BENZO(IJ)QUINOLIZINE-2-CARBOXYLIC ACID COMPOUNDS, THERAPEUTIC COMPOSITION CONTAINING SAME AND PROCESS FOR PRODUCING SAME

ACIDES BENZO(IJ)QUINOLIZINE-2-CARBOXYLIQUES, COMPOSITIONS THERAPEUTIQUES QUI EN RENFERMENT, ET METHODE D'OBTENTION

English Abstract

ABSTRACT OF THE DISCLOSURE
A benzo[ij]quinolizine-2-carboxylic acid
compound, a composition containing the compound, and
processes for production of the compound are described;
the compound is

Image (I)

wherein R1 represents a hydrogen atom or a lower alkyl
group; R2 represents a hydrogen atom or a halogen atom;
R3 represents a lower alkyl group substituted with one or
more of a halogen atom and a hydroxy group, a lower
alkanoyl group substituted with one or more halogen atoms,
a phenylalkyl group substituted with one or more lower
alkoxy groups on the phenyl ring, a lower alkanesulfonyl
group substituted with one or more halogen atoms, a lower
alkenyl group or a lower alkynyl group; or a pharmaceu-
tically acceptable salt thereof. The compounds have an
antimicrobial activity, and are particularly effective on
those bacteria resistant to conventional antibiotics and
can be maintained at high concentration levels in blood
for extended periods of time.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:

1. A process for preparing a benzo[ij]quinolizine-
2-carboxylic acid compound represented by the formula (I)

Image (I)

wherein R1 represents a hydrogen atom or a lower alkyl group;
R2 represents a hydrogen atom or a halogen atom; R3 represents
a lower alkyl group substituted with one or more of a halogen
atom and a hydroxy group, a lower alkanoyl group substituted
with one or more halogen atoms, a phenylalkyl group substituted
with one or more lower alkoxy groups on the phenyl ring, a
lower alkanesulfonyl group substituted with one or more halogen
atoms, a lower alkenyl group, or a lower alkynyl group; or a
pharmaceutically acceptable salt thereof, which comprises select-
ing a process from the group of processes consisting of:
(a) reacting a benzo[ij]quinolizine-2-carboxylic acid
compound represented by the formula (II)

Image (II)

wherein R4 represents a halogen atom, a lower alkanesulfonyl-
oxy group or an arylsufonyloxy group, and R1 and R2 have the
same meaning as defined hereinbefore, with a piperazine compound
represented by the formula (III)

73


Claim 1 continued

Image (III)

wherein R3 has the same meaning as defined hereinbefore to give
a compound of the formula (I),
(b) reacting a compound of the formula (XXVI)

Image (XXVI)

wherein R1, R2 and R3 have the same meaning as defined herein-
before and R5 and R6 each represents a hydrogen atom or a
lower alkyl group, with a tertiary nitrogen containing aromatic
heterocyclic compound or a trialkylamine in the presence of
an anion donating compound to form a compound of the formula
(XXVII)

Image (XXVII)

wherein R1, R2, R3, R5 and R6 have the same meaning as defined
hereinbefore; Y? represents a tertiary nitrogen atom-containing
aromatic heterocyclic residue being bonded through said nitrogen
atom or a trialkyl ammonium group; and Z ? represents an anion,
and then hydrolyzing compound to give a compound of the formula
(I)

74


Claim 1 continued

(c) reacting a compound represented by the formula
(XX)

Image (XX)

wherein R1 and R2 have the same meaning as defined hereinbefore,
with a compound represented by the formula (XXI)
R3X (XXI)

wherein R3 has the same meaning as defined hereinbefore to give
a compound formula (I).

2. A process for preparing a benzo[ij]quinolizine-2-
carboxylic acid compound of the general formula (I) as claimed
in claim 1 or a pharmaceutically acceptable salt thereof
wherein R2 represents a halogen atom.

3. A process as claimed in claim 2 wherein R2 represents
chlorine or fluorine.
4. A process as claimed in claim 1(a) wherein the propor-
tion of the compound of formula (III) to the compound of formula
(II) is at least equimolar.

5. A process as claimed in claim 4 wherein the molar
proportion of the compound of the formula (III) to the compound
of the formula (II) is 1:1 to 5:1.



6. A process as claimed in claim l(a) wherein the
reaction is carried out in the presence of a deoxidizing agent.

7. A process as claimed in claim l(a) whereln the
reaction is carried out at a temperature of from about 100°C
to about 250°C for from about 5 hours to about 20 hours.

8. A process as claimed in claim 7 wherein the reaction
is carried out at a temperature of from about 140°C to about
200°C.

9. A process as claimed in claim l(a) wherein the
reaction is carried out at a pressure of from about 1 atms. to
about 10 atms.

10. A process as claimed in claim l(c) wherein R3 repre-
sents a lower alkanoyl group substituted with one or more
halogen atoms and the reaction is carried out in the presence
of a deoxidizing agent at a temperature of from about 0°C to
about 100°C for from about 0.5 hours to about 6 hours.

11. A process as claimed in claim 10 wherein the reaction
is carried out at about room temperature.

12. A process as claimed in claim 10 wherein the propor-
tion of the compound of formula (XXI) to the compound of
formula (XX) is at least equimolar.

13. A process as claimed in claim 10 wherein R3 represents
a lower alkyl group substituted with one or more of a halogen
atom and a hydroxy group, a phenylalkyl group substituted with one
or more lower alkoxy groups on the phenyl ring, a lower alkane-
sulfonyl group substituted with one or more halogen atoms, a

76





Claim 13 continued


lower alkenyl group or a lower alkynyl group, and wherein the
proportion of the compound of formula (XXI) to the compound
of formula (XX) is at least equimolar.


14. A process as claimed in claim l(c) wherein the
reaction is carried out at a temperature of from about room
temperature to about 150°C for from about 1 hour to 10 hours.


15. A process as claimed in claim 14 wherein the reaction
is carried out at a temperature of from about 50°C to about
100°C.


16. A process as claimed in claim 10 wherein the reaction
is carried out in the presence of a deoxidizing agent.


17. A process as claimed in claim 10 wherein the reaction
is carried out in an inert solvent.


18. A process as claimed in claim l(b) wherein the propor-
tion of said tertiary nitrogen atom-containing aromatic hetero-
cyclic compound or trialkylamine and said anion donating compound,
respectively, to the compound of the formula (XXVI) are at
least equimolar.



19. A process as claimed in claim 18 wherein the propor-
tion of said tertiary nitrogen atom-containing aromatic hetero-
cyclic compound or trialkylamine and said anion donating
compound, respectively, to the compound to the formula (XXVI)
are each on a molar basis from 1/1 to 2/1.




77

20. A process as claimed in claim l(b) wherein said first
reaction step is carried out at a temperature of from about
room temperature to about 120°C for about 0.5 hours to about
6 hours.


21. A process as claimed in claim 20 wherein said first
reaction step is carried out at a temperature of from about
50°C to about 100°C.


22. A process as claimed in claim l(b) wherein said
hydrolysis is carried out in the presence of an acid or an
alkali.


23. A process as claimed in claim l(b) wherein said
hydrolysis is carried out in an inert solvent.


24. A process as claimed in claim l(b) wherein said
hydrolysis is carried out in an aqueous medium containing a
trialkylamine.


25. A process as claimed in claim l(b) wherein said
hydrolysis is carried out in the presence of a lower alcohol.


26. A process as claimed in claim l(b) wherein said
hydrolysis is carried out at a temperature of from about
20°C to about 150°C for from about 0.5 hours to about 6 hours.



27. A process as claimed in claim 26 wherein said
hydrolysis is carried out at a temperature of from about 80°C
to about 120°C.


28. A process as claimed in claim l(a).




78

29. A process as claimed in claim 1(b).


30. A process as claimed in claim l(c).


31. Compounds of the general formula (I) as defined in
claim 1 and pharmaceutically acceptable salts thereof whenever
prepared by a process as claimed in claim 1 or an obvious
chemical equivalent thereof.


32. Compounds of the general formula (I) as defined in
claim 1 and pharmaceutically acceptable salts thereof whenever
prepared by a process as claimed in claim 28 or an obvious
chemical equivalent thereof.


33. Compounds of the general formula (I) as defined in
claim 1 and pharmaceutically acceptable salts thereof whenever
prepared by a process as claimed in claim 29 or an obvious
chemical equivalent thereof.


34. Compounds of the general formula (I) as defined in
claim 1 and pharmaceutically acceptable salts thereof whenever
prepared by a process as claimed in claim 30 or an obvious
chemical equivalent thereof.


35. Compounds of the general formula. (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
wherein R2 is defined in claim 2 whenever prepared by a process

as claimed in claim 2 or an obvious chemical equivalent thereof.


36. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
wherein R2 is defined in claim 3 whenever prepared by a process
as claimed in claim 3 or an obvious chemical equivalent thereof.




79

37. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 4 or an
obvious chemical equivalent thereof.


38. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 5 or an
obvious chemical equivalent thereof.


39. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 6 or an
obvious chemical equivalent thereof.


40. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 7 or an
obvious chemical equivalent thereof.


41. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 8 or an
obvious chemical equivalent thereof.


42. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 9 or an

obvious chemical equivalent thereof.





43. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
wherein R3 is defined in claim 10 whenever prepared by a process
as claimed in claim 10 or an obvious chemical equivalent

thereof.

44. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
wherein R3 is defined in claim 10 whenever prepared by a process
as claimed in claim 11 or an obvious chemical equivalent thereof.


45. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
wherein R3 is defined in claim 10 whenever prepared by a
process as claimed in claim 12 or an obvious chemical equivalent
thereof.


46. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
wherein R3 is defined in claim 13 whenever prepared by a
process as claimed in claim 13 or an obvious chemical equivalent
thereof.


47. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 14 or an
obvious chemical equivalent thereof.



48. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof
whenever prepared by a process as claimed in claim 15 or an
obvious chemical equivalent thereof.




81

49. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof wherein
R3 is defined in claim 10 whenever prepared by the process as
claimed in claim 16 or an obvious chemical equivalent thereof.


50. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof wherein
R3 is defined in claim 10 whenever prepared by the process as
claimed in claim 17 or an obvious chemical equivalent thereof.


51. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 18 or an obvious
chemical equivalent thereof.


52. Compounds of the general formula II) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 19 or an obvious
chemical equivalent thereof.


53. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 20 or an obvious
chemical equivalent thereof.


54. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 21 or an obvious

chemical equivalent thereof.




82

55. Compounds of the general formula (1) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 22 or an obvious
chemical equivalent thereof.


56. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 23 or an obvious
chemical equivalent thereof.


57. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 24 or an obvious
chemical equivalent thereof.


58. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-

ever prepared by a process as claimed in claim 25 or an obvious
chemical equivalent thereof.

59. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 26 of an obvious
chemical equivalent thereof.


60. Compounds of the general formula (I) as defined in
claim 1 and the pharmaceutically acceptable salts thereof when-
ever prepared by a process as claimed in claim 27 or an obvious
chemical equivalent thereof.




83 .

