Substituted 4-oxy-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives as gastric antisecretory agents for use in the treatment of peptic ulcer disease.

BRIEF DESCRIPTION OF THE INVENTION 
In accordance with this invention there is provided a process for treating 
peptic ulcer disease which comprises administering to an animal suffering 
from peptic ulcers, a substituted 4-oxy-3-carboxy or 
cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivative. 
The anti-ulcer agents of this invention function as anti-secretory agents 
to reduce (1) total gastric volume, (2) hydrogen ion secretion, or (3) 
hydrogen ion concentration. The reduction of any one of these parameters 
aids in attenuating the general debilitating influence of a peptic ulcer. 
The use of compounds exhibiting anti-secretory activity in the curative 
and/or prophylactic treatment of peptic ulcer disease is an established, 
beneficial procedure. 
DETAILED DESCRIPTION OF THE INVENTION 
The anti-secretory agents useful in the process of this invention are of 
the formula: 
##STR1## 
in which R.sup.1 is hydrogen, alkyl of 1 to 6 carbon atoms, aralkyl of 7 
to 9 carbon atoms, or alken-(3,4,5 or 6)-yl of 3 to 6 carbon atoms; 
R.sup.2 is hydrogen, alkoxycarbonyl of 2 to 7 carbon atoms; carboxy, 
carbamyl, N-alkylcarbamyl of 2 to 7 carbon atoms, N-alkoxyethylcarbamyl of 
4 to 9 carbon atoms, hydrazido or cyano; 
R.sup.4 is hydrogen, alkyl of 1 to 6 carbon atoms; 
R.sup.5 and R.sup.6 are independently hydrogen or alkyl of 1 to 6 carbon 
atoms 
or a pharmaceutically acceptable alkali metal salt thereof. 
By pharmaceutically acceptable alkali metal salts, applicants intend to 
embrace the sodium and potassium salts of the 4-hydroxy substituted 
1,8-naphthyridine derivatives. 
The antisecretory agents disclosed herein are produced by conventional 
techniques from known materials or compounds readily preparable by the 
medicinal chemist. 
Each of the anti-secretory agents disclosed was found active in the 
following scientifically recognized, standard test for anti-secretory 
activity: 
Male Charles River rats of Sprague-Dawley strain and 190 to 240 gm. body 
weight are food deprived for 24 hours with water ad libitum until the 
test. Groups of ten rats each are assigned to either control or drug 
treatment. Pyloric ligation was performed under ether anesthesia through a 
midline laparotomy, and either control vehicle (0.25 methylcellulose) or 
drug in control vehicle was administered intraduodenally. The rats are 
sacrificed by CO.sub.2 asphyxiation four hours after pyloric ligation. The 
stomachs are removed and the gastric contents emptied into graduated 
centrifuge tubes. The gastric samples are centrifuged for 20 minutes and 
those obviously contaminated by food, blood, or feces are discarded. The 
volume of gastric fluid is recorded and the acid concentration of 1.0 ml. 
sample aliquots is measured by electrometric titration to pH 7.0 with 0.1 
N NaOH. The calculated product of gastric volume (ml/4 hr) and acid 
concentration (mEq/L) estimates the total acid output (TAO, mEq/4 hr) over 
the four-hour test period. An analysis of variance is performed on these 
data to determine statistically significant (p&lt;0.05) deviation between 
control versus drug-treated groups. 
The dosage regimen for therapeutic use of the antisecretory agents 
disclosed herein will vary with the mode of administration, size and age 
of the person under treatment as well as the severity of the dysfunction. 
Therefore, treatment of peptic ulcer disease must be individualized for 
the patient under the guidance of the attending physician. 
The compounds of this invention may be administered by conventional oral or 
parenteral routes as solids, liquids or isotonic solutions. Conventional 
adjuvants known to the art may be combined with the compounds disclosed 
herein to provide compositions and solutions for administration purposes 
although it is considered desirable and feasible to use the compounds neat 
or pure without additives other than for the purpose of providing suitable 
pharmaceutically acceptable solid or liquid dosage unit forms.

The following examples illustrate several techniques applicable in the 
preparation of the anti-secretory agents of this invention. An index of 
gastric anti-secretory activity is reported at the end of each example 
illustrating the production of a compound disclosed herein. The activity 
is expressed as percentage inhibition of acid secretion in drug treated 
animals in comparison to control animals based upon intraduodenal (i.d.) 
administration of 32 mg/kg of the tested compound, unless indicated 
otherwise. 
