Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1325gO6
-- 2
This is a divisional application of copending
application Serial No. 473,501, filed February 4, 1985.
B~CKGROUND OF THE INVENTION
The Journal of Medicinal Chemistry, 23, 1358
(1980) discloses certain substituted quinoline-3-
carboxylic acids having the structural formula:
C~ ~C02H
', 10
C2H5
See also U.S. Patent 4,146,719.
European Patent Publication 78362 describes 1-
cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-
quinoline-3-carboxylic acids.
Certain 7-heterocyclic substituted 1,8-
naphthyridines are disclosed in Eur. J. Mcd. Chcm.-Chimica
Therapeutica, 29, 27 (1977).
The above references teach that these compounds
possess antibacterial activity.
SUMMARY OF THE INVENTION
.
The present invention relates to a compound of
the formula:
~ . O
F ~ CO2R
Z ~ X ~ N
I
LCD:sg
132~806
DRT-l -3-
wherein Z is a group of the formula
~ (C~2)n\
R2-N N-
CH2C~2 where n is 2-3 and ~2`is hydrogen,
~i lower alkyl or acetyl,
~; , ~
y N-
: `
where Y is O or S, or
(CH2) , N-
~ R3
where n' is 4-6 and R3 is hydrogen or
~, .
hydroxyl; X is CF, or N; Rl is hydrogen or lower
alkyl, or a pharmaceutically acceptable acid-addition
or base salt thereof.
The present invention includes, as novel inter-
-1 10 mediates, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-
difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxy-
; lic acid, and l-cyclopropyl-6-fluoro-7-chloro-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as
: 15 well as lower alkyl esters or salts thereof.
The invention also includes a pharmaceutical
composition which comprises an antibacterially
effective amount of a compound having structural
formula I and the pharmaceutically acceptable acid-
addition or base salts thereof in combination with apharmaceutically acceptable carrier.
The invention further includes a method for
treating bacterial infections in a mammal which
comprises administering an antibacterially effective
amount of the above defined pha.maceutical composition
to a ~ammal in need ~hereof.
132~8~6
DRT-l -4-
DESCRIPTION OF T~ PREFERRED E~BODIME~TS
. The compounds of the invention having the
structural formula I may be readily prepared by
treating a corresponding compound having the struc-
-. 5 tural formula II
:-- O
F~ C2Rl
L X NJ
.~`~
.,.
:,';
wherein Rl and X are as defined above and L is a
leaving group, preferably fluorine or chlorine with an
.; amine corresponding to the group Z.
If the group Z contains an alkylamine
` substituent, said substituent may, if desired, be
`i protected by a group which renders it substantially
inert to the reaction conditions. Thus, for example,
protecting groups such as the following may be
utilized:
carboxylic acyl groups such as formyl, acetyl,
trifluoroacetyl;
- - aLkoxycarbonyl sroups such as ethoxycarbonyl,
t-butoxycarbonyl, B~B~B-trlchloroethoxycarbon
20 g-iodoethoxycarbonyl;
aryloxycarbonyl groups such as benzyloxycarbonyl,
~-methoxybenzyloxycarbonyl, phenoxycarbonyl;
silyl groups such trimethylsilyl; and groups such as
trityl, tetrahydropyranyl, vinyloxycarbonyl,
25 o-nitrophenylsulfenyl, diphenylphosphinyl,
- P-toluenesulfonyl, and benzyl, may all be utilized.
The protecting group may be removed, after the
- 132~806
DRT-l ~5~
reaction if desired, by procedures known to those
skilled in the art. For example, the ethoxycarbonyl
- group may be removed by acid or base hydrolysis ~nd
the trityl group may be removed by hydrogenolysis.
m e reaction between the compound of structural
formula II and a suitably protected amine, if
necessary, of group Z may be performed with or without
a solvent, preferably at elevated temperature for a
sufficient time so that the reaction is substantially
complete. The reaction is preferably carried out in
~. .
~' the presence of an acid acceptor such as an alkali
metal or alkaline earth metal carbonate or
bicarbonate, a tertiary amine such as triethylamine,
pyridine, or picoline. Alternat-vely an excess of the
amine of the group Z may be utilized as the acid
~yi~
acceptor.
Convenient solvents for this reaction are non-
reactive solvents such as acetonitrile, tetra~
,~j hydrofuran, ethanol, chloroform, dimethylsulfoxide,
- 20 dimethylformamide, pyridine, picoline-, water, and the
like. Solvent mixtures may also be utilized.
