Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1310 r$ J
SPECIFICATION .
NAPHTYLHYDRINE ANTIBACTERIAL COMPOUNDS
This invention relates to new naphthyridine
derivativesc having antibacterial properties,
compositions containing the new naphthyridine
derivative<.~ and methods of treating mammalian patients
with the neaw naphthyridine derivatives. __
Ii: is known that certain naphthyridine
compounds ~!xhibit antibacterial properties, notably
certain 7-piperazinyl-4-oxo-1,8-naphthyridine-3-
carboxylic acids. In European Patent No. 9,425, there
are disclosed certain 7-piperazinyl-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives
which are substituted in the 1 position with an alkyl or
vinyl subst:ituent.
This invention relates to novel antibacterial
agents and, more particularly, to 7-substituted
amino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acids and derivatives thereof having the
formula : . 0 0
II
/ C-ORl
R , _.
(I)
wherein R is selected from the group consisting of an
aromatic heterocyclic ring having 5 to 6 atoms of which _
1 or 2 atoms are independently selected from S, 0 and N
and the remaining atoms being carbon atoms; substituted
1
13 ~ 0 r~~~
_2_
derivatives of the aromatic heterocyclic ring wherein
the aromatic heterocyclic ring is monosubstituted with
C1 to C6 alkyl; and a phenyl group of the formula:
R2
(II)
wherein R2 is one, two or three substituents
independently selected from hydrogen, halogen, Cl to -
C6 alkyl, halo-substituted C1 to C6 alkyl, cyano,
methylenedioxy, a group having the formula -Y-R3
wherein -Y- is -0- or -S- and R3 is hydrogen or Cl
to C6 alkyl, and an amine having the formula:
R~
-
R5
wherein R4 and R5 are each independently hydrogen or
Cl to C6 alkyl.
R1 is hydrogen or a carboxy-protecting group.
Z is an amino group having the formula:
'6
-N
-
wherein R6 is hydrogen or C1 to C6 alkyl, and R~ .
is C1 to C6 alkyl, NH2, mono-(Cl-C4)
alkylamino or di-(C1-C4) alkylamino.
Alternatively, Z can be an aliphatic
heterocyclic ring having 5 to 7 atoms and, in
particular, 1 or 2 hetero atoms which are independently
selected from the group consisting of S, 0, N and
combinations thereof, with the remaining atoms in the
aliphatic heterocyclic ring being carbon atoms. More
1340~18,~,
-3-
particularly, the aliphatic heterocyclic ring has the
formula:
-
H
Z 2
wherein R8 is selected from the group consisting of
CH2, (CHZ)2 and a group of the formula
-(CH2)nR9- wherein R9 is selected from the group
consisting of -S-, -0- and -N- and n is 0, 1, or 2.
Also included are substituted derivatives of such
aliphatic heterocyclic rings wherein the aliphatic
heterocyclic ring is substituted with one, two or three
substituents independently selected from C1 to C6
alkyl, an amine group having the formula:
R10
~R11
wherein R10 and R11 are each independently selected
from the group consisting of hydrogen, C1 to C6
alkyl; hydroxy-substituted C1 to C6 alkyl, C1 to
C3 alkylamino-substituted C1 to C6 alkyl, hydroxy,
halogen, alkanoyl, alkanoylamido and amino-substituted
C1 to C6 alkyl.
Representative aromatic heterocyclic groups
include pyridyl, pyrazinyl, thiazoyl, furyl and
thienyl.
Illustrative of such aliphatic heterocyclic
groups are piperazinyl groups, piperidinyl groups,
pyrrolidin:yl groups, morpholino groups, thiomorpholino
groups and homopiperazinyl groups (i.e., hexahydro-1-H_-
1 , 4-diazep:inyl) .
m~~~~z
Representative -Y-R3 groups include hydroxy,
mercapto, loweralkoxy, such as methoxy, ethoxy, propoxy,
etc., as well as thio analogs thereof, namely
methylmercapto, ethylmercapto, etc.
As used herein, the term "halogen" refers to
chloro, bromo, fluoro and iodo groups, while the term
"Cl to C6 alkyl" refers to lower alkyl groups
including methyl, ethyl, propyl, isopropyl, butyl, etc,.
As used herein "C1 to C6 alkyl" includes
both branched or straight chained alkyl. Representative
of halo-substituted and hydroxy-substituted C1 to C6 -
alkyls include chloromethyl, chloroethyl, chloropropyl,
hydroxyethyl, trifluoromethyl, etc.
0 As used herein, the term "alkanoyl" refers to
i
R12-~- wherein R12 is C1 to C6 alkyl.
As used herein, the term "alkanoylamido" refers
to R13-~-NH- wherein R13 is C1 to C6 alkyl.
0 As used herein, the term "carboxy-protecting
group" ref~srs to a carboxy group which has been
esterified with one of the commonly used carboxylic acid
protecting ester groups employed to block or protect the
carboxylic acid functionality while reactions involving
other functional sites of the compound are carried out.
In addition, a carboxy protecting group can be used as a
prodrug whereby the carboxy protecting group can be
hydrolyzed enzymatically to release the biologically
active parent acid. Such protected carboxy groups are
noted for their ease of cleavage by hydrolytic methods
to the corresponding carboxylic acid. Further, such
carboxy-protecting groups can be relatively easily
cleaved to yield the corresponding free carboxy group.
Such carboxy-protecting groups are well known to those
skilled in the art, having been extensively used in the
protection of carboxyl groups in the penicillin and
cephalosporin fields, as described in U.S. Patent Nos.
_ 5 _ 134o~1~z
3,840,556 and 3,719,667. Representative protecting groups
include C1 to C8 alkyl (e. g., methyl, ethyl, tertiary
butyl), benzy:l and substituted derivatives thereof such as
alkoxy and nit=robenzyl groups, dialkylaminoalkyl (e. g.
dimethylaminoethyl), acyloxyalkyl groups such as
pivaloyloxymet;hyl and propionyloxy methyl.
The' chiral centers of the compounds of the
invention may have either the "R" or "S" configuration.