EXAMPLE 1 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester 
A mixture of 26 g. of 2-hydroxy-6-methylnicotinic acid methyl ester 
obtained by the procedure of Mariella et al., J.A.C.S., 74, 1915 (1952) in 
200 ml. of phosphorus oxychloride was heated under reflux for 6 hours. The 
phosphorus oxychloride was removed in a rotary evaporator and the residue 
was poured onto 1 liter of cracked ice. The mixture was extracted with 250 
ml. of diethyl ether. The ether was dried over magnesium sulfate, filtered 
and removed in a rotary evaporator to afford 18.0 g. of pure 
2-chloro-6-methylnicotinic acid methyl ester. 
Anal. Calcd. for C.sub.8 H.sub.8 NClO.sub.2 : C, 51.77; H, 4.34; N, 7.55. 
Found: C, 51.67; H, 4.08; N, 7.34. 
To a cold solution of 5.4 g. (0.12 mole) of anhydrous ethyl amine in 5 ml. 
of ethanol was added 11.1 g. (0.06 mole) of 2-chloro-6-methylnicotinic 
acid methyl ester. The mixture was heated in a glass autoclave over a 
steam bath for 5 hours. The mixture was then evaporated in a rotary 
evaporator and the residue was added to 100 ml. of water and was basified 
with concentrated ammonium hydroxide. The mixture was then extracted with 
100 ml. of chloroform. The chloroform layer was dried over magnesium 
sulfate, filtered and was evaporated to give 
2-ethylamino-6-methylnicotinic acid methyl ester as an oil which was used 
without further purification. 
For characterization purposes, a hydrochloride was prepared by dissolving a 
few ml. of free base in ethyl acetate and adding dropwise a saturated 
solution of hydrogen chloride in diethyl ether. A few drops of ethanol was 
added. The solid which formed was removed by filtration and recrystallized 
from ethyl acetate-ethanol and dried in vacuo at 56.degree. (m.p. 
123.degree.-125.degree. C.). 
Anal. Calcd. for C.sub.10 H.sub.15 ClN.sub.2 O.sub.2 : C, 52.06; H, 6.12; 
N, 12.15. Found: 51.69; H, 6.44; N, 12.00. 
To a solution of 3.98 g. (0.02 mole) of 2-ethylamino-6-methylnicotinic acid 
methyl ester in 50 ml. of anhydrous diethyl ether was added 1.5 g. (0.01 
mole) of ethyl malonyl chloride. The mixture was stirred at room 
temperature for 1 hour. The mixture was filtered and the filtrate was 
evaporated in a rotary evaporator. The residue was added to a solution of 
0.23 g. of sodium in 50 ml. of absolute ethanol and was warmed for 5 
minutes. The mixture was cooled and the insoluble material was collected 
and was dissolved in water. Acidification of the water solution with 
glacial acetic acid afforded a precipitate which was collected, air dried 
and was recrystallized from heptane to give 1.2 g. of product, m.p. 
147.degree.-151.degree. C. 
Anal. Calcd. for C.sub.14 H.sub.16 N.sub.2 O.sub.4 : C, 60.86; H, 5.84; N, 
10.14 Found: C, 60.88; H, 6.00; N, 9.99. 
Precentage inhibition--50% 
EXAMPLE 2 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester 
A stirred mixture of 12 g. of 2-hydroxy-6-methylnicotinic acid in 100 ml. 
of phosphorus oxychloride was heated under reflux for 3 hours. The 
phosphorus oxychloride was removed in a rotary evaporator and the residue 
was poured onto 500 ml. of ice. The mixture was stirred at room 
temperature for 3 hours and was filtered. The filter cake was collected, 
air dried and was recrystallized from ethyl acetate to give 7.0 g. of 
2-chloro-6-methylnicotinic acid, m.p. 158.degree.-60.degree. C. (Ref. 
Zalay et al., U.S. Pat. No. 3,838,120; m.p. 142.degree.-9.degree. C. 
A mixture of 7 g. of 2-chloro-6-methylnicotinic acid in 100 ml. of 60% 
aqueous ethylamine was heated in an autoclave in a steam bath for 24 
hours. The solution was evaporated in a rotary evaporator and the residue 
was dissolved in 150 ml. of benzene and this solution was evaporated in a 
rotary evaporator. This process of benzene treatment was repeated. After 
evaporation, the residue was treated with 100 ml. of benzene and was 
filtered. The filtrate was evaporated and the residue was triturated with 
100 ml. of diethyl ether. The insoluble material was collected and was 
recrystallized from ethyl acetate to afford 1.0 g. of 
2-ethylamino-6-methylnicotinic acid, m.p. 107.degree.-110.degree. C. 