~ Convenient reaction temperatures are in the range
i~ of from about 20 to about 150C; higher temperatures
- usually require shorter reaction times.
m e removal of the protecting group may be
accomplished either before or after isolating the
' product.
Alternatively, the compound of formula I wherein
is N, R1 is hydrogen and Z is piperazine may be
prepared by removal of its precursor carboethoxy-
piper~zine derivative and/or ester thereof. The
piperazine may then be alkylated by known means to
form the lower alkyl piperazine derivatives of
formula I.
132~806
DR.-l -6-
- The above compound, namely l-cyclopropyl-6-
.j fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-
naphthyridine-3-carboxylic acid, its 4-lower
x alkylpiperazinyl, or its 4-carboethoxypiperazinyl
derivative and/or esters thereof are also useful as
intermediates to prepare a compound of formula II
wherein X is N and L is fluorine or chlorine. The
piperazine groups may be cleaved and displaced by
- - a hydroxyl group by treating with a mixture of nitric
and sulfuric acids, which hydroxyl compound is further
~ ~ displaced by group L, fluorine, or chlorine. For
':~ example, treatment of the hydroxyl compound with
phosphorus-oxychloride under known conditions affords
j the chloro compound of formula II.
h 15 The starting material l-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-[1-(4-carboethoxy)piperazinyl]1,8-
~1 naphthyridine-3-carboxylic acid and its ethyl ester
-~ may be prepared as described in the Preparative
Examples.
;~ 20 m e starting compound of formula II, wherein X is
rc CF and L is F, namely l-cyclopropyl-6,7,8-trifluoro-
;- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid may be
prepared by a series of reactions starting from
~- 2,3,4,5-tetrafluorobenzoic acid and detailed also in
the Preparative Examples. m e acid chloride of
2,3,4,5-tetrafluorobenzoic acid is reacted with
r dilithium salt of malonic acid half ethyl ester to
afford after hydrolysis 2,3,4,5-tetrafluoro-B-oxo-
benzenepropanoic acid, ethyl ester. This colnpound is,
in turn, treated with triethylorthoformate and acetic
anhydride, cyclopropylamine, potassium t-butoxide,
and aqueous hydrochloric acid to give the desi-ed
intermediate.
The amines corresponding to group Z are known and
either commercially available or capable of being
prepared by methods known in the art.
1~25~6
DRT-l ~7~
The compounds of the invention display anti-
bacterial activity when tested by tne microtitration
dilution method ~s described in ~eifetz, et al,
`Antimicr. Agents & Chemoth., 6, 124 (1974), which is
S incorporated herein by reference.
` By use of the above referenced method, the
followed minimum inhibitory concentration values ~MICs
in ~g/ml~ were obtained for representative compounds
of the invention.
~Y
.. . .
.
,~;
~;''
, . .
-.', l
, .
1325806
DRT-l -a-
~ u~ ~,
~ ~ ~ O ~ ~ O O
o
o ~ o o o O O O O O O O
__ _________________~___
r
3
~x
~ c~ o o o o o o o o o o
rJo `~ 1 vl ~1
__ _____________________
O ~ ~ ,~
E~ _i O
O O O O O O O O ~D
E x ~ I v I
E~ S r_ _____________________
;l C ~ _1/ ~ I N N ~ ~ ~ ~ ~
'6 0 ~ O O O ' O O _l O
_ E x ~ I
_1 O
E~ ~ ~ rj
rJ o ~ _--____________________--_
~: V 1:~ _~
~ _ ~ O~ I r,r~
)--I ~ _ r N ~ O
~ ~ D I I Nt` XU~ N
Z S t ~ ~ ~ )-~ ~ 1 ~7 1
~: ~ ~ ~ J s~ J
o :~: ¢ ~ ~ (a rn
~a~
E~ ~ ~ ~ ~ ~ O ~ O
~ E ro ''5 O ~ e
~ , e u ~ s, u ~ ~
C rn ~ ~ ~ O
Z ,~ .,~ O ~ ~ C
C
~a u o o a~
:r u c
~ S.~ ~ ~ u U ~ :~
O a~ R t) U V U U
_ ~ ~ ~ O O ~ U U
u S ~ C u U O O O
~ u _~ o o O U v r~
~ ~ cJ Ul E _I _1 0 0 0
~ O
s~ ~ r ,C ~ Q ~ I
S ~ V
U ~ O
C U~--I S- ulJJ ~.1 ~I LJ .U I
rnrn rnU~
132~8~6
DRT-l -9-
The compounds of the invention are capable of
forming both pharmaceutically acceptable acid addition
and/or base salts. Base salts are formed with metals
or amines, such as al~ali and alkaline earth metals or
organic amines. Examples of metals used as cations
are sodium, potassium, magnesium, calcium, and the
like. Examples of suitable amines are N,N'-
dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, N-methylglucamine,
and procaine.