Description

1 15~232
- 1 -


BENZO[ij]QUINOLIZINE-2-CARBOXYLIC ACID COMPOUNDS,
THERAPEUTIC COMPOSITION CONTAINING SAME
AND PROCESSES FOR PRODUCING SAME



BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain ben20[ij]-
quinolizine-2-carboxylic acid compounds and pharmaceu-
tically acceptable salts thereof which are useful as
antimicrobial agents, processes for preparing the same,
and pharmaceutical compositions containing the benzo[ij]-
quinolizine-2-carboxylic acid compound or a salt thereof.
2. Description of the Prior Art
It is known that certain types of polyhetero-
cyclic compounds exhibit antimicrobial activities. For
example, U.S. Patent 3,917,609 to Gerster et al. discloses
substituted derivatives of l,2-dihydro-6-oxo-6H-pyrrolo-
~3,2,1-ij]quinoline which are useful as antimicrobial
agents or as intermediates for the preparation of anti-
microbial agents.
Also, U.S. Patents 3,896,131, 3,985,882,
3,969,463, 4,001,243 and 4,014,877 to Gerster et al. and
British Patent Application GB 2020279A disclose 6,7-

dihydro-1-oxo-lH,5H-benzo[ij]quinolizine derivatives
having antimicrobial activities.


1 15~232


SUM~ARY OF T~IE INVENTION
As a result of extensive research it has now
been found that some benzo[ij~quinolizine-2-carboxylic
acid derivatives have a potent antimicrobial activity and
low toxicity, that they show no desrease in activity in
the presence of serum, and that they are effective against
bacteria which are resistant to conventional antibiotics
such as penicillin, ampicillin, streptomycin, etc.
This invention is based on the above finding
and provides a benzo[ij]quinolizine-2-carboxylic acid
compound represented by the formula ~I)



R2 0
R3-N N~COOH (I)


~ Rl

wherein Rl represents a hydrogen atom or a lower alkyl
group; R2 represents a hydrogen atom or a halogen atom;
R3 represents a lower alkyl group substituted with one or
more of a halogen atom and a hydroxy group, a lower
alkanoyl group substituted with one or more halogen atoms,
a phenylalkyl group substituted with one or more lower
: alkoxy groups on the phenyl ring, a lower alkanesulfonyl

1 15~232


1 group substituted with one or more halogen atoms, a lower
alkenyl group or a lower alkynyl group; and pharmaceu-
tically acceptable salts thereof.
In another aspect this invention provides a
pharmaceutical composition containing the compound of the
formula (I) or a pharmaceutically acceptable salt thereof
in an antimicrobially effective amount.
Further, this invention provides processes for
preparing compounds of formula (I) and pharmaceutically
acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The term "halogen" as used herein includes a
chlorine atom, a bromine atom, an iodine atom and a
fluorine atom.
The term "lower alkyl" as used herein refers to
a straight or branched chain alkyl group having 1 to 4
carbon atoms such as a methyl group, an ethyl group, a
propyl group, an isopropyl group, a butyl group, a tert-
butyl group and the like.
The term "lower alkanoyl" as used herein refers
to a straight or branched alkanoyl group having 2 to 4
carbon atoms such as an acetyl group, a propanoyl group,
a butanoyl group, an isobutanoyl group and the like.
The term "lower alkanesulfonyl" as used herein
refers to a straight or branched alkanesulfonyl group
having 1 to 4 carbon atoms such as a methanesulfonyl group,
- 3 -

1 15~232
- 4


1 an ethanesulfonyl group, a propallesulfonyl group, an
isopropanesulfonyl group, a butanesulfonyl group, a tert-
butanesulfonyl group and the like.
The term "arylsulfonyl" as used herein refers
to a benzenesulfonyl group, a naphthalenesulfonyl group
and the like. The aryl ring included in the arylsulfonyl
group may be substituted with one or more of a halogen
atom, a lower alkyl group, a hydroxy group, a nitro
group and the like.
The term "phenylalkyl" as used herein refers
to a phenylalkyl group consisting of a phenyl group and
a straight or branched alkylene group having 1 to 4
carbon atoms such as a benzyl group, a 2-phenylethyl
group, a 3-phenylpropyl group, a 4-phenylbutyl group,
a l-phenylethyl group, a l,l-dimethyl-2-phenylethyl
group and the like.
Examples of the lower alkyl group substituted
with one or more of a halogen atom and a hydroxy group as
used herein include a trifluoromethyl group, a trichloro-
methyl group, a dichloromethyl group, a tribromomethylgroup, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloro-
ethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl
group, a 3,3,3-trichloropropyl group, a 3-fluoropropyl
group, a 4-chlorobutyl group, a 3-chloro-2-methylethyl
: group, a hydroxymethyl group, a 2-hydroxyethyl group,

- 4

l 15~232
- 5


1 a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a
4-hydroxybutyl group, a 2-hydroxypropyl group, etc.
Examples of the lower alkanoyl group substi-
tuted with one or more halogen atoms as used herein
include a trifluoroacetyl group, a trichloroacetyl group,
a tribromoacetyl group, a 2,2-dichloropropionyl group,
a monochloroacetyl group, a 2-chlorobutyryl group, a
pentafluoropropionyl group, a heptafluorobutyryl group,
etc.
Examples of the phenylalkyl group substituted
with one or more alkoxy groups containing, e.g., from 1
to 3 carbon atoms, on the phenyl ring thereof include
a 4-methoxybenzyl group, a 2-isopropoxybenzyl group, a
3,4-dimethoxybenzyl group, a ~-3,4-dimethoxyphenethyl
group, an ~-3,4-dimethoxyphenethyl group, a ~-2,3,4-
trimethoxyphenethyl group, a 3-(4-ethoxyphenyl)propyl
group, a 4-(4-methoxyphenyl)butyl group, etc.
Examples of the lower alkanesulfonyl group
substituted with one or more halogen atoms include a
trifluoromethanesulfonyl group, a trichloromethanesulfonyl
group, a tribromomethanesulfonyl group, a dichloromethane-
sulfonyl group, a 2,2,2-trifluoroethanesulfonyl group, a
2,2,2-trichloroethanesulfonyl group, a 2-chloroethane-
sulfonyl group, a 1,2-dichloroethanesulfonyl group, a
3,3,3-trifluoropropanesulfonyl group, a 3,3,3-trichloro

1 15~232
- 6


1 propanesulfonyl group, a 3-fluoropropanesulfonyl group,
a 4-chlorobutanesul~onyl group, a 3-chloro-2-methyl-
ethanesulfonyl group, etc.
Examples of the lower alkenyl group containing,
e.g., from 2 to 4 carbon atoms, as used herein include
a vinyl group, an allyl group, a crotyl group, a l-methyl-
allyl group, etc.
Examples of the lower alkynyl group containing,
e.g., from 2 to ~ carbon atoms, as used herein include
an ethynyl group, a 2-propynyl group, a 2-butynyl group,
a l-methyl-2-propynyl group, etc.
The compounds of this invention of the formula
(I) and the salts thereof exhibit excellent antimicrobial
activity broadly on gram-positive and negative bacteria
at low concentrations. They are useful compounds which
show particularly potent antibacterial activity on
Streptococcus, Pseudomonas, Enterobacter, Proteus, etc.,
on which conventional synthetic antibacterial agents are
not effective or only slightly effective. In addition,
they show a high antibacterial activity on coliform
bacilli, staphylococci, etc., which are major causes of
infectious diseases and are also effective on Serratia,
Klebsiella, etc., which also cause infectious diseases
that have recently attracted wide attention of many
workers in the field, and therefore they are very useful
clinically.
- 6

1 15~232



1 As stated above, the compounds of this invention
are advantageous not only because they are characterized
by a broad antimicrobial spectrum and potent activity,
but also because they not only show no decrease in anti-
microbial activity in the presence of a serum, but rather
show a tendency towards increased activity. This phenom-
enon is surprising to one skilled in the art since it has
hitherto been observed that conventional pharmaceuticals
having antimicrobial activity show decreased activity in
the presence of a serum. This strongly suggests that the
compound of this invention can exhibit potent antimicrobial
activity in the blood.
The oral toxicity of the compounds of this
invention is very low as compared with the effective oral
dosage thereof.
The compounds of this invention have excellent
antimicrobial activity on those bacteria which are resist-
ant or have acquired resistance to conventional anti-
biotics such as penicillin, cephalosporin, ampicillin,
streptomycin, erythromycin, Kanamycin, nalidixic acid, etc.
~ Vhen administered orally the compounds of this
invention are absorbed readily and their blood level or
activity in the blood level is maintained at high levels
so that they can exhibit potent antimicrobial activity
also in this respect.

- 7

2 3 2



1 Representative examples of the compound of this
invention include the following compounds. This list is
provided for illustration only and is not intended to
limit to scope of this invention.
(1) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(2) 8-(4-trifluoroacetyl-1-piperazinyl)-9-fluoro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(3) 8-(4-trifluoroacetyl-1-piperazinyl)-10-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(4) 8-(4-trichloroacetyl-1-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
; carboxylic acid
(5) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-
5-ethyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-
carboxylic acid
(6) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-
5-butyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(7) 8-(4-monochloroacetyl-1-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid



.

1 I5~232



1 (8) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
(9) 8-(4-trifluoromethanesul~onyl-1-piperazinyl)-9-
fluoro-5-methyl-6,7-dihydro-1-oxo-1~-1,5H-benzoEij]-
quinolizine-2-carboxylic acid
(10) 8-[4-(2,2,2-trifluoroethanesulfonyl)-1-
piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-
benzo[ij]quinolizine-2-carboxylic acid
(11) 8-[4-(2-chloroethyl)-1-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quizolizine-2-
carboxylic acid
(12) 8-(4-tribromoacetyl-1-piperazinyl)-9-bromo-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(13) 8-[4-(2-chlorobutyl)-1-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(14) 8-(4-trifluoroacetyl-1-piperazinyl)-5-methyl-
6,7-dihydro-1-oxo-lH~5H-benzo[ij]quinolizine-2-carboxylic
acid
(lS) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
;~ acid




1 15~2~2
- 10 -


1 (16) 8-(4-allyl-l-piperazinyl)-9-chloro-5-methyl-
6,7-dihydro-1-oxo-lH,511-benzo[ij]quinolizine-2-carboxylic
acid
(17) 8-(4-crotyl-1-piperazinyl)-9-chloro-S-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
(18) 8-(4-allyl-1-piperazinyl)-S-methyl-6,7-dihydro-
l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
(19~ 8-(4-allyl-1-piperazinyl)-9-chloro-6,7-dihydro-
1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
(20) 8-(4-allyl-1-piperazinyl)-9-fluoro-5-methyl-
: 6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
(21) 8-(4-trifluoromethyl-1-piperazinyl)-10-chloro-
! S-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-
carboxylic acid
(22) 8-(4-trifluoromethyl-1-piperazinyl)-9-chloro-
S-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-
carboxylic acid
: 20 (23~ 8-(4-trichloromethyl-1-piperazinyl)-9-chloro-
S-methyl-6~7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(24) 8-[4-(2,2,2-trifluoroethyl)-1-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,51-1-benzo[ij]-
quinolizine-2-carboxylic acid
~,

- 10 -

1 15~232



I (25) 8-[4-(~-chlorobutyl)-1-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,51-1-benzo[ij]quinolizine-2-
carboxylic acid
~ 26) 8-(4-tri~luoromethyl-1-piperazinyl)-9-fluoro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(27) 8-(4-trifluoromethyl-1-piperazinyl)-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-earboxylic
acld
(28) 8-[4-~2,2,2-trifluoroethyl)-1-piperazinyl]-9-
chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(29) 8-(4-trifluoromethyl-1-piperazinyl)-9-chloro-5-
ethyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(30) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(31) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-fluoro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(32) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-10-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid


- 11 -
, .

