Note: Descriptions are shown in the official language in which they were submitted.
~;~55~i73
THE INVENTION
This invention relates to a novel class of trihalo(amine)-
gold(III) complexes which are useful as anti-tumor agents in
mammals. These compounds exhibit excellent activity against
maliynant tumor cells in animals as well as low mammalian
to~.icity.
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It is a further object of this invention to provide gold
complexes which may be administered both orally and paren-
terally.
In its broadest aspects, this invention relates to gold
complexes having the formula: AULX3 where Au represents gold, L
is a nitrogen-containing ligand such as an aliphatic amine, an
aromatic amine or a heterocyclic amine and X is chloride or
bromide.
More specifically, this invention relates to compounds of
: the formula:
L \ A /
X/ , \X
wherein:
Au represents gold in its trivalent state, i.e., Au(III);
L is a member selected from the group consisting of a
pyridine of the formula:
wherein Rl is selected from arnong:
Cl 6 alkyl as, for example, methyl, ethyl,n-propyl
and the like;
carboxy;
C2 6 alkanoyl as, for example, acetyl,n-propionyl or
n-butyryl and the like;
carboxy Cl 6 alkyl as, for example, carboxymethyl or
carboxyethyl and the like;
carbinol;
hydroxy; and
Cl 6 alkoxy as, for example, methoxy, ethoxy, or
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n-propoxy and the like;
a pyridazine of the formula:
I 1/~ R2
\ N ~
wherein R is selected from among:
hydrogen and the same groups as Rl;
a pyrimidine of the formula:
N
- ~N
a pyrazine of the formula:
N 3
an imidazole of the formula:
N
R2~N
l3
wherein:
R3 is Cl 6 alkyl as, for example, methyl, ethyl and
the like;
a pyrazole of the formula:
R2 ~ N
N /
R4
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wherein;
R4 is hydrogen or Cl 6 alkyl as, for example,
methyl, ethyl, and the like; and
alkylamine as, for example, an alkylamine of from
about 1-6 carbon atoms but, preferably, a lower
alkylamine of from about 1-3 carbon atoms such as
methylamine, ethylamine, isopropylamine and the
like;
an arylamine of the formula:
NH2
(R5) ~ ~1
wherein R5 is Cl 6 alkyl, Cl_6 alkoxy, hydroxy, C2_6
alkanoyl, or halo such as chloro,
bromo, or fluoro and the like and n is an integer
having a value of 0-3; and
X is selected from the group consisting of chloro or
bromo with the proviso that X represents chloro when L repre-
sents 3-pyridylacetic acid.
The "proviso" in the definition of "X" excludes a species
which is inactive as an anti-tumor agent under the test condi-
tions hereinafter described. This species is the product
formed when X represents bromo and L represents 3-pyridylacetic
acid, that is, the tribromo(3-pyridylacetic acid)gold(III3 of
Example 10. See in this regard the ~ILS data for this compound
in Table 1, infra. By contrast, the complex which results when
X is chloro and L is 3-pyridylacetic acid [i.e., trichloro-
(3-pyridyacetic acid)gold(III3J exhibits a pronounced anti-
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tumor effect.
The compound wherein L is pyridine (Rl is hydrogen) isreferred to in the literature but no utility is suggested. It
is useful herein to produce active pharmaceutical compositions.
A preferred embodiment of this invention relates to
gold(III) complexes in which the nitrogen containing ligand is
a mono substituted pyridine or imidaæole of the formula:
L \ / X
Au
xl/ \xl
wherein Ll is a member selected from the group
consisting of a pyridine of the formula:
~ N~L Rl
wherein Rl is selected from among carboxy, C2 6
alkanoyl, carboxy Cl_6 alkyl, carbinol, hydroxy and
Cl_6 alkoxy; and
an imidazole of the formula:
R2~"f
R
wherein R is hydrogen and R3 is Cl_4 alkyl; and
xl is selected from the group consisting of chloro or
bromo, with the proviso that Xl represents chloro
when Ll represents 3-pyridylacetic acid.
This class of complexes exhibits a pronounced anti-tumor
activity in mammals and it is useful in oral and parenteral
administrations over a wide range of dosages.
An especially preferred subgroup within this embodiment
consists of Au(III)Ll(X )3 complexes in which L represents a
ligand selected from the group consisting of (1) a pyridine
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substituted by carboxy or C2_6 alkanoyl, or ( 2) an N-Cl 4 al~yl
imidazole; and Xl is chloro or bromo. Typical of the
nitrogen-containing ligands (Ll) falling with this subgroup
are, for example, nicotinic acid, 3-acetylpyridine and
N-methylimldazole. The corresponding complexes exhibit the
highest ascertained order of anti-tumor activity when compared
against other complexes in this series and against known
analogs.