Pharmaceutically acceptable acid addition salts
are formed with organic and inorganic acids.
Examples of suitable acids for salt formation are
hydrochloric, sulfuric, phosphoric, acetic, CitLic,
oxalic, malonic, salicylic, malic, gluconic, fumaric,
succinic, ascorbic, maleic, methanesulfonic, and the
li~e. The salts are prepared by contacting the free
base form with a sufficient amount of the desired acid
to produce either a mono or di, etc salt in the
conventional manner. The free base forms may be
regenerated by treating the salt form with a base.
For example, dilute solutions of aqueous base may be
utilized. Dilute aqueous sodium hydroxide, potassium
carbonate, ammonia, and sodium bicarbonate solutions
are suitable for this purpose. The free base forms
~ differ from their respective salt forms somewhat in
certain physical properties such as solubility in
polar solvents, but the salts are otherwise equivalent
to their respective free base forms for purposes of
the invention. Use of excess base where Rl is
hydrogen gives the corresponding basic salt.
The compounds of the invention can exist in un-
solvated as well as solvated forms, including hydrated
forms. In general, the solvated forms, including
hydrated forms and the l ~e are equivalent to the
unsolvated forms for purposes of the invention.
132~
DRT-l -10-
The term "lower alXyl~ contemplates an alkyl group
of both straight and branched carbon chains of from
one to about three carbon atoms except when
specifically stated o be greater tnan three car~on
i 5 atoms. Representative of such groups are methyl,
ethyl, propyl, isopropyl, and the like.
Certain compounds of the invention may exist in
optically active forms. The pure D isomer, pure L
isomer as well as mixtures thereof; including the
racemic mixtures, are contemplated by the invention.
Additional assymmetric carbon atoms may be present in
a substituent such as an alkyl group. All such
isomers as well as mixtures thereof are intended to be
included in the invention.
A preferred class of compounds of the present
invention are those of formula I where Z is
l-piperazinyl or 4-lower alkyl-l-piperazinyl.
Par.icularly preferred are those compounds of
formula I wherein Z is l-piperazinyl or 4-methyl-1-
piperazinyl and their pharmaceutically acceptable
salts.
The compounds of the invention can be prepared
and administered in a wide variety of oral and
parenteral dosage forms. It will be obvious to those
skilled in the art that the following dosage forms may
comprise as the active component, either a compound of
formula I or a correspondin~ phar~aceutically
acceptable salt of a compound of formula I.
For preparing pharmaceutical composi.ions from
the compounds described by this invention, inert,
pharmaceutically acceptable carriers can be either
solid or liquid. Solid form preparations include
powders, tablets, dispersable granules, capsules,
cachets, and suppositories. A solid carrier can be
one or more substances which may also act as diluents,
flavoring agents, ~olubilizers, lubricants, suspending
132~80~
DRT-l -11-
agents, binders, or tablets disintegrating agents; it
can also be an encapsulating material. In powders,
the carrier is a finely divided solid which is in
admixture with ihe finely divided active compound. In
., 5 the tablet the active compound is mixed with carrier
` havinq the necessary binding properties in suitable
proportions and compacted in the shape and size
desired. The powders and tablets preferably contain
from 5 or 10 to about 70 percent of the active -
ingredient. Suitable solid carriers are magnesium
carbonate, magnesium sterate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methyl
cellulose, sodium carboxymethyl cellulose, a low
melting wax, cocoa butter, and the like. The term
i 15 ~preparationn is intended to include the formulation
of the active compound with encapsulating material as
carrier providing a capsule in which the active com-
ponent (with or without other carriers) is surroun2ed
by carrier, which is thus in association with it.
Similarly, cachets are included. Tablets, powders,
cachets, and capsules can be used as solid dosage
forms suitable for oral administration.