Representative of the preferred compounds of the
invention inc7_ude 1-phenyl-6-fluoro-1, 4-dihydro-4-oxo-7(1-
piperazinyl)-7_, 8-naphthyridine-3-carboxylic acid, 1-phenyl-
6-fluoro-1, 4--dihydro-4-oxo-7-(1-4methyl)piperazinyl-1, 8-
naphthyridine--3-carboxylic acid, 1-p-fluorophenyl-6-fluoro-
1, 4-dihydro-~6-oxo-7(1-piperazinyl)-1, 8-naphthyridine-3-
carboxylic acid, 1-(3,4-dichloro)phenyl-6-fluoro-1, 4-
dihydro-4-oxo-7(1-piperazinyl)-1, 8-naphthyridine-3-
carboxylic acid, 1-p-hydroxyphenyl-6-fluoro-1, 4-dihydro-4-
oxo-7(1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid,
1-p-fluorophenyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-4-methyl)
piperazinyl-1, 8-naphthyridine-3-carboxylic acid, 1-0, p-
difluorophenyl.-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-
piperazinyl)-7., 8-naphthyridine-3-carboxylic acid, 1-0, p-
difluorophenyl.-6-fluoro-1, 4-dihydro-4-oxo-7(3-amino-1-
pyrrolidinyl)-1, 8-naphthyridine-3-carboxylic acid, 1-0, p-
difluorophenyl.-6-fluoro-1, 4-dihydro-4-oxo-7(3-amino-4-
methyl-1-pyrrc>lidinyl)-1, 8-naphthyridine-3-carboxylic acid
and 1-0, p-difluorophenyl-6-fluoro-1, 4-dihydro-4-oxo-7(cis-
3-aminomethyl-4-chloro-1-pyrrolidinyl)-1, 8-naphthyridine-3-
carboxylic acid.
Al~o included within the scope of the present
invention are pharmaceutically acceptable salts of the
foregoing comb>ounds. As use herein, the term
~~~0~82
-6-
"pharmaceutically acceptable salts" refers to non-toxic
acid addition salts and alkaline earth metal salts of
the compounds of Formula I. The salts can be prepared
in situ during the final isolation and purification of
the compounds of formula I, or separately by reacting
the free base or acid functions with a suitable organic
acid or base. Representative acid addition salts
include the hydrochloride, hydrobromide, sulphate,
bisulphatE~, acetate, oxalate, ualerate, oleate,
palmitate,, stearate, laurate, borate, benzoate, lactate,
phosphate,. tosylate, mesylate, citrate. maleate,
fumarate, succinate, tartrate, glucoheptonate,
lactobionate, lauryl sulfate salts and the like.
Representative alkali or alkaline earth metal salts
include the sodium, calcium, potassium and magnesium
salts, etc. It has been found that the compounds of the
present invention possess antibacterial activity against
a wide sps~ctrum of gram positive and gram negative
bacteria, as well as enterobacteria. The compounds of
the inuent.ion are therefor useful in the antibiotic
treatment of susceptible bacterial infections in both
humans and animals. In addition, the compounds, by
reason of their in vitro activity, may be used in scrub
solutions for surface inhibition of bacterial growth.
Susceptible organisms generally include those
gram positive and gram negative, aerobic and anaerobic
organisms whose growth can be inhibited by the compounds
of the invention such as Staphylococcus, Lactobacillus,
Streptococcus, Sarcina, Escherichia, Enterobacter,
Klebsiella,, Pseudomonas, Acinetobacter, Proteus, 15
Citrobacter, Nisseria, Baccillus, Bacteroides,
Peptococcus, Clostridium, Salmonella, Shigella,
Serratia, Haemophilus, Brucella, and other organisrns.
In addition to exhibiting highly effective antibacterial
activity, the compounds of the invention exhibit
v \
i 3 4 fl'~~~
increased and improved solubility characteristics as
compared with prior naphthyridine-3-carboxylic acid
compounds in the art.
"fhe compounds of Formula I may also be
formulated into compositions together with
pharmaceutically acceptable carriers for parenteral
injection, for oral administration in solid or liquid
form, for rectal administration, and the like.
Compositions according to the invention for
parentera7. injection may comprise pharmaceutically
acceptable sterile aqueous or nonaqueous solutions,
suspensions or emulsions. Examples of suitable
nonaqueous carriers, diluents, solvents or vehicles
include propylene glycol, polyethylene glycol, vegetable
oils, such as olive oil, and injectable organic esters
such as ethyl oleate. Such compositions may also
contain adjuvants such as preserving, wetting,
emulsifying, and dispersing agents. They may be
sterilized, for example, by filtration through a
bacteria-retaining filter, or by incorporating
sterilizing agents into the compositions. They can also
be manufactured in the form of sterile solid
compositions which can be dissolved in sterile water, or
some other sterile injectable medium immediately before
use.
Solid dosage forms for oral administration
include capsules, tablets, pills, powders and granules.
In such solid dosage forms, the active compound is_
admixed with at least one inert diluent such as sucrose,
lactose or starch. Such dosage forms can also comprise,
as is normal practice, additional substances other than
diluents, ~e.g., lubricating agents such as magnesium
stearate. In the case of capsules, tablets and pills,
the dosage forms may also comprise buffering agents.
Tablets an~~ pills can additionally be prepared with
enteric co~~tings.
~34~78~
-8-
Liquid dosage forms for oral administration
include pharmaceutically acceptable emulsions,
solutions, suspensions, syrups and elixers containing
inert diluents commonly used in the art, such as water.
Besides such inert diluents, compositions can also
include adjuvants, such as wetting agents, emulsifying
and suspending agents, and sweetening, flavoring and
perfuming agents. .
Compositions for rectal administration are
preferably suppositories which may contain, in addition
to the active substance, excipients such as cocoa butter
or a suppository wax.
Actual dosage levels of active ingredient in
the compositions of the invention may be varied so as to
obtain an amount of active ingredient eff.ectiue to
achieve antibacterial activity in accordance with the
desired method of administration. The selected dosage
level therefore depends upon the nature of the active
compound administered, the route of administration, the
desired duration of treatment and other factors.
