Note: Descriptions are shown in the official language in which they were submitted.
16~5~693
2,4,6-TRIIODO-5-~ETHOXYACETA~IDO-N-METHYLISOPHTHALAMIC
ACID AND SALTS, ACYL HALIDES AND E.STERS THER~F
BACT'~.ROUND OF THE INVENTION
This invention relates to the field of organic chemistry,
and more particularly to 2,4,6-triiodo-5-methoxyacetamido-
N-methylisophthalamic acid and certain salts, acyl halides
and esters thereof. These compounds are useful as x-ray
contrast agents.
G. B. Hoey (U.S. Patent 3,145,197/1964) disclosed 5-acetamido-
2,4,6-triiodo-N-methylisophthalamic acid and its salts and
their utility as components of aqueous x-ray contrast media.
Subsequently, the coined terms "iothalamic acid" and
"iothalamate" were applied to these compounds. A profuse
literature relating to the radiological uses of these com-
pounds has been published in succeeding years.
H. Priewe et al. of Schering ~. (DAS 1,129,260/1962) disclosed
the preparation of 3-acetamido-5-methoxyacetamido-2,4,6-
triiodobenzoic acid and proposed its use as an x-ray contrast
agent. They reported this compound as having an LD50 (i.v.
in rats) of 16 g/kq.
Subsequently, H. Pfeiffer et al., also of Schering A~,
(DOS 2,118,219/1972), reported that, notwithstanding the
favorable toxicity data in rats, this compound causes strong
circulatory distur~ances in dogs and man.
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1~53693
The use, as x-ray contrast media, of aqueous solutions of
salts of various 2,4,h-triiodoisophthalamic and other 2,4,6-
triiodobenzoic aeids with pharmaceutieallv acceptable eations,
e.g., sodium, ealeium, magnesium and alkanolamines, such as
ethanolamine, diethanolamine and meglumine (N-methylglucamine),
is well known to those skilled in the art.
SUMMARY OF THE INVENTION
Among the objects of the invention may be mentioned the
provision of new isophthalamic acid derivatives; the provision
1~ of new 2,4,6-triiodoisophthalamic acid compounds; the provision
of compounds of the type indicated which are useful for the
preparation of roentgenographie eontrast media; and the
provision of methods of preparing sueh eompounds. Other objects
will be in part apparent and in part pointed out hereinafter.
The present invention is direeted to 2,4,6-triiodo-5-methoxy-
aeetamido-N-methylisophthalamic acid and salts and acyl halides
and ester derivatives thereof. The salts of the aeid with
pharmaceutieally aeceptable cations are useful in the prepara-
tion of x-ray contrast media intended primarily for intra-
vascular administration. Other salts, sueh as ammonium salts,are useful as intermediates. Esters of the aeid are useful
in x-ray eontrast media intended primarily for use in instilla-
tion procedures. Aeyl halide derivatives of the aeid are
useful as intermediates for the preparation of amides and
other non-ionie derivatives.
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1053693 P(1-0002
In a preferred method, 5-amino-2~4~6-triiodo-N-met1lyl-
isophthalamic acid is acylated by rcaction with methoxyacetyl
chloride, which may be generated in situ by treating methoxy-
acetic acid with thionyl chloride. The æylation reaction
is carried out utilizin~ a polar aprotic solvent, preferably
N,N-dimethylacetamide, as a reaction medium. Other polar
aprotic solvents that may be utilized include dimethylformamide,
N-methylpyrrolidone, etc.
Alternatively, the acid of the invention may be prepared as
follows:
5-Amino-2,4,6-triiodo-N-methylisophthalamic acid is treated
with an haloacetyl halide, such as bromoacetyl chloride or
chloroacetyl chloride, in N,N-dimethylacetamide to give a
S-haloacetamido-2,4,6-triiodo-N-methylisophthalamic acid.
The solvent is removed and the product is treated witll sodium
methoxide in methanol to provide 2,4,6-triiodo-S-methoxy-
acetamido-N-methylisophthaiamic acid.
