Antimicrobial compounds of the following formula are disclosed: ##STR1## wherein Het is selected from the goup consisting of pyrryl, pyrrolidyl, tetrazolyl of the formula ##STR2## wherein R.sup.1 is lower alkyl or benzyl and oxadiazolyl of the formula ##STR3## wherein R.sup.2 is lower alkyl, trifluoromethyl or --NH.phi.--; X is hydrogen and when Het is pyrryl or pyrrolidyl, X may be fluorine. Pharmaceutically acceptable carboxylate salts and esters of the acids are also disclosed.

TECHNICAL FIELD 
This invention relates to derivatives of the heterocyclic system known as 
benzo[ij]quinolizine. More specifically, it relates to 
6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acids 
substituted at the 8-position and pharmaceutically-acceptable carboxylate 
salts and esters thereof. The use of these compounds as antimicrobial 
agents and pharmaceutical compositions containing these compounds are also 
included within the scope of the invention. 
BACKGROUND ART 
U.S. Pat. Nos. 3,896,131 and 3,985,882 described 
benzo[ij]quinolizine-2-carboxylic acids which are useful antimicrobial 
agents. The prior art compounds may contain various substituents in the 8, 
9 or 10-position including amino (--NH.sub.2),N,N-dimethylamino 
[(CH.sub.3).sub.2 N--], alkanamido and trifluoroacetamido groups. However, 
prior to the present invention, it was not known that compounds 
substituted in the 8-position with five-membered-nitrogen-containing 
heterocyclic nuclei exhibit useful antimicrobial activity. 
DESCRIPTION OF THE INVENTION 
The invention relates to derivatives of benzo[ij]quinolizine-2-carboxylic 
acid of the formula 
##STR4## 
wherein Het is selected from pyrryl, pyrrolidyl, tetrazolyl of the formula 
##STR5## 
wherein R is lower alkyl or benzyl, and oxadiazolyl of the formula 
##STR6## 
wherein R.sup.2 is lower alkyl, trifluoromethyl or --NH.phi.; X is 
hydrogen; and when Het is pyrryl or pyrrolidyl, X may also be fluoro; and 
pharmaceutically-acceptable carboxylate salts, esters and alkylaminoalkyl 
ester salts thereof. 
The term "lower" as used herein to describe "alkyl" means an alkyl group 
having 1 to 4 carbon atoms in straight or branched chain configuration. 
Compounds of the invention have an optically active carbon at the 
5-position. All such optical isomers are included within the scope of the 
invention. 
It is well known in the art that pharmaceutically acceptable salts such as 
alkali metal, alkaline earth, aluminum, iron and other metal and amine 
salts of pharmaceutically active acids are the equivalents of the acids, 
and in some cases may even offer advantages in absorption, formulation and 
the like. Salts of the free acid compounds of the invention are readily 
prepared by reaction of the acid with a base and evaporation to dryness. 
The base may be organic, e.g., sodium methoxide or an amine, or inorganic, 
e.g., sodium hydroxide. 
Esters of the acids of Formula I may be obtained as intermediates during 
the preparation of the acids, or, in some cases, the esters may be 
prepared directly using standard synthetic methods. The esters exhibit 
antimicrobial activity but are primarily of interest as synthetic 
intermediates, although in some instances hydrolyzable or salt-forming 
esters may be of interest as therapeutic agents. Preferred esters of the 
invention are alkyl esters and alkylaminoalkyl esters having one to four 
carbon atoms in the alkyl group. Especially preferred are aminoalkyl 
esters which will form salts, e.g., hydrochlorides, such as the 
dimethylaminoethyl esters. 
The esters are readily prepared by reacting the free acid of Formula I with 
thionyl chloride to provide the novel acyl chloride derivative. The acyl 
chloride is reacted with the appropriate alcohol to provide the desired 
ester. 
The antimicrobial activity of the compounds of the present invention can be 
demonstrated by the known, standard plate dilution method for bacterial 
susceptibility to antibiotics. The culture medium employed permits 
susceptibility testing of fastidious microorganisms towards antibiotics, 
sulfonamides and other chemotherapeutic agents. Tryptone soy agar (oxoid) 
of the following composition is the culture medium. 
