Note: Descriptions are shown in the official language in which they were submitted.
g~
This invention relates to new and useful vinyl derivatives having
antibacterial activities, a process for preparing them, and also to their
use.
In the course of our studies on antibacterial agents of the 1,4-
dillydro_4_o~o_1,8_naphthyridine (or 1,4-dihydro-4-oxo quinoline)-3-carboxylic
acid type, ~e found that compounds resulting from the introduction of a vinyl
group into the l-position of 1,8-naphthyridine nucleus (or quinoline nucleus)
and a l-piperazinyl group or 4-allcyl-1-piperazinyl group into its 7-position
are useful as antibacterial agen~s, especially against Pseudomonas aeruginosa.
l~ This invention provides compounds of the following formula
,COOH (I)
C~C~12 ,.
wherein A is a ~CH-group or nitrogen atom, and Rl is a hydrogen atom or an
alkyl group having 1 to 6 carbon atoms, and salts thereof.
Compounds of the above formula in which Rl is a hydrogen atom,
metlyl group or ethyl groupj and their salts are especially preferred.
Especially suitable compounds are: 1,4-dihydro-7-(1-piperazinyl)-
4-o~o-1-vinyl-1,8-naphthyridine-3-carboxylic acid, 1,4-dihydro-7-(4-methyl-
l-piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylic acid, and 1,4-dihydro-
7-(4-ethyl-1-piperazinyl)-4-oxo-1-villylquinoline-3-carboxylic acid, and
~O phar~aceutically acceptable acid addition salts, preferably hydrochloride
and methanesulfonate.
The compounds of formula (I) are synthesized by: (i~ reacting a
compound of fo~mlla (a) ~ (a)
I 1 2
Y Z
.
7~18
wherein X is a halogen atom, R3 is hydrogen or an alkyl group o-f 1 to 6
carbon atoms and Y and Z are different from each other and one of Y and Z
represents a hydrogen atom ~hile the other represents a halogen atom, a lower
alkoxy group, a benzyloxy group, an alcoholic hydroxy group, an acyloxy group,
an arylsulfonylo~y group, a lower alkylsulfonyloxy group~ an S-aryldithio-
oarbonyloxy group, a lo~er s-alkyldithiocarbonyloxy group, a lower dialkyl-
amino group, a cyclic amino group or a group that can form a tertiary amine
N-oxide or a quaternary ammonium salt or a quaternary ammonium hydroxide by
bonding to the -CH-CH2 or CH-CH2 moiety of the 1,H-CH2 group, with a compound
Y Z Y Z
10 ot` ~ellcral formula (b)
Rl - N~ H (b)
wherein Rl is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or
an acyl group, to fo~l a compound of the general formula I-A
O ~:
Rl - N N COOR3 I-A
IH-lcH2
Y Z
and subjecting the compound of formula I-A to heat to elimina~e Y and Z and,
if Rl is acyl or R3 is alkyl subjecting the product to hydrolysis to convert
R' or R to ~ydrogen; (ii) heating a compound of fo
R' /--~N /
1 \ I
CH-CH2
Y Z
wherein ~ and R3, Y and Z are as defined above except that when A is nitro-
~ 3
75~
gen and Ri is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms
neither Y nor Z is halogen to eliminate Y and Z and, if Rl is acyl or R3
is alkyl subjecting the product to hydrolysis to replace Rl or R3 by hydro-
gen, (iii) hydrolysing a compound of formula
_ N N ~ COOR3
C}~CH2
~herein A and R3 are as defined above and Rl is an alkyl group having 1 to
6 carbon atoms or an acyl group other than an acetyl group, provided that
t~hen ~ is a nitrogen atom Rl is an acyl group other than an acetyl group;
~iv) reacting a compound of formula
tO ~ ~~3
wherein X and R3 are as defined above, with a compound of formula
Rl" - N\__~H
~hcrein Rl" is an alkyl group of 1 to 6 carbon atoms and, if R3 is other
than a hydrogen atom, hydrolysing the product to obtain a compound of
formula I in which Rl is alkyl of 1 to 6 carbon atoms.
If required the products of formula I can be converted into
pharmaceutically acceptable salts.
Specific examples of the acyl group represented by Rl are acid
residues generally used as a protective group, such as formyl, acetyl,
trifluoroacetyl, benzoyl, benzyloxycarbonyl, ethoxycarbonyl, or tert.-
~ _ 4 _
7~l~
butoxycarbonyl.
The deriva~ives of the alcoholic hydroxy groups as Y and Z include,
for examRle, acyloxy groups such as acetyloxy or ethoxycarbonyloxy; aryl-
sulfonyloxy groups such as tosyloxy or benzenesulfonyloxy, or lower alkyl-
sulfonylo.Yy groups such as methanesulfo~yloxy or ethanesulfonyloxy; or
S-aryldithiocarbonyloxy groups such as S-tolyldithiocarbonyloxy or
. ~ j - 4a -
~7~7~
S-phenyldithiocarbonyloxy~ or lower S-alkyldithiocarbonyloxy such as S-
-metllyldithiocarbonyloxy or S-ethyldithiocarbonyloxy groups.