Generally, daily dosage levels of the compounds of
Formula I of about 0.1 to about 750, more preferably
about 0.25 to about 500 and most preferably about 0.5 to
about 300 mg. of active ingredient per kg. of body
weight are effective when administered orally to a
mammalian patient suffering from an infection caused by
a susceptible organism. If desired, the daily dose may
be divided into multiple doses for administration,.e.g.,
two to four times per day.
Compounds according to this invention can be
prepared b~~ the reaction illustrated below:
. i . 0
/ OORl ZH (IV)' ~F / (' COOR
1
Z ~N~N~
I
R . R
(III) (I)
134 o r8z
_g_
wherein X is a halogen or mesylate or methoxy group and
R, R1 and Z are the same as described above.
The reaction may be performed by heating a
compound of the formula (III) with an amine of formula
(IU) at a temperature of from 20°C to 150°C, in the
presence of a suitable organic polar or non-polar
solvent such as dimethylsulfoxide, sulfolane,
dimethylformamide, pyridine, dimethylacetamide, .
1-methyl-2~=pyrrolidinone, water, tetrahydrofuran or
methylene chloride. It is desirable to carry out the
reaction in the presence of an acid-acceptor such as
triethylam~ine, potassium carbonate and the like at a
molar ration of 1.0 to 1.2 moles of the acid-acceptor
per mole oi= the compound of the formula (III). The
amine (IU) can also be used as acid acceptor in which 2
or more mo:Lar excess of this reagent is used. The
compounds of the formula (III) may be prepared in
accordance with the following reaction scheme, in which
X, R are as described above.
_ ~, \
~340~1$~
-10-
o
II o 0
II
-oR;L . F ~ ~I_oH ~ r ~ c-ci
--
X ~ X~x ~ x w I
~x
. ,
(2) (2A)
"OR
II I~-OR1 . H _ ~ 1 OR
X ~~Y ~ ORl
~(3) . . (4)
w 0 0
II II
C-ORl II II
~ H2~'R --~ F ~ C-ORl--~
X . X .H ORl (5) X ~
X H NH
I
(6) R
0 0
II
-ORl
x ~r,J.~
N
R
(III)
1340 ~8~
-11-
l:n accordance with the foregoing reaction
scheme, the the known nicotinic acid ester (1) is
hydrolyzed with mineral acid to the free acid (2) which
can then tie concerted to its acid chloride (2A) by
. treatment with thionyl chloride. Displacement of the
acid chloride (2A) with malonic acid half ester (D) in
the presence of n-butyl lithium yields the
beta-ketoester (3).
The beta-ketoester (3) is then treated with a
trialkylorthoforrnate (4) in the presence of an acid
anhydride, preferably acetic anhydride, followed by
reaction with substituted or unsubstituted amine (5) to
obtain the enaminoketoester (6). In the
trialkylorthoformate (4), R1 may be an alkyl group of,
for example, from 1 to 10 carbon atoms, but is
preferably loweralkyl, such as ethyl. Reaction with the
trialkylorthoformate is preferably conducted at elevated
temperatures, such as from about 50°C to about 150°C,
preferably from about 100°C to about 140°C, to obtain an
oily liquid, which may be isolated or unisolated, as
desired (shown in brackets in the reaction scheme).
Reaction of the latter with the substituted or
unsubstituted amine (5) is preferably conducted in an
appropriate aprotic or non-aprotic solvent, preferably
methylene chloride or tetrahydrofuran, and may be
conducted at room or suitable elevated temperature, as
desired.
Tlhe enaminoketoester (6) is then cyclized, such
as by treatment with a strong base as defined above,
preferably sodium hydride, to obtain the 1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid ester (III).
Cyclization is conducted in the the presence of an
aprotic so~L~ent, such as dimethoxyethane,
bis(2-methoxyethyl)ether, dimethylformamide,
tetrahydrof-uran or chlorobenzene, and is preferably
1340'~g?
-12-
conducted at temperatures of about 20°C to about 145°C,
more preferably at the reflux temperature of the solvent
employed.
T'he ester (III) (R1=alkyl) can also be
subjected to hydrolysis, such as by treatment with
sodium hydroxide, or dilute mineral acid to form the
free acid (III) (R1=H).
The 1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid (I, Rl=H) can then be concerted into
the corresponding ester, if desired, by conventional
esterification procedures, such as by treating the free
acid (I, R.1=H) with the appropriate alcohol in the
presence o~F an acid catalyst, by converting the free
acid (I, R.1=H) into the corresponding acid chloride
followed by displacement of the chloro radical with the
appropriate alcohol, or by treating the sodium salt of
the acid (:I, R1=H) with a suitable reactive halide,
such as ch:Loro-methylpiualate in dimethoxyethane to
obtain, for example, the piualoyloxymethyl ester (I)
where Rl is -CH20COC(CH3)3.
The foregoing may be better understood from the
following examples, which are presented for purposes of
illustration and are not intended to limit the scope of
the inuent:iue concepts. As used in the following
examples, ithe references to compounds, such as (1), (2),
(3), etc., and to substituents, such as R, Rl, R2,
etc., refer to the corresponding compounds and
substitueni~s_in the foregoing reaction scheme and'in
formulae I, II and III.
