 3 6 9 0 5
[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp
268-269C (dec.).
Example 62
PreParation of pivaloYloxymethyl 10-[3-(benzyloxycarbonyl-
amino)-l-Pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2~3-dihydr
7H-pyrido[3,2,1-ii]-1,3,4-benzoxadiazine-6-carboxylate
A mixture of 10-[3-(benzyloxycarbonylamino)-1-pyrroli-
dinyl]-9-fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4 -benzoxadiazine-6-carboxylic acid (290 mg)
obtained in Example 29, pivaloyloxymethyl chloride (130
~1), anhydrous potassium carbonate (166 mg) and dry
dimethylformamide (10 ml) was stirred at 45C for 8 hours.
The solvent was then removed under reduced pressure. The
residue was dissolved in dichloromethane. The dichloro-
methane solution was washed with water and dried over
anhydrous sodium sulfate. The solvent was evaporated off
under reduced pressure and the residue was recrystallized
from ethyl acetate to give 325 mg of pivaloyloxymethyl
10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3
-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4
-benzoxadiazine-6-carboxylate; mp 185-188C: FAB-MS m/z 597
(MH ).
Example 63
Preparation of Pivaloyloxymethyl 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
Pivaloyloxymethyl 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 was prepared from pivaloyl-
oxymethyl 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-
-fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-
_ - 68 - 1 336905
-1,3,4 -benzoxadiazine-6-carboxylate (200 mg) obtained in
Example 62, analogously to Example 30, and was obtained as
pale brown powder after precipitation from a mixture of
ethyl acetate and n-hexane; H NMR (CDC13) ~: 1.22
(9H, s), 1.6-2.4 (2H, m), 2.99 (3H, s), 3.3-4.0 (5H, m),
4.98 (2H, s), 5.96 (2H, s), 7.64 (lH, d, J=14.4 Hz), 8.37
(lH, s); FAB-MS m/z 463 (MH ).
Example 64
Preparation of ethyl 10-[3-(benzyloxycarbonylamino)-1-
pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-
[3,2,1-ii]-1,3,4-benzoxadiazine-6-carboxylate
A mixture of 10-t3-(benzyloxycarbonylamino)-1-pyrroli-
dinyl]-9-fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4 -benzoxadiazine-6-carboxylic acid (337 mg)
obtained in Example 29, ethyl iodide (84 ~1), anhydrous
potassium carbonate (193 mg) and dry dimethylformamide (12
ml) was stirred at 45C for 6 hours. The solvent was removed
under reduced pressure, and the residue was dissolved in
dichloromethane. The dichloromethane solution was washed
with water, dried over anhydrous sodium sulfate and concen-
trated under eeduced pressure. The residue was then applied
onto a column of silica gel and eluted with a mixture of
chloroform and acetone (20:1). The pure fractions were
combined, concentrated to dryness under reduced pressure and
the residue was recrystallized from ethyl acetate to give
271 mg of ethyl 10-[3-(benzyloxycarbonylamino)-1-pyrroli-
dinyl]-9-fluoro -3-methyl-7-oxo-2,3-dihydro-7H-pyrido-
[3,2,1-ij]-1,3,4 -benzoxadiazine-6-carboxylate, mp
204-207C; FAB-MS m/z 511 (MH ).
-
- 69 - 1 336~05
Example 65
Preparation of ethYl 10-(3-amino-l-Pyrrolidinyl)-g-fluoro-3
methyl-7-oxo-2~3-dihYdro-7H-pyrido[3~2~ 3~4-benzoxa
s diazine-6-carboxylate
Ethyl 10-~3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-
-fluoro-3 -methyl-7-oxo-2,3-dihydro-7H-pyrido~3,2,1-ij]-
-1,3,4 -benzoxadiazine-6-carboxylate (200 mg) obtained in
L0 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 (4:1). The
pure fractions were combined and concentrated to dryness
under reduced pressure. The residue was further purified by
preparative TLC (silica gel; CHC13/MeOH, 3:1) and
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 187-192C (dec.); FAB-MS m/z 377 (MH ).
Example 66
Preparation of 10-(3-amino-l-pYrrolidinyl)-9-fluoro-3-methyl-
7-oxo-2~3-dihydro-7H-pyrido[3~2~1-ijl-1~3~4-benzoxadiazine-6-
carboxylic acid hYdrochloride
The pH of a solution of 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-carboxylic acid (20 mg) obtained in
Example 30 in water (1 ml) was adjusted to 1.0 with 6N-HCl.