1 15~232
- l2 -


1 (33) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
(34) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-
6,7-dihydro-1-oxo-lH,S~-I-benzo[ij]quinolizine-2-carboxylic
acid
(35) 8-[4-(2,3-dihydroxylpropyl)-1-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
~36) 8-[4-(4-hydroxybutyl)-1-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(37) 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
~ 38) 8-[4-(2-propynyl)-1-piperazinyl]-9-fluoro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(39) 8-~4-(2-propynyl)-1-piperazinyl]-5-methyl-6,7-
dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acld
(40) 8-[4-(2-propynyl)-1-piperazinyl~-9-fluoro-6,7-
dihydro-l-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic
acid

' :
- 12 -
. .

1 15~232
- :13 -


1 (41) 8-[4-(1-methyl-2-propynyl)-1-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,511-benzo[ij]-
quinolizine-2-carboxylic acid
(42) 8-[4-(2-propynyl)-1-piperazinyl]-10-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(43) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
10 (44) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-fluoro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(45) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-chloro-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
(46) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
(47) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-10-
fluoro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-
quinolizine-2-carboxylic acid
(48) 8-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid


- 13 -

232
- l4 -


1 (49) 8-[4~ 3,4-dimethoxyphenethyl)-1-piperazinyl]-
9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
(50) 8-{4-[3-(4-ethoxyphenyl)propyl]-1-piperazinyl}-
9-chloro-5-methyl-6,7-dihydro-1-oxo-111,5H-benzo[ij]-
quinolizine-2-carboxylic acid
~ Sl) 8-[4-~-2,3,4-trimethoxyphenethyl)-1-
piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-
benzo[ij]quinollzine-2-carboxylic acid
(52) 8-(4-trifluoroacetyl-1-piperazinyl)-9-bromo-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(53) 8-(4-trifluoromethyl-1-piperazinyl)-9-bromo-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(54) 8-(4-allyl-1-piperazinyl)-9-bromo-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
(55) 8-(4-pentafluoropropionyl-1-piperazinyl)-5-
methyl-6~7-dihydro-l-oxo-lH~5t-l-benzo[ij]quinolizine-2
carboxylic acid
(56) 8-(4-heptafluorobutyryl-1-piperazinyl)-9-

chloro-6,7-dihydro-1-oxo-111,5h benzo~ij]quinolizine-2-
ca~rboxylic acid

' '
- 14 -

- 15 -


1 (57) 8-(4-pentafluoropropionyl-1-piperazinyl)-10-
chloro-S-metllyl-6,7-(li}ly(lro-i-oxo-111,511-benzo[ij]quinolizine-
2-carboxylic acid
(58) 8-(4-heptafluorobutyryl-1-piperazinyl~-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(59) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-

9-chloro-6,7-dihydro-1-oxo-111,5H-benzo[ij]quinolizine-2-
carboxylic acid
(60) 8-(4-pentafluoropropionyl-1-piperazinyl)-9-
chloro-6,7-dihydro-1-oxo-lH,51~-benzo[ij~quinolizine-2-
carboxylic acid
(61) 8-(4-heptafluorobutyryl-1-piperazinyl)-10-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-
2-carboxylic acid
(62) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
(63) 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-
~: 20 1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
`:



~ - 15 -
~:

1 156232
- 16 -


1 The compounds of this invention of the formula
(I) can be prepared by various alternative procedures,
for example, by reacting a benzo[ij]quinolizine-2-
carboxylic acid compound of the formula ~II)


tll)

Rl



wherein R4 represents a halogen atom, a lower alkane-
- sulfonyloxy group or an arylsulfonyloxy group, and Rl
and R2 have the same meaning as defined above, with a
piperazine compound of the formula ~III)

\ 3
HN\___/N-R (III)
;




wherein R3 has the same meaning as defined above.
The term "lower alkanesulfonyloxy" represented
by R4 refers to a straight or branched alkanesulfonyloxy
group having 1 to 4 carbon atoms such as a methane-
sulfonyloxy group, an ethanesulfonyloxy group, a propane-

;~ sulfonyloxy group, an isopropanesulfonyloxy group, a
~ butanesulfonyloxy group, a tert-butanesulfonyloxy group

: and the like.


. - 16 -

1 1 SB232


1 The term "arylsulonyloxy" as used herein
includes a benzenesulfonyloxy group, a naphthalene-
sulfonyloxy group and the like. The aryl ring included
in the arylsulfonyloxy group may be substituted with one
or more, and preferably from one to three, of a halogen
atom, a lower alkyl group, a lower alkoxy group, a
hydroxy group, a nitro group and the like.
With respect to the compounds of the formula
(Il) which can be used as the starting material for
preparing the compounds of this invention represented by
the formula (I), some of those in which R4 represents a
halogen atom are known compounds as described in U.S.
Patents 3,917,609, 3,896,131, 3,985,882, 3,969,463,
4,001,243 and 4,014,877 and others can be easily prepared
by appropriate selection of starting materials according
to known processes as described in Japanese Patent
Publication No. 6156/76 and U.S. Patent 4,014~877.
They can also be prepared by Reaction Scheme-2 herein-
; below. On the other hand, the compounds of the formula
(II) in which R4 represents a lower alkanesulfonyloxygroup or an arylsulfonyloxy group, i.e., compounds oE the
formula (IIa) are novel and can be prepared, for example,
-by the Reaction Scheme-l below.


;~ ~
- 17 -
~; ,
'

l 15~232
- 18 -


Reaction Scheme-l
OH OH

R2~ ~Rl ~ `~--~0
H ~l
(IV) (V)
~ R X ~VI) ~ R7X (VI)
oR7 oR7




R2 ~ Reduction R2 ~
N Rl ~ N O
H H
~VIII) (VII)
, COORg
C2H50CH C ~cooR8 (IX)

oR7

R ~ Cyclization R2 0
;!~,COOR8

CH=C~COOR8)2 R O ~ N~
.~ (X) l J~ 1
: " ~' R
(XI)


COOH
Hydrolysis
> R70 ~ N')

~Rl
(IIa)
'
- 18 -

1 l~B232
- 19 -


l In the Reaction Scheme-l abo~e, R7 represents a lower
alkanesulfonyl group or an arylsulfonyl group; R8 repre-
sents a lower alkyl group; X represents a halogen atom;
and Rl and R2 have the same meaning as defined above.
Thus, the compounds of the formula (IIa~ can be
prepared by reacting a compound of the formula (IV~ with
a compound of the formula (VI) to form a compound of the
formula (VIII), further reacting this compound with a
compound of the formula ~IX) to obtain a compound of the
formula (X), and cyclizing the compound of the formula
(X) to form a compound of the formula (XI), which is then
subjected to hydrolysis.
Of the compounds of the formula (VIII) those
in which Rl represents a hydrogen atom can also be
prepared by reacting a compound of the formula (V) wi~h
a compound of the formula (VI) to form a compound of the
formula (VII) and reducing this compound.
In Reaction Scheme-l above, a suitable amount
of the compound of the formula (VI) to be reacted with
the compound of the formula (IV) is at least an approxi-
mately equimolar amount. Preferably l to 2 mols of the
compound of the formula (VI) are reacted per mol of the
compound of the formula (IV).
The reaction proceeds usually in an inert
solvent in the presence of a deoxidizing agent in an
amount of at least an approximately equimolar amount,
- 19 -

1 15~232
- 20 -


l and preferably 1 to 2 mols of the deoxiclizin~ agent per mol
of the compound of the formula (IV) at a temperature of
about 0 to about 100C, preferably at room temperature
for about 0.5 to about 6 hours, thereby yielding the
compound of the formula (VIII).
Examples of suitable deoxidizing agents include
alkali metal hydroxides such as sodium hydroxide, potassium
hydroxide, etc., inorganic carbonates such as sodium
carbonate, potassium carbonate, potassium hydrogen
carbonate, sodium hydrogen carbonate, sodium hydrogen
carbonate, etc., tertiary amines such as pyridine,
quinoline, triethylamine, etc.
Examples of suitable inert solvents include
lower alcohols such as methanol, ethanol, isopropanol,
etc., ethers such as dioxane, tetrahydrofuran (THF),
diglyme, etc., aromatic hydrocarbons such as benzene,
toluene, etc., dimethyl sulfoxide ~DMSO), dimethylformamide
(DMF~, hexamethylphosphoric triamide (HMPTA), pyridine,
etc.
More particularly~ in Reaction Scheme-l, the
reaction between the compound of the formula tVIII~ and
the compound of the formula (IX) can be effected in the
absence of solvents or in the presence of solvents such
as the above-described lower alcohols, DMF, DMSO, and
HMPTA and acetonitrile and the like. Preferably the
reaction is conducted in the absence of solvents.
- 20 -

2~2
- Zl -


1 The compound of the formula ~IX) can be used in
excess amounts over the equimolar amount relative to the
compounds of the formula (VIII), preferably in an
equimolar amount in the absence of solvents and in an
amount of from about 1.1 to 1.5 mols per mol of the
compound of the formula (VIII) in the presence of solvents.
The reaction can generally be carried out at a temperature
of from room temperature (from about 15 to 30C) to about
150C, and preferably from 100 to 130C, for a period of
from about 0.5 to about 6 hours thereby easily yielding
the compound represented by the formula (X).
The subsequent cyclization reaction of the thus-
obtained compound of the formula (X) can be effected in
accordance with conventional cyclization reactions, for
example, by heating the compound of the formula (X) or
by using an acidic substance such as phosphorus oxychloride,
phosphorus pentachloride, phosphorus trichloride, thionyl
chloride, concentrated sulfuric acid, polyphosphoric acid
and the like. When the cyclization is effected by heating,
it is preferred to heat the compound of the formula (X)
in a solvent such as high boiling point hydrocarbons or
high boiling point ethers, for example, diphenyl ether
tetraphosphoric acid, diethylene glycol dimethyl ether,
etc., at a temperature of from about 100 to about 250C,
and preferably from 150 to 200C for a period of from