Specific examples of ~leaving amino group" as Y and Z are -N(CH3)2,-
N(C~H5)2, - N ~ (CH3)3I , - ~ (C2H5)3O ~ , and -~(CH3)2
Pre~erred groups represented by -CH-CH2 are those in which Y is
a hydrogen atom, and Z is a halogen atom ~especially, a chlorine or bromine
atom), arylsulfonyloxy group, lower alkylsulfonyloxy group or "leaving amino
group`' .
This reaction is performed by reacting the compounds (a) with (b),
if desired, in a solvent. Preferably, the reaction is carried out in the
presence of a base, as a dehydrohalogenating agent, such as sodium bicarbonate,
sodium carbonate, potassium carbonate or triethylamine. The compounds ~a)
and ~b) are used in stoichiometric c~nounts. However, generally, the compound
(b) is used in excess, and may be made serve also as the dehydrohalogenating
agent. The compound (b) may be used in the form of hydrate or acid addition
salt o~, for example, hydrochloric acid.
The reaction temperature is about 20 to 270C., preferably about
50 to 200C., especially preferably about 70 to 130C.
The solvent used in this reaction should be selected depending upon
the properties of the starting materials to be used. Examples of the solvent
are alcohols such as ethanol or propanol, aromatic hydrocarbons such as ben-
zene or toluene, halogenoalkanes such as dichloroethane or chloroform, ethers
such as tetrahydrofuran, dioxane or diphenyl ether, acetonitrile, dimethyl sul-
foxide, dimethylformamide, and water. They may be used either alone or in
a~l~ixture.
Wl~en Rl' of the compound [I-~ obtained by this reaction is an acyl
group or when R3 of this con~ound is an alkyl group having 1 to ~ carbon atoms,
the compound, with or withou~ isolation and purification, is subjected to a
hydrolysis reaction by an usual method to form a compound[~ in which Rl or R3
is a hydrogen atom. When R2 f the compound ~-~ is a group represented by
-~H-ÇH2 the compound, with or without isolation and purification, is subjected
t~ an elimination reaction by heating it to form a compound ~I~ in which R2
--5~
,
~7~79~3
is a vinyl group.
The hydrolysis reaction is carried out by contacting the compound
LI-~ (Rl' = acyl group or R3 = alkyl group) with water. Generally, the
reaction is carried out in ~he presenee o~ a catalyst such as an acid or base
in order to promote the reaction. Examples of the acid are inorganic acids
such as hydro~lloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid
or phosplloric acid, and organic acids such as acetic acid, oxalic acid or tol-
uenesulfonic acid. Examples of the base are alkali metal hydroxides such as
sodium hydroxide or barium hydroxide, alkali metal carbonates such as sodium
carbonate or potassium carbonate9 and sodi~n acetate.
l`his reaction can also be performed by directly hPating the material
ln the presence of the above acid, and then adding water. The solvent is
usually water, but depending upon the properties of the material, an inert
solvent such ~s ethanol, dioxane, ethylene glycol dimethyl ether, benzene or
acetic acid can also be used together with water. The reaction temperature
may be from room temperature to about 200C., preferably 70 to 120C.
The elimination reaction is carried out by simply heating the com-
pound ~ R2 = ~ ~ ~~ 2)~ or heating it in the presence of an appropriate
catalyst such as an acidic substance, an acid anhydride or a base. Examples
o the catalyst are ordinary acids such as hydrochloric acid, sulfuric acid,
polyphosphoric acid, phosphoric anhydride, formic acid, acetic acid, toluene-
sulfonic acid, or potassium bicarbonate, Lewis acids such as thionyl chloride,
phosphorus oxychloride, boron trifluoride or zinc chloride, alkali hydroxides
alkali carbonates, metal hydrides such as sodium hydride, alkali metal alkoxldes
such as sodium ethoxide, sodium methoxide or potassium tert.-butoxide, pyridine,
collidine, benzyltrimethylammonium hydroxide, acetic anhydrida, phthalic
anhydride, silver oxide, iodine, and tert.-butyl lithi~n.
The reaction temperature is ~usuaLly about 50 ~o about 270C. The
reaction proceeds without a solvent, but preferably, an inert solven* is usedO
Ex~mples of the s~lvent are wate~ alcohols, acetic acid, dimethylformamide,
dimethyi sulfoxide, ether, benzene, dioxane, tetrahydrofuran and pyridine.