A stirred mixture of 0.5 g. of 2-ethylamino-6-methylnicotinic acid in 30 
ml. of ethyl chloroformate was heated under reflux for 24 hours. The 
mixture was filtered and the filtrate was evaporated in a rotary 
evaporator. The residue was recrystallized from ethyl acetate (petroleum 
ether was added to initiate precipitation) to give 0.1 g. of 
1-ethyl-7-methyl-2H-pyrido[2,3-d][1,3]oxazine-2,4[1H]-dione, m.p. 
100.degree.-12.degree. C. (ref. Zalay et al., U.S. Pat. No. 3,838,120, 
m.p. 116.degree.-17.degree. C.). 
To a solution of 0.046 g. (0.002 g. atom) of sodium in 20 ml. of ethanol 
was added 0.32 g. (0.002 mole) of diethyl malonate. After stirring for 5 
minutes the solution was evaporated in a rotary evaporator. The residue 
was dissolved in 15 ml. of N,N-dimethylformamide and 0.2 g. (0.001 mole) 
of the previous compound was added. The mixture was heated under reflux 
for 1.5 hours. The mixture was cooled, diluted with a little water and was 
acidified with concentrated hydrochloric acid. The precipitate which 
formed was collected to give a few mg. of the title compound, m.p. 
138.degree.-40.degree. C. 
EXAMPLE 3 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester sodium salt 
To a solution of 0.23 g. (0.01 g. atoms) of sodium in 100 ml. of ethanol 
was added 2.76 g. (0.01 mole) of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester prepared by the method of Example 1. The mixture was 
stirred at room temperature for 2 hours. The mixture was filtered and the 
filter cake was dissolved in boiling ethanol. After cooling, the solution 
was diluted with diethyl ether to the cloudy point. Further cooling 
produced a precipitate which was collected to give 1.1 g. of the title 
compound, m.p. &gt;300.degree. C. 
Anal. Calcd. for: C.sub.14 H.sub.15 N.sub.2 O.sub.4 Na.1/2H.sub.2 O: C, 
54.72; H, 5.25; N, 9.12 Found: C, 54.64; H, 4.94; N, 9.17 
EXAMPLE 4 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxamid 
e 
A mixture of 1 g. of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester (prepared as in Example 1) in 20 ml. of a saturated 
ethanolic ammonia solution was heated in an autoclave placed in a steam 
bath for 4 hours. The mixture was cooled and was filtered. The filter cake 
was triturated with 50 ml. of a 20% aqueous acetic acid solution. The 
insoluble material was collected, air dried and was recrystallized from 
ethanol to afford 0.4 g. of the title compound, m.p. 240.degree.-2.degree. 
C. 
Anal. Calcd. for: C.sub.12 H.sub.13 N.sub.3 O.sub.3 : C, 58.29; H, 5.30; N, 
17.00. Found: C, 57.92; H, 5.52; N, 16.91. 
Percentage inhibition: 12% 
EXAMPLE 5 
1-Ethyl-1,2-dihydro-4-hydroxy-N-methyl-7-methyl-2-oxo-1,8-naphthyridine-3-c 
arboxamide 
A stirred mixture of 4 g. of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester (prepared as in Example 1) and 30 ml. of 40% aqueous 
methylamine in 20 ml. of methanol was heated under reflux for 5 hours. The 
solution was cooled, diluted with 100 ml. of water and was acidified with 
glacial acetic acid. The precipitate which formed was collected, air dried 
and was recrystallized from heptane to give 1.9 g. of the title compound, 
m.p. 150.degree.-4.degree. C. 
Anal. Calcd. for C.sub.13 H.sub.15 N.sub.3 O.sub.3 : C, 59.76; H, 5.79; N, 
16.08. Found: C, 59.49; H, 5.84; N, 15.85. 
Percentage inhibition: 54% 
EXAMPLE 6 
1-Ethyl-1,2-dihydro-4-hydroxy-N-(2-methoxyethyl)-7-methyl-2-oxo-1,8-naphthy 
ridine-3-carboxamide 
A stirred mixture of 1.38 g. (0.005 mole) of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester (prepared as in Example 1) and 0.75 g. (0.01 mole) of 
2-methoxyethylamine in 20 ml. of ethanol was heated under reflux for 5 
hours. The solution was left at room temperature overnight. The 
precipitate which formed was collected and was stirred in 100 ml. of a 20% 
aqueous acetic acid solution for 30 minutes. The insoluble material was 
collected, air dried and was recrystallized from heptane to give 0.9 g. of 
the title compound, m.p. 118.degree.-20.degree. C. 