Liquid form preparations include solutions
suspensions and emulsions. As an example may be
~5 mentioned water or water-propylene glycol solutions
for parenteral injection. Such solutions are prepared
so as to be acceptable to biological systems
(isotonicity, pH, etc). Liquid preparations can also
be formulated in solution in aqueous polyethylene
glycol solution. Aqueous solutions suitable for oral
use can be prepared by dissolving the active component
in water and adding suitable colorants, flavors,
stabilizing, and thickening agents as desired.
Aqueous suspension suitable for oral use can be made
by dispersing the finely divided active component in
water with viscous material, i.e., natural or
1325806
DRT-l -l2-
synthetic gums, resins, methyl cellulose, sodium
carboxymethyl cellulose, and cther well-known
suspending agents.
Preferably, the pharmaceutical preparation is in
unit dosage form. In such form, the preparation is
subdivided into unit doses containing appropriate
quantites of the active component. The unit dosage
form can be a packaged preparation, the package con-
taining discrete quantities of preparation, for
example, packeted tablets, capsules, and powders in
vials or ampoules. The unit dosage form can also be a
capsule, cachet, or tablet itself or it can be the
appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of
I lS preparation may be varied or adjusted from 1 mg to
100 mg according to the particular application and the
potency of the active ingredient.
! In therapeutic use as agents for treating bacter-
ial infections the compounds utilized in the pharma-
! 20 ceutical method of this invention are administered at
! the initial dosage of about 3 mg to about 40 mg per
! kilogram daily. A daily dose range of about 6 mg to
about 14 mg per kilogram is preferred. The dosages,
however, may be varied depending upon the requirements
of the patient, the severity of the condition being
treated, and the compound being employed.
Determination of the proper dosage for a particular
situation is within the skill of the art. Generally,
treatment is initiated with smaller dosages which are
less than the optimum dose of the compound.
Thereafter, the dosage is increased by small
i increments until the optimum effect under the
circumstances is reached. For convenience, the total
daily dosage may be divided and administered ir.
portions during the day if desired.
132~0~
DRT-l -13-
The following nonlimiting examples illustrate the
; inventors' preferred methods for preparing the
compounds of the invention.
EXAMPLE 1
5. Route A
l-Cycloprop~1-6-fluoro-1,4-dihydro-4-oxo-7-
(l-piperazinyl)-1,8-naphthyridine-3-carboxYlic acid.
A suspension of 0.7 g (1.6 mmole) of ethyl
l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-
(ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-
3-carboxylate (see Example H), 6 ml of 10~ aqueous
sodium hydroxide and 2 ml of ethanol was refluxed for
three hours. m e reaction was filtered through a
fiber glass pad to clarify and acidified to pH 1.5
lS with 6.0 M hydrochloric acid and lyophilized. The
~ residue was dissolved in 10 ml of ammonium hydroxide
; and the solution concentrated in vacuo. The
; precipitate which formed was removed by filtration,
~ashed with aqueous ethanol, ether and dried in vacuo
. 20 to give 0.04 g of the title compound, ~p 274-276C.
i.
Route
; l-Cyclopropyl-6-fluoro-l~4-dihydro-4-oxo-7-
(l-piperazinyl)-1,8-naphthyridine-3-carbox~lic acid.
A solution of 10.2 g ~25 mmole) of l-cyclopropyl-
25 6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-
piperazinyl]-1,3-naphthyridine-3-carboxylic acid (see
Example J), 100 ml of 10~ aqueous sodium hydroxide and
40 ml of ethanol was refluxed for 'hree hours. The
solution was concentrated to 125 ml and acidified to
pH 7.3 with glacial acetic acid. The resulting
precipitate was removed ~y filtration, washed t~ith 50%
aqueous ethanol, ether and dried in vacuo to give
7.2 g of the title compound, mp 274-276.
. 132~80~
DRT-l -14-
EXAMPLE 2
l-Cyclopropyl-6-fluoro-1,4-dihydro-7-(4-:nethyl-1-
piperazinyll-4-oxo-1,8-naphthyridine-3-carboxYlic
a_.
A suspension of 1.3 g (4.0 mmole) of l-cyclo-
propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
1,8-naphthyridine-3-carboxylic acid, 13.3 ml of 3795
formalin and 13.3 ml of 88% formic acid was refluxed
for four hours. The resulting solution was evaporated
in vacuo. The residue was suspended in aqueous
ethanol, the resulting precipitate removed by
filtration, washed with water and dried in vacuo to
give 1.24 g of the title compound, mp 236-237C.