- 21 -

l 1S~232
- 22 -


1 about 0.5 to about 6 hours. lYhen the cyclization iseffected using an acidic substance, the cyclization can
be conducted in the presence of the acid substance in an
approximately equimolar amount to a large excess amount,
preferably 10 to 20 molar excess acid, relative to the
amount of the compound of the formula (X) at a temperature
of about 100 to about 150C for a period of about 0.5 to
about 6 hours, whereby the desired compounds of the
formula (XI) can be produced advantageously.
In the above Reaction Scheme-l, the hydrolysis
of the compound of the formula (XI) into the compound of
the formula (IIa) can be achieved by a conventional
hydrolysis procedure in the presence of a typical
hydrolyzation catalyst, for example, a basic compound
such as sodium hydroxide, potassium hydroxide, barium
hydroxide and the like, or an inorganic acid such as
sulfuric acid, hydrochloric acid, nitric acid and the
like or organic acid such as acetic acid, an aromatic
sulfonic acid and the like. The hydrolysis can be carried
out in a solvent such as water, the above-described
alcohols, ethers, and ketones such as acetone, methyl
ethyl ketone, dioxane, ethylene glycol, etc., and acetic
acid and the like at a temperature of from room tempera-
ture to about 200C, preferably 5Q to 150C for a period
of about 0.5 to about 6 hours, thereby easily yielding
the compound represented by the formula ~IIa).
- 22 -


1 l~B2~2
- 23 -


1 The reaction between the compound of the
formula (V) and the compounds of the formula ~VI) can be
conducted in the same manner as the reaction of the
compound of the formula (lV) with ~he compound of the
formula (VI), thus yielding a compound of the formula
(VII).
In Reaction Scheme-l above, the reduction of
the compounds of the formula (VII) can be conducted
catalytically or using a conventional hydrogenating agent
such as a combination of sodium borohydride or lithium
aluminum hydride and a lower fatty acid, e.g., acetic
acid, trifluoroacetic acid, propionic acid, etc.
Suitable amounts of sodium borohydride or
lithium aluminum hydride and the lower fatty acid are
from an approximately equimolar amount to a large excess
amount, preferably from 3 to 5 mols per mol of the
; compound of the formula (VII).
The reduction reaction using a hydrogenating
agent can proceed advantageously in an inert solvent
such as the above-described ethers, aromatic hydrocarbons,
lower fatty acids, e.g., acetic acid, trifluoroacetic
acid, propionic acid, etc., at a temperature of from
room temperature to about 100C, preferably from 50 to
100C for about 1 to about 6 hours, thus yielding the
compound of the formula ~VIII) in which Rl represents a
hydrogen atom.
- 23 -

1 15~232
- 24 -

Reaction Scheme-2

Nitration X ~ R

(XIII)
~ Reduction
N~12 ~ of Nitro Group
X~'~Rl

Reduction
~XIV)
\ Reduction of
\ Pyridine
Replacement of \ing
Amino Group by ~
Halogen NH2

X ~ H

N Rl (XVII~
~XV)

~`. Reduction of /Replacement of
Pyridine Ring / Amino by Halogen
~ X \ / k/

X~ R
H
(XVI~


- 24 -

- 2 5


(XVI )

~COOR8

~ C2H50CHsC~ 8 ~IX)
X O
X~ X~COOR8
lRl Cyclization J~N~J

CH=C (COOR8) 2 U~R1
~XVI I I ) (XIX3

O
, l ~ ~COOH

Hydro ly s i s ~ R

(I Ib)
,: j



.~ ;::

,:


~ ~,
.
- 25 -

~`

l 156232
- 26 -


1 In the above formulae, R-, R8 and X have the
same meaning as defined above.
In the Reac~ion Scheme-2 above, nitration of the
compound of the formula (XII) can proceed under conven-
tional conditions for nitration of aromatic compounds,
e.g., in the absence of solvents or in the presence of a
suitable inert solvent using a nitration agent.
Suitable examples of the inert solvent include
acetic acid, acetic anhydride, concentrated sulfuric acid,
etc.
Suitable examples of nitration agent include
fuming nitric acid, concentrated nitric acid, a mixed
acid (a mixture of nitric acid and sulfuric acid, fuming
sulfuric acid, phosphoric acid or acetic anhydride),
alkali metal nitrates such as potassium nitrate and
sodium nitrate, and sulfuric acid, etc.
The reaction proceeds advantageously in the
presence of at least equimolar amount, preferably excess
; amount, of the nitration agent with respect to the
2Q starting compound at a temperature of preferably O to
15C for 1 to 4 hours.
Reduction of the nitro group of the compound of
the formula (XIII) obtained in the above nitration can be
conducted in an inert solvent in the presence of a
reducing agent such as a mixture of iron, zinc, tin,

- 26 -

1 1 5B2~
- 27 -


1 stannous chloride and an acid (e.g., hydrochloric acidand sulfuric acid) or a mixture of iron, iron sulfite,
zinc or tin and hydroxide, sulfate, sulfite, etc., of an
alkali metal. Alternatively, the reduction can he
carried out catalytically using a reducing catalyst such
as palladium on carbon in an inert solvent.
~ xamples of suitable inert solvents include
water, acetic acid, methanol, ethanol, dioxane, etc.
The conditions under which the above reduction
of nitro group is carried out can be suitably selected.
For example, the reduction using a mixture of stannous
chloride and hydrochloric acid as a reducing agent can
proceed advantageously at a temperature of from 70 to
lOO~C for from 0.5 to 1 hour using at least equimolar
amount, and preferably from 1 to 2 mols of the reducing
agent per mol of the starting compound. When the reduc-
tion is carried out catalytically, it can proceed advanta-
geously at room temperature for from 0.5 to several hours.
The amino group of the compound of the formula
(XIV) thus obtained can be replaced by halogen by the
application of the Sandmeyer reaction involving diazota-
tion. Diazotation of the compound of the formula (XIV)
can proceed advantageously in a solvent such as water,
hydrochloric acid, sulfuric acid, etc., in the presence
of a diazotation agent such as a mixture of sodium sulfite

- 27 -

1 156232
- 2~ -


1 or potassium nitrite and hydrochloric acid or sulfuricacid at a temperature of -30C to room temperature for
0.5 to 2 hours. Subsequently, the diazonium salt of the
compound of the formula (XV) thus obtained, without
isolation, can be reacted, with a halogenating agent such
as cuprous chloride, cuprous bromide, etc., in an amount
of at least equimolar amount, preferably 1 to 2 mols of
the halogenating agent per mol of the starting compound
at a temperature of 0 to 50C for 0.5 to 2 hours to form
a compound of the formula (XV).
Reduction of the pyridine ring of the compound
of the formula (XV) can be carried out catalytically in
an inert solvent such as dioxane, tetrahydrofuran, acetic
acid, water, etc., under acidic condition using various
acids capable of forming a quinolinium salt such as acetic
acid, hydrochloric acid, sulfuric acid, etc., in the
presence of a catalytic reduction agent such as platinum-
carbon, palladium-carbon, r~odi~ll-carbon, ruthenium-carbon,
etc., at a temperature of room temperature to 50C for 1
to 10 hours, thus yielding a compound of the formula (XVI).
Alternatively, the compound of the formula ~XVI~
can also be prepared by reducing the pyridine ring of the
compound of the formula (XIV) to form a compound of the
formula (XVII) and then replacing the amino group of the
compound of the formula (XVII) by halogen atoms. The

- 28 -

l 156232
- 29 -


1 reduction of the pyridine ring of the compound of the
formula ~XIV) can be carried out in the same manner as
the reduction of the pyridine ring of the compound of
the formula (XV). Also, The replacement of the amino
group of the compound of the formula (XVII) by a halogen
atom can be conducted in the same manner as the replacement
of the amino group of the compound of the formula (XIV)
by a halogen atom.
~urther, the compound of the formula (XVII) can
be prepared by reducing the compound of the formula (XIII)
in the same manner as the reduction of the pyridine ring
of the compound of the formula (XIV).
Reaction between the compound of the formula
(XVI) thus-obtained and the compound of the formula (IX)
can be carried out under the same conditions as the reac-
tion between the compound of the formula (VIII) and that
of the formula (IX).
Cyclization of the compound (XVIII) which is
formed in the above reaction and hydrolysis of the
cyclized compound of the formula (XIX) can proceed in
the same manner as the cyclization of the compound of
the formula (X) and the hydrolysis o the compound of
the formula ~XI), respectively, thus yielding the compound
of the formula (IIb).


- 29 -

1 156232
- 30 -


1 Some of the compounds of the formula (III),
another starting compound used in this invention, are
known compounds and others can be prepared with ease
according to known processes.
In the reaction between the compound of theformula (II) and the compound of the formula (III) in the
Reaction Scheme-l the proportion of the latter to the
former is usually at least equimolar, and preferably from
1 to 5 mols of the latter per mol of the former, and the
reaction can generally proceed in an inert solvent such
as water, the above-described lower alcohols, aromatic
hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO,
DMF and HMPTA being preferred. In the reaction, the
above-described deoxidizing agent can be used.
The reaction can proceed advantageously at a
pressure of from 1 to 20 atms, and preferably from 1 to
10 atms, and at a temperature of 100 to 250C, and prefer-
ably from 140 to 2Q0C, for from 5 to 20 hours, thus
yielding the compound of the formula (I) of this invention.
Further, the compound of the formula (I) of this
invention can be prepared by reacting a compound of the
formula (XX) with a compound of the formula (XXI) in the
presence of the above-described deoxidizing agent as
shown in Reaction Scheme-3 below.


- 30 -

2 3 2
- 31 -


_eaction Scheme-3

R2 0 R2 0
~ COOH ~ COOH

HN N ~ N~ R3N N ~ N
~Rl ~R
(XX) (XXI) (I~

In the above formulae, Rl, R2, R3 and X have
the same meaning as defined above.
The compounds of the formula (XX) used in the
above reaction are novel compounds and can be prepared,
for example, by reacting a compound of the formula (II)
with piperazine under the same conditions under which
the compounds of the formula (II) is reacted with the
compound of the formula (III).
More particularly, the reaction between the
compounds of the formula (XX) and the compound of the
formula (XXI) can be carried out by one of the processes
described hereinbelow depending on the definition of R3
of the compound of the formula (XXI).
i) l~hen R3 represents a lower alkanoyl group
substituted with one or more halogen atoms:
In th;s case, the reaction proceeds under
conventional conditions for acylation7 e.g., without any
solvent or in an inert solvent such as the above-described
- 31 -


l 15~232
- 32 -


1 ethers, aromatic hydrocarbons, DMSO, I)~F, HMPTA, pyridine
and halogenated hydrocarbons such as chloroform, methylene
chloride, etc., in the presence of the above-described
deoxidizing agent at a temperature of 0 to 100C, prefer-
ably at a vicinity of room temperature, for about 0.5 to
6 hours.
With respect to the proportion of the starting
compounds, the compound of the formula (XXI) can be used
in at least equimolar amount, preferably 1 to 2 mols per
mol of the compound of the formula (XX) in the presence
of solvents and in excess amounts over the equimolar
amount relative to the compound of the formula (XX) in
the absence of solvents.
ii) When ~3 represents a group other than the
halogen substituted lower alkanoyl group:
The reaction can proceed under conventional
conditions for alkylation or aralkylation without solvents
or in an inert solvent using at least equimolar amount,
preferably 1 to 2 mols, of the compound of the formula
(XXI) per mol of the compound of the formula (XX~ at a
temperature of room temperature to 150C, preferably 50
to 100C, for 1 to 10 hours. The reaction can also be
carried out using the above-described deoxidizing agent.

l 1~6~32
- 33 -


1 Examples of su;table inert solvent include
water, alcohols such as methanol, ethanol, isopropanol,
butanol, amyl alcohol, isoamyl alcohol, etc., the above-
described aromatic hydrocarbons, ethers, DMSO, DMF,
HMPTA, etc., with DMSO, DMF and HMPTA being preferred.
Furthermore, the compound of the formula (I~ of
this invention can be prepared according to the process
shown in Reaction Scheme-4 below.