It is essential for activity tha-t the nitrogen atom of the
imidazole nucleous be substituted by a lower alkyl moiety, a
fact which can be demonstrated by comparing the ~ILS values for
trichloro(imidazole)gold(III) and trichloro(N-methylimidazole)-
gold(III) in Table 3. Thus, whereas, the former (Example 9) is
inaetive in bringing about a regression of S 180 ascites at all
doses tested, the latter eompound (Example 4) is deeidedly
active within the 20-40 mg/kg range.
PREPARATIV~ MET~IOD
The products o~ this invention may be obtained by treating
equimolar amounts of alkali mètal tetrahaloaurate with the
appropriate amine (L). The precipitate which forms is filtered
from solution and it may be washed with water to afford a
purified product:
L \ X
KAux4 + L ~ AU
X X
wherein AU represents gold in the trivalent state, L is an
aliphatic amine, an aromatic amine or a heterocyclic amine of
the type hereinbefore described and X is chloro or bromo. The
reaction is preferably conducted with stirring at temperatures
below about 25C and, most preferably, at temperatures of about
OC.
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This process is conducted in an aqueous solution such as
water but other media as, for example, an alcohol such as
methanol or ethanol also may be employed.
Certain of the products, for example, the [Au(nicotinic
acid)X3] and [Au(pyridylacetic acid)X3] of Examples 1, 4, 10
and ll are soluble in 1~ sodium bicarbonate solution to the
extent of 12.8 mg/ml.
The infrared spectral data shows intense AuCl bands at
approximately 350 cm 1 for all analyzed complexes and this is
consistent with the assigned structure for the products.
Gold content was determined by the gravimetric method
described by F. E. Beamish in "The Analytical Chemistry of the
Noble Metals"; Pergamon Press, Oxford, page 321 (1966).
PHARMACOLOGY
The products of this invention are useful in the treatment
of tumors in anlmals as, for example, Sarcoma 180 ascites
tumors in mammals such as mice. This anti-tumor effect also
may extend to other sarcomas and to such other tumors as the
following: lymphoid leukemia, lymphosarcoma, myelocytic
leukemia, malignant lymphoma, squamous cell carcinoma, adeno-
carclnoma, scirrhous carcinoma, malignant melanoma, seminoma,
teratoma, choriocarcinoma, embryonalcarcinoma, cystadeno-
carcinoma, endometroidcarcinoma or neuroblastoma and the like.
In addition, said complexes may be useful as anti-viral,
anti-inflammatory, anti-bacterial and anti-parasitic agents.
They may be administered parenterally or orally in admix-
ture with a non-toxic pharmacologically acceptable inert
carrier or diluent in any of the usual pharmaceutical forms.
These include solid and liquid oral unit dosage forms such as
tablets, capsules, powders and suspensions or solutions and
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suspensions for subcutaneous, intramuscular, intravenous or
intra-arterial injection.
The term "unit dosage" refers to physically discrete units
which may be administered in single or multiple dosages each
containing a predetermined quantity of the active ingredient in
association with the required diluent, carrier or vehicle. The
quantity of active ingredient is the amount of the complex
which is needed to produce the desired therapeutic effect.
A typical unit dosage consists essentially of from about
5-250 mg. of active ingredient; however, the form in which said
ingredient is administered and the frequency of administration
is usually determinative of the concentration. Thus, for
example, oral unit dosage forms containing 5-250 mg. of active
ingredient may be administered one or more times per day
depending upon the severity of the tumor which is sought to be
treated and the condition of the host animal~ By contrast,
parenteral administration generally requires from about 10-125
mg. of the active ingredient per unit dosage administered as a
daily dose or as a fraction thereof depending upon whether the
regimen calls for administration once, twice, three or four
times daily.
By contrast to the "unit dosage", the effective dose is
that dosage which is needed to achieve the desired anti-tumor
effect. In general, this dosage lies within the range of from
about 2-480 mg. of the active ingredient per kg. of body weight
of the host animal. A preferred concentration lies within the
range of from about 5-250 mg./kg. of body weight. For oral
administration it has been found that an effective dose of
8-480 mg./kg. is most suitable, whereas, in the case of paren-
teral administration it is usually advisable to employ from
about 2-80 mg./kg. These dosages are well below the to~ic or
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lethal dose and they may be varied over a wide range for
adjustment to the patient which is being treated.