______________________________________ 
Oxoid tryptone 15 g. 
Oxoid soy peptone 5 g. 
Sodium chloride 5 g. 
Oxoid agar-agar No. 3 
15 g. 
Water 1 liter 
______________________________________ 
Using this test, the compounds of the invention have been found to have a 
broad spectrum of activity against gram-positive and gram-negative 
microorganisms. 
The compounds of the invention are active against microorganisms either in 
the absence or presence of 10 percent horse serum. 
The test procedure used to determine activity as employed in connection 
with the present invention provides information on the amount of a 
compound required to give complete inhibition, partial inhibition or no 
inhibition of microbial growth on the agar plates. In the tests, the test 
compound is added to the agar medium to give concentrations of zero, one, 
ten and one hundred milligrams per liter. A series of plates with these 
concentrations is prepared. Ten percent horse serum is added to one series 
of such plates. Aliquots of broth culture of each of twelve species of 
microorganisms are innoculated onto the agar plates containing the various 
test compound concentrations. The plates are incubated at 37.degree. C. in 
a 10 percent carbon dioxide atmosphere for 18-24 hours. The microbial 
growth on each plate is read visually, and minimal inhibitory 
concentrations are recorded. Some of the microorganisms which are used for 
this test are: 
1. Staphylococcus aureis 
2. Bacillus subtilis 
3. Escherichia coli 
4. Pseudomonas aeruginosa 
5. Streptococcus sp.* 
6. Asperigillus niger 
7. Candida albicans 
8. Acinetobacter lwoffi 
9. Acinetobacter anitratum 
10. Klebsiella pneumoniae 
11. Streptococcus fecaelis 
12. Serratia marcescens 
FNT *strains isolated from dental caries in rats or hamsters at the National 
Institute of Dental Health and grown in PFY or APT agar. 
All of the compounds of the invention possess antimicrobial activity 
towards one or more of the above microorganisms. 
Some of the compounds of the invention have also shown activity against one 
or more anaerobic bacteria, for example, Bacteroides sp. and Clostridium 
welchii. Some compounds of the invention have shown useful activity 
towards Erwinia amylovora, a gram-negative microorganism responsible for 
the plant disease known as fire blight. 
It will be understood by those skilled in the art that the species used are 
representative indicator species, as it would be impractical to screen 
against all microorganisms. It is well known in the art that broad 
spectrum activity can be predicted on the basis of activity shown against 
selected representative species of microorganisms. 
Some of the compounds of the invention are active when administered orally 
to animals. They are excreted in the urine, and are effective urinary 
tract antibacterials in mammals. It is also contemplated that they may be 
used in the treatment of pulmonary infections, soft tissue infections, 
burn infections and bacteremias. 
All of the compounds of the invention are active against microorganisms in 
vitro or topically. In vitro activity is useful in itself, since 
antimicrobial agents may be used for disinfecting and sterilizing, e.g., 
medical and dental equipment, as components of disinfecting solutions. The 
compounds of the invention are also active in vivo in animals. 
The acute oral toxicity of the compounds of the invention is generally 
moderate to low compared with the effective oral dose, and they have an 
acceptable therapeutic ratio (LD.sub.50 /ED.sub.50). 
The carboxylic acid compounds of the invention are ordinarily white or 
yellowish crystalline or amorphous materials when purified. They are 
substantially insoluble in water, lower alcohols or hydrocarbons and are 
more soluble in halogenated solvents, N,N-dimethylformamide and the like. 
The esters are generally somewhat more soluble in organic solvents. The 
salts, especially the alkali metal salts, have appreciable solubility in 
water and lower alcohols. 
The compounds of the invention may be formulated by incorporating them into 
conventional pharmaceutical vehicles, either organic or inorganic, which 
are suitable for oral or intraperitoneal application. For in vitro or 
topical use, simple aqueous solutions or suspensions are most conveniently 
employed. For this purpose, concentrations of the order of 100 parts per 
million up to about 5 parts per thousand are suitable, and the formulation 
is used by immersing objects to be treated therein, or by local 
application to an infected area. 