In this reaction, Rl' and/or R3 of the compound [-A~ may be replaced
-6-
by a hydrogen atom depending upon the nature of Rl' and/or R3, and the react-
ion conditions applied.
The starting compound of the general formula (a) can be obtained as
follows: For example, by alkylating a known compound of the general formula
~ ~ COOR3
wherein X, R3 and A are the same as defined above, with CH2Z-CHY-
-halogen ~Z and Y are the same as defined above ), a starting compound (a)
in which R2 is -CH-IH2 group ~z and Y~are the same as defined above) is
ob~ained. By sù~jeZcting this compound to a similar elimination reaction to
lQ tllo abova, a starting compound (a) in which R2 is a vinyl group can be
obtaill~d .
The compounds prepared by the above procedure of the present invent-
ion can be isolated and purified by ordinary methods. The compounds rI~ can
be obtained in the free state or in the form of a salt depending upon the
selection of the starting compounds and the reaction conditions. Furthermore,
the compounds rI~ can be converted to their pharmaceutically acceptable acid
addition or alkali metal salts by treatment with acids or alkalies. ~ `
Th~ acids may be a variety of organic and inorganic acids, examples of which
are hydrochloric acid, acetic acid, lactic acid, succinic acid, oxalic acid
and methanesulfonic acid. The alkalies may be potassium and sodium hydroxides
and carbonates.
A clinical dosage of the compound LI] depends on the body weight,
age and administration route but it is generally in the range of 100 mg - 5
g/day, preferably of 20Q mg -3`g/day.
The compounds ~I~ may be used as medicinss, for example, in the
form of pharmaceutical preparations containing the compound in admixture with
an organic or inorganic, solid or liquid pharmaceutical adjuvant suitable for
peroral~ parsnteral9 enteral or local administration. Pharmaceutically accept-
able adjuvants are substances that do not react with the compounds, and in-
clude, for example3 water gelatin, lactose, starch~ cellulose, preerably
.- . .. . . , ,,........ ., ~, , .
~C~747~38
microcrystalline cellulose, carboxymethyl cellulose, methyl cellulose, sor-
bitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propy-
lene glycol, polyalkylene glycols, methylparaben and other known medicinal
adjuvants. The pharmaceutical preparations may be, for example, powder, tab-
lets ointments, suppositories, creams or capsules, or in liquid ~orm as
solutions, suspensions or emulsions. They may be s~erilized and/or contain
ass.istants such as preserving, stabilizing, we~ting or emulsifying agents,
salts for regulating the osmotic pressure or buffers. They may further con-
tain other therapeutically ~aluable substances. The preparations are ~ormed
by conventional methods.
The antibacterial activities of the ~ypical compounds of this in-
vent.ion are shown in Tables I-III together with some of the known compounds.
In the Tables II and III, the ED50 and LD50 values were calculated
in accordance with the Bcherns-Kaerber method. ~Arch. Exp. Path, Pharm.,
62, 480 ~193]~ .
The numbers of the tested compounds are those described in the
Example.
The known compounds, N~ and compound No. A are as follows:
NA: l-Ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid
(Nalidixic acid), which is disclos~d in ~nited States Patent
No. 3,149,104.
No.A: l-Ethyl-7-dimethylamino 4-oxo-1,8-naphthyridine-3-carboxylic
acid, which is disclosed in United States Patent No. 3,149,104.
~747~ill~il
1) In vitro antibacterial activity against 3 strains of bacteria
- ~ MIC ~u~7m ~ _
. Escherichia Shigella Pseudomonas
coli flexneri aeruginosa
No. Compound K-12 ~ .. Tsuchijima
1* ~ ~ ~ ~ 1 3 10
~ H=CH2 _
2 ~~A-CH2 1 1 3
_ _
~15~ ~
___ ,-
4 H3- ~ ~N ~ L 1 3 lO
5* _ Cl=CI~_ _ __ 1 3 .
D ~l~ ~
COOH I I >
. .~ .... .. . .......... .. ,.... , ... ..
NA O ____________ ~
~ I ~,COUI I 1 3 ~ 100
* Hydrochloride
- ,, -, . - ~ . .. .
79~3
The minimum inhibitory concentration (MIC) was determined by the
well known serial dilution method.
Experimental conditions:
Mcduum: nutrient broth, pH 7.0 ~5 m~/tube)
Inoculum: one drop of 1:105 dilution of an overnight broth culture
per tube
Incubation temperature and time: 37C, 48 hours
-9a-
~7~7g~
2) In vivo efficacy against systemic infection with Pseudomonas
aeruginosa and Salmonella typhimurium in mice.