Anal. Calcd. for C.sub.15 H.sub.19 N.sub.3 O.sub.4 : C, 59.00; H, 6.27; N, 
13.76. Found: C, 58.68; H, 6.53; N, 13.70. 
Percentage inhibition: 40% 
EXAMPLE 7 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid hydrazide 
A stirred mixture of 1.38 g. (0.005 mole) of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester (prepared as in Example 1) and 0.32 g. (0.01 mole) of 
hydrazine in 30 ml. of ethanol was heated under reflux for 1 hour. The 
mixture was filtered and the filter cake was triturated with 100 ml. of 
20% aqueous acetic acid. The insoluble material was collected, air dried 
and was recrystallized from ethanol to give 0.7 g. of the title compound, 
m.p. 211.degree.-13.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.14 N.sub.4 O.sub.3 : C, 54.95; H, 5.38; N, 
21.37. Found: C, 54.75; H, 5.33; N, 21.32. 
Percentage inhibition: 24% 
EXAMPLE 8 
1,7-Dimethyl-1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester 
To 10 g. (0.05 mole) of methyl 2-chloro-6-methylnicotinate in 50 ml. of 
methanol was added a chilled solution of 4 g. (0.13 mole) of methylamine 
in 25 ml. of methanol. This was placed in an autoclave and heated on a 
steam bath for 4 hours. The reaction was then stripped, added to water, 
made very basic with concentrated NH.sub.4 OH and extracted once with 
CHCl.sub.3. The CHCl.sub.3 was washed once with water, dried and stripped 
giving 7 g. of a viscous liquid residue of 6-methyl-2-methylaminonicotinic 
acid, methyl ester. This product was then used directly without further 
purification. 
To a solution of 9.0 g. (0.05 mole) of methyl 
2-methylamino-6-methylnicotinate in 150 ml. of anhydrous diethyl ether was 
added 3.75 g. (0.025 mole) of ethyl malonyl chloride. The mixture was 
stirred at room temperature for 3 hours. The mixture was filtered and the 
filtrate was dissolved in 10 ml. of ethanol. This solution was added to a 
solution of 1.15 g. (0.05 g. atoms) of sodium in 75 ml. of ethanol. The 
mixture was stirred at room temperature for 5 minutes and was filtered. 
The filter cake was triturated with 100 ml. of water and this mixture was 
acidified with glacial acetic acid. The insoluble material was collected, 
air dried and was recrystallized from ethyl acetate to give 1.5 g. of the 
title compound, m.p. 143.degree.-5.degree. C. 
Anal. Calcd. for C.sub.13 H.sub.14 N.sub.2 O.sub.4 : C, 59.53; H, 5.38; N, 
10.68. Found: C, 59,83; H, 5.16; N, 10.78. 
Percentate inhibition: 51% 
EXAMPLE 9 
1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1-propyl-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester 
A stirred mixture of 37.1 g. (0.2 mole) of methyl 
2-chloro-6-methyl-nicotinate, 11.8 g. (0.02 mole) of propylamine and 21.2 
g. (0.02 mole) of sodium carbonate in 200 ml. of ethanol was heated under 
reflux for 5 hours. The mixture was filtered and the filtrate was 
evaporated in a rotary evaporator. The residue was triturated with 200 ml. 
of water and was extracted with 100 ml. of diethyl ether. The ether layer 
was dried over magnesium sulfate, filtered and was evaporated to give 31 
g. of an oil. A small amount of this oil was dissolved in diethyl ether 
and was acidified with an etheral hydrochloric acid solution. On cooling, 
the oil which separated crystallized to yield 
6-methyl-2-propylaminonicotinic acid methyl ester, hydrochloride. The 
solid was collected and was recrystallized from ethyl acetate to give the 
analytical sample, m.p. 113.degree.-15.degree. C. 
Anal. Calcd. for C.sub.11 H.sub.17 ClN.sub.2 O.sub.2 : C, 53.99; H, 7.00; 
N, 11.45. Found: C, 53.50; H, 7.12; N, 11.53. 
To a solution of 30.7 g. (0.015 mole) of methyl-2-propylaminonicotinic acid 
methyl ester in 250 ml. of anhydrous diethyl ether was added 11.25 g. 
(0.0075 mole) of ethyl malonyl chloride. The mixture was stirred at room 
temperature for 2 hours. The mixture was filtered and the filtrate was 
evaporated in a rotary evaporator. The residue was dissolved in 20 ml. of 
ethanol and this solution was added to a solution of 3.4 g. (0.015 g. 
atom) of sodium in 200 ml. of ethanol. After stirring at room temperature 
for 5 minutes, the mixture was diluted with water and was acidified with 
concentrated hydrochloric acid. The precipitate which formed was 
collected, air dried and was recrystallized from heptane to afford 3.4 g. 
of the title compound, m.p. 128.degree.-30.degree. C. 