The amount of compound to be used to treat, e.g., a microbial urinary 
infection by oral administration will be an effective amount less than a 
toxic amount. The amount to be administered to control an infection will 
depend on the species, sex, weight, physical condition and many other 
factors, but this judgment is well within the skill of the medical art. 
Usually the amount will be less than 100 mg/kg per dose. Conveniently this 
is administered in the form of conventional pharmaceutical preparations 
such as capsules, tablets, emulsions, solutions and the like. Excipients, 
fillers, coatings, etc. are generally employed with tablets or capsules, 
as is well known in the art. 
It is known to the art that antimicrobial agents are used as growth 
promoters in various animal and bird species. Although not yet verified, 
it is inferred from the outstanding antimicrobial activity that the 
compounds of the invention can be used for this purpose also. The 
compounds of the invention may also be used for the control of microbial 
(e.g., Erwinia amylovora) infections of plants, e.g., by spraying or 
dusting formulation of these compounds on the affected area. 
The compounds of the invention are prepared starting with known compounds. 
The 9-fluoro-substituted compounds start with the known 6-fluoroquinaldine 
which is nitrated with fuming nitric and sulfuric acids in the presence of 
sodium nitrite catalyst to provide the compound 
6-fluoro-5-nitro-quinaldine. 
The nitro group is reduced catalytically, for example, in the presence of 
palladium on charcoal. If this reaction is carried out in the presence of 
acetic anhydride, the product is the compound 
5-acetamido-6-fluoroquinaldine. This intermediate is further reduced 
catalytically in the presence of platinum on charcoal to provide the 
compound 5-acetamido-6-fluorotetrahydroquinaldine. 
The tetrahydroquinaldine intermediate is condensed with diethyl 
ethoxymethylenemalonate by heating without solvent at 
100.degree.-200.degree. C. (preferably 140.degree.-150.degree. C. for two 
hours) for several hours. The intermediate is the compound of the formula 
(II) 
##STR7## 
This intermediate is an oil which need not be isolated or purified. 
Instead, polyphosphoric acid is added, and the solution is heated at 
100.degree.-140.degree. C. to effect a condensation to provide an ester of 
the acids of Formula I wherein Het is acetamido. The next step is 
saponification of the esters and hydrolysis of the acetamido group to 
provide 
8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid, a key intermediate. 
Compounds of the invention wherein X is hydrogen are prepared from 
5-aminoquinaldine by blocking the amino group as acetamido and converting 
to 
8-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carbox 
ylic acid, then hydrolyzing to the 8-amino compound. 
The 8-amino intermediate (wherein X is hydrogen) is converted to the 
8-cyano derivative by the sequence of diazotization in the presence of 
fluoroboric acid, isolation of the fluoroborate salt and heating the salt 
in the presence of a cyanide salt, preferably cuprous cyanide, in a very 
polar solvent such as dimethyl sulfoxide. 
In order to prepare the intermediate 
8-cyano-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid one starts with 2-fluorobenzoic acid and nitrates. Nitration 
with concentrated nitric and concentrated sulfuric acids at moderate 
temperatures (15.degree.-25.degree. C.) provides 2-fluoro-5-nitrobenzoic 
acid. Catalytic reduction, e.g., with palladium on charcoal catalyst, 
provides 5-amino-2-fluorobenzoic acid. Condensation of this aromatic amine 
with crotonaldehyde in the presence of ferrous sulfate heptahydrate and 
sodium m-nitrobenzenesulfonate provides 5-carboxyl-6-fluoroquinaldine. The 
carboxyl group is reacted with thionyl chloride to provide the carboxyl 
chloride which is reacted with ammonium hydroxide to provide 
5-carboxamido-6-fluoroquinaldine. Dehydration of the carboxamido group in 
pyridine with trifluoroacetic anhydride in an inert solvent such as 
dichloromethane provides 5-cyano-6-fluoroquinaldine. This intermediate 
condenses with diethyl ethoxymethylenemalonate to yield an intermediate of 
Formula II where the 5-position is substituted by cyano. Condensation in 
polyphosphoric acid provides the benzo[ij]quinolizine ring, but the cyano 
group may be partially hydrolyzed and again require dehydration with 
pyridine and trifluoroacetic anhydride. Hydrolysis of the carboxylic ester 
group in the 2-position may also be required to obtain the desired 
intermediate. 