In this invention the term "pharmacologically acceptable
inert carrier or diluent" denotes a non-toxic substance which,
when mixed with the active ingredient, renders it more suitable
for administration. Compositions intended for oral administra-
tion may include such carriers or diluents as corn starch,
potato starch, sodium carboxymethyl cellulose, ethyl cellulose,
cellulose acetate, powdered gum tragacanth, gelatin, alginic
acid, agar, stearic acid or the sodium, calcium and magnesium
salts of stearic acid, sodium lauryl sulfate, polyvinylpyrroli-
done, sodium citrate, calcium carbonate and dicalcium phos-
phate. Said compositions may also contain non-toxic adjuvants
and modifiers such as dyes, buffering agents, preservatives,
surfactants, emulsifiers, flavoring agents or biocides and the
like.
Tablets are prepared by mixing a complex of this invention
in a suitably comminuted or powdered form with a diluent or
base such as starch, kaolin, dicàlcium phosphate and the like.
The resulting mixture can be granulated by wetting with a
binder such as a syrup, starch (paste), acacia mùcilage or
solutions of cellulosic or polymeric materials, whereafter, the
wetted mixture is forced through a screen. As an alternative
to granulating, the powdered mixture can be run through a
tablet machine and imperfectly formed sl~gs broken into gran-
ules. The granules are lubricated to prevent sticking to the
tablet-forming dies via the addition of stearic acid, a stear-
ate salt, talc or mineral oil and the lubricated mixture is
then compressed into tablets. The complexes can also be
combined with free flowing inert carriers followed by
compression into tablets without going through the granulating
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or sluyging steps. A protective coating or sealing coat of
shellac, sugar or polymeric material and a polished coating of
wax can also be provided. Dyestuffs may be added to distin-
guish different unit dosages.
Capsules are formula-ted by preparing a powdered mixture,
according to the procedure hereinbefore described and pouring
said mixture into preformed gelatin sheaths. A lubricant such
as talc, magnesium stearate or calcium stearate can be added as
an adjuvant prior to the filling operation. A glidant such as
colloidal silica may be added to improve the flow characteris-
tics and a disintegrating or solubilizing agent may also be
added to enhance the effectiveness of the medicament upon
inyestion.
Powders are prepared by comminuting the compound to a fine
size and mixing with a similarly comminuted pharmaceutical
diluent or carrier such as an edible carbohydrate as, for
example, starch. Sweetenlng agents and flavorings, preserva-
tives and dispersiny and/or coloring agents may also be
employed.
Oral fluids such as syrups and elixirs are prepared in
unit dosage form so that a given quantity of medicament, such
as a teaspoonful, will contain a predetermined amount of the
active ingredient. Suspensions can be formulated by dispersing
the active ingredient in a non-toxic vehicle in which it is
essentially insoluble.
Fluid unit dosage forms for parenteral administration can
be prepared by placing a measured amount of the complex in an
ampoule or vial which is sterilized and sealed. An accompany-
ing vial or vehicle can be provided for mixing with said
complex prior to administration.
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This invention also provides for combining two or more of
the subject complexes into a single unit dosage form or,
alternatively, combining one or more of said complexes with
other known anti-tumor agents, therapeutic agents or nutritive
agents and the like so as to enhance or complement the anti-
tumor effect.
The preferred compositions for oral administration are
tablets in which the gold complex is present in quantities of
5-250 mg. but, preferably, 20-lO0 mg. in a pharmaceutically
acceptable orally ingestible solid carrier. If desired, the
composition may also contain flavors, binders, lubricants and
other excipients known in the art.
A preferred alternative Eor oral administration is the
soft gelatin capsule. Such a composition may contain from
5-250 mg. but, preEerably, 20-lO0 mg. by weight of active
ingredient dissolved or suspended in vegetable oil, peanut oil,
alcohol or glycerine and the like.
The following embodiments illustrate representative unit
dosage forms.
Compressed Tablet
.
A tablet suitable for swallowing is prepared by mixing the
following ingredients:
Trichloro(Nicotinic Acid)gold(III) 50 mg.
Niacinamide 50 mg.
Calcium Pantothenate 20 mg.
Magnesium Sulfate 50 mg.
Zinc Sulfate 50 mg.
~agnesium Stearate 10 mg.
230 mg.
The trichloro(nicotinic acid)gold(III), niacinamide, calcium
pantothenate, magnesium sulfate, zinc sulfate and magnesium
12
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stearate (5.0 mg.) are mixed and compressed into slugs. The
slugs are then broken into granules and sifted through an 8
mesh screen. Additional magnesium stearate (5.0 mg.) is added
and the mixture is then compressed into tablets suitable for
oral administration.