EXAMPLE 3
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxvlic acid
To 1. 00 g ( 3.53 mmol) of l-cyclopropyl-6,7,8-tri-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in
10.0 ml of acetonitrile and 0.54 g (3.53 mmol) of 1,8-
diazobicyclo~5.4.0]undec-7-ene, was added 1.70 g
(19.7 mmol) of piperazine. The mixture was refluxed
for one hour and then stirred overnight. It was
concentrated, dissolved in ammonium hydroxide and
filtered. The filtrate was then concentrated to one-
half volume and filtered to give 0.67 g of the
title compound, mp >270C.
EXAMPLE 4
l-cvciopropvl-6~8-difluoro-l~4-dihvdro-7-(3-hydr
pyrrolidinyl)-4-oxo-3-auinolinecarboxvlic acid
A mixture oE 2.1 g (7.8 ramol) of l-cyclopropyl-
6,7,8-trifluoro-1,~-dihydro-4-oxo-3-quinoline
1325~
DRT-l -15-
; carboxylic acid, 20 ml acetonitrile, 1.2 g ~7.8 ~mole)
1,8-diazobicyclo~5.4.0~undec-7-ene and 0.7 g
(7.8 ~mole) of 3-hydroxyp~rrolidine was refluxed for
. 2.5 hours. m e reaction was allowed to cool and
stirred at room temperature for 48 hours. The
- resulting precipitate was filtered, washed with
diethyl ether, then taken up in isopropyl alcohol.
The solid was filtered and washed with ether until
dry to give 2.0 g of the title compound, mp 276-278C.
EXAMPLE 5
The following compounds are prepared by reacting
an approximately equimolar amount of l-cyclopropyl-6,
7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid (see Example L) and the desired amine or blocked
amine corresponding to group Z in formula I in
acetonitrile and an equimolar amount of l,8-diazo-
bicyclo[5.4.0]undec-7-ene at reflux for one hour,
then stirring at room temperature overnight, filter-
ing, washing with diethyl ether and drying:
1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl)-
1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-
morpholinyl)-oxo-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-
thiomorpholinyl)-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
;l-pyrrolldinv1)-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-
- (l-piperidinyl)-3-quinolinecarboxylic acid.
EXAI~PLE 6
In the same manner 25 ~xample 3, the following
compounds are prepared from l-cyclopropyl-6-fluoro-
. 1325806
DRT-l -16-
7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
car~oxylic acid (see Example K) and the desired
~ amine or blocked amine:
- l-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(4-
~j 5 thiomorpholinyl)-1,8-naphthyridine-3-carboxylic
acid, mp 288-291C.
! 1 -cyc lopropyl-1,4-dihydro-6-fluoro-7-(4-morpholinyl)-
4-oxo-1,8-naphthyridine-3-carboxylic acid;
' l-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-
pyrrolidinyl)-l,a-naphthyridine-3-carboxylic acid;
l-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-piperi-
dinyl)-1,8-naphthyridine-3-carboxylic acid; and
l-cyclopropyl-1,4-dihydro-6-fluoro-7-(1-homo-
piperidinyl)-4-oxo-1,8-naphthyridine-3-carboxylic
lS acid.
PREPARATIVE EXAMPLES FOR INTE~DIATES
EXAMPLE A
4-[6-(Cyclopropylamino)-3-nitro-2-pyridinyl]-
l-piperazinecarboxylic acid, ethyl ester
' 20 A solution of 126.0 g (0.4 mole) of 4-(6-chloro-
3-nitro-2-pyridinyl)-1-piperazinecarboxylic acid,
` ethyl ester ~prepared as described in European Patent
Publication ~io. 9425), 76.1 g (0.5 mole) of 1,8-
diazabicyclo[S.4.0]undec7-ene (DBU), 28.6 g (0.5 mole)
of cyclopropylamine and 500 ml of absolute ethanol was
stirred at room temperature for 48 hours. The
solution was then heated at reflux for four hours and
concentrated in vacuo. The residue was partitioned
between chloroform and water. The chloroform laye.
--, ,, , . . _ .
was dried over magnesium sulfate and concentrated in
vacuo. The residue was triturated witn ether to give
64.0 g of the title compound, mp 100-103C.