Table II
Pseudomonas aeruginoSa**Salmonella typhimurium***
ED50 (mg/kg) ED50 ~mg/kg)
Compound ip ~ o
1* 3~9 86.6 19.3 22.9
2 17.8 50 3.4 8.8
3 19.3 66.7 - 11.5
4 38.6 192.0 < 12.5 ~ 50
5* 1.4 135.0 5.5 51.5
_____________________________________________________________ ______
No A > 100 > 200 > 50 > 100
NA > 100 ~ 200 18.9 18.9
*hydrochloride
**Experimental conditions:
Organism: Pseudomonas aeruginosa No. 12
Mice: male mice ~ddY-S) weighing 20 g approximately.
Infection: intraperitoneal infection with 50 ~o 100 LD50 ~about
5 x 103 cells/mouse) of a bacterial suspension in 4%
gastric mucin.
Medication: t~ice, about 5 minutes and 6 hours after infec~ion.
Drug: an alkaline solution ~pH 8-9) for intraperitoneal adminstra-
tion.
Observation: 7 days.
ip: intraperitoneal administration.
po: oral administration.
***Exper~mental conditions:
Organism Salmonella typhimurium S 9
Mice: male mice ~ddY-S) weighing 20 g approximately
Infection: Intraperitoneal infection with 50 to 100 LD50 ~abou~ 105
cells/mouse) of a bacterial suspension in a nutrient
broth.
-10- ,
.. .
~7479~3
Medication: twice a day for 4 days from the day of infection.
Drug: an alkaline solution ~ph 8-9) for intraperitoneal
administration and suspension in 0.2% carboxymethyl
cellulose for oral administration.
Observation: 14 days.
ip: intraperitoneal administration.
po: oral administration.
3) Acute toxicity in mice
Table III
**LDso (mg/kg)
Compound Po
l* >2000
2 >2000
3 >2000
5* >2000
_____________________.____________________
NA 1516
*hydrochloride
**Experimental conditions:
' Mice: female mice ~ddY-S~ weighing 20 g approximately.
Drug: Suspension in 0.2% carboxymethyl cellulose for oral
administration.
The follouing Examples further illustrate the present invention.
Example 1
1~4-Dihydro-4-oxo-7-~l-pipera2inyl)-l vinyl-1~8-naphthyridine-3
carboxylic àcid ~ydrochloride. CCompound_l)
.
To a solution of 2.5 g of 7-chloro-1,4-dihydro-4-oxo-1-vinyl-1,
8-naphthyridine-3-carboxylic acid in 80 m~ of ethanol was added 5.8 g of piper-
azine hexahydrate. The mixture was heated to reflux for 2 hours and concent-
rated to dryness under reduced pressure. To the resulting resid~e~ was added
lO m~ of lN-HC~. The crystal that separa~ed on cooling was collec~ed and
dissolved in 40 ml of hot water. The solution with 0.5 g of charcoal was
warmed for several minutes and filtered. The filtrate, aftGr addition of
7~7~8
6 m( of lN-HC-(, was cooled to give 2.7 g of the product as colorless neQdles,
m.p. 285-287C. ~decomp.)
Example 2
1,4-Dihydro-7-~4-methyl-1-piperazinyl)-4~oxo-1-vinylquinoline-3-
carboxylic acid (Compound ?) and its hydrochloride. (Comp~und 10)
A mixture containing 5.0 g of 7-chloro-1,4-dihydro-4-oxo-1-vinyl-
~uinoline-3-carboxylic acid, 75 m~ of dimethyl sulfoxide and 15 ml of 1-
methylpiperazine was heated to 110C for 3 hours with stirring and then con-
centrated to dryness under reduced pressure~ The residue was triturated with
methanol to give crystals, which were collected and recrys~allized from dime-
thylforma~ide--water ~1:1) to afford 2.85 g of the hydrochloride, m.p ~ 300C~
The hydrochloride ~1:5 g~ was dissolved in 200 m~ of hot water
and ncutralized with lN-NaOH solution. The crystals that separated on cool-
ing were collected and recrystallized from acetonitrile to give 1.2 g~of the
compound 2 as slightly hygroscopic pale yellow needles, m.p. 224-225C.
Example 3
7-~4-Ethyl-l-piperazinyl)-1,4-dihydro-4-:oxo-1-vinylquinoline-3-
car~ox~lic acid, m~p., 211-213CJ CCompound 3) was prepared in the same manner
as in Example 2 using l-ethyl-piperazine in place of l-methylpip~razine.
ExamPle 4
1~4-Dihydro-7-~4-methyl-1-piperazinyl~4-oxo-1-vinyl~1,8-naphthyridine
-3-carboxylic acid ~Compound 4).
To a solution of ~1.4 g of 7-chloro-1,4-dihydro-4-oxo-1-vinyl-1>
8-napllthyridine-3-carboxylic acid in 50 m~ of ethanol was added 1.5 g of 1-
methylpiperazine. The mixture was heated to reflux for 1.5 hour and concent-
rated to dryness under reduced pressure. The resulting solid was was~hed with
cold ethanol and recrystallized from ethanol to give 1.2 ~ of the product
as pale yellow needles, m. p. 238-239C.