2,4,6-Triiodo-5-methoxyacetamido-N-methylisophthalamoyl
; chloride or other acyl halides of the invention may be made
by the following general method.
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1053693 PG-0002
2~4~6-Triiodo-5-methoxyacetamido-N-methylisoph~halamic scid
is treated with excess thionyl halide in N,N-dimethylacetamide.
After removing the unreactcd thionyl halide by evaporation
under reduced pressure, the product is suitablc for use as
an intermediate in situ. Alternatively, the product is
isolated by evaporating the solvent under vacuum.
~rhe lower alkyl 2,4,6-triiodo-5-methoxyacetamido-N-methyl-
! isophthalamates of the invention may be prepared by the
following general method. A 2,4,6-triiodo-5-methoxyacetamido-
N-methylisophthalamoyl halide is treated with excess anhydrous
i lower alkanol in N,N-dimethylacetamide in the presence of
`1 potassium carbonate. After the reaction is complete, the
reaction mixture is filtered to remove the inorganic salts
and the lower alkyl 2,4,6-triiodo-S-methoxyacetamido-N- ~ ~
methylisophthalamate is isolated by evaporating the excess 1~-
alcohol and the solvent.
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PG-0002
1053693
Example 1
A solution of methoxyacetyl chloride in N,N-dimethylacetamide
wns prepared by adding thionyl chloride (41.76 ~., 0.36 mole)
dropwise, with stirring, to a cooled solution of methoxyacetic
acid (32.4 g., 0.36 mole) in N,N-dimethylacctamide (150 ml.)
at æuch a rate that the temperature of tbe reaction mixture
was maintained at 0-10 C. After the addition the solution
J was stirred at 0-5 C. for one hour. To this solution of
.~f methoxyacetyl chloride (at 0-8 C.) was added, in portions,
a slurry of 5-amino-2,4,6-triiodo-N-methylisophthalamic acid
(85 8 g., 0.15 mole) in N,N-dimethylacetamide (150 ml.).
After the addition of the slurry, tle reaction mixture was
stirred at 0-5 for 2 hours after which the temperature was
ralsed eo 25-30. When the reaction mixture reached room
temperature, a clear solution was obtained, and was allowed
to stand overnight.
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Water (90 ml.) was atded to the solution witll cooling (solution
~ temperature below 25) and the solution was stirred for 30 min.
Water and N,N-dimethylacetamide were evaporated under vacuum,
leaving a white solid residue. The product was slurried in
water (100 ml.) and ~N NH40H (500 ml.) was added, followed
by 50% NaOII (about 10 ml.) until a clear solution was obtaincd.
Tlle solution was filtered and was then addcd dropwise to a
s~irring mix-urc of wacer (500 ml.) and sulf-lric acid (100 ml.)
with coolin~. Th~ rR~ultin~ precipitaLe of 2,4,6-triiodo-S-
methoxyacctamido-N-mctllylifiopll-halamlc acid w~s collect~d and
dricd.
1~ 5
1053693 PG-0002
Yield, 90 g. (93%). Examination by TLC with two systems --
ethyl acetate:methanol:acetic acid (10 5 1) and isobutyl
alcohol:isopropyl alcohol:ammonium hydroxide (28~/o N}~3)
(10:4:4) showed a single spot in each casc. IR and MMR
spectra are in agreement with the postulated structure.
An analytical sample was further purified by preparin~ a
¦ solution of the sodium salt, adding this solution dropwise
I to a cold stirred solution of 6N hydrochloric acid, slurrying
the precipitated free acid in water, collecting the acid and
drying it. Anal. Cslc'd- for C12~ 3N25 C~ 22-38%; H~
1.72%; I, 59.12%; N, 4.35%; N.E., 643.93. Found: C, 22.08%;
H, 1.80%; I, 58.90%; N, 4.27%;:N.E., 648.61; M.P. 285.8-287.8 C.
(dec.).