Example 1
l-Phenyl-6-fluoro-1,4-dihydro-4-oxo-7
1- i erazinyl)-1,8-naphthyridine-3-carboxylic acid
To a solution of l.g of dichlorofluoro
nicotinic acid ester (1) (X=C1, R1=C2H5) in 5 ml'
134 0'~~
-13-
of trifluoroacetic acid, 6 ml. 6 N HC1 is added. The
solution is heated for 16 hours and cooled and extracted
with a methylene chloride. The methylene chloride
solution is extracted with saturated sodium bicarbonate
solution. The aqueous extract is acidified to pH 3 and
then extracted with methylene chloride. Rfter drying,
it yields n.767 g, pale yellow solid (2) (X=Cl). This
compound (.2) (0.5 g.) is then suspended in 10 m)..
benzene an~j 1.7 ml. of thionyl chloride and 2 drops of
dimethylformamide. Rfter refluxing for 30 minutes, the
reaction mixture is evaporated to dryness to give the -
acid chloride (2A). This is added to a solution of
2.54 g. of ethyl malonate monoester in 20 ml. of THF
solution containing 0.52 g. of n-butyl lithium at
-65oC. ThES solution is allowed to warm up to room
temperaturE~, and then acidified and extracted with
ether. Thsa ether extract is washed with saturated
NaHC03 and then water, and dried to yield 0.49 g. of
the ketoest:er (3) (X=CI, R1=C2H5).
(b) A solution of 3.8 g. of beta-ketoester (3)
(R1=C2H5 X=:C1) in 3.,5 ml. of triethylorthoformate
and 10 ml. of acetic anhydride is heated at 135°C for
1-1/2 hours with the removal of the ethyl acetate formed
during the reaction. The solution is evaporated under
reduced pressure to a mobile oil. The oil is then
dissolved in 150 ml. of methylene chloride and 1.5 ml.
of aniline is added into the solution. After 1 hour,
the solution, is evaporated to dryness and purified.
through silica gel column yielding 3.7 g. (6), wherein
Rl=C2H5 and R=phenyl, X=C1).
(c) To a cold solution of 3.5 g. of the
preceding product (6), R1=C R=phenyl, X=C1, in 100 ml.
tetrahydrofuran is slowly added 240 mg. of a 60% sodium
hydride-in-oil suspension. It is then heated for 1 hour
and cooled, and 1 liter of water is added. The mixture
1340 l8~
-14-
is then filtered and the solid is washed with a 1:1
hexane/ether solution to obtain 2.1 g. (III) wherein
R1=C2H5, F!=phenyl, X=C1.
(:d) To a suspension of 5.2 g, of (III)
(Rl=C2H5, R=phenyl, X=C1) in 30 ml. THF is added a
sodium hydroxide solution (0.74 g. in 20 ml. H20).
The mixture is heated at 80°C for 1 hour resulting in a
clear solution which is evaporated under reduced
pressure to dryness. The solid is dissolved in 200 ml.
H20, and f ml, acetic acid is added. The resulting
precipitate is filtered and washed with cold water,
crystallized to produce 7-chloro-1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
(III) (R=phenyl, X=C1, R1=H).
(e) To a solution of 2.0 g, of 7-chloro-1-
phenyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid in 20 ml. of 1-methyl-2-pyrrolidinone
at 65°C is added 2 ml, piperazine. After stirring at
65°C for 20 hours, the solvent is removed by reduced
pressure to dryness. Ethanol is added to the residue
and the resulting mixture is filtered and washed with
ether and then washed with very small amounts of cold
water to give (I) (R1=H, R=phenyl, Z=NVNH), The
resulting dried solid is suspended in 30 ml. H20 and 5
ml. 1N HC1 is added to and warmed to dissolve. Removal
of the solvent under reduced pressure gives
hydrochloride salt of 1-phenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(1-piperazinyl)-1.8-naphthyridine-3-carboxylic
acid (1) (Rl=H, R=phenyl, Z= ~ H).
To the hydrochloride salt is added one molar
equivalent of an aqueous solution of sodium hydroxide,
and the resulting precipitate is filtered to obtain
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
1,8-naphthyridine-3carboxylic acid.
134orr~z
-15-
(f) Alternately, the title compound is
prepared as follows: To a solution of 1.6 g. of
compound (III) (R1=C2H5, R=phenyl, X=CI) (product
of 1(c) in 50 ml. of methylene chloride is added 1 ml.
of triethylamine and 710 mg. of N-acetylpiperazine.
After heating for 2 hours, the solvent is washed with 50
ml. of 1 N HC1 solution and then with water. The
methylene chloride solution is dried and evaporated to.
dryness, yielding 2.1 g. of compound (I) (R1=C2H5,
R=phenyl, Z=N~ICOCH3).
A suspension of 2.1 g. of the preceding
compound (I) in 25 ml. of 3 N HC1 solution is heated at
80°C for 6 hours. The solvent is removed giving the
hydrochloride salt of (I) (R1=H, R=phenyl, Z=N NH).
The solid is dissolved in 100 ml. water. The pH of the
solution is adjusted to pH 7 by the addition of 10~
sodium.hydroxide. The precipitate is filtered and
washed with cold water yielding 1.8 g. of
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
1,8-naphthyridine-3-carboxylic acid (R1=H, R=phenyl,
Z=N; ,NH ) .
Example 2
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-acetyl-
1-piperazinyl)-1,8-naphthvridine-3-carboxylic acid
In the described fashion as Example 1(f), one
can obtain the intermediate (I) (R1=C2H5,
R=phenyl, '.Z=N~~COCH3). A solution of 2.1 g of this
compound in 30 ml THF and 200 mg of sodium hydride-in 5
ml H20 is 'heated at reflux for 8 hours. The solvent
is evaporated off at reduced pressure and the residue is
redissolved in 200 ml water. Acidification with acetic
acid yields a precipitate which is filtered to give
i-phenyl-6~-fluoro-1,4-dihydro-4-oxo-7-(4-acetyl-1-
piperazinyl)-1,8-naphthyri~ine-3-carboxylic acid
(R1=H, R=phenyl, Z=N~ - ~ CH3
i
1340 rlEz
-16-
Example 3
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4
methyl)piperazinvl)-1,8-naphthvridine-3-carboxylic acid
The procedure of Example 1 can be repeated,
replacing N-acetylpiperazine in Exarnple 1(f) with
N-methyl-piperazine to obtain 1-phenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-(4-methyl)piperazinyl)-1,8-
naphthyridine-3-carboxylic acid (1) (R1=H, R=phenyl,
Z=- -~H )and its hydrochloride salt.
3,
Example 4.