The 8-cyano intermediate wherein X is hydrogen may also be prepared using 
the latter route starting with the known compound 5-carboxylquinaldine. It 
has been found that this is the preferred synthetic route for both the 
9-fluoro and the 9-hydro compounds. 
The 8-pyrryl compounds of the invention are prepared by reacting the 
corresponding 8-amino compounds by heating with 
2,5-dimethoxytetrahydrofuran in an organic acid such as acetic acid. 
The 8-pyrrolidyl compounds of the invention are prepared by catalytic 
reduction of the corresponding 8-pyrryl compounds. Suitable catalysts 
include palladium on charcoal and rhodium on alumina. 
The 8-tetrazolyl compounds of the invention are prepared by reacting the 
corresponding 8-cyano intermediate with hydrazoic acid generated by action 
of ammonium chloride on sodium azide. This reaction is carried out in a 
strongly polar solvent such as N,N-dimethylformamide. 
The 8-tetrazolyl compound of the invention is used as an intermediate to 
prepare compounds wherein the 2-position of the tetrazole ring is 
substituted by alkyl of one to four carbon atoms or benzyl. This reaction 
is carried out by reacting the proton of the tetrazole ring with a strong 
base such as sodium hydride, and then reacting an alkyl or benzyl halide 
with the activated nitrogen of the tetrazole ring. 
The 8-tetrazolyl compounds of the invention are also used to prepare the 
8-oxadiazolyl compounds of the invention by reaction with organic 
anhydrides such as trifluoroacetic anhydride, acetic anhydride or other 
anhydrides. The resulting 8-oxadiazolyl compounds are substituted at the 
2-position of the oxadiazolyl moiety. 
The 8-tetrazolyl compounds of the invention are also reacted with organic 
isocyanates to provide 8-oxadiazolyl compounds substituted at the 
2-position of the oxadiazolyl moiety by an arylamino or alkylamino group.

The invention may be further illustrated by reference to the following 
non-limiting examples. 
Preferred compounds of the invention due to their potency and broad 
spectrum of activity are the compounds of Examples 2, 3, 9, 10, 12, 13, 14 
and 15. 
EXAMPLE 1 
Part A. 6-Fluoro-5-nitroquinaldine 
To 3.5 l of fuming sulfuric acid was added, with cooling, 600 g (3.73 
moles) of 6-fluoroquinaldine in small portions. To this mixture was added 
about 0.1 g of sodium nitrite, followed by the dropwise addition of 261 ml 
of fuming red nitric acid over a six hour period while maintaining the 
temperature at 5.degree.-10.degree. C. The mixture was stirred at 
20.degree. C. for sixteen hours and poured into 3 gallons of ice. The 
mixture was basified with ammonium hydroxide, with cooling. The 
precipitated solid was separated by filtration, then dissolved in about 
two liters of warm toluene. The solution as dried over magnesium sulfate, 
filtered and evaporated to provide the yellow solid 
6-fluoro-5-nitroquinaldine, m.p. 105.degree.-108.degree. C., which was 
recrystallized from 1,2-dichloroethane. The structural assignment was 
confirmed by nuclear magnetic resonance and infrared spectral analyses. 
Part B. 5-Acetamido-6-fluoroquinaldine 
To a mixture of 20 g (0.1 mole) of 6-fluoro-5-nitroquinaldine in 180 ml of 
ethyl acetate and 20 ml of acetic anhydride was added 3 g of ten percent 
palladium on charcoal. The mixture was hydrogenated with hydrogen gas at 
50 psi on a Parr apparatus for 20 minutes. The theoretical amount of 
hydrogen (25 psi) was used. On cooling the mixture solidified to a yellow 
mass. About 200 ml of ethanol was added, and the mixture was heated to 
dissolve the product. The catalyst was removed by filtration through 
celite and the filtrate was evaporated to dryness, leaving a yellow solid. 
The solid was triturated with 200 ml of water and neutralized with ten 
percent sodium hydroxide solution. Filtration and drying provided white 
crystals of 5-acetamido-6-fluoroquinaldine, m.p. 232.degree.-235.degree. 