' 1325g~6
DRT-l -17-
EXAMPLE B
4-[6-tAcetvlcvclopropylamino)-3-nitro-2-Dvridinyl]-
l-piperazinecarbox~lic acid, ethyl ester
; A solution of 64.0 g (0.19 mole) of 4-[6-(cyclo-
propylamino)-3-nitro-2-pyridinyl~-1-piperazine-
car~oxylic acid, ethyl ester, 115 ml of acetic
anhydride and 115 ml of acetic acid was heated on a
steam bath for 36 hours. The solvents were removed in
vacuo, the residue was triturated with a mixture of
ethanol and toluene which was also evaporated in vacuo
to give 68.3 q of the title compound, mp 90-93C.
EXAMPLE C
4-[6-(Acetylcyclopropylamino)-3-amino-Z-pyridinyl]-l-
piperazinecar~oxylic acid, ethyl ester
A .nixture of 17.0 g (45 mmole) of 4-6-(acetyl-
cyclopropylamino)-3-nitro-2-pyridinyl-1-piperazine-
carboxylic acid, ethyl esteL, 1.5 g of Raney nic~el
and 180 ml of absolute ethanol was shaken in a
atmosphere of hydrogen at about 50 psi and room
temperature for approximately 24 hours. The catalyst
was removed by filtering through Celite and the
solvent removed in vacuo to give 15.2 g of the title
compound, m2 149-150C.
EXAMPLE D
2-[4-(Ethoxycarbonyl)-l-piperazinyll-6-
(acetylcycloDropvlamino)-3-pvridinediazonium
tetrafluor3bora~e
A solution of 20.8 g ;60 mmole) of 4-[6-(acetyl-
cyclopropylamino)-3-amino-2-pyridinyl]-1-piperazine-
carboxylic acid, ethyl ester, 44 m7 of ethanol and27 ml of 48% tetrafluoroboric acid was cooled to 0C
132~
DRT-l -13-
and treated dropwise with a solution of 4.56 g
(66 mmol) of sodium nitri~e in 8 ml of water under a
nitrogen a'~osphere keeping the te~perature 0-5C.
After the addition was complete, the reaction was
stirred at 0-5C for one hour and treated with 150 ml
of anhydrous ether keeping the temperature below 10C.
The solid was removed by filtration, the precipitate
was washed with ethanol/ether (1:1), ether and dried
in vacuo to give 24.5 g of the title compound, mp
100-105C (dec.).
EXAMPLE E
4-[6-(Acetvlcvclopropylamino)-3-fluoro-2-pYridinvl]-
l-piperazinecarboxylic acid, ethYl ester
To 800 ml of refluxing toluene was added in
: 15 portions, as a solid, 46.2 g (0.1 mole) of
- 2-[4-(ethoxyuarbonyl)-1-piperazinyll-6-(acetyl-
cyclopropylamino)-3-pyridinediazonium tetrafluoro-
borate. After the addition was ccmplete, the reaction
was refluxed for ten minutes and the toluene was
decanted from tbe insoluble precipitate. The toluene
was evaporated in vacuo and the residue was partition-
ed between chloroform and water. The chloroform layer
was washed with 5% a~ueous sodium bicarbonate, water,
dried over magnes.um sulfate and evaporated in vacuo
to give 13.7 g of the title compound, as a viscous
oil. An additional 10.2 g could be obtained by
partitioning the original toluene insoluble material
in chloroform and water. The organic layer was washed
with 5% aqueous sodium bicarbonate, dried over
magnesium sulfate, evaporated in vacuo and the residue
was chromatographed on silica gel eluting with
chloroform/etAyl acetate (6:4). This fraction was
also a viscous oil which did not crystallize upon
standing. Both fractions were of sufficient purity to
be used as is in the ensuing steps.
~ 132~6
DRT-l -19-
E.YAMPLE F
!
4-[6-(CycloeropvlaminQ~-3-fluoro-2-pyridinyl]-1-
piperazinecarboxylic acid, ethvl ester
A solution of 21.9 g (63 mmole) of 4-[6-(acetyl-
cyclopropylamino)-3-fluoro-2-pyridinyl~-1-piperazine-
carboxylic acid, ethyl ester, 170 ml of 15%
hydrochloric acid and 235 ml of methanol was refluxed
for one hour and allowed to stir at room temperature
for 18 hours. The methanol was removed in vacuo and
the aqueous acid was made basic with 1.0 N sodium
hydroxide to pH 10.5. The mixture was extracted with
chloroform, the chloroform layer washed with water,
dried over magnesium sulfate, and evaporated in vacuo
to give 17.6 g of the title compound, mp 6~-70C.