Example 5
1,4-Dihydro-4-oxo-7-~1-piperazinyl)-1-vinylqui.noline-3-carboxylic
acid hydrochloride, m.p. 283-287C, ~decomp.) ~Compound 5) was prepared in the
same manner as in Example 2 using piperazine in place of l-methylpiperazine.
-12-
' , ' ' .
~i~7~791~
Example 6
1,4-Dihydro-4-oxo-7-~l-piper-aziny~ viny~ 8-naphthyridine-3
carboxylic acid hydrochloride ~Compound 1~.
To a solution of 4.0 g ~f ethy. 7-chloro~ 2-chloroethyl)-1,4-
~ihydro-4-oxo-1,8-naphthyridine-3-carboxylate in 40 m~ of ethanol was added
6.0 g of l-ethoxycarbonylpipera~ine. The mixture was heated to reflux for 1.5
hour and concentrated to dryness ~mder reduced pressure. To the residue were
added 50 m~ of ethanol and 50 m~of 10% XO~I solution, and the mixture was heated
again to reflux for 1.5 hour. After removal of the e~hanol by distillation,
the resulting aqueous solution was acidified with concentrated hydrochloric
acid to give 2.9 g of the product, m.p. 285-287C (decomp.).
r~ lple 7
1,4-Dihydro-7-t4-methyl-1-piperazinyl)-4-oxo-1-vinyl-1,8-naphthy-
ridine-3-carboxylic acid ~Compound 4).
To a solution of 2.2 g of ethyl 7-~chloro-1-~2-chloroethyl)-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate in 30 m~ of e~hanol was added
2.0 g of l-methylpiperazine. The mixture was heated to reflux for 1.5 hours,
then concentrated to dryness under reduced pressure and the residue was ex-
tracted with chloroform. The extract NaS dried over anhydrous sodium sulfa~e
~md the chloroform was evaporated to leave 3.3 g of crude crystals~ which
were dissolved in a mixture of 30 m~ of 10% NaOH and 30 m~ of ethanol. The
resulting mixture was heated to reflux fo~ 2 hours. After removal of the
ethanol, the mixture was acidified with acetic acid, then neutraliæed with 7%
NaHC03 solution and extracted with chloroform. The chloroform was evaporated
to leave the crystalline residue, which was recrystallized from ethanol to
give 1.22 g of the product as pale yellow needles, m.p. 238-239G.
Example 8
Ethyl 1-~2-chloroethyl)-7-~4-ethoxycarbonyl-1-piPerazinyl)-
1,4-dihydro-4-oxo-1;8-naphthyridine-3-carboxylate ~Com~eound 7); Intermediate.
To a solution of 16.5 g of ethyl 7-chloro-1-~2-chloroethyl)~
4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate in 170 m~ of ethanol was added
24.0 g of l-ethoxycarbonyl-piperazine and the mixture was heated to reflux for
-13-
` ~7~9~
1.5 hour. After concentration to dryness under reduced pressure the residue
was extracted with chloroform. The extract was dried over anhydrous sodium
sulfate, and concentrated to give a crude product which was recrystalli~ed from
ethyl acetate to give 20.0 g of the product as colorless needles, m.p. 174-
175C.
I`x~mylc 9
Ethyl 1-~2-chloro thyl)-1,4-dihydro-7-~4-methyl-1-piperazinyl)-4-
oxo-1,8-naphthyridine-3-carbo~ylate ~Com~ound 8); Intermediate.
A mixture containing 2.2 g of ethyl 7-chloro-1-~2-chloroethyl)-1,
4-dihydro-4-oxo-1~8-naphthyridine-3-carboxylate, 2.0 g of l-methylpiperazine
~d 30 m~ of ethanol was heated to reflux for 1.5 hour. After concentration
to ~ryness under reduced pressure the residue was extracted with chloroform. -~
Thc extract ~as dried and distilled to remove the chloroform ~o give crude
crystals, which were recrystallized from a mixture o n-hexane and acetone
to yield 2.1 g of the product as pale yellow needles, m.p. 125-127C.
Example 10
1,4-Dihydro-4-oxo-7-~l~pipera2inyl)-l-vinyl-1,8-naphthyridine-3-
carboxylic acid hydrochloride. ~Compound 1).
~ Ethyl 1-~2-chloroethyl~-1,4-dihydro-7-C4-ethoxycarbonyl-1-pipera-
zinyl)~4-oxo-1,8-n~phthy~dine-3-carboxylate (3.36 g) was dissolved in 55 m~
of ethanol by heating to reflux. To the solution was added 55 mY of 10~ NaOH
solution. The mixture was heated on a steam bath for 1 hour, concentrated
to about 40 m~, heated again for 2.5 hours, then acidified with IN-HC~, and
cooled to give a precipitate which was collected and dissolved in 50 m~ of
hot water. The solution was treated with charcoal and filtered. The filtrate,
after addition of 5 m~ of IN-MC,~, was allowed to stand at room ~emperature
to give 2.19 g of product as colorless needles, m.p 285-2S7C ~decomp.).