C. The structural assignment was confirmed by infrared spectral analysis. 
Part C. 5-Acetamido-6-fluorotetrahydroquinaldine 
In one liter of acetic acid was dissolved 95 g of 
5-acetamido-6-fluoroquinaldine. To this mixture was added 10 g of five 
percent platinum on charcoal. The mixture was hydrogenated with hydrogen 
gas at 30 psi on a Parr apparatus for five hours. The amount of hydrogen 
used was 61 psi (versus 62 psi theoretical). The catalyst was removed by 
filtration, the filtrate was concentrated to 250 ml and decanted into cold 
stirred sodium hydroxide solution. The white precipitate was separated by 
filtration and triturated with a chloroform/hexane (50/50) mixture to 
provide white crystals of 5-acetamido-6-fluorotetrahydroquinaldine, m.p. 
168.degree.-170.degree. C. The structural assignment was confirmed by 
infrared spectral analysis. 
Part D. Diethyl 
2-[N-(5-Acetamido-6-fluorotetrahydroquinaldinyl)]methylenemalonate 
A stirred mixture of 6.4 g (28.8 mmole) of 
5-acetamido-6-fluorotetrahydroquinaldine and 8 g (37 mmole) of diethyl 
ethoxymethylenemalonate was heated at 140.degree.-150.degree. C. for two 
hours. Ethanol was allowed to evolve. The product, diethyl 
2-[N-(5-acetamido-6-fluorotetrahydroquinaldinyl)]methylenemalonate was not 
isolated. 
Part E. 
8-Amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic Acid 
The reaction mixture of part D, containing diethyl 
2-[N-(5-acetamido-6-fluorotetrahydroquinaldinyl]methylenemalonate was 
treated with 25 g of polyphosphoric acid and warmed to 100.degree. C. for 
5 minutes while stirring. Foaming was observed, demonstrating that 
reaction had commenced. The external heating was removed and stirring was 
continued for ten minutes. Heat was reapplied and the mixture was 
maintained at 100.degree. C. for 0.5 hour. The cyclized product was then 
hydrolyzed (ester portion) and deacetylated (acetamido group) by adding 
150 ml of water and 25 ml of methanol, basifying cautiously with fifty 
percent sodium hydroxide solution and heating at reflux for 2.5 hours. 
Filtration through decolorizing charcoal and celite and decantation into 
rapidly stirring dilute acetic acid provided a tan solid, hydrated 
8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid, m.p. 300.degree. C. Analysis: Calculated for C.sub.14 
H.sub.13 FN.sub.2 O.1/3H.sub.2 O; %C, 59.5; %H, 4.8; %N, 9.9; Found: %C, 
59.1; %H, 4.5; %N, 9.8. 
EXAMPLE 2 
To a suspension of 1.0 g of 
8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid in 20 ml of warm galcial acetic acid was added 1.0 g 
2,5-dimethoxytetrahydrofuran. The mixture was heated at reflux for 30 
minutes. The product which precipitated was separated by filtration and 
washed with water to provide yellowish-white crystals of 
6,7-dihydro-9-fluoro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizin 
e-2-carboxylic acid hydrate, m.p. 300.degree. C. Analysis: Calculated for 
C.sub.18 H.sub.15 FN.sub.2 O.sub.3.1/3H.sub.2 O: %C, 65.0; %H, 4.7; %N, 
8.4; Found: %C, 64.8; %H, 4.5; %N, 8.4. The structural assignment was 
confirmed by infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 3 
To a solution of 3.6 g of 
6,7-dihydro-9-fluoro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizin 
e-2-carboxylic acid in 50 ml of trifluoroacetic acid was added 2.0 g ten 
percent palladium on charcoal. The mixture was hydrogenated on a Paar 
apparatus for two hours at 50 psi at 50.degree. C. The mixture was 
filtered, and the filtrate was evaporated. The residue was mixed with 50 
ml of water and the pH adjusted to 5 by the addition of ten percent sodium 
hydroxide solution and acetic acid. The precipitate obtained was 
recrystallized from aqueous N,N-dimethylformamide (80%) to provide tan 
crystals of 
6,7-dihydro-9-fluoro-5-methyl-1-oxo-8-(1-pyrrolidyl)-1H,5H-benzo[ij]quinol 
izine-2-carboxylic acid, m.p. 243.degree.-245.degree. C. Analysis: 
Calculated for C.sub.18 H.sub.19 FN.sub.2 O.sub.3 : %C, 65.5; %H, 5.8; %N, 
8.5; Found: %C, 65.8; %H, 5.8; %N, 8.5. The structural assignment was 
confirmed by infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 4 
Using the method of Example 1 and starting with the known compound 
5-acetamidoquinaldine, 
8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic 
acid hydrate, m.p. 238.degree.-240.degree. C., was obtained. Analysis: 
Calculated for C.sub.14 H.sub.14 N.sub.2 O.sub.3.H.sub.2 O: %C, 60.9; %H, 
5.8; %N, 10.1; Found: %C, 61.2; %H, 5.9; %N, 10.3. 