~ Example 2 --
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- 2,4,6-Triiodo-5-methoxyacetsmido-N-methylisophthalamic acid
(6.005 ~.) was dissolved in water with NaOH solution at
pH 7.4 to form a supersaturated solution (7.0 ml.). ~len --
the solution was allowed to stand at room temperature overnight, ~. -
crystalllzation occurred. The crystsls were collected and
~; 20 dried.
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1~53693
The sodium salt (2.71 g.) was then dissolved in water to
form an 82% w/v solution (3.3 ml.). After the solution was
allowed to stand at 2~ overnight some crystallization
occurred. The solution was stirred and the supernatant was
taken (by centrifugation) for specific gravity measurement
(sp. gr. 1.43) and for water determination (found, 49.7~ w/v
by Karl Fischer method). The solubility of the sodium salt
i in water was therefore determined to be about 70~ w/v at 24.
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The solubility is highly temperature dependent.
Example 3
2,4,6-Triiodo-5-methoxyacetamido-N-
methylisophthalamoyl chloride
A solution of 2,4,6-triiodo-5-methoxyacetamido-N-methyl-
isophthalamic acid in N,N-dimethylacetamide is treated with
an excess of thionyl chloride. After the reaction, the
excess thionyl chloride is removed by evaporation and the
product is suitable for use as intermediate in situ.
Example 4
Ethyl 2,4,6-triiodo-5-methoxy-
acetamido-N-methylisophthalamate
A solution of 2,4,6-triiodo-5-methoxyacetamido-N-methyl-
isophthalamoyl chloride in N,N-dimethylacetamide (prepared
as in Example 4) is treated with absolute ethanol in the
presence of potassium carbonate. After the reaction is complete,
the inorganic salts are removed by filtration and the filtrate
is evaporated to dryness to provide ethyl 2,4,6-triiodo-5-
methoxyacetamido-N-methylisophthalamate.
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~53693 :
Example S
A buffered stabilized solution of sodium 2,4,6-triiodo-5-
methoxyacetamido-N-methylisophthalamate is prepared bv adding
with stirring, sufficient sodium hydroxide pellets to a slurry
of 2,4,6-triiodo-5-methoxyacetamido-N-methylisophthalamic acid
(494 g.) in water (650 ml.) to dissolve the acid and provide
a neutral to faintly acid solution, adding calcium disodium
.~ edetate (400 mg.), trisodium citrate dihydrate (2.47 g.),
t, adjusting the pH to the range 6-7, if necessary, by titration
with 5 _ sodium hydroxide solution, diluting the solution to
about 900-950 ml., titrating to pH 7.4 with 0.1 N sodium
hydroxide, and finally adjusting the volume to exactly 1000 ml.
The resulting solution, containing 292 mg. iodine per milli-
liter is subdivided into vials and is sterilized by autoclaving.
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Example 6
:.
A buffered, stabilized solution of meglumine 2,4,6-triiodo-
5-methoxvacetamido-N-methylisophthalamate is prepared by
stirring sufficient meglumine (N-methylglucamine) into a
slurry of 2,4,6-triiodo-5-methoxyacetamido-N-methylisophthalamic
acid (338 g.) in water (250 ml.) to dissolve the acid and
provide neutral to faintly acid solution, adding calcium
disodium edetate (55 mg.), making the solution faintly alkaline
(pH ~.4) by the careful addition of a solution of meglumine,
adding sodium dihydrogen phosphate (70 mg.) with stirring,
readjusting the pH to 7.4 and diluting the solution to 500 ml. - :
The resulting solution, containing 400 mg. of iodine per ~ -
milliliter, is subdivided into vials and is steriliæed by
autoclaving.