- 33 -

1 156232
- 34 -


Re ac t i on Sch eme - 4

R4
COOR8
lRl 2 5\COCH
R2 H R6
~XXII) (XXIII)


R~ 1 Cyclization

CH = C R5
\ COCH
R~
(XXIV)
R2 IR5




j~ R6 +HN N- R3

l (III)
(XXV)




- 34 -

l 1562~2
- 35 -



R ~ COCH

R -N N \ ~`N
\J
~Rl
(XXVI)
R2 R5




~ COC/~ Z~

R3-N N ~ N ~ \ R6 Hydrolysis
/ I I
Rl
(XXVII)


R2 0
R3-N N ~ COOH


~ ~Rl
(I)




- 35 -

1 156232
- 36 -


1 In the above formulae, Rl, R2, R3 and R4 have
the same meaning as defined above; R5 and R6 each repre-
sents a hydrogen atom or a lower alkyl group; R8 repre-
sents a lower alkyl group; Y~ represents a tertiary
nitrogen atom containing aromatic heterocyclic residue
being bonded through the nitrogen atom or a trialkyl
ammonium group; and Z~ represents an anion.
In the Reaction Scheme-4, the compounds of the
formulae (XXIV), (XXV) and (XXVI) can be prepared under
the same conditions as the reactions in which the
compounds of the formulae (X) and (XI) are prepared and
the reaction between the compound of the formula (II) and
the compound of the formula ~III), respectively.
The compound of the formula (XXVII) can be
prepared by reacting the compound of the formula (XXVI)
with a tertiary nitrogen atom containing aromatic hetero-
cyclic compound or a trialkylamine in the presence of an
anion donating compound.
Examples of suitable tertiary nitrogen atom
containing aromatic heterocyclic compound include pyridine,
alkyl substituted pyridines such as picoline, lutidine,
etc., quinoline, alkyl substituted quinolines such as
quinaldine, lepidine, etc.
Examples of suitable trialkylamine include those
having 1 to 6 carbon atoms, for each alkyl moiety, e.g.,

- 36 -

ll5~232
- 37 -


1 trimethylamine, triethylamine, tripropylamine, triiso-
propylamine, etc.
Examples of suitable anion donating compound
include compounds capable of releasing a halogen ion and
compounds capable of releasing sulfate, phosphate,
perchlorate ions, e.g., iodine, bromine, chlorine,
sulfuric acid, phosphoric acid, perchloric acid, etc.
The tertiary nitrogen atom containing aromatic
heterocyclic compound or the trialkylamine described
above and the anion donating compound can be used in at
least equimolar amount, preferably 1 to 2 mols per mol of
the compound of the formula (XXVI~, respectively.
The reaction can proceed in an inert solvent
such as the above-described lower alcohols, aromatic
hydrocarbons, ethers, DMSO, DMF, HMPTA, pyridine, etc.,
at a temperature of from room temperature to 120C,
preferably 50 to 100C, for about 0.5 to 6 hours. The
compound of the formula ~XXVII) thus obtained can be used
in the subsequent hydrolysis after isolation from the
reaction mixture and purification or without isolation.
Hydrolysis of the compound of the formula
~XXVII~ can be carried out in a suitable solvent in the
absence or presence of an acid or an alkali, preferably
in the presence of an alkali. Examples of the alkali
include alkali metal hydroxides such as sodium hydroxide,

1 15~232
- 38 -


1 potassium hydroxide, etc., alkaline earth metal hydroxidessuch as calcium hydroxide, etc., ammonium hydroxide or
carbonates o~ these metals or ammonium.
As for the solvents the above-described lower
alcohols, aromatic hydrocarbons, ethers, water, pyridine,
DMF, DMS0, HMPTA, etc., can be used. The hydrolysis can
also proceed in an aqueous medium in which a trialkylamine
such as trimethylamine, triethylamine, etc., is present.
In the above hydrolysis, the reaction is accelerated by
the addition of a lower alcohol.
The reaction proceed advantageously at a temper-
ature of 20 to 150C, preferably 80 to 120C for about 0.5
to 6 hours, thus yielding the desired compound of the
formula (I).
The compounds of this invention of the formula
~I) prepared as described above can form pharmaceutically
acceptable salts with acids when the compound of the
formula ~I) has a basic group, and this invention also
includes within its scope such pharmaceutically acceptable
salts. The pharmaceutically acceptable acids which can be
` ~ used for the salt formation can be various organic or
inorganic acids, for example, hydrochloric acid, sulfuric
acid, nitric acid, hydrobromic acid, phosphoric acid,
acetic acid, oxalic acid, malonic acid, succinic acid,
maleic acid, fumaric acid, malic acid, mandelic acid,
ethanesulfonic acid, p-toluenesulfonic acid and the like.
- 38 -

1 15~2:32
- 3~ -


1 The compounds of the formula (I) can be converted
into a corresponding carboxylate by reacting the carboxylic
acid with a pharmaceutically acceptable basic compound.
Examples of basic compounds are inorganic basic compounds
such as sodium hydroxide, potassium hydroxide, calcium
hydroxide, aluminum hydroxide, sodium hydrogen carbonate
and the like and organic basic compounds such as morpholine,
piperazine~ pyridine, piperidine, ethylamine, dimethylamine,
triethylamine, aniline and the like.
The compounds of the formula (I) and the salts
thereof obtained as described above can be isolated from
the respective reaction mixtures upon completion of the
reaction and purified by conventional procedures, for
example, by solvent extraction, dilution, precipitation,
recrystallization, column chromatography and the like.
As is apparent to those skilled in the art, thecompounds of the formula (I) can exist in optically active
forms and this invention includes such optical isomers
within its scope.
In using the benzo[ij]quinolizine-2-carboxylic
acid compounds of this invention of the formula (I) and
the salts thereof as antimicrobial agents these compounds
can be formulated into pharmaceutical compositions together
with ordinary pharmaceutically acceptable carriers.
Suitable carriers which can be used are, for example,

- 39 -

1 1 5B232
dilucnLs or e.~;cil):ielltt; s~ ; fillcrs, cxten(lcrs, binders,
~et:tin~ agell~s, dis;lltc~rants, surface active agents and
lubricall~s ~hich are usually cmployed to prepare such
drugs dcpending on the type of dosage forms.
Various dosagc forms o the therapeutic agents
as an antimicrobial agent can be sclected according to the
purpose o the therapy. Typical dosage forms which can be
used are tablets, pills, po~ders, liquid preparations,
suspensions, emulsions, granules, capsules, suppositories,
injectable preparations ~solutions, suspensions, etc.),
ointments, etc.
In molding a pharmaceutical composition containing
the compounds of the forrnula (I) or the pharmaceutically
acceptable salt thereof as an active ingredient into a
tablet form, a wide range of carriers known in the art can
be used. Examples of suitable carriers include excipients
~,
such as lactose, white sugar, sodium chloride, glucose
solution~ urea, starch~ calcium carbonate, kaolin, crystal-

line cellulose and silicic acid, binders such as water,
ethanol, propanol, simple syrup, glucose, starch solution,
gelatin solution, carboxymethyl cellulose, shellac, methylcellulose, potassium phosphatc and polyvinyl pyrrolidone,
disintegrants such as dried starch, sodium alginate, agaT
powder, laminaria powder, sodium hydrogen carbonate,
calcium carbonate, Tween, sodium lauryl sulfate, stearic

* Trade Mark 4 o




'A

1 15623~
- 41 -


1 acid monoglyceride, starch, and lactose, disintegration
inhibitors such as white sugar, stearic acid glyceryl
ester, cacao butter and hydrogenated oils, absorption
promotors such as quaternary ammoniwn bases and sodium
lauryl sulfate, humectants such as glycerol and starch,
adsorbents such as starch, lactose, kaolin, bentonite
and colloidal silicic acid, and lubricants such as
purified talc, stearic acid salts, boric acid powder,
Macrogol (trade name for a polyethylene glycol produced
by Shinetsu Chemical Industry Co., Ltd.) and solid
polyethylene glycol.
The table~s, if desired, can be coated, and made
into sugar-coated tablets, gelatin-coated tablets,
enteric-coated tablets, film-coated tablets, or tablets
comprising two or more layers.
In molding the pharmaceutical composition into
pills, a wide variety of conventional carTiers known in
the art can be used. Examples of suitable carriers are
excipients such as glucose, lactose, starch, cacao butter,
hardened vegetable oils, kaolin and talc, binders such as
gum arabic powder, tragacanth powder, gelatin, and
ethanol, and disintegrants such as laminaria and agar.
In molding the pharmaceutical composition into
a suppository form, a wide variety of carriers known in
the art can be used. Examples of suitable carriers include

- 41 -

l 15B232
- 42 -


1 polyethylene glycol, cacao butter, higher alcohols, estersof higher alcohols, gelatin and semi-synthetic glycerides.
When the pharmaceutical composition is formulated
into an injectable preparation, the resulting solution and
suspension are preferably sterilized, and are isotonic with
respect to the blood. In formulating the pharmaceutical
composition into the form of a solution or suspension,
all diluents customarily used in the art can be used.
Examples of suitable diluents are water, ethyl alcohol,
propylene glycol, ethoxylated isostearyl alcohol,
polyoxylated isostearyl alcohol, polyoxyethylene sorbitol,
and sorbitan esters. Sodium chloride, glucose ar glycerol
may be incorporated into a therapeutic agent, e.g., as
a nephritis treating agent in an amount sufficient to
prepare isotonic solutions. The therapeutic agent may
further contain ordinary dissolving aids, buffers, pain-
alleviating agents, and preservatives, and optionally
coloring agents~ perfumes, flavors, sweeteners, and other
drugs.
l,~hen the pharmaceutical composition is formulated
into a paste, a cream and a gel, white vaseline, paraffin,
glycerol, cellulose derivatives, polyethylene glycol,
silicone, etc., can be used as a diluent.
The amount of the compound of the formula (I)
and the pharmaceutically acceptable salts thereof of this
invention as an active ingredient to be incorporated into
- 42 -