EXAMPLE 5 
To a suspension of 3.0 g of 
8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic 
acid in 30 ml of glacial acetic acid was added 3.0 g of 
2,5-dimethoxytetrahydrofuran and the mixture was heated on a steam bath 
for 1.5 hours. Cooling produced a solid which was separated by filtration 
to provide 
6,7-dihydro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carbo 
xylic acid, m.p. 303.degree.-305.degree. C. Analysis: Calculated for 
C.sub.18 H.sub.16 N.sub.2 O.sub.3 : %C, 70.1; %H, 5.2; %N, 9.1; Found: %C, 
69.5; %H, 5.1; %N, 9.2. The structural assignment was confirmed by 
infrared spectral analysis. 
EXAMPLE 6 
Using the method of Example 5, 3.0 g of 
8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic 
acid was converted to 
6,7-dihydro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carbo 
xylic acid. The crude product was dissolved in 50 ml of trifluoroacetic 
acid and 2 g of rhodium on alumina was added. The mixture was hydrogenated 
at 20.degree. C. for 18 hours at 50 psi of hydrogen gas. The mixture was 
filtered, evaporated to dryness and dissolved in 10 percent sodium 
hydroxide solution. The solution was acidified with glacial acetic acid. 
The product was recrystallized from N,N-dimethyformamide to provide tan 
crystals of 
6,7-dihydro-5-methyl-1-oxo-8-(1-pyrrolidyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylicacid, m.p. 170.degree.-174.degree. C. Nuclear magnetic resonance 
analysis showed water and N,N-dimethyl formamide present in the solid. 
Analysis: Calculated for C.sub.18 H.sub.20 N.sub.2 
O.sub.3.1/10(CH.sub.3).sub.2 NCHO.1/2H.sub.2 O: %C, 66.8; %H, 6.6; %N, 
9.2; Found: %C, 66.7; %H, 6.2; %N, 9.2. 
EXAMPLE 7 
Step A 
To 250 ml of hot 48% fluoroboric acid was added 50 g of 
8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic 
acid. The solution was gradually cooled to 0.degree. C. and 16.8 g of 
sodium nitrite in 50 ml of water was added slowly with vigorous stirring. 
After stirring about 30 minutes at 0.degree. C., 250 ml of an ice water 
mixture was added. Stirring was continued for about thirty minutes. The 
solid was separated by filtration and washed sequentially with an 
isopropanol-fluoroboric acid mixture, isopropanol, an isopropanol-diethyl 
ether mixture, and diethyl ether. The product, 
8-diazonium-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carbox 
ylic acid fluoroborate, was a gold solid. 
Step B 
A mixture of 81 g of cuprous cyanide and 57 g of sodium cyanide in 550 ml 
of dimethyl sulfoxide was heated on a steam bath until the solids were 
dissolved. After cooling to 25.degree. C., 55 g of 
8-diazonium-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carbox 
ylic acid fluoroborate in 275 ml of dimethyl sulfoxide was added slowly 
with rapid stirring. The temperature was maintained below 30.degree. C. 
for one hour after the completion of the addition. The mixture was then 
poured into 5 liters of water. The tan solid was separated by filtration 
and recrystallized from N,N-dimethylformamide to provide 
8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic 
acid, m.p. &gt;300.degree. C. Analysis: Calculated for C.sub.15 H.sub.12 
N.sub.2 O.sub.3 : %C, 67.2; %H, 4.5; %N, 10.4; Found: %C, 67.1; %H, 4.8; 
%N, 10.1. 