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7
1- rrolidinyl)-1,8-naphthyridine-3-carboxylic acid
In the described fashion as Example 1 replacing
piperazine in Example 1(e) with pyrrolidine, one can
obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-
7(1-pyrrolidinyl)-l,8naphthyridine-3-carboxylic acid in
good yield (I) (R1=H, R=phenyl, Z=-N~ ).;
Example 5
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-hydroxy-
1-pyrrolidinyl)-1,8-na~hthyridine-3-carboxylic acid
The procedure of Example 1 can be repeated
replacing piperazine in Example 1(e) with 3-hydroxy-
pyrrolidine to obtain 1-phenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(3-hydro.xy-1-pyrrolidinyl)- 1,8-naphthyridine-
3-carboxylic acid (I) (R1=H, R=phenyl, Z=-~H),
Example 6 '
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-amino
1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid
In the described fashion as Example 1 replacing
N-acetylpiperazine in Example 1(f) with
3-acetamido-pyrrolidine, one can obtain 1-phenyl-6-
fluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-1,8-
naphthyridine-3-carboxylic acid hydrochloride salt (I)
NHZ
(R1=H, R=phenyl, Z=-N~ ).
t
1~~o7~z
-17-
Example 7
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7
(1-plp~~ridinyl)-1,8-naphthyridine-3-carboxylic acid
The procedure of Example 1 can be repeated
replacing piperazine in Example 1(e) with piperidine to
obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-
7-(1-piperidinyl)-1,8-naphthyridine-3-carboxylic acid
(I) (Rl=H, R=phenyl, Z=-L~ ).
Example 8
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-acetamido-
1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid
In the described fashion as Example 1,
replacing N-acetylpiperazine in Example 1(f) with
3-acetomido-pyrrolidine, one car obtain the ester (I)
(R1=CZHS, R=phenyl, Z=N~NHCOCH3). Following
the procedure of Example--~2 this ester (I) yields
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-acetamido-1-
pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid.
Example 9
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7
4-mor~holinvl)-1,8-naphthyridine-3-carboxylic acid
In the described fashion as Example 1 replacing
piperazine in Example 1(e) with morpholine, one can
obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-
(4-morpholinyl)-1,8-naphthyridine-3-carboxylic acid (I)
(R1=H, R=phenyl, Z=- ~0)in good yield.
Example 10
i-phenyl-6-fluoro-1-4,dihydro-4-oxo-7
(4-thiomorpholinyl)-1,8-naphthyridine-3-carboxylic acid
The procedure of Example 1 can be repeated
replacing piperazine in Example 1(e) with thiomorpholine
to obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-
(4-thiomorpholinyl)-1,8-naphthyridine-3-carboxylic acid
(I) (R1=H, R=phenyl, Z=N~ ).
13~0~8~
-18-
Example 11
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-
1-plpErrazinyl)-1,8-naphthyridine-3-carboxylic acid
l:n the described fashion as Exarnple 1 replacing
N-acetylpi.perazinyl in Example 1(f) with 2,6-dimethyl
piperaziner, one can obtain 1-phenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(:~,5-dimethyl-1-piperazinyl)-1,8-naphthyridine-3-
carboxylic: aci~Ch~drochloride salt (I) (Rl=H,
R=phenyl, Z=-N~HH3).
CH3 Example 12
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7
(1-homopiperazinyl)-1,8-naphthvridine-3-carboxylic acid
fhe procedure of Example 1 can be repeated
replacing N-acetylpiperazine in Example 1(f) with
homopipera~zine to obtain 1-phenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(1-homopiperazinyl)-1,8-naphthyridine-
3-carboxylic acid and ~its hydrochloride salt (I)
(R1=H, R=phenyl, Z=-N~H).
'vExample 13
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-
dimethylamino)-1,8-naphthyridine-3-carboxylic acid
I.n the described fashion as Example 1 replacing
piperaziner in Example 1(e) with dimethylamine, one can
obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(dimethyl-
amino)-1,8-naphthyridine-3-carboxylic acid (I) (R1=H,
R=phenyl, Z=-N(CH3)2).
Example 14
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(N
2-hydroxyethylamino)-1,8-naphthvridine-3-carboxylic acid
1'he procedure of Example 1 can be repeated
replacing piperazine in Example 1(e) with N-2-hydroxy-
ethylamine~ to obtain 1-phenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(N-2-hydroxyethylamino)-1,8-naphthyridine-3-
carboxylic acid (I) (R1=H, R=phenyl, Z=-NIiC2H4-OH).
134?8~
-19-
Example 15
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7
(hvdrazyl)-1,8-naphthvridine-3-carboxylic acid
In the described fashion as Example i replacing
piperazine in Example 1(e) with hydrazine, one can
obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-
(hydrazyl)-1,8-naphthyridine-3-carboxylic acid and its
hydrochloride salt (I) R1=H, R=phenyl, Z=-NHNH2).
Example 16
1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7
(2,2-dimethylhydrazyl)-1,8
naphthyridine-3-carboxylic acid
The procedure of Example 1 can be repeated
replacing piperazine in Example 1(e) with 1,1-dimethyl-
hydrazine to obtain 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-
7-(2,2-dimethylhydrazyl)-1,8-naphthyridine-3-carboxylic
acid and its hydrochloride salt (I) (R1=H, R=phenyl,
Z=NH-N(CH3)2).
Example 17
1-p-Fluorophenyl-6,fluoro-1,4-dihydro-4-oxo-7
(1-plpE~razinvl)-1,8-naphthyridine-3-carboxylic acid
(a) In the described fashion as Example 1(b)
replacing aniline with p-fluroraniline, one can obtain
the enaminoketoester (6) (R1=C2H5,
R=p-fluorophenyl, X=C1).
(b) By following the Example 1(c), the
preceding compounds) can yield 7-chloro-1-p-
fluorophenyl-6-fluoro- 1,4-dihydro-4-oxo-
1,8-naphthyridine-3-carboxylic acid ester (III)
(R=p-fluorophenyl, X=C1, R1=C2H5).