Anal. Calcd. for C.sub.15 H.sub.18 N.sub.2 O.sub.4 : C, 62.05; H, 6.25; N, 
9.65 Found: C, 61.90; H, 6.24; N, 9.63 
Percentage inhibition: 59% 
EXAMPLE 10 
1-Allyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester 
A stirred mixture of 9.25 g. (0.05 mole) of methyl 
2-chloro-6-methylnicotinate, 2,85 g. (0.05 mole) of allylamine and 5.3 g. 
(0.05 mole) of sodium carbonate in 50 ml. of ethanol was heated under 
reflux for 5 hours. The mixture was filtered and the filtrate was 
evaporated in a rotary evaporator. The residue was diluted with 50 ml. of 
water and was extracted with 50 ml. of diethyl ether. The ether layer was 
dried over magnesium sulfate, filtered and was evaporated. The residue was 
passed through a neutral aluminum oxide column using ethyl acetate as the 
eluent. Evaporation of the ethyl acetate gave 3.1 g. of product. A small 
amount of this oil was dissolved in diethyl ether containing a few drops 
of ethanol and this solution was acidified with an ethereal hydrochloric 
acid solution. The precipitate which formed was collected and was 
recrystallized from ethyl acetate to give 2-allylamino-6-methylnicotinic 
acid methyl ester, m.p. 140.degree.-2.degree. C. 
Anal. Calcd. for C.sub.11 H.sub.15 ClN.sub.2 O.sub.2.1/2H.sub.2 O: C, 
52.49; H, 6.42; N, 11.13. Found: C, 52.96; H, 5.94; N, 11.26. 
To a solution of 2.88 g. (0.015 mole) of 2-allylamino-6-methylnicotinic 
acid, methyl ester in 50 ml. of anhydrous diethyl ether was added 1.12 g. 
(0.0075 mole) of ethyl malonyl chloride. The mixture was stirred at room 
temperature for 4 hours. The mixture was filtered and the filtrate was 
evaporated in a rotary evaporator. The residue was dissolved in 5 ml. of 
ethanol and this solution was added to a solution of 0.23 g. (0.01 g. 
atoms) of sodium in 20 ml. of ethanol. The mixture was stirred at room 
temperature for 5 minutes. The mixture was diluted with water and was 
acidified with glacial acetic acid. The mixture was extracted with diethyl 
ether and the ether layer was dried over magnesium sulfate, filtered and 
was acidified with an etheral hydrochloric acid solution. The mixture was 
filtered and the filtrate was evaporated. The residue was recrystallized 
from heptane to give 10 mg. of the title compound, m.p. 
110.degree.-112.degree. C. 
Anal. Calcd. for C.sub.15 H.sub.16 N.sub.2 O.sub.4 : C, 62.49; H, 5.59; N, 
9.72. Found: C, 62.22; H, 5.49; N, 9.62. 
Percentage inhibition: 23% 
EXAMPLE 11 
1-Benzyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid, ethyl ester 
To 15 g. (0.081 mole) of methyl 2-chloro-6-methylnicotinate in methanol was 
added 17.3 g. (0.162 mole) of benzylamine and this mixture was refluxed 
for 5 hours. The reaction was then stripped, added to water, made very 
basic via NH.sub.4 OH, extracted into CHCl.sub.3, rinsed with water, dried 
and stripped. Chilling and scratching produced 4 g. of a solid 
2-benzylamino-6-methylnicotinic acid, methyl ester that was filtered off 
and rinsed with petroleum ether, m.p. 76.degree.-80.degree. C. 
Recrystallized from ethanol-m.p. 84.degree.-88.degree. C. 
Anal. Calcd. for C.sub.15 H.sub.16 N.sub.2 O.sub.2 : C, 70.29; H, 6.29; N, 
10.93. Found: C, 70.43; H, 6.32; N, 10.95. 
To a solution of 3.6 g. (0.014 mole) of methyl 
2-benzylamino-6-methylnicotinate in 50 ml. of anhydrous diethyl ether was 
added 1.05 g. (0.007 mole) of ethyl malonyl chloride. The mixture was 
stirred at room temperature for 3 hours. The mixture was filtered and the 
filtrate was evaporated in a rotary evaporator. The residue was dissolved 
in 5 ml. of ethanol and this solution was added to a solution of 0.32 g. 