The clear solution was then lyophilized and the residue was
crystallized from water/ethanol (1:2) to give 19 mg of
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-carboxylic
-- - 70 - 1 336905
acid hydrochloride, mp 226-228C (dec.).
Example 67
PreParation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-
7-oxo-2~3-dihYdro-7H-pyrido[3~2~ ]-l~3~4-benzoxadiazine-6
carboxylic acid hydrochloride
9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3
-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-car-
boxylic acid hydrochloride was obtained analogously to
Example 66, mp 264-266C (dec.).
Example 68
Preparation of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-
2~3-dihydro-7H-pyrido[3~2~1-ii]-1~3~4-benzoxadiazine-6-car-
-boxYlate
9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H
-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (14
mg) obtained in Example 9 was suspended in water (0.4 ml),
and lN sodium hydroxide (40 ~1) was added with stirring.
The clear solution was lyophilized and the residue was
crystallized from water/ethanol (1:4) to give 12 mg of
sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H
-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylate, mp
~300C.
Example 69
PreParation of 9-fluoro-3-(2-fluoroethYl)-10-(4-methyl-1-
piPerazinyl)-7-oxo-2~3-dihydro-7H-pyrido[3~2~1-ij]-1~3~4-
benzoxadiazine-6-carboxylic acid
9-Fluoro-3-(2-fluoroethyl)-10-(4-methyl-1-piperazinyl)-7
-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine
- - 71 - ^ 1 336905
-6-carboxylic acid was prepared from ethyl 8-benzyloxy-6,7-
-difluoro-l-(formylamino)-4-oxo-1,4-dihydro -3-quinolinecar-
boxylate obtained in Reference example (f), following a
series of procedures of Reference example (g, h and i)
(using 1-bromo-2-fluoroethane instead of methyl iodide),
Example 1 and Example 5, and was obtained as crystals, mp
220-224C; MS mtz 394 (M ) after recrystallization from
methanol.
Examples 70-77
There were obtained the following compounds starting
from the compound obtained in Example 1 by using a manner
analogous to the one described in Example 5 or Examples
29/30.
. O
F~,CO2H
20 R5R6N ~ IN ~ CH~
Exampl-R5R6N ~eltin~ po~ne Recry talllz~tion ~AB-MS m/Z
70cH~ 5 ~ 262 (dec.) MeOH 432 ~MH )
CH,O,
3071 ~ _ 22~-230 ~dec.) ~tOH/hexane 379 ~MH )
H~N
0~."
72 ~ ~ _ 240-245 ~dec.) EtOH/hexane 365 tM~)
Ph ",
73 ~IN ~ 253-255 ~dec.) MeOa/ether 425 ~MH )
CH~ .
H ,N ~ 240-241 MeOH 363 ~MH )
_ - 72 - l 336905
Exa p1e R5R6N M~ltin~ point olvent FAB-MS m/Z
CH~ ~ ~300 (t~c.) EtOH/CHC13/hexane 363 ~
10 76 , H~_ 220-223 (~-c.~ EtOH 453 ~R )
77 CH,N~-' ill-214 tdec.) EtoH/cHcl3 391 tM~
~ _ 73 _ 1 336905
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.