E~MPLE G
For Route A
[[CyclopropYl[6-~4-(ethoxycarbonyl)-l-piPera~inyl]
5-fluoro-2-pYridinvl]amino]methylene]propanedioic
acid, diethYl ester
A solution of 3.8 g (12.3 mmole) of 4-16-(cyclo-
propylamino)-3-fluoro-2-pyridinyl]-1-piperazine-
car~oxylic acid, ethyl estar, 2.7 g (12.3 mmole) of
diethyl (ethoxymethylene)malonate and 50 ml of xylene
was refluxed for 24 hours. The solvent was removed in
vacuo and the residue was chromatographed over silica
gel eluting with chloroform/ethyl acetate (80/20) to
give 2.3 g of the title compound as a viscous oil
which was used without further purification.
- 132~06
DRT-l -20-
EXAMPLE H
For Route A
Ethyl l-Cyclopropyl-6-fluoro-1,4-dihYdro-4-oxo-
7-[4-(ethoxycarbonyl)-1-piperazinvl]-l,a-
-, S naphthyridine-3-carboxylate
A solution of 2.3 g (4.8 mmole) of [[cyclo-
propyl[6-[4-(ethoxycarbonyl)-1-piperazinyl]-5-
fluoro-2-pyridinyl]amino]methylene]propanedioic
acid, diethyl ester, in 15 ml of acetic anhydride was
treated dropwise with 5 ml of 98% sulfuric acid
keeping the temperature 55-6~C. When the addition
was complete, the reaction was stirred for one hour
and poured onto S0 g of ice. The aqueous suspension
was extracted with chloroform, the chloroform layer
washed with water, dried over magnesium sulfate,
filtered, and evaporated in vacuo. The residue was
triturated with several portions of ethanol/toluene
which were also removed in vacuo to give 0.4 g of the
title compound, mp 184-186C. An additional 0.5 g of
product could be obtained by concentrating the
original aqueous fraction, mp 184-186C.
EXAMPLE I
For ~oute ~ -
4-[6-[Cvclopropyl(2,2-dimethyl-4,6-dioxo-1,3-dioxan-
5-vlidine)amino]-3-fluoro-2-pyridinyl]-1-p perazine-
carboxvlic acidl ethvl ester
A solution of 17.6 g (57 mmole) of 4-[6-(cyclo-
propylamino)-3-fluoro-2-pyridinyl~ piperazine-
carboxylic acid, ethyl ester, 11.6 g (63 mmole) of 5-
30 (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione
and 250 ml of methanol was stirred at room temperature
for four hours. The solid was removed by filtration,
washed with methanol, ether and dried in vacuo to give
17.6 g of the title compound, mp 177-178C.
13258~6
DRT-l -21-
EXAMPLE J
For Route
l-CycloDropyl-6-fluoro-l~4-dihydro-4-oxo-7-[4-
(ethoxycarbonyl)-l-piperazinvl]-3-carboxYlic acid
- 5 A solution of 17.0 g (37.0 mmole) of
4-[6-[cyclopropyl (2,2-dimethyl-4,6-dioxo-1,3-
; dioxan-5-ylidene)amino]-3-fluoro-2-pyridinyl]-1-
- piperazinecarboxylic acid, ethyl ester in 125 ml of
acetic anhydride was treated dropwise with 35 ml of
`'t' 10 98% sulfuric acid keeping the temperature 50-60C.
When the addition was complete, the reaction was
stirred for two hours and poured onto 600 g of ice.
The mixture was stirred was stirred for one hour and
the resulting precipitate was removed by filtration,
~ 15 washed with water and dried in vacuo to give 10.2 g of
ci~ the title compound, mp 277-279C.
EXAMPLE R
.1
l-CycloDropyl-6-fluoro-1,4-dihYdro-7-hYdroxY-4-oxo-
1,8-naphthyridine-3-carboxylic acid
To a solution of 2 ml of 70% nitric acid in
i 10 ml of 98% sulfuric acid was added in portions
l.Og (3.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-
dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-
carboxylic acid, keeping the temperature between
25-30C. The resulting solution was stirred at
room temperature for 18 hours and poured onto lO g
of ice. The mixture was stirred at room temperature
for 24 hours, concentrated in vacuo, the pH adjusted
to 12 with aqueous sodium hydroxide, and filtered
through a fiber glass pad. The filtrate was
acidified to p~ 3.5 with 6.0 M hydrochloric acid,
the resulting precipitate removed by filtration,
- 132~806
DRT-1 -22-
washed with water then ether and dried in vacuo to
give 0.23 g of the title compound, mp 3ZS-327C.