l 15~232
- ~3 -


1 a pharmaceutical composition useful as an antimicrobial
agent is not particularly limited, and can vary over a
wide range. A suitable therapeutically effective amount
of the compound of the general formula (I) and the
pharmaceutically acceptable salts thereof of this inven-
tion is usually from about 1 to about 70% by weight,
preferably 5 to 50% by weight, based on the total weight
of the composition.
There is no particular restriction on the manner
of using the therapeutic agent and the therapeutic agent
can be administered by routes suitable for the particular
forms of the therapeutic agent. For example, the tablets,
pills, liquid preparations, suspensions, emulsions,
granules, and capsules are orally administered. The inject-
able preparations are intravenously administered either
alone or together with ordinary auxiliary agents such as
glucose and amino acids. Furthermore, as required, the
injectable preparation can be administered intramuscularly,
intracutaneously, subcutaneously, or intraperitoneally.
The suppository is administered intrarectally and the
ointment is coated on the skin.
The dosage of the antimicrobial agent is suitably
selected according to the purpsoe of use, the symptons,
etc. Usually, a preferred dosage of the compound of this
invention is about 10 mg to 5 g/kg body per day in 3 to 4
multiple doses.
- 43 -


l 1S~232- 44 -


1 I. Antimicrobial Activ~
Test ~lethod
The antimicrobial activity of the followingtest compounds on various test organisms listed below was
determined by the serial dilution method on agar plate
(lleart Infusion agar produced by Difco Co.) (See
CHEMOTH~RAPY, 22, pp. 1126-1128 (1974))and the minimum
inhibitory concentrations (mcg/mQ) obtained were determined.
A sample of each test organism was prepared so
that the population of the or~anism was about 1 x 108
cells/mQ (O.D. 660 m~ = 0.13 to 0.14).
Compound of Invention Tested
1. 8-(4-Trifluoroacetyl-l-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-
- carboxylic acid
2. 8-[4-(2-Trifluoroethyl)-l-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
3. 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
4. 8-~4-Pentafluorobutyryl-l-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-
; quinolizine-2-carboxylic acid


- 44 -

11~6232
~,5


5. 8-[4-(2-}-Iydroxyethyl)-l-piperazinyl~-9-fluoro-
5-methyl-6,7-dihydro-l-oxo-111,5~1-benzo[ij]quinolizine-2-
carboxylic acid
6. 8-[4-(4-Methoxybenzyl)-l-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
7. 8-(4-Allyl-1 piperazinyl)-9-chloro-5-methyl-
6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
8. 8-[4-(2-Propynyl)-l-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-l-oxo-lH,SH-benzo[ij]quinolizine-2-
carboxylic acid
Comparison Compounds
A. l-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-
naphthyridene-3-carboxylic acid (nalidixic acid)
B. 9-Fluoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-
benzo[ij]quinolizine-2-carboxylic acid (flumequine)
Microorganisms Tested
S.a Staphylococcus aureus FDA 209 P
S.p Streptococcus pyogenes IID S-23
E.c Bscherichia coli NHHJ JC-2 (IFO 12734)
K.p Klebsiella pneumoniae
P.r Proteus rettgeri NIH 96
S.t Salmonella typhi 0-9Ol (NCTC 8393)
S.s Shigella sonnei FW 33

- 45 -

1 15B232
- 46 ~


l S.m Serrat _ marcescens IFO 12648
P al Pseudomonas aeruginosa E-2
.
P.a2 Pseudomonas aeruginosa NCTC 10490
P a3 Pseudomonas aeruginosa ATCC 10145
The results obtained are shown in Table 1 below.




i




- 46 -

1156232
- 47 -


O

~o ~ ~ ~
cd u~ ~ ~ O
. ,i o ~ ~ ~ ~ ~ C~
~1~ A ~I
C`~
r 1 --I ~ ~ N U~. . g
Pl ~ ~o ~O

~ U~
t~ ~i ~i 0 0 0 ~ 1 ~ O

~ ~n ~ o~ ao co a~
~1 . ~
~ ~ tn Oooooooo~o
~ .
-~ ~
~3 C,) ~ U~ o o o o o o o o ~ o
O E~
~ ~ _i O O OO O O O ~1 O
E-~ ~
~ ~ ~ c~ o ooooa) oo
co
~ o o o o o o o o ~ o

O~ CA ~ C~000~ 'D
r~ ,I cO
~ ~ o o o o o o o _i ~ o

: u~ ~D u~ ~ ~ ~ ~
~ c~ O a
~ ~ V~

~ ~ ~ o~o~ X
d
U~ ~ o ~i ~ o o o o o


c --I ~ ~ ~;r u~ ~ r~ co 'C
C~

- 47 -

11~6232
- 48 -


1 From the results shown in Table 1 above it can
be seen that the compound of this invention exhibited
potent antibacterial activity as compared with nalidixic
acid and flumequine.
II. Acute Toxicity
The acute toxicity of the compounds of this
invention having the formula (I) was determined by
intravenous administration (i.v.) in mice which had not
been fed for 12 hours prior to the test. LD50 values
~50% lethal dose) obtained for all the compounds were at
least 500 mg/kg.
The present invention is further illustrated by
the following Reference Examples, Examples and Preparation
Examples, but they are not to be construed as limiting
the scope of this invention. Unless otherwise indicated,
all parts, percents and ratios are by weight.
Unless otherwise indicated, Elemental Analysis
was carried out at a temperature of 70 to 80C at reduced
pressure (1 to 2 mmHg) for 6 hours using P2O5 as a
dessicant.
REFERENCE EXAMPLE
5-Hydroxy-3,4-dihydrocarbostyril ~10 g) was
added to 100 mQ of methanol having dissolved therein 3.8 g
of potassium hydroxide and the mixture was stirred at room
temperature for 30 minutes followed by removing methanol

- 48 -

1 15~23~
- 49 -


1 under reduced pressure. Benzene was added to the residue
to form crystals and then benzene was removed by distilla-
tion. ~he residue thus obtained was suspended in 50 mQ
of dimethylformamide and 10.6 g of methanesulfonyl chloride
was added dropwise to the suspension while ice-cooling
with stirring. After adding 3.5 g of methanesulfonyl
chloride and resulting mixture was stirred at room temper-
ature for 4 hours. After the completion of the reaction
the solvent was removed under reduced pressure and the
residue was purified through silica gel column chromatog-
raphy ~silica gel: Wako C-200, a trade name for a product
of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystal-
lization of the eluate from water-containing ethanol gave
5.7 g of S-methanesulfonyloxy-3,4-dihydrocarbostyril as
colorless prismatic crystals having a melting point of
227 to 231C.
REFERENCE EXAMPLE 2
In an analogous manner as in Reference Example 1,
5-(p-toluenesulfonyloxy)-3,4-dihydrocarbos~yril having a
melting point of 215 to 216C was obtained.
REFERENCE EXAMPLE 3
5-Methanesulfonyloxy-3,4-dihydrocarbostyril
~4.5 g~ was suspended in 90 mQ of dioxane and 35 g of
NaB~4 was added to the suspension. Then, 5.3 mQ of acetic
acid was added dropwise to the mixture. After heat-

- 49 -

1 1 5~232
- 50 -


l refluxing the resulting mixture for 1 hour the solvent
was removed under reduced pressure. A saturated aqueous
solution of sodium bicarbonate was added to the residue
to form precipitates which were filtered and washed with
chloroform. The filtrate was extracted with chloroform
and the chloroform layer was dried over Na2SO4 followed
by removing the solvent. Ihe residue was purified through
a silica gel column chromatography (silica gel: Wako C-200,
a trade name for a product of Wako Junyaku Co., Ltd.;
eluent: chloroform) and the eluate thus obtained was
crystallized from petroleum ether. Recrystallization of
the crystals thus obtained from ~ethanol gave 1.9 g of
5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as color-
less prisms having a melting point of 74 to 76C.
REFERENCE EXAMPLE 4
In an analogous manner as in Reference Example 3,
5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline
having a melting point of 112 to 113C was obtained.
REFERENCE EXAMPLE 5
Ethyl ethoxymethylenemalonate (21.6 g) was added
to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydro-
quinoline and the mixture was heated at 110C on an oil
bath for 30 minutes while stirring, during which time
distillation of ethanol was observed. After heating,
240 g of polyphosphoric acid prepared from 120 g of

- 50 -

1 l~B23X
- 51 -


1 pl-osphoric acid and 120 g of phosphorus pentoxide was
added to the mixture and the mixture was allowed to react
on an oil bath at 140C for 45 minutes. After completion
of the reaction, the mixture was allowed to cool to room
temperature and poured into 400 mQ of water, followed by
rendering the mixture neutral with a 40% aqueous sodium
hydroxide solution to precipitate crystals. The crystals
thus obtained were mixed with 150 mQ of a 10% aqueous
sodium hydroxide solution and the mixture was heat refluxed
for 40 minutes during which time the crystals were
dissolved to form a uniform solution. The solution was
treated with activated carbon while hot and filtered.
The filtrate was allowed to cool and adjusted to a pH of
2 to precipitate crystals which were filtered. Recrystal-
lization of the crude crystals thus obtained from dimethyl-
formamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-
l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as
white needles having a melting point of 270 to 275C.
REFERENCE EXAMPLE 6
In an analogous manner as in Reference Example 5,
8-(p-toluenesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid having a melting point of
300C or more was obtained.
REFERFNCE EXAMPLE 7
8-Chloro-6,7-dihydro-l-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid (19.2 g) and 35.5 g of
- 51 -

1 15~232
- 52 -


1 anhydrous piperazine were added to 350 m~ of anhydrous
dimethyl sulfoxide and the mixture was heated on an oil
bath at 170 to 180C for 6 hours while stirring. After
completion of the reaction, the solvent was removed under
reduced pressure. 500 mQ of water was added to the
residue and the pH of the mixture was adjusted to a pH of
2 followed by filtering water-insoluble materials. The
filtrate was concentrated to 100 mQ under reduced pressure
and rendered alkaline ~pH=9) with a 10% aqueous sodium
hydroxide solution. After extracting the aqueous alkali
solution with chloroform-soluble materials, the aqueous
alkali solution layer was allowed to stand to precipitate
crystals which were filtered. The crude crystals thus
obtained were dissolved in 10 mQ of a 10% aqueous sodium
hydroxide solution and the solution was treated with
activated carbon and adjusted to a pH of 8 with a 10%
aqueous hydrochloric acid solution to precipitate
crystals which were filtered and washed with water
sufficiently. Recrystallization of the crystals from
20 dimethylformamide gave 6.5 g of 8-(1-piperazinyl)-6,7-
dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
as white needles having a melting point of 267 to 268C.
8-(1-Piperazinyl)-6,7-dihydro-1-oxo-lH,SH-benzo-
; [ij]quinolizine-2-carboxylic acid (6.4 g) thus obtained
was suspended in 50 mQ of water and 15 mQ of a 10% aqueous