~B~ Ethyl 7-C4-acetyl-1-piperazinyl)-1-~2-bromoethyl)-1,4-dihydro-4-
oxo-1,8-naphthyridine-3-carboxylate C2.25 g~ was worked up as in Example 10
CA) to give 1.36 g of the product, m.p. 285-287C. (decomp.).
Exam~e_ll
1,4-Dihydro-4-oxo-7-Cl-p perazinyl~ inyl-1,8-naphthy~id~ne-3-
-1~-
carboxylic acid hydrochloride ~Compound l)_
To a mixture of 5 m~ of ethanol and 10% KOH was added 1.0 g of
ethyl l-(2-chloroethyl)-1,4-dillydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine
-3-carboxylate. ll~e mixture was heated to reflux for 1 hour and, after
concentratioll to llalf of the original volume, heated for an additional 45
minutes. Tlle reaction mixture was acidified with acetic acid and filtered.
'll~c 11trate was acidified witl- 10% HC~ and allowed to stand at room
tem~erature overnight to give a precipitate, which was collected and
waslled with ethanol to give 0.76 g of the product as colorless needles
m.p. 285-287C ~decomp.~.
Exanlplc 1
~ Dihydro-4-oxo-7-~4=methyl-l-piperazinyl)-l-vinyl-l~8-naph
tl~yridino-3-carbo~ylic acid ~Compound 4)
To 0.80 g of ethyl 1-(2-chloroethyl)- 1,4 -dihydro-7-(4-
methyl-l-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylate was added 10 mQ
of a 10% aqueous solution of sodium hydroxide. The mixture was heated
at 90-95C for 30 minutes and neutralized with acetic acid while cooling.
The resulting mixture was extracted with chloroform. The extract was washed
with water and concentrated to leave a yellow solid which was collected
alld recrystallized from ethanol to give 0.56 g of the product as pale yellow
cedles, m.p. 238-239C.
Example 13
1,4-Dihydro-4-oxo-7-(l-piperazinyl~-l-vinyl-1~8~naphthyr-dine-3
carboxylic acid (Co_pound 9) and its methanesulfonate (C_mpound ~
A suspension of 2.0 g of ethyl, 1,4-dihydro-4-oxo-7-(1-piperazinyl)
-I-vinyl-1,8-naphthyridine-3-carboxylate in 20 m~ of 5% NaOH solution was
heated to 85C for 15 minutes. The clear solution was acidified with ace~ic
acid and then neutralized wi~h 7% NallC03 solu-tion. The crystals that se-
parated on cooling were collected by filtration and recrystallized from ethanol
30 to give 1.68 g of the product (compound 9) as pale yellow needles~ m.p.
261-263C (decomp.).
To a suspension of 1.0 g of the compound 9 in 15 m~ of water were
- 15 -
~:
,- . . - , ' ~::
7~
added 0.5 m-(of methanesulfonic acid and then 100 m4 of ethanol. The yellow
solution was cooled to 0 to give a precipita~e, which was collected and
washed with ethanol. The precipitate was dissolved in 10 m~ of water and
filtered to remove insoluble materials. To the ~iltrate was added ethanol
to form 1.1 g of the methanesulfonate as yellow needles, m.p. 299-301C
~decomp ?
Iixample 14
1,4-Dihydro-7-~4-methyl-1-piperazinyl~-4-oxo-l-vinylquinoline
-3-carboxylic acid (Com~ound 2~
A suspension of 2.5 g of ethyl 1,4-dihydro-7-(4-methyl-1-piperazinyl)
-4-oxo-1-vinylquinoline-3-carboxylate in 20 m~ of 5% NaOH solution was heated
to 85C for 30 minutes. The clear solution was acidified with acetic acid
atl~l subseqllently neutralized with 7% Na}lC03 solution to give a precipitateJ
which was collected by filtration and recrystallized from acetonitrile to
yield 1.83 g of the product as pale yellow needles, m.p. 224-2~5C.
Example 15
1,4-Dihydro-7-~4-methyl-1-piperazinyl)-4-oxo-1-vinyl-1,8-naphthyri-
dine-3-carboxylic acidl m.p. 238-239C, ~Compound 4) ~as prepared in the
same manner as in Example 13 using ethyl 1,4-dihydro-7-~4-methyl-1-pipera~
2n zinyl)-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate as a starting material.