(0.014 g. atoms) of sodium in 50 ml. of ethanol. After stirring at room 
temperature for 5 minutes, the mixture was diluted with water and was 
acidified with glacial acetic acid. The precipitate which formed was 
collected, air dried and was crystallized from ethanol to give 0.9 g. of 
the title compound, m.p. 155.degree.-7.degree. C. 
Anal. Calcd. for C.sub.19 H.sub.18 N.sub.2 O.sub.4 : C, 67.44; H, 5.36; N, 
8.28 Found: C, 67.22; H, 5.41; N, 8.25 
Percentage inhibition: 30% 
EXAMPLE 12 
1-Ethyl-1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylic acid, 
ethyl ester 
To a cold diethyl ether solution containing about 2.8 g. (0.067 mole) of 
diazomethane generated from 10 g. of nitrosomethyl urea and 30 cc. of 40% 
potassium hydroxide (see Organic Synthesis, Col. 1, Vol. II, page 166) was 
added in portions 9.45 g. (0.06 mole) of 2-chloronicotinic acid. After the 
evolution of nitrogen had ceased the reaction mixture was allowed to stand 
at room temperature overnight. The solvent was removed in a rotary 
evaporator leaving 2-chloro-nicotinic acid, methyl ester as a residual oil 
whose infrared spectrum indicated no OH absorption was present. The oil 
was used directly in the next step. The above compound has also been 
described by F. G. Mann and J. A. Reid, J. Chem. Soc., 1952, 2057. 
To 10 g. (0.06 mole) of methyl 2-chloronicotinate in 50 ml. of methanol was 
added 6.0 g. (0.13 mole) of ethylamine in 25 ml. of methanol and this was 
placed into an autoclave and heated on a steam bath for 4 hours. Then the 
reaction solution was stripped, water added, made very basic via NH.sub.4 
OH, extracted into CHCl.sub.3, washed with water, dried and then stripped 
to dryness to yield 2-ethylaminonicotinic acid, methyl ester. An HCl-salt 
was prepared by adding the crude residue to ethyl acetate and then adding 
ethereal-HCl. The product precipitated out of solution and was collected 
on a filter and rinsed with petroleum ether to give 7 g. of product with a 
m.p. of 140.degree.-5.degree. C. 
Anal. Calcd. for C.sub.9 H.sub.13 N.sub.2 ClO.sub.2 : C, 49.88; H, 6.05; N, 
12.93. Found: C, 49.85; H, 6.05; N, 13.08. 
To a solution of 9.0 g. (0.05 mole) of methyl 2-ethylaminonicotinate in 400 
ml. of anhydrous diethyl ether was added 3.75 g. (0.25 mole) of ethyl 
malonyl chloride. The mixture was stirred at room temperature for 3 hours 
and was then filtered. The filtrate was evaporated in a rotary evaporator 
and the residue was dissolved in 15 ml. of ethanol and this solution was 
added to a solution of 1.15 g. (0.05 g. atoms) of sodium in 150 ml. of 
ethanol. The mixture was stirred at room temperature for 10 minutes. The 
mixture was diluted with water to the cloudy point and was then acidified 
with glacial acetic acid. The precipitate which formed was collected, air 
dried and was recrystallized from heptane to give 0.7 g. of the title 
compound, m.p. 122.degree.-5.degree. C. 
Anal. Calcd. for C.sub.13 H.sub.14 N.sub.2 O.sub.4 : C, 59.53; H, 5.38; N, 
10.68. Found: C, 59.41; H, 5.33; N, 10.66. 
Percentage inhibition: 35% 
EXAMPLE 13 
1-Ethyl-1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylic acid, 
ethyl ester 
To a suspension of 25 g. of 2,3-pyridinedicarboxylic anhydride in 350 ml. 
of methyl ethyl ketone was bubbled a stream of ammonia gas for 15 minutes. 
The mixture was filtered and the filter cake was dissolved in 250 ml. of 
water. To this solution was bubbled a stream of sulfur dioxide. The 
precipitate which formed was collected to give 9.0 g. of 
2-carbamylnicotinic acid, m.p. 178.degree.-82.degree. C. dec. (Ref. Mann 
et al., J. Chem. Soc., 2057 (1952); m.p. 172.degree. C. dec.). 
To a suspension of 2.0 g. of 2-carbamylnicotinic acid in 20 ml. of 
N,N-dimethylformamide was added 5.5 g. of lead tetra-acetate. The mixture 
was stirred at a temperature of 50.degree.-60.degree. C. for 1 hour. The 
mixture was poured into 20 ml. of water. The precipitate was collected to 
give 0.65 g. of 2H-pyrido[2,3-d][1,3]oxazine2,4[1H]dione, 
224.degree.-6.degree. C. dec. (Ref. Beckwith et al., J. Chem. Soc., (C) 
2756 (1969); m.p. 217.degree.-19.degree. C.). 