- 52 -

1 15~232
- 53 -


1 hydrochloric acid solution was added to the resulting
solution. After removing the insoluble materials by
filtration, water was distilled off to obtain 5.7 g of
8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid hydrochloride as white
amorphous crystals having a melting point of 300C or more.
REFERENCE EXAMPLES 8-11
In an analogous manner as in Reference Example 7,
the following compounds were obtained:
Reference Example 8
8-(1-Piperazinyl)-5-methyl-6,7-dihydro-1-oxo-
lH,SH-benzo[ij]quinolizine-2-carboxylic acid as colorless
needles having a melting point of 264 to 265C.
Reference Example 9
8-(1-Piperazinyl)-9-chloro-5-methyl-6,7-dihydro-
l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as
white rhombic crystals having a melting point of 246 to
247C.
Reference Example 10
8-(1-Piperazinyl)-10-chloro-6,7-dihydro-1-oxo-
lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride
as white amorphous crystals having a melting point of
300C or more.
Reference Example 11
8-~1-Piperazinyl~-9-chloro-6,7-dihydro-1-oxo-
lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride
- 53 -

1 15G232
- 5~ -


1 as white amorphous crystals having a melting point of 300C
or more.
REFERENCE EXAMPLE 12
6-Chloroquinaldine (11 g) was dissolved in 15 mQ
of concentrated sulfuric acid and the solution was ice-
cooled. Then, a solution of 7.1 g of potassium nitrate
dissolved in 20 mQ of concentrated sulfuric acid was added
to the solution dropwise, during which operation the
reaction temperature was maintained at 10C or less.
After completion of addition the mixture was agitated at
the same temperature as above for 1 hour and then poured
onto 200 g of ice. Subsequently, the mixture was rendered
alkaline with 10% sodium hydroxide taking care that the
internal temperature should not be raised to above 20C,
thus forming pale yellow precipitates. The precipitates
were collected by filtration, washed with water and
recrystallized from ethanol to obtain 12.3 g of 5-nitro-6-
chloroquinaldine as pale yellow rhombic crystals having
a melting point of 123 to 124C.
REFERENCE EXAMPLE 13
To 50 m~ of concentrated hydrochloric acid
having dissolved therein 25 g of stannous chloride was
added 6.7 g of 5-nitro-6-chloroquinaldine and the mixture
was allowed to react on a water bath at a temperature of
; 80 to 90C for 30 minutes. The reaction mixture was ice-

- 54 -
.

1 1 5~23~
1 coole~ el~lele(l .~ e (~ll l.0) ~ith 30% sodium
hydroxicle alld fi.ltercd ~lnd extractcd t~;tll 500 mQ o~
chl~lc-~orm all~ (`elite (di~tomaccous earth). After drying
over ~Inhydrous sodium sulfatc the chloroform fraction
~;as concelltIatcd and recrystalli.zed from a m;xture of
bcnzclle and hexclne to obt~lin 4.5 g of 5-amino-~-chloro-
~uinaldine as colorless plates having a melting poin~ of
196 to 197C.
~EFERE~IC~ E~ArlPLE 14
5-~mino-6-chloroqui.naldine (~ g) was dissolved
in 40 mQ of concentrated hydrochloric acid and the
resulting solution was cooled with ice. Then, a solution
of 2.1 g of sodium nitrite dissolved in 5 mQ of water
was added thereto drop~ise while ice-cooling. After
continuing the reaction at the same temperature as above,
the reaction mixture was added to a solution of 7 g of
cuprous chloride dissolved in 15 mQ of concentrated
hydrochloric acid and the resulting mixture was allowed
to react on a water bath at a temperature of 50C for 1
2~ hour, during which time vigorous formation of nitrogen
gas was observed. Subsequently, the reaction mixture was
cooled, rendered alkaline with 30% sodium hydroxide, ancl
filtered and extracted using 300 mQ of chloroform and
Celite (diatomaceous earth). After drying over anhydrous
sodium sulfatc the chloro-form fraction was concentrated

* Trade Mark 55




A

1 15~232
- 56 -


1 and recrystallized from a mixture of isopropanol and
water to give 3.5 g of 5,6-dichloroquinaldine as white
needles having a melting point of 84 to 85C.
REFERENCE EXAMPLE l 5
5,6-Dichloroquinaldine (5 . 5 g) was dissolved
in 50 mQ of acetic acid and 0.1 g of 5% platinum-carbon
was added to the solution, which was then subjected to Parr's
llydrogenationr.lethod to reduce thc compound catalytically at a
hydrogen gas pressure of 4 kg/cm . After theoretical
amount of hydrogen was absorbed the reaction mixture was
filtered and the filtrate was concentrated under reduced
pressure. After rendering it alkaline with 50 mQ of water
and 20% sodium hydroxide, the residue was extracted with
100 mQ of chloroform. The extract was dried by the
addition of anhydrous potassium carbonate and concentrated
to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine
as oily product.
NMR analysis data ~ln CDC~3)
a: 1.23 (d, 3H, J=6Hz), 1.7 (m, 2H), 2.72 (m, 2H),
3.28 (m, lH), 3.75 (m, lH), 6.62 (q, 2H, J=9Hz)
REFERENCE EXAMPLE 16
A mixture of 3.2 g of 5,6-dichloro-1,2,3,4-
;~ tetrahydroquinaldine and 3.2 g of diethyl ethoxymethylene-
f~ malonate was allowed to react by heating at 160C for 30
minutes. Then, 13 g of polyphosphoric acid prepared from

;:
~ - 56 -

:

,. . .

1 15~23~
- 57 -


1 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric
acid was added to the mixture and the resulting mixture
was allowed to react by heating at 140 to 150C for 1
hour. After completion of the reaction, the mixture was
poured onto 100 g of ice, followed by rendering the
mixture to pH 4 to 5 with a 40~ aqueous sodium hydroxide
solution to precipitate crystals. The crystals were
collected by filtration, dried and mixed with 50 mQ of a
10% aqueous sodium hydroxide solution. The mixture was
allowed to react at 100 to 110C for 1 hour. After cool-
ing, the reaction mixture was rendered acidic with
concentrated hydrochloric acid to precipitate crystals.
Recrystallization of the crystals thus obtained from
ethanol gave 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydro-
l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid having
a melting point of 269 to 271C.
REFERENCE EXAMPLE 17
~ lexamethylphosphoryl triamide (20 mQ) was added
to a mixture of 3 g of 8,9-dichloro-5-methyl-6,7-dihydro-
1-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid and
5 g of anhydrous piperazine and the mixture was heated
with stirring at 150 to 160C for 3 hours. After the
completion of the reaction, the solvent was removed there-
from under reduced pressure and the residue was washed
~ with 10 mQ of ethyl acetate. The crystals obtained were
.~
- 57 -

1 1 5B232
- 58 -


1 dissolved in 100 mQ of water and the solution was
adjusted to pH 4 with acetic acid. Insoluble substances
were removed by filtration and the filtrate was treated
with activated carbon. The aqueous solution thus obtained
was concentrated under reduced pressure and the residue
was recrystallized from a mixture of isopropanol and water
to give 1.8 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-
dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid hydrochloride having a melting point of 300C or more.
The hydrochloride salt was dissolved in water
with adding a 2% aqueous sodium hydroxide solution and
adjusted to pH 9 with lN hydrochloric acid to obtain
white crystals having a melting poir.t of 246 to 247C.
EXAMPLE
A mixture of 2.5 g of 8-~1-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid and S0 mQ of trifluoroacetic
anhydride was heated under reflux for 3 hours. After
completion of heating, excessive trifluoroacetic anhydride
was distilled off under reduced pressure and 50 mQ of
water was added to the residue followed by stirring to
precipitate white crystals. Recrystallization of the
crystals from dimethylformamide gave 2.3 g of 8-(4-
trifluoroacetyl-l-piperazinyl)-9-chloro-5-methyl-6,7-
dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid

- 58 -

1 15~232
- 59 -


l as white rhombic crystals having a melting point of 300Cor more.
Elemental Analysis for C2UHlgCQF3N3O4 (molecular weight:
457.5)
C H N
Calc'd (%): 52.31 4.11 9.22
Found (%): 52.464.15 9.18
EXAMPLE 2
A mixture of 1 g of 8-(l-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-
carboxylic acid, 15 mQ of dimethylformamide, 1.2 mQ of
2,2,2-trifluoroethyl iodide and 2 mQ of triethylamine was
! heated at 80C for 5 hours. After cooling, insoluble
substances were removed by filtration and the filtrate
was concentrated under reduced pressure. The residue was
mixed with 30 mQ of water and insoluble substances were
removed by filtration. After concentrating it under
reduced pressure, the filtrate was purified through a
silica gel column chromatography (silica gel: Wako C-200,
a trade name for a product of Wako Junyaku Co., Ltd.;
eluent chloroform-methanol (9:1 by volume)) to obtain
0.5 g of 8-[4-~2,2,2-trifluoroethyl)-1-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid-iodide-monohydrate as white
~- rhombic crystals having a melting point of 298 to 299C.

- 59 -

1 15~23~
- 60 -


EXAMPL~ 3
1 A mixture of 0.8 g of 8-(1-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine hydrochloride monohydrate, 0.4 mQ of propargyl
bromide, ~.8 mQ of triethylamine and 10 mQ of dimethyl-
formamide was allowed to react by heating at 90C for 5
hours. After completion of the reaction insoluble
substances were removed by filtration. After concentra-
tion under reduced pressure the filtrate was purified
through a silica gel column chromatography (silica gel:
Wako C-200, a trade name for a product of Wako Junyaku
Co., Ltd.; eluent: chloroform-methanol (8:1 by volume))
to obtain 0.3 g of 8-[4-(2-propynyl)-1-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine as pale yellow rhombic crystals having a
melting point of 211 to 213C.
EXAMPLE 4
A mixture of 1 g of 8-~1-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid, 0.6 mQ of triethylamine, 0.6 mQ oftrifluoromethanesulfonyl chloride and 15 mQ of dimethyl-
formamide was stirred at room temperature for 3 hours.
After completion of stirring, the solvent was removed
under reduced pressure to concentrate the reaction mixture.
By the addition of 30 mQ of water to the concentrate pale
~'
- 60 -

2 3 2
- 6l.


yellow crystals precipitated. Recrystallization of the
crystals from a mixture of dimethyl:formamide and water
gave 0.7 g of 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-
9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid as pale yellow powder having
a melting point of 232 to 235C.
EXAMPLES 5-10
In an analogous manner as in Example 4, the
following compounds were prepared:
10 Example 5
8-(4-Allyl-l-piperazinyl)-9-chloro-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid
Melting point: 226 to 227C
Example 6
8-[4-(2-Chloroethyl)-l-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 284 to 285C
20 Example 7
8-~4-(4-Methoxybenzyl)-l-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinalizine-2-
carboxylic acid
Melting point: 270 to 272C


- 61 -

1 15~232
- 62 -


1 Example 8
8-[4-~2-Hydroxyethyl)-l-piperazinyl~-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 228 to 230C
Example 9
8-(4-Pentafluoropropionyl-l-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
Melting point: 296 to 297C
Example 10
8-(4-Heptafluorobutyryl-l-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
Melting point: 269.5 to 270.5C
Example 11
;




: 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-
` 5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
: carboxylic acid
Melting point: 288 to 290C
EXAMPLE 12
A mixture of 3.1 g of 8,9-dichloro-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
, .
acid, 9.1 g of l-trifluoroacetylpiperazine and 50 mQ of
~: HMPTA was heated at 160C for 4 hours under atmosphere of

- 62 -

~ .