Soft Gelatin Capsule
A soft elastic gelatin capsule is filled with the follow-
ing ingredients:
Trichloro(3-Acetylpyridine)gold(III) 100 mg.
Wheat germ oil 50 mg.
Sunflower seed oil 100 mg.
250 mg.
The trichloro(3-acetylpyridine)gold(III) and wheat germ
oil are mixed with sunflower seed oil and the resulting mixture
is poured into gelatin capsules suitable for oral
administration. An alternative embodiment provides for
substituting sunflower seed oil and wheat germ oil with equal
amounts of peanut oil to obtain an otherwise similar capsule
which is also suitable for oral administration.
Dry Filled Capsule
A hard dry-filled capsule may be prepared from the follow-
ing ingredients:
Trichloro(Nicotinic Acid)gold(III) 75 mg.
Niacinamide 50 mg.
Calcium Pantothenate lO mg.
135 mg.
The trichloro(nicotinic acid)gold(III) is reduced to a No.60 powder. Niacinamide and calcium pantothenate are passed
through a No. 60 bolting cloth and the ingredients are added to
the trichloro(nicotinic acid)gold(III). This combination of
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ingredients is mixed for 10 minutes and then poured into a No.
3 size gelatin capsule.
Dry Powder
The following composition illustrates a representative
dosage in dry powder form. In this embodiment the active
ingredient is combined with up to 60~ by weight of a suitable
flavoring agent. All quantities are in a weight-percent
relationship.
Trichloro(N-~ethylimidazole)gold(III) 25-90%
Flavoring Agent 10-60%
Preservative 0-1.0%
The trichloro(N-methylimidazole)gold(III), flavoring agent
and preservative are thoroughly blended to afford a homoseneous
dry powder. The resulting formulation may be blended with
other therapeu-tic agents to afford combination-type medicinals.
Alternatively, said powder may be dissolved in a pharmacologi-
cally acceptable diluent to afford a solution which is suitable
for oral administration.
Compositions intended for parenteral administration may
include such diluents and carriers as water-miscible solvents
as, for example, sesame oil, groundnut oil and aqueous propy-
lene glycol. Typical of said compositions are solutions which
contain the active ingredient in sterile form. An embodiment
illustrating a dosage form suitable for intravenous injection
is set forth below.
Parenteral Solution
Injectable solutions can be formulated by mixing an
ampoule of active ingredient with an ampoule of sterile
diluent:
Ampoule: Trichloro(Nicotinic Acid)gold(III) 100 mg.
Ampoule: Sterile 1~ NaHCO3 (Diluent for
Injection) lO cc.
1~
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The trichloro(nicotinic acid)gold(III) and aqueous NaHCO5 are
mixed thoroughly immediately prior to administration. If
desired, one or more other active ingredients may be added to
provide an injectable solution having enhanced therapeutic
activity.
The following embodiments illustrate the methods by which
the products (I) of this invention are obtained, however, it is
to be understood that said embodiments are merely illustrative
and they are not to be construed as being limitative of the
invention herein described and claimed.
Example 1
Trichloro(Nicotinic Acid)Gold(III)
Potassium tetrachloroaurate (KAuCl4 2H2O; 1.04g,2.5
mmoles) was dissolved in water (10 ml) and the solution cooled
to 0C. A suspension of nicotinic acid (0.308g, 2.5 mmoles) in
water (5 ml) was added and the mixture was stirred at 0C for
10 minutes. The resulting yellow product was filtered, washd
with two 10 ml portions of water and vacuum dried to afford
0.79g (74.1%) of trichloro~nicotinic acid)gold(III).
Gold Analysis for AuC6H5NO2Cl3 2H2O:
Calculated: 42.59%
Found: 42.47%
Example 2
Trichloro(N-Methylimidazole)Gold(III)
The procedure of Example 1 was repeated except that an
equmolar quantity of N-methylimidazole was substituted for the
nicotinic acid therein described. The resulting trichloro-
(N-methylimidazole)gold(III) afforded the following analysis:
Analysis for AuC4H6N2Cl3~H2O
% Au % C % H _% N
Calculated: 48.82 12.46 1.57 7.27
Found: 49.21 12.20 1.53 7.15
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The procedure of Example 1 also was used to produce a
variety of other trivalent gold complexes. The following
equation and Table illustrate this procedure, the starting
materials employed and the products obtained thereby:
KAuCl4 + L ~~ AuLcl3
TABLE 