F.xample 16
7-~4-Ethyl-l-piperazinyl)-1,4-dihytrG-4-oxo-1-vinylquinoline-3-
carboxylic acid, m.p. 211-213C, ~Compound 3) was prepared in the same manner
as in Example 14 using ethyl 7-(4-ethyl-1-piperazinyl~-1,4-dihydro-4-oxo-
l-vinylquinoline-3-carboxyla~e as a starting material.
Example 17
1,4-Dihydro-4-oxo-?-(1-~iperazinyl)-1-vinyl-1 8-naphthyridin~
-3-carboxylic acid ~Compound 9) and its hydrochloride ~Compound 1)
A mixture containing 5.0 g of ethyl 7-~4-ethoxycarbonyl-1-pipera-
zinyl)-1~4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxyla~e, 50 m-~ of
ethanol and 50 m~
-16-
.. . . . .
7~
of 10% KOH was heated to reflux for 1.5 hours and, after removal of the
ethanol by distillation, heated for an additional 30 minutes. The mixture
~as acidifed with acetic acid and filtered to remove insoluble materials.
The filtrate was acidified with concentrated HC~ to give a
precipitate, wllicll was collected M d washed with e~hc~nol to give 3.8 g of
tl~e pro~uct as hydrochloride. m.p. 285-287C ~decomp.).
A suspension of the hydrochloride (3.0 g) in 30 m~ of water was
made alkaline ~Yith 10% KOH and filtered. The filtrate was adjusted to
pH 7-8 with acetic acid to glve a precipitate, which was collected and re-
ln crystallized from eth M ol to give 3.2 g of the product as pale yellow needles,
m.p. 261-263C (decomp.).
`.x~lmplc 18
1,4-Dillydro-4-oxo-7-(1-piperazinyl)-1-vinylquinoline-3- carboxy-
lic acid hydrocllloride ~Compound 5) and its methanesulfonate ~Compound 11).
A mixture containing 5.0 g of 1,4-dihydro-7-~4-ethoxycarbonyl-1-
piperazinyl)-4-oxo-1-vinylquinoline-3-carboxylic acid, 80 m~ of 10% NaOH
solution M d 35 m~ of ethanol was heated to reflux for 1.5 hours. After
evaporation of ethanol under reduced pressure the mixture was treated with
charcoal and filtered. The filtrate was adjusted to pH 1 with hydrochloric
~cid to give a precipitate, which was collected and recrystallized from
50% eth M ol to yield 3.95 g of the hydrochloride as yellow crystals, m.p.
283-287C ~decomp~).
To a suspension of 2.3 g of the hydrochloride in 10 m~ of water
was added 6 m~ of methanesulfonic acid. The resulting solution was filtered
~nd 250 m~ of eth M ol was added to the filtrate to give a precipitate,
which was collected and washed with ethanol. The precipitate was dissol~ed
in 15 m~ of water. Ethanol was added to the solution to form 1.7 g of ~he
methanesulfonate as yellow needles, m.p. 305C (decomp.).
Example 19
1,4-Dihydro-4-oxo-7-~1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-
carboxylic acid hydrochloride ~Compou~d 1).
Ethyl 7-C4-acetyl-1-pipera~inyl~-1,4-;dihydro-4-oxo-1-vinyl-1,
-17-
: : . . , . , :
:~97~7~3
8-naphthyridine-3-carboxylate ~1.6 g) ~as dissolved in 30 mi of 10% NaO~I
solution by heating at 90C for 1 hour. The solution was filtered to
remove insolublf~ materials and the filtrate was acidified with concentrated
hydrochloric acid to give 1.0 g of the product, m.p. 285-287C ~decomp.).
Example 20
1,4-Dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine
-3-carboxylic acid hydrochloride ~Col~o~d 1).
A suspension of 3.0 g of ethyl 1,4-dihydro-4-oxo-7-~4-trifluoro-
acetyl-l-piperazinyl)-l-vinyl-1,8-naph~hyridine-3-carboxylate in 20 m-
~
10 of 70% K2C03 solution was heated to 80C for 30 minutes. The solution
was acidified with concentra~ed hydrochloric acid to give 2.2 g of the
pro;luct, m.p. 285-287C ~decomp.).
Ex~lmpl~ 21
1,4-Dihydro-4-oxo-7-~1-piperazinyl~-1-vinylquinoline-3-
carboxylic acid hydrochloride ~Compound 5~.
A mixture containing 3.0 g of 7-C4-formyl-1-piperazinyl)-1,4-
dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid and 40 m~ of 10% aqueous
hydrochloric acid was heated to 90C for 1 hour and then concentrated to
dryness under reduced pressure. Addition of ethanol to the residue
20 gave a solid, I~hich was collected and recryst.allized from 50% e~hanol to
yield 2.6 g of the product, m.p. 283-287C Cdecomp.).