1 15~232
- 63 -


1 argon. After complction of the reaction, the solvent wasremoved by distillation under reduced pressure and the
residue was washed with water. Recrystallization of the
residue from dimethylformamide gave 2.3 g of 8-(4-
trifluoroacetyl-l-piperazinyl~-9-chloro-5-methyl-6,7-
dihydro-l-oxo-111,5~1-benzo[ij]quinolizine-2-carboxylic
acid as white rhombic crystals having a melting point of
300C or more.
EXAMPLE 13
A mixture of 1.6 g of 8,9-dichloro-6,7-dihydro-
5-methyl-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid, 3.2 g of l-propargylpiperazine and 25 mQ of HMPTA
was heated with stirring at 160C for 5 hours under
atmosphere of argon. After completion of the reaction,
the solvent was removed by distillation and the residue
was washed with water. The residue was dissolved in 100 mQ
of water and insoluble substances were removed by filtra-
tion. The aqueous fraction was extracted with 200 mQ of
chloroform and the chloroform fraction was dried over
anhydrous sodium sulfate. After concentration, the
concentrate was purified through a silica gel column
chromatography tsilica gel: Wako C-200, a trade name for
a product of Wako Junyaku Co., Ltd.; eluent: chloroform-
methanol (9:1 by volume)~ to obtain 1.2 g of 8-[4-(2-
propynyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-


- 63 -

1 156232
- 64 -


1 1-oxo-111,51-1-benzo[ij]quinolizine-2-carboxylic acid having
a melting point of 211 to 213C.
EXAMPLES 14-21
In an analogous manner as in Example l3, the
following compounds were obtained:
Example 14
8-~4-Allyl-l-piperazinyl)-9-chloro-5-methyl-
6,7-dihydro-1-oxo-lH~SH-benzo[ij]quinolizine-2-carboxylic
acid
Melting point: 226 to 227C
Example 15
8-[4-t4-Methoxybenzyl)-l-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point:. 270 to 272C
Example 16
~,
8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo~ quinolizine-2-
carboxylic acid
Melting point: 228 to 230C
: Example 17
;,
: 8-[4-(2-chloroethyl)-1-piperazinyl]-9-chloro-
:~ ~ 5-methyl-6j7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 284 to 285C

- 64 -
., .

1 15~232
- 65 -


1 Example 18
8-(4-Pentafluoropropionyl-l-piperazinyl~-9-
chloro-S-methyl-6,7-dihydro-1-oxo-lH,5~ benzo[ij]-
quinolizine-2-carboxylic acid
Melting point: 296 to 297C
Example 19
8-~4-lleptafluorobutyryl-1-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-l}l,SH-benzo[ij]quinolizine-2-
carboxylic acid
10 ~ Melting point: 269.5 to 270.5C
Example 20
8-(4-Trifluoromethanesulfonyl-l-piperazinyl)-9-
chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 232 to 235C
Example 21
8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
: carboxylic acid
Melting point: 288 to 290C
P.XAMPLP. 22
A mixture of 2.75 g of 8-(4-trifluoroacetyl-1-
piperazinyl)-9-chloro-5-methyl-2-acetyl-6,7-dihydro-1-
oxo-lH,5H-benzo[ij]quinolizine, 3 g of iodine and 20 mQ of
, ` :
pyridine was heated at lQ0C for 1 hour. After completion
~ ',
- 65 -
-

l 156232
- 6~ -


1 of the reaction, crystals precipitated were collected byfiltration and washed with 10 mQ of cool pyridine and
with 10 mQ of methanol to obtain 8-(4-trifluoroacetyl-1-

piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-
benzo[ij]quinolizine-2-carbonylmethylpyridinium iodide.
This compound was mixed with S0 mQ of methanol and 50 mQ
of a 10% aqueous sodium hydroxide solution and the
resulting mixture was refluxed for 1 hour. After comple-
tion of the reaction methanol was removed by distillation
and the reaction mixture was adjusted to pH 7 with N
hydrochloric acid to give 1.8 g of 8-(4-trifluoroacetyl-
l-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-
benzo[ij]quinolizine-2-carboxylic acid as white rhombic
crystals having a melting point of 300C or more.
EXAMPLES 23-32
In an analogous manner as in Example 22, the
following compounds were prepared:
Example 23
8-[4-(2,2,2-Trifluoroethyl)-l-piperazinyl]-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid
Melting point: 298 to 299C
Example 24
8-[4-C2-Hydroxyethyl)-l-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij3quinolizine-2-
carboxylic acid
Melting point: 228 to 230C
- 66 -

l 156232
67 -


1 Example 25
8-[4-(2-Chloroethyl)-l-piperazinyl]-9-chloro-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 284 to 285C
Example 26
8-(4-Allyl-l-piperazinyl)-9-chloro-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic
acld
Melting point: 226 to 227C
Example 27
8-[4-~4-Methoxybenzyl)-l-piperazinyl]-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 270 to 272C
Example 28
8-[4-(2-Propynyl)-l-piperazinyl]-9-chloro-5-
:~ methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 211 to 213C
. ~
Example 29
8-(4-Pentafluoropropionyl-l-piperazinyl)-9-
chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzoCij]-
quinolizine-2-carboxylic acid
Melting point: 296 to 297C
: :~
- 67 -

l 156232
- 68 -


1 Example 30
8-(4-Heptafluorobutyryl-l-piperazinyl)-9-chloro-
5-methyl-6,7-dihydro-1-oxo-lH,5}1-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 269.5 to 270.5C
Example 31
8-(4-Tri1uoromethanesulfonyl-1-piperazinyl)-5-
methyl-6,7-dihydro-1-oxo-lH,5H-benzo~ij]quinolizine-2-
carboxylic acid
Melting point: 232 to 235C
Example 32
8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-
5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Melting point: 288 to 290C
EXAMPLE 33
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-
6,7-d;hydro-1-oxo-lH~5H-benzo[ij]quinolizine-2-carboxylic
acid, 9.1 g of l-(trifluoromethyl)piperazine and 200 mQ
of anhdyrous dimethyl sulfoxide was heated with stirring
in an autoclave at 150 to 160C for 18 hours under
; nitrogen gas flow at a pressure of 10 atms. After comple-
tion of the reaction, the solvent and excessive piperazine
compound were removed by distillation under reduced
pressure and a mixture of methanol and ethanol was added

- 68 -

1 15~2~2
- 69 -


l to the residue. The precipitates formed were collectedby filtration and washed with ether. The crystals
obtained were suspended in a mixture of 200 mQ of water
and 40 mQ of a l0% aqueous hydrochloric acid solution
and insoluble substances were removed by filtration. The
filtrate was rendered neutral with saturated aqueous
solution o-f sodium bicarbonate and purified through column
chromatography using Amberlite LH-20 (a trade name for a
product of Tokyo Organic Chemical Industries Ltd.)
(eluent: water, ethanol). Recrystallization of the
eluate from dimethylformamide gave 1.7 g of 8-~4-trifluoro-
methyl-l-piperazinyl)-6,7-dihydro-l-oxo-lH,5H-benzo[ij]-
quinolizine-2-carboxylic acid as white rhombic crystals
having a melting point of 300C or more.
EXAMPLE 34
A mixture of 4.5 g of 8-~p-toluenesulfonyloxy)-
9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-
quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoroacetyl)-
piperazine and 200 mQ of anhydrous dimethyl sulfoxide was
heated with stirring in an autoclave at 150 to 160C for
17 hours under nitrogen gas flow at a pressure of 10 atms.
The reaction mixture was treated in the same manner as
Example 33 to obtain 2.3 g of 8-C4-trifluoroacetyl-1-
piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-
benzo[ij]quinolizine-2-carboxylic acid as white rhombic
crystals having a melting point of 300C or more.
- 6~ -

l 15~232
- 70 -


I~XAMPLE 35
A mixture of 3.37 g of 8-methanesulfonyloxy-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid, 9.1 g of l-(trifluoromethyl)piperazine and 200 mQ
of anhydrous dimethyl sulfoxide was heated with stirring
in an autoclave at 170 to 180C for 20 hours under nitrogen
gas flow at a pressure of 8 atms. The reaction mixture
was treated in the same manner as Example 33 and further
treated with concentrated hydrochloric acid to obtain
1.7 g of 8-~4-trifluoromethyl-1-piperazinyl)-6j7-dihydro-
l-oxo-lH,5H-benzo[ij3cuinolizine-2-carboxylic acid hydro-
chloride as white rhombic crystals having a melting point
of 300C or more.
PREPARATION EXAMPLE
8-(4-Trifluoroacetyl-l-piperazinyl)-9- 200 mg
chloro-5-methyl-6,7-dihydro-1-oxo-
lH,5H-benzo[ij]quinolizine-2-
carboxylic acid hydrochloride
Glucose 250 mg
Distilled water for injectionq.s. to make
5 mQ
The active compound and glucose were dissolved
in distilled water for injection, and the solution was
poured into a 5 mQ ampoule. The air was purged with
nitrogen, and the ampoule was sealed and sterilized at
121C for 15 minutes to obtain an injectable preparation.


- 7Q -

l 156232
- 71 -


1 PREPARATION EXAMPLE 2
8-(4-Trifluoroacetyl-l-piperazinyl)- l00 g
9-chloro-5-methyl-6,7-dihydro-l-oxo-
lH,5H-benzo[ij]quinolizine-2-
carboxylic acid
Avicel (trade name for a product of 40 g
Asahi Kasei Kogyo Kabushiki Kaisha)
Corn starch 30 g
Magnesium stearate 2 g
TC-5 (trade name for hydroxypropyl-l0 g
methyl cellulose, produced by Shinetsu
Chemical Industry Co., Ltd.)
Polyethylene Glycol-6000 3 g
~molecular weight, 6000)
Caster oil 40 g
Methanol 40 g
The active compoundJ Avicel, corn starch and
~` magnesium stearate were mixed and ground, and then
tableted using a conventional pounder (R l0 mm) for sugar
coating ~produced by Kikusui Seisakusho Co., Ltd.).
The resulting tablets were coated with a film coating
agent composed of TC-5, polyethylene glycol-6000, castor
.,:
;~ oil and methanol to produce film-coated tablets.


:,

.:
' ~
`: ~

- 71 -
- -

l 15~232
- 72 -


l PREPAR~TION EXAMPLE 3
8-(4-Trifluoroacetyl~l-piperazinyl)- 2 g
9-chloro-5-methyl-6,7-dihydro-l-oxo-
lH,5~1-benzo[ij]quinolizine-2-
carboxylic acid
Purified hydrous lanolin S g
Japan wax 5 g
White petrolatum 88 g
Total: l00 g
Japan wax was heat-molten and the active
compound, purified hydrous lanolin and white petrolatum
were added thereto followed by heat-melting. The mixture
was stirred until it began to solidify to prepare an
ointment.
While the invention has been described in
detail and with reference to specific embodiments
thereof, it will be apparent to one skilled in the art
.:~ that various changes and modifications can be made
-~ therein without departing from the spirit and scope
thereof.




- 72 -