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~ 1053693
Example 7
To a stirred slurry of 592 g. of 2,4,6-triiodo-5-methoxy-
acetamido-N-methylisophthalamic acid in 600 ml. of water are
added at 55 C., l.n3 g. of magnesium chloride hexahydrate,
2.31 g. of calcium chloride dihydrate, 20 g. of sodium
hydroxide pellets, 52.2 g. of N-methylglucamine, 110 mg. of
calcium disodium edetate, and 125 mg. of sodium dihydrogen
phosphate. The formulation is then adjusted to pH 7.4 using
a solution of 7.8 g. of N-methylglucamine and 3 g. of sodium
hydroxide in 50 ml. of water. The pH adjustments are effected
under a nitrogen atmosphere. After diluting to a final volume
of a little less than l,000 ml., the solution is stirred under
nitrogen overnight at room temperature, readjusted to pH 7.4
`I the next day, and diluted to a final volume of 1,000 ml. This
formulation contains 350 mg. iodine per milliliter. It is
subdivided into ampuls and sterilized by autoclaving.
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1053693
Satisfactory intravenous urograms are obtained when anv of
the preparations described in Examples 5-7 is administered to
dogs at a dosage of 350 mg. I/kg.
Toxicity evaluations by three different techniques were
carried out on solutions of the meglumine salts of the
2,4,6-triiodo-5-methoxyacetamido-N-methylisophthalamic acid
of the invention and of the known compound iothalamic acid.
The techniques utilized are outlined below.
I. Acute Intravenous Toxicit~ Studies in Mice
Swiss Albino mice (Charles River) were dosed in the lateral
tail vein with solutions of the iodinated compound containing
28.27% of iodine, injected at the rate of l ml/min. Following
injections the animals were observed for immediate reactions
and then daily throughout a seven day observation period.
The LD50 values were calculated by the method of Litchfield
and Wilcoxon (J. of Pharmac. and Exptl. Therap. 96:99-113,
1949)-
II. Intracerebral Toxicity in Mice
Swiss Albino mice (Charles River) were used. Fixed volumes
of solutions of various concentrations of the iodinatedcompounds were injected intracerebrally via a 27 gauge needle,
(1/4 inch length) according to the method of Haley, et al.
(Br. J. of Pharmac. 12:12-15, 1957). The animals were observed
immediately after injections and daily throughout a seven day ~-
observation period. The LD50 values were calculated by the
method of Litchfield and Wilcoxon (J. of Pharmac. and Exptl.
Therap. 96:99-113, (1949). ~- ~
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1~53693
III. Intracisternal Toxicity in Rats
Sprague Dawley (Carworth) rats were used. The method used
is a variation of the procedure outlined bv Melartin et al.
(Invest. Rad. 5:13-21, 1970). After dosing, the animals were
housed individually, and observed for immediate reactions
and periodically for a two day observation period. The LD50
values were calculated accordinq to the method of Litchfield
and Wilcoxon, (J. of Pharmac. and Exptl. Therap. 96:99-115,
1949).
The results of these toxicity evaluations are set forth in
Table 1.
Table 1
Toxicity Values for Meglumine Salts of
2,4,6-Triiodo-5-Methoxyacetamido-N-Methyl-
isophthalamic Acid and lothalamic Acid
LD5n of Meglumine Salt*
Intracerebral Intracisternal
Acid I.V. (Mice) (Mice) (Rats)
2,4,6-Triiodo-5- fi700 700 40
Methoxyacetamido-
, N-methylisophthal-
' amic Acid
Iothalamic Acid 5742 280 86
*All Ln50 values are expressed in terms of mq. contained
iodine/kg. animal body weiqht.
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1053693 PG-0002
The impressive IV LDso value for the meglumine salt of
2,4,6-triiodo-5-methoxyacetamido-N-metllylisophthalamic acid
suggests th~t this and other non-toxic water soluble salts
of this acid would be superior x-ray contrast agents for
intravenous urography and other intrsvascular roentgenographic
procedures.
In view of the above, it will be seen that the several
ob~ects of the invention are achieved and other advsntageous
results obtained.
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As various changes could be made in the above products and
methods without departing from the scope of the invention,
it is intended that all matter conta}ned in the above
description shall be interpreted as illustrative and not in
::
. a limiting sense.
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