To 20 ml. of dry N,N-dimethylformamide was added 0.19 g. (0.004 mole) of 
50% sodium hydride. Then a suspension of 0.65 g. (0.004 mole) of 
2H-pyrido[2,3-d][1,3]oxazine-2,4[1H]dione in 10 ml. of 
N,N-dimethylformamide was added. After 0.248 g. (0.008 mole) of ethyl 
iodide was added the mixture was stirred at room temperature for 2 hours. 
The mixture was slowly diluted with water and the precipitate which formed 
was collected, air dried, and was recrystallized from ethanol to give 0.2 
g. of 1-ethyl-2H-pyrido[2,3-d]-[1,3]oxazine-2,4[1H]dione, m.p. 
143.degree.-5.degree. C. 
Anal. Calcd. for C.sub.9 H.sub.8 N.sub.2 O.sub.3 : C, 56.25; H, 4.20; N, 
14.58. Found: C, 56.19; H, 4.25; N, 14.61. 
To a solution of 0.115 g. (0.005 g. atom) of sodium in 20 ml. of ethanol 
was added 1.6 g. (0.01 mole) of diethyl malonate. After stirring for 5 
minutes the solution was evaporated in a rotary evaporator. The residue 
was dissolved in 15 ml. of N,N-dimethylformamide and 0.96 g. (0.005 mole) 
of 1-ethyl-2H-pyrido[2,3-d]-[1,3]oxazine-2,4[1H]dione was added. The 
mixture was heated under reflux for 1.5 hours. The mixture was cooled, 
diluted with a little water and was acidified with concentrated 
hydrochloric acid. The precipitate which formed was collected, air dried 
and was recrystallized from heptane to give 0.2 g. of the title product, 
m.p. 120.degree.-2.degree. C. 
EXAMPLE 14 
1-Ethyl-1,2-dihydro-4-ethoxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid, ethyl ester 
A stirred mixture of 1 g. of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester in 20 ml. of thionyl chloride was heated under reflux 
for 3 hours. The thionyl chloride was removed in a rotary evaporator and 
the residue was recrystallized from ethyl acetate to give 0.3 g. of 
1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester, m.p. 143.degree.-5.degree. C. 
Anal. Calcd. for C.sub.14 H.sub.15 ClN.sub.2 O.sub.3 : C, 57.05; H, 5.13; 
N, 9.51. Found: C, 57.21; H, 4.93; N, 9.55. 
To a solution of 0.11 g. (0.005 g. atoms) of sodium in 20 ml. of ethanol 
was added 1.47 g. (0.005 mole) of 
1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid, ethyl ester. The mixture was heated under reflux for 4 hours. The 
mixture was cooled and was diluted with water. The precipitate which 
formed was collected, air dried and was recrystallized from heptane to 
give 0.5 g. of the title compound, m.p. 77.degree.-9.degree. C. 
Anal. Calcd. for C.sub.16 H.sub.20 N.sub.2 O.sub.4 : C, 63.14; H, 6.62; N, 
9.21. Found: C, 63.17; H, 6.68; N, 9.17. 
Percentage inhibition: 62% 
EXAMPLE 15 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carbonitri 
le 
A stirred mixture of 10 g. of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxami 
de (prepared as in Example 4) in 200 ml. of phosphorus oxychloride was 
heated under reflux for 3 hours. The phosphorus oxychloride was evaporated 
in a rotary evaporator. To this residue was quickly added 400 ml. of ice 
water. The insoluble material was collected, air dired and was 
recrystallized from ethanol to give 5.5 g. of 
4-chloro-1-ethyl-1,2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carbonitri 
le, m.p. 215.degree.-17.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.10 ClN.sub.3 O: C, 58.19; H, 4.07; N, 
16.96. Found: C, 57.93; H, 4.24; N, 16.81. 
A stirred mixture of 7.41 g. (0.03 mole) of 
4-chloro-1-ethyl-1,2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carbonitri 
le, 2.13 g. (0.03 mole) of pyrrolidine and 3.18 g. (0.03 mole) of sodium 
carbonate in 100 ml. of ethanol was heated under reflux for 1 hour. The 
mixture was filtered and the filter cake was triturated with 200 ml. of 
water. The insoluble material was collected, air dried and was 
recrystallized from 2-ethoxyethanol to give 7.4 g. of 
1-ethyl-1,2-dihydro-7-methyl-2-oxo-4-(1-pyrrolidinyl)-1,8-naphthyridine-3- 
carbonitrile, m.p. 211.degree.-13.degree. C. 