(c) In the described fashion as Example 1(f)
the above ester (III) reacting with N-acetylpiperazine
can give the desired 1-p-fluorophenyl-6-fluoro-
1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-
1340?82
-2~-
3-carboxy7.ic acid (I) (R1=H, R=p-fluoro-phenyl,
Z=- ~g) and its hydrochloride salt.
Example 18
I:n the described fashion as Example 1(f),
replacing the ester (III) (R=phenyl, X=C1,
R1=C2H5) uiith the ester (III) of the product of
Example 17(b) (R=p-fluorophenyl, X=C1, R1=C2H5)
and also replacing N-acetylpiperazine pith an ,
appropriate amine such as N-methylpiperazine,
3-acetamido-4-methylpyrrolidine, 3-hydroxy-pyrrolidine,
3-acetamidopyrrolidine, piperidine, morpholine,
thiomorpholine,, 2-methyl piperazine, homopiperazine,
diethylamine, 2,2-dimethylhydrazine and
cis-3-aminomethyl-4-chloro-1-pyrrolidine, one can obtain
the following compounds:
(a) 1-p-fluorophenyl-6,fluoro-1,4-dihydro-
4-oxo-7-(4-methyl-1-piperazinyl)-1,8-naphthyridine-3-
carboxylic acid (1) (R1=H, R=p-fluorophenyl,
Z=-N~ -I~H3 ) .
(b) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(3-amino-4-methyl-1-pyrrolidinyl)-1,8-
naphthyridine-3-carboxylic acid (I) (R =H,
1
R=p-fluorophenyl, Z=-~~2).
'~''CH
(c) 1-p-fluorophe yl-6-fluoro-1,4-dihydro-4-
oxo-7-(3-hydroxy-1-pyrrolidinyl)-1,8-naphthyridine-3-
carboxylic acid (I) (R1=H, R=p-fluorophenyl,
Z=-~ OH )
(d) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-{3-amino-1~-pyrrolidinyl)-1,8-naphthyridine-3-
carboxylii~acid (I) (R1=H, R=p-fluorophenyl,
Z=_N~ 2).
(e) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(1-piperidinyl)-1,8-naphthyridine-3-carboxylic
acid (I) (R1=H, R=p=fluorophenyl, Z=-N~ ).
.~3~0'~$~
-21-
(f) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(4-nnorpholinyl)-1,8-naphthyridine-3-carboxylic
acid (I) ~;R1=H, R=p-fluorophenyl, Z=-~p),
(9) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(4-i=hiomorpholinyl)-1,8-naphthyridine-3-carboxylic
acid (I) ~;R1=H, R=p-fluorophenyl, Z=-~).
I:h) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(3-methyl-1-piperazinyl)-1,8-naphthyridine-~C)i3
carboxylic: acid (I) (Rl=H, R=p-fluorophenyl, Z=-N~NH).
(;i) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-
oxo-7-(1-hiomopiperazinyl)-1,8-naphthyridine-3-carboxylic
acid (I) (R1=H, R-p-fluorophenyl, Z=-Nw NH).
(j) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(diethylamino)-1,8-naphthyridine-3-carboxylic acid
(I) (R1=H, R=p-fluorophenyl, Z=-N(CZHS)2).
(k) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-
oxo-7-(2,e'-dimethylhydrazyl)-1,8-naphthyridine-3-
carboxylic acid (I). (R1=H, R=p-fluorophenyl,
Z=-NH-N(CH3)2).
(1) 1-p-fluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(cis-3-aminomethyl-4-chloro-1-pyrrolidinyl)1,8-
naphthyridine-3-carbo~xyl'c acid (I), (R1=H,
R=p-fluorophenyl, Z=~~H2 ).
'~-~'~ 1
Example 19
1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-
1-pl.perazlnyl)-1,8-naphthyrldlne-3-carboxVllC acid
(a) In the described fashion as Example 1(b)
replacing aniline with 2,4-difluoroaniline, one can
obtain the enaminoketoester (6) (R1=C2H5,
R=2,4-difluorophenyl, X=C1).
(b) By following the Example 1(c), the
preceding Compound (6) can yield 7-chloro-1-
o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxylic acid ester (III). _
(R=2,4-difluorophenyl, X=C1, R1=C2H5).
l
-~2 2-
(c) In the described fashion as Example 1(f),
the above .acid ester (III) reacting with
N-acetylpiperazine can give the desired 1-o,p-difluo.ro-
phenyl-6-f'luoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
1,8-naphthyridine-3-carboxylic acid (I). (R1=H,
R=2,4-difluorophenyl, Z=-~H)and its hydrochloride
salt.
Example 20
In the described fashion as Example 1(f),
replacing the acid ester (III) (R=phenyl, X=C1,
R1=C2H5) with the acid ester (III) of the product
of Example 19(b) (R=2,4-difluorophenyl, X=Cl,
R1=C2H5) and also replacing N-acetylpiperazine
with an appropriate amine such as N-methylpiperazine,
3-amino-4-methylpyrrolidine, cis-3-aminomethyl-4-chloro-
pyrrolidine, 3-acetamidopyrrolidine, piperidine,
morpholine, thiomorpholine, 2-methylpiperazine,
homopipera;zine, diethylamine and
3-N-ethyl-IV-acetylaminomethyl-1-pyrrolidine, one can
obtain the following compounds:
(a) 1-o,p-difluorophenyl-6-fluoro-1,4-
dihydro-4-oxo-7-(4-methyl)piperazinyl)-1,8-naphthyridine-
3-car~ylac acid (I). (R1=H, R=o,p-difluorophenyl,
Z=-N/~N-Cli ) and its hydrochloride salt.
U 3
(b) 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(3~-amino-4-methyl-1-pyrrolidinyl)-1,8-
naphthyrid:ine-3-carboxylic acid (I). (R1=H,
NP2 ~
R=o,p-difluorophenyl, Z=-~ 1 .
H
1-o,p-difluorophe yl-6-fluoro-1,4-
dihydro-4-oxo-7-(cis-3-aminomethyl-4-chloro-1-
pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid (I).