10-[3-(aminomethyl)-4-methyl-1-pyrrolidinyl]-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
10-[3-[(ethylamino)methyl]-4-methyl-1-pyrrolidinyl]-9-fluoro-
3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4_benzoxa_
diazine-6-carboxylic acid,
10-[3-(aminomethyl)-4-chloro-1-pyrrolidinyl]-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
10-~3-(aminomethyl)-4-fluoro-1-pyrrolidinyl]-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
10-[3-chloro-4-[(methylamino)methyl]-1-pyrrolidinyl]-9-fluoro-
3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
9-fluoro-10-[3-fluoro-4-[(methylamino)methyl]-1-pyrrolidinyl]-
3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
10-[3-chloro-4-[(ethylamino)methyl]-1-pyrrolidinyl]-9-fluoro-
3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
10-[3-[(ethylamino)methyl]-4-fluoro-1-pyrrolidinyl]-9-fluoro-
3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
_ - 74 - ~ 336905
9-fluoro-10-[3-methoxy-4-(methylamino)-1-pyrrolidinyl]-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
10-[3-(ethylamino)-4-methoxy-1-pyrrolidinyl]-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
9-fluoro-10-(3-hydroxy-4-methoxy-1-pyrrolidinyl)-3-methyl-7-
10 oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-
carboxylic acid,
10-(3-amino-4-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,
10-(3-amino-4-fluoro-1-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-chloro-4-(methylamino)-1-pyrrolidinyl]-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
9-fluoro-10-[3-fluoro-4-(methylamino)-1-pyrrolidinyl]_3_
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid,
9-fluoro-3-methyl-10-(1-oxide-4-thiomorpholinyl)-7-oxo-2,3-
dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic
acid,
9-fluoro-10-[3-hydroxy-4-(methylamino)-1-pyrrolidinyl]-3-
methyl-7-oxo-2,3-dihydro-7~I-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid.
_ - 75 ~ 1 336905
Example 78
PreParation of 10-[3-[(4-aminobenzyl)amino]-1-pyrrolidinyl]-
9-fluoro-3-methYl-7-oxo-2~3-dihydro-7H-pyrido[3~2~ ]
1,3,4 -benzoxadiazine-6-carboxylic acid
10-[3-[(4-Aminobenzyl)amino]-l-pyrrolidinyl]-9-fluoro-3-
methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxa-
diazine-6-carboxylic acid was prepared analogously to the
methods described in Example 47 and 53, starting from
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-carboxylic
acid which was obtained in Example 30: mp. 180-182C
(dec.), FAB-MS m/z 453 (MH ).
L5
Example 79
PreParation of 9-fluoro-10-[3-[[(dimethylamino)methylenel-
amino]-l-pyrrolidinYl]-3-methyl-7-oxo-2~3-dihydro-7H-pyrido-
r 3,2,1-ii]-1,3,4-benzoxadiazine-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]-1,3,4-
-benzoxadiazine-6-carboxylic acid ~14 mg) obtained in
Example 30 and N,N-dimethylformamide dimethylacetal (6 ~1)
in dry DMF (0.5 ml) was stirred at room temperature for 8.5
hours. The precipitate was collected by filtration, washed
with DMF and ether, and recrystallized from DMF to give 8 mg
of 9-fluoro-10-[3-[[(dimethylamino)methylene]amino]-1
-pyrrolidinyl]-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]
-1,3,4-benzoxadiazine-6-carboxylic acid as pale yellow
crystals; mp. 218-220C (dec.), FAB-MS m/z 404 (MH ).
1 3369~5
- 76 -
Example 80
PreParation of sodium 9-fluoro-3-methyl-10-(4-methyl-1-
piperazinYl)-7-oxo-2~3-dihydro-7H-pyrido[3~2~l-ij]-l~3~4
benzoxadiazine-6-carboxylate
9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-Z,3-
dihydro-7H-pyrido[3,2,1-ij]-1,3,4-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-1-piperazinyl)-7-oxo-2,3-
-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-car-
boxylate, after drying in vacuo at 80C for 2 days; mp
252-254C (dec.), FAB-MS m/z 385.
The following Examples illustrate pharmaceutical
preparations containing a compound provided by the present
zo invention:
Example A
Interlocking gelatin capsules each containing the follo-
wing ingredients were manufactured in the conventional
manner per se:
9-Fluoro-3-methyl-10-(4-methyl-1-
piperazinyl)-7-oxo-2,3-dihydro-7H-
pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-
6-carboxylic acid 200mg
Luviskol (water-soluble polyvinylpyrrolidone) 20mg
Mannitol 20mg
Talc 15mg
Magnesium stearate 2mq
257mg
` -
1 336905
Example B
Tablets each containing the following ingredients were
manufactured in the conventional manner per se:
9-Fluoro-3-methyl-lO-(4-methyl-l-
piperazinyl)-7-oxo-2,3-dihydro-7H-
pyrido[3,2,l-ij]-l,3,4-benzoxadiazine-
6-carboxylic acid 200mg
Starch 44mg
Carboxymethylcellulose calcium 30mg
Crystalline cellulose 40mg
Magnesium stearate 6mq
32Omg