EXAMPLE 8 
A mixture of 1.4 g (5 mmole) of 
8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic 
acid, 0.75 g (11 mmole) of sodium azide, 0.6 g (11 mmole) of ammonium 
chloride and 50 ml of N,N-dimethylformamide was heated at 120.degree. C. 
for three days in a sealed vessel followed by decantation into 100 ml of 
water. To this mixture was added 2 ml of glacial acetic acid, and the 
mixture was cooled. The solid was separated by filtration and 
recrystallized from aqueous N,N-dimethylformamide to provide white needles 
of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid, m.p. 270.degree. C. (dec.). Analysis: Calculated for 
C.sub.15 H.sub.13 N.sub.5 O.sub.3 : %C, 57.9; %H, 4.2; %N, 22.5; Found: %C 
57.8; %H, 4.0; %N, 22.7. The structural assignment was confirmed by 
infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 9 
A solution of 3.5 g (11.2 mmole) of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid in 100 ml of N,N-dimethylformamide was heated to reflux, 
then allowed to cool. Sodium hydride (1.2 g of a 50% oil dispersion, 22 
mmoles) was added and the mixture was heated at 60.degree. C. for 20 
minutes. To this mixture was added 5 ml (80 mmoles) of methyl iodide. The 
solution was stirred for four hours at 20.degree. C. The mixture was 
warmed to 100.degree. C. for 5 minutes, then 300 ml of water was added. 
After cooling the solid was collected by filtration and treated with 105 
ml of 1.0% sodium hydroxide solution and 25 ml of methanol. This mixture 
was heated on a steam bath for 30 minutes. The mixture was filtered, 
concentrated to 75 ml and cooled. The product obtained was white crystals 
of sodium 6,7 
-dihydro-5-methyl-8-(2-methyl-5-tetrazolyl)-1-oxo-1H,5H-benzo[ij]quinolizi 
ne-2-carboxylate hydrate, m.p. 242.degree. C. (dec). Analysis: Calculated 
for C.sub.16 H.sub.14 N.sub.5 NaO.sub.3.1.5H.sub.2 O: %C, 51.3; %H, 4.6; 
%N, 18.7; Found: %C, 51.2; %H, 4.7; %N, 18.9. 
EXAMPLE 10 
To a solution of 1.7 g (5.4 mmole) of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid in 50 ml of N,N-dimethylformamide was added 0.6 g of sodium 
hydride (60% oil dispersion). The mixture was heated at 60.degree. C. for 
20 minutes, then 2.5 ml of ethyl iodide was added. After stirring for four 
hours without heating, the mixture was heated to 100.degree. C. for five 
minutes. Water (150 ml) was added and the mixture was cooled. The product 
collected was crystals of ethyl 
6,7-dihydro-8-(2-ethyl-5-tetrazolyl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinoli 
zine-2-carboxylate. This product was treated with 50 ml of 1 N sodium 
hydroxide solution and 15 ml of methanol and heated on a steam bath for 
thirty minutes. The mixture was decanted into cold dilute 30% aqueous 
acetic acid with stirring. The product collected was white crystals of 
6,7-dihydro-8-( 
2-ethyl-5-tetrazolyl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxyli 
c acid which was triturated with a hexane-chloroform mixture to remove 
traces of mineral oil. It melted at 253.degree. C. (dec.). Analysis: 
Calculated for C.sub.17 H.sub.17 N.sub.5 O.sub.3 : %C, 60.2; %H, 5.0; %N, 
20.6; Found: %C, 60.1; %H, 5.0; %N, 20.5. The structural assignment was 
confirmed by infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 11 
To a solution of 1.0 g (3.2 mmole) of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid in 30 ml of N,N-dimethylformamide was added 0.3 g sodium 
hydride (50% dispersion in oil). This mixture was heated at 60.degree. C. 