(R1=H, R=o,p-difluorophenyl, Z NH2 ).',
(~i) 1-o,p-difluorophen~ltluoro-1,4-
dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-1,8- _
naphthyrid:ine-3-carboxylic acid (I). (R1=H,
R=o, p-difluorophenyl, Z=-N~'~1;2 ) .
1340r1gz
-23-
(c) 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(1-piperidinyl)-1,8-naphthyridine-3-carboxylic
acid (I). (Rl=H, R=o,p-difluorophenyl, Z=-N~).
(f) 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(4-morpholinyl)-1,8-naphthyridine-3-carboxylic
acid (I). (Rl=H, R=o,p-difluorophenyl, Z=-N~).
(g) 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(4-thiomorpholinyl)-1,8-naphthyridine-3-
carboxylic acid (I). (R1=H, R=o,p-difluorophenyl,
Z=_~).
(h) 1-o,p-difluorophenyl-6-fluoro-1,4-
dihydro-4-oxo-7(3-methyl-1-piperazinyl)-1,8-
naphthyridine-3-carboxylic acid (I). R1=H,
/'TCH3
R=o,p-difluorophenyl, Z =-N~NH).)
(i) 1-o,p-difluorophenyl-6-fluoro-1,4-
dihydro-4-oxo-7-(1-homopiperazinyl)-1,8-naphthyridine-3-
carboxylic acid (I). (Rl=H, R=o,p-difluorophenyl,
Z=-N~H).
~/V (j) 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(diethylamino)-1,8-naphthyridine-3-carboxylic
acid (I). (R1=H, R=o,p-difluorophenyl,
Z=-N(C2H5)2).
(k) 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-
4-oxo-7-(3-ethylaminomethyl-1-pyrrolidinyl)-1,8-
naphthyridine-3-carboxyli ~ acid (I). (R1=H,
R=o,p-difluorophenyl, Z=N~~CH2-NHC2H5).
ExVample 21
In the described fashion as Exarnple 1
(a, b, c), replacing aniline With an appropriate amine
(R-NH2), one can obtain the additional 1-substituted,
7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylic acid ester III as listed in Table I.
1340~18~
-24-
~a
a~
c
.~,
o c .-,
a~
>~ c
x o ~ v .c r,
I
N L C .C C1 >~
V
G
II r-Iri.~ ' ~ O .~ >r
l.
.-I r-1'i I .-i>r >i?~ .-iG7. C CL C a
x >.>, >, >~ C C C w >~ .-I.-i-.,ra v >,
C C C; C d d N I x >r ?,E U ,C CL
-I N U C~ N .C .C.C d' O C C r0 a (3,I rl
a .c.~c~; ~ w o,I~.1 a o ~,..-Iv o ~ >,
O.c1 Co C1.>y >.>, >, ~ .C .G>. E .u 1 .1
c
a o o a .-,x x x x >, a, a,.c .a sz.rl >,
..
a a a >~ O O O O .C o O .N ?~ tQ ?, 'O
N
x fx O O O .C .C a a a .a C C N S U C .r
~ ~C
~-Ir.i~ y ~ ~ ~ ~ rtt.-aE ~ a W a
a
-I~ ~~ a) N ?~>~ >r 1 >.,E .I N C! U ?~
?,
_ w U ca E E .Cs .n ~r U N w E E E GL
w
H 1 I I I I I I I I 1 I I 1 I I
I
H O L1 O ~ I1 V'N N N p, (yL1 (1 C1 M er
M
H
C
H
W
a
as
N
O
C y
w N C
N C ~..i
~ra C -..I
C G~ ...r .-i ...i
N C .-I ~..i a
O -.I N ~.~I C >~,
G C ~0 ~ G1
v N U O ~~a N r0 O O ~-I
N v Cl N C C C ~ C N O ~ G >r ~ N
C C C C ~.I ~..I ~.~a r-I r0 U C C LL N .C C C
C ~.~ ~'.I ~.~ ..a r-I r-~ r-I w >r C U) ~.-r N .C 1! ~..~ ~.a
v .-i ~ .-I .-i ~.-I .~I .a I x ~.~ .L1 E U CL N ~ N
E .,.r .~ .,.r .,.a C G C 'd' O '-1 O rtJ a O E -.a rtt
v C C C C ~0 rtf b 1 a ~~ C ,.i U -,.I I a a
U ~~ b ~ N t0 >y >r >~~ >r 'D C ~.~ >, E ~ M >v ?~
~o N o 0 0 ~-I x x x x >, m E s .-, y 1 p, p,
1-a x a a a >, O O O O .G O ~C ~ >~~ O O O O
Z O O O .~ ~C a a a ~.~~ C ..a O ,C G C C C
CJ R'.. ~ r-I rl 1J L ~ 'O 'Cf ~O (O '>? E L ~'~i ~rl ~..1 .,..a
pG ~r ~-a ~c ~C tV N ?~ >, >. 1 >r I ~.r N E E E E
U U E E ~ .C ~ d' U ~~ rtJ E t0 rtf b r0
N I I I 1 I 1 I I ~ I ~ I I I 1 I I
C O C1 O CL (1 C' ,N N N p, N (1, p, (~, ~ ~~ M
r-I
C ~ ~ ~ ~ ~
a r6 ~ U TJ N W aT s ~..r ~n ~C .-~ E C O CL CT
1340782
-25-
r,
C C '
N N
x
C1 G1
x x
0 0
w w
v
.c c
I y
~r .i
>. r-11 >.
o ~, o .c
N .1 C
ro~ C! O N
d to .~ .-i
I
.~.tW y~ U b'
I
I I
N M M M M
v v
c c
.~ .,
C C
b ro
x x
v o 0
a~ c N .