The following Examples 22 *o 25 illustrate the preparation of
.intermediates.
~ .
Ethyl 7-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-13,8-naphthri-
dine-3- arboxylate
To suspension of 20.2 g of ethyl 7-chloro-1,4-dihydro-'1-oxo-
1,8-naphthyridine-3-carboxylate in 500 m~ of dimethylformamide was added
a solution of 16.5 g of pot:assium carbonate in 25 me of water. To the
mixture kept at 75C was added 57.5 g of 1-bromo-2-chloroethane with stir-
ring, then the resulting mixture was maintained at 75C for 3.5 hours and
filtered to remove insoluble materials. Ille filtrate was concentrated to
-18-
dryness under reduced pressure. The residue was extracted with chloroform.
The extract was washed with water and dried. The chloroform was evaporated
to leave crystals, which were recrystalli~ed from ether to give 22 g of the
product as colorless needles, m.p. 14S-149C.
Bxalllple 23
7-Cllloro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic
acid
A mixture containing 5.0 g of ethyl 7-chloro-1-(2-chloroethyl)
-1,4-dihydro-4-oxo-1,8-naph-thyridine-3-carboxylate, 4.3 g of sodium
methoxide and 30 miof methanol was heated to reflux for 1 hour, and con-
centrated to about 10 m~and water (20 m~) was added. The resulting solu-
tion was heate~ again to 90C for 5 hours, cooled, and acidified ~ith acetic
~cid to give a precipitate, which was collected ~Id washed with methanol.
Ti~e precipitate l~as added to 20 m4 of phosphorus oxychloride and the mix-
ture l~as heated to 90C for 45 minutes. After removal of an excess of
phosphorlls oxychloride by distillation under reduced pressure, the residue
t~as poured into ice-water. The mixture was extracted with chloroform.
The extract was washed with water, dried, and concentrated to dryness to
give a crude solid, which was recrystalli~ed from ethanol to give
2~ 2.9 g of the product, m.p. 235-238C.
~xample 24
Ethyl 7-chloro-l-(2-chloroe-t-hyl)-l~z~-dihydro-4-oxoquinoline-3
carboxylate.
To a mixture containing 23.4 g of e-thyl 7-chloro-1,4-dihydro-4-
oxoquinoline-3-carboxylate and 6.9 g of 65% sodium hydride was added 90 g
of 2-tosyloxyethyl chloride. The resulting mixture was heated to 100C for
4 hours. After concentration to dryness, the residue was extracted with
chloroform. The extract was washed with water and dried over ~nhydrous sod-
ium sulfate. The solvent was removed by the distillation to leave a solid
~0 which was recrystallized from ethanol to give the product, m.p. 207.5-209.5C.
Example 25
7-Chloro-1~4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid.
-19--
. - - ~ , . . : . . :
.
~7~7~3
To 15 g of ethyl 7-chloro~ 2-chloroe~hyl)-lj4-dihydro-4-oxo-
quinoline-3-carboxylate were added 240 mQ of 10% aqueous solution of sodium
hydroxide and 100 m~ of ethanol. The resulting mixture was refluxed for
1 hour and filtered with decolorizing charcoal. The pH of the filtrate
W;IS adjusted to 1 witll hydrochloric acid and it was chilled to give a
prec;pitate ~Y}IiC}l was collected, washed with water, and recrystallized from
dimethylfo~namide to yield the product, m.p. 269-299.5C.
Ex~lple A
1,4-Dihydro-7-(1-piperazinyl)-4-oxo-
1-vinyl-1,8-naphthyridine-3-carboxylic
acid llydrochloride .............................. 250 g
Starch ~.~.~.. ~............ ~.... ~... ~..... O....... ~ 54 g
Calcium carboxymethyl cellulose ................... 40 g
Microcrystalline cellulose ........................ 50 g
Magnesium stearate ................................ 6 g
The above components were blended, granulated and made into
tablets in a manner known per se. Thus, 1000 tablets each weighing 400
mg were formed.
Example B
1,4-Dihydro-7-C4-methyl-1-piperazinyl~-
4-oxo-1-vinylquinoline-3-carboxylic
acid ............................................. 250 g
Starch ............................................ 50 g
Lactose ........................................... 35 g
Talc .............................................. 15 g
The above components were blended and granulated and ~illed into
1,000 capsules in accordance with the conventional methods.
Example C
1,4-Dihydro-7-~4-ethyl l-piperazinyl)-
4-oxo-1-vinylquinoline-3-carboxylic
acid .............................................. 5 g
Sorbitol .......................................... 30 g
-2~-
~8
Sugar ..................... ~ 40 g
Methylparaben ............. .......................Smal l amount
Sodium carboxymethyl cellulose .................... Small amount
Flavour ........................................... Small amount
l~ater to make .................................... 100 m~
-21 .
. .
; -