for 30 minutes, then allowed to cool at 20.degree. C. To this stirred 
mixture was added 4.0 ml (6.5 g, 35 mmole) of 1-iodo-n-butane in 5 ml of 
N,N-dimethylformamide. Stirring was continued for four hours. The mixture 
was then warmed to 80.degree. C., and 85 ml of water was added. A solid 
formed which was isolated by decanting. To the solid was added 25 ml of 
methanol and 45 ml of 1 N sodium hydroxide solution. The mixture was 
heated on a steam bath for one hour, then poured into 35 ml of acetic acid 
and 50 ml of ice. The solid was separated by filtration, washed with 5:1 
hexane/chloroform mixture and recrystallized from aqueous 
N,N-dimethylformamide. The product was off-white crystals of 
8-(2-n-butyl-5-tetrazolyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quino 
lizine-2-carboxylic acid, m.p. 179.degree. C. Analysis: Calculated for 
C.sub.19 H.sub.21 N.sub.5 O.sub.3 : %C, 62.1; %H, 5.8; %N, 19.1; Found: 
%C, 62.2; %H, 5.7; %N, 19.2. The structural assignment was confirmed by 
infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 12 
Using the method of Example 11, but reacting with 2.7 g (16 mmole) of 
benzyl bromide in 5 ml of N,N-dimethylformamide the product obtained was 
8-(2-benzyl-5-tetrazolyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinol 
izine-2-carboxylic acid, m.p. 251.degree. C. Analysis: Calculated for 
C.sub.22 H.sub.19 N.sub.5 O.sub.3 ; %C, 65.8; %H, 4.8; %N, 17.5; Found: 
%C, 65.9; %H, 4.8; %N, 17.8. The structural assignment was confirmed by 
infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 13 
A mixture of 0.5 g of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid and 50 ml of trifluoroacetic anhydride was heated at reflux 
for 3.5 days. Evaporation provided a residue which was diluted with water. 
The solid was recrystallized from aqueous N,N-dimethylformamide to provide 
white crystals of 
6,7-dihydro-5-methyl-1-oxo-8-[2-(5-trifluoromethyl-1,3,4-oxadiazolyl)]-1H, 
5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 267.degree.-268.degree. C. 
Analysis: Calculated for C.sub.17 H.sub.23 F.sub.3 N.sub.3 O.sub.3 : %C, 
53.9; %H, 3.2; %N, 11.1; Found: %C, 53.6; %H, 2.9; %N, 11.2. The 
structural assignment was confirmed by infrared and nuclear magnetic 
resonance spectral analyses. 
EXAMPLE 14 
A mixture of 0.5 g of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid and 50 ml of aceitc anhydride was heated at reflux for 24 
hours. Evaporation provided a residue which was triturated with hot water. 
The mixture was cooled, the product separated by filtration and 
recrystallized from aqueous N,N-dimethylformamide to provide white 
crystals of 
6,7-dihydro-5-methyl-8-[2-(5-methyl-1,3,4-oxadiazolyl)]-1-oxo-1H,5H-benzo[ 
ij]quinolizine-2-carboxylic acid, m.p. 295.degree. C. Analysis: Calculated 
for C.sub.17 H.sub.15 N.sub.3 O.sub.4 : %C, 62.8; %H, 4.6; %N, 12.9; 
Found: %C 62.7; %H, 4.4; %N, 12.6. The structural assignment was confirmed 
by infrared spectral analyses. 
EXAMPLE 15 
A mixture of 1.0 g of 
6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-c 
arboxylic acid and 5 ml (46 mmole) of phenyl isocyanate was heated at 
150.degree. C. for one hour. The mixture was then cooled and water was 
added. The solid was separated by filtration and recrystallized twice from 
aqueous N,N-dimethylformamide to provide 
6,7-dihydro-5-methyl-8-[2-(5-N-anilino)-1,3,4-oxadiazolyl)]-1-oxo-1H,5H-be 
nzo[ij]quinolizine-2-carboxylic acid solvated with N,N-dimethylformamide 
m.p. &gt;300.degree. C. Analysis: Calculated for C.sub.22 H.sub.18 N.sub.4 
O.sub.4.C.sub.3 H.sub.7 NO: %C, 63.1; %H, 5.3; %N, 14.7; Found: %C, 63.1; 
%H, 5.3; %N, 15.1.