Anal. Calcd. for C.sub.16 H.sub.18 N.sub.4 O: C, 68.06; H, 6.43; N, 19.85. 
Found: C, 68.24; H, 6.57; N, 19.84. 
A stirred mixture of 0.5 g. of 
1-ethyl-1,2-dihydro-7-methyl-2-oxo-4-(1-pyrrolidinyl)-1,8-naphthyridine-3- 
carbonitrile in 15 ml. of 20% aqueous sodium hydroxide containing 15 ml. of 
ethanol was heated under reflux for 3 hours. The solution was cooled and 
was acidified with concentrated hydrochloric acid. The precipitate which 
formed was collected, air dried and was recrystallized from ethanol to 
afford 0.2 g. of the title compound, m.p. 274.degree.-6.degree. C. 
Anal. Calcd. for Cl.sub.2 H.sub.11 N.sub.3 O.sub.2 : C, 62.87; H, 4.84; N, 
18.33. Found: C, 62.62; H, 4.61; N, 17.97. 
Percentage inhibition: 39% 
EXAMPLE 16 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid 
A stirred mixture of 1 g. of 
1-ethyl-1,2-dihydro-4-ethoxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic 
acid ethyl ester (prepared as in Example 14) in 15 ml. of 20% aqueous 
sodium hydroxide containing 5 ml. of ethanol was heated under reflux for 4 
hours. The mixture was cooled and was acidified with glacial acetic acid 
and was diluted with water. The precipitate which formed was collected, 
air dried and was recrystallized from ethanol to afford 0.3 g. of the 
title compound, m.p. 162.degree.-5.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.12 N.sub.2 O.sub.4 : C, 58.06; H, 4.87; N, 
11.29. Found: C, 57.76; H, 4.94; N, 11.22. 
Percentage inhibition: 56% 
EXAMPLE 17 
1-Ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine 
A stirred mixture of 0.5 g. of 
1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyli 
c acid ethyl ester was heated under reflux for 5 hours in 20 ml. of a 20% 
sodium hydroxide solution was cooled and was acidified with glacial acetic 
acid. The precipitate which formed was collected, air dried and was 
recrystallized from ethanol to give 0.2 g. of the title compound, m.p. 
320.degree.-3.degree. C. dec. 
Anal. Calcd. for C.sub.11 H.sub.12 N.sub.2 O.sub.2 : C, 64.69; H, 5.92; N, 
13.72. Found: C, 64.47; H, 5.99; N, 13.59. 
Percentage inhibition: 33@16 mg/kg. 
EXAMPLE 18 
1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid 
ethyl ester 
A mixture of 5 g. of 2-chloro-6-methylnicotinic acid methyl ester and 1 g. 
of ammonia in 25 ml. of methanol was heated in an autoclave in a steam 
bath for 10 hours. The mixture was evaporated in a rotary evaporator, 
diluted with water and was basified with concentrated ammonium hydroxide. 
The mixture was extracted with diethyl ether. The ether layer was dried 
over magnesium sulfate, filtered and was evaporated to give about 2.5 g. 
of 2-amino-6-methylnicotinic acid methyl ester as an oil which was used in 
the next step without further purification. 
To a solution of 7.9 g. (0.047 mole) of methyl 2-amino-6-methyl-nicotinate 
in 250 ml. of anhydrous diethyl ether was added 3.5 g. (0.0235 mole) of 
ethyl malonyl chloride. The mixture was stirred at room temperature for 4 
hours. The mixture was filtered and the filtrate was evaporated in a 
rotary evaporator. The residue was triturated with 25 ml. of cold ethanol. 
The insoluble material was collected and was recrystallized from heptane 
to yield 1.8 g. of 2-[(3-ethoxy-1,3-dioxopropyl)amino]-6-methyl-3-pyridine 
carboxylic acid ethyl ester, m.p. 92.degree.-5.degree. C. 
Anal. Calcd. for C.sub.14 H.sub.18 N.sub.2 O.sub.5 : C, 57.13; H, 6.17; N, 
9.52. Found: C, 57.18; H, 6.20; N, 9.51. 
The filtrate from the previous reaction was added to a solution of 1.08 g. 
(0.047 g. atom) of sodium in 150 ml. of ethanol. The mixture was stirred 
for 5 minutes and was diluted with water and was acidified with glacial 
acetic acid. The precipitate which formed was collected, air dried and was 
recrystallized from ethanol to afford 0.2 g. of the title compound, m.p. 
190.degree.-3.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.12 N.sub.2 O.sub.4 : C, 58.06; H, 4.87; N, 
11.29. Found: C, 57.64; H, 4.89; N, 11.20.