7-Chloro-l-cyclopropYl-6-fluoro-1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid
A suspension of 0.19 ~ t0.72 mmole) of
l-cyclopropyl-6-fluoro-1,4-dih~dro-7-hydroxy-4-oxo-
1,8-naphthyridine-3-carboxylic acid in 2 ml of
phosphorus oxychloride was heated at reflux for
1/2 hour. The resulting solution was cooled to
room temperature and the solvent was removed in
vacuo. The residue was triturated with ice-water
and the resulting solid was removed by filtration,
washed with water, then ether and dried in vacuo
to give 0.11 ~ of the title compound, mp 209-212~C.
EXAMPLE L
l-Cyclopropyl-6,7,8-trifluoro-1,4-dihYdro-4-oxo-3-
quinolinecarboxylic Acid
2,3,4,5-Tetrafluoro-~-oxo-benzenepropanoic Acid,
yl Ester
To 30.0 g (155 mmol) of 2,3,4,5-tetrafluoro-
benzoic acid in 75 ml of dichloromethane was added
14.8 ml ~1.1 equivalents) of oxalyl chloride. The
~ mixture was then treated with three drops of dry
N,N-dimethylformamide and the vigorous reaction was
stirred at room temperature overnight. The m-xture
was then concentrated to an oil, taken up in
toluene, and reconcentrated to afford 2,3,4,5-tetra-
fluorobenzoyl chloride which was used in the next
! , step.
To 40.92 g (310 ~mol) of malonic acid half
ethyl ester in 700 ml of dry tetrahydrofuran at -35C
was added a stream of n-butyllithium until one
132~8~
DRT-l -23-
equivalent was delivered. The mixture was maintained
at -15 to -30C during the addition, then warmed to
-5C treated with 10 mg of bipyridyl. The remainder
of the n-butyllithium was added at this temperature
until the indicator turned pink. A total of 282 ml
of 2.2 N n-butyllithium was added. The mixture was
recooled to -78C and a solution of 2,3,4,5-tetra-
fluorobenzoyl chloride in 100 ml of dry tetrahydro-
furan was added ~eeping the temperature constant. The
reaction mixture was stirred for 45 minutes after the
acid chloride addition. It was warmed to -35C and
poured into 155 ml of 2 N hydrochloric acid. To this
~ixture was added one liter of water and 1.5 liters of
dichloromethane. The aqueous phase was separated and
extracted with an additional 1.5 liters of
dichloromethane. The combined organic phases were
washed with 50% saturated sodium bicarbonated and then
1 N hydrochloric acid. The dichloromethane was dried
(magnesium sulfate) and concentrated to a solid which
was triturated with cold pentane to give 37.8 g of
2,3,4,5-tetrafluoro-~-oxo-benzenepropanoic acid,
ethyl ester, mp 63-65C.
l-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylic Acid
To 17.6 g (66.6 mmol) of the 2,3,4,5-tetrafluoro-
B-oxo-benzenepropanoic acid was added 14.6 g
(~ 1.5 equivalents) of triethylorthofor~ate and
16.19 g (2.38 equivalents) of acetic anhydride. The
mixture was refluxed for two hours at 120 ~and was
then cooled to 80C and concentrated in vacuo. The
mixture was diluted with t-butanol, cooled to 10C,
and 3.8 g (1.05 equivalents) of cyclopropylamine in
120 ml of t-butanol was added. The mixture was
stirred at 20C for 30 minutes and then warmed to 50C
overnight. At this temperature 7.5 g of potassium
1325~6
DRT- 1 --2 4-
t-butoxide was added in 50 ml of t-butanol and the
mixture was stirred for four hours . It was f iltered
and the solids dissolved in 250 ml of hot acetic acid
and 200 ml of 3 N hydrochloric acid was added in
5 portions cver four hours at 100C. me mixture was
cooled and the solids collected to give 15.44 g (82%)
of the l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-
oxo-3~uinolinecarboxylic acid, mp 226-228C.