~1 a~ w ~o
o .c a. a~
N Lr~ .C C
ro roo I v
...i sr-..mr ,-i
s ~ .c I
.u w ~ o
O O O w
C C C O N
d rl.1 rl
E 6 E ~ I
ro roro U d' n
1 I 1 I ~ .-1
N M M M M 00
O~
V fnJJ ~ ' M
:L3~U'~82
-26-
Example 22
In the described fashion of Example 1(f),
replacing t:he acid ester (III) (R1=phenyl, X=C1,
R1=C2H5) with the acid ester (III) of the
compounds 7.isted in Table I of Example 21 and also
replacing ~!-acetylpiperazine with an appropriate arnine
such as N-methylpiperazine, N-acyl piperazine,
pyrrolidiner, 3-hydroxypyrrolidine, .
3-acetamidopyrrolidine, 3-dimethylaminopyrrolidine,
piperidine, morpholine, thiomorpholine,
2,6-dimethylpiperazine, homopiperazine, dimethylamine
and 2,2-dimethylhydrazine, one can obtain the following
additional compounds as summarized in Table II.
1340'lR2
-27-
1
0
I 1 1
c
a a a .,
~
v v v .-~.~ ~ .-I .-i .-r E
r.i
c1 sz, n. >.~ >, ~, ~, >. m
~
~r?~ ~r ..~ .~ .~ C C I 1 C C .-~
C C C
C C C GL C1 C1 ..i..-~ ?~ >r .~ .~ >,
.a -i .a
.,.,.,..,.1 ~ ~ ~o'O x x I 1 .C
'O w 'Q 'O ~o
N N N ?~ ?~ ?i -1.a O O O O 1.i
.,.~.,..i.~ -~ .-I
m m m .a ~ ~c ~,~, a L C c v
.~ .-, ~., ,~ .-~ -~ -, -~
_ a a a w y ~ O O ~D 'O ~ ~ E
?, ~., ~., O O O O O
x v v v v G) v a a ~1 ~Y E E .rl
I G G" f; a L l~ a H
IIN L1WL 1~ E E E a LJ .C. .C m m' ~
~ W W w-1 a a a f..~1.~
--rI I I ?,~., 1 I 1 I I
N N N ~y ?r ?~ ?~ ~
x w w w z z Z c~n, M M M M M
m m m p, p, p, CL C1
'D
N
C
r-I r.~~ 1
m >,.1 ~. >, o
c >, c c c ~ .., .i .-, .1
v c v v 1 r-I..r >. >, ~ ~., ~,
O .Cv .C .C - ?~E C G C C C
w .c a, Q. ~r v m v v v v v
7rCL O ?t .-t I .Crl .C .C .C .C .C
x >. .u x ?, rr oa>. n. c~. c1 d cz,
w o x w o w >, o .c o 0 0 .~ o
C a O m a ..a ~ a y a a a ?, a
.~~
~ ~p~ U ~p a ~ O N O O O .C O
I ?~ ~
O ~ y a >. ~. v c E ~ ~--Im ..~
'D >.
.Cv v .C O. E -~...~ ~ ,C .-1 N .-i
~ C
E I E E 1 I I w ~O w U w E w
a v
O - I 1 - - - 1 I I I I 1 I
ar ~C
U w L1 C1 sr ~a M O f1 O LL O t1 GL
p, CL
'O ...i
NU! p.,'~t r-i.fit~1 ?1 O
D C ~rC C GL ri C ri r.l ri .-i
' .-1
u v C Q v I ?~ n-1 ~r ~t ?v ?~ ~Y
1
H x pc v .~ .c - c E C C C Cc
,a~ N w ~ n~ w ~ v m v v v v v
y-~ U >r 11O ~ ~ I .C .~ C ~ .C .C s
~
a x >,.u x ~., .., a' a, tz.a, . w c1
a.
E,w .-~o x a o w >. o ~ 0 0 0 ~ o
C c>~a O m a ...~~ a ~ a a a >.,
a
'Q ~ U 'O W J p U O O O ~ O
.i
O ?~ ~ a ?~ >r N ~ E C rl C t~
7v
.i.C v v ~ CL E .-i ..a ~-I~ .-a v .-i
C
E U I E E 1 t 1 w ~p w U w E w
U
O II- I I - _ _ 1 t I I 1 I 1
.C
U x er W i1 a' ~ M O C' O C1 O LL CL
GL
v
C
...a
C v N .i
v C C .~i
E ~ ..a
O
v v v ~O 'a a
U C C .~ .~ a
m v v v .,~..~ r., ,..,
c c c w w o o w
.'.,..a ..., ...,.,, " a I
ro m
o o ~ >, c
a Sd a a S-t CL (1,
.i
v v v v a a I 1
C c1 w w v v >. ~. O O m
~ v v v ..~ .,~ .~, c c n. a ~a ~ ,-,
I
N N C C G LL Ll, LL ..1 -rl ?~ ?~ .1 ,-i
~r
m .a ..,.,~.1 ~-~ .i w w x x E E .c
a N N N ?~ ? Wy .-1 r-1 O O m m ll
v m m m s .a .c .~ ~.I a ~, ,~ " v
a a a ~ L ~ O O 'D 'D U ~ E
-.r v N d N v N a a ~ ?v U U
GL G,C1 E E E a a ~ ,c m m ~p
.r ..a..aI 1 I >, >, I I I I 1
p. LLL1 Z E Z G1 GL M M M M M
~J
Q . . .
U .-iN M d If1 l0 I~ p~ p~ O ~..~ N M
m ri r1 n-1
ri
1340'~~z
-28-
~. ~, >. >.
c c I c o 1 c
.., .~,c r,
r-1r1 rl rlri .1 rl ri ri .?i N r-~?~ r-1 rl rl n-1 ra
r-1
~ >, ~. ~,>, >, ~ o o .c ro E ~ o ~ ~, ~ >.
>,
c C C C c c c .c .c y a ro +~ .c C C c C
c
c1 c~.v v -1 v a~ -.~.,
..~ .1
'fl'O '1?'a.-1ri ri a 1r E C1 ?~ E S-r .-iri 'Q N
N ?v
ro rl ..a.iO O O O O .a .~ .C .~ O O O -~ ro
ro N
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It. will be understood that carious changes and
modifications can be made in the details of procedure,
formulations and use without departing from the spirit of
the in~enti.on, especially as defined in the following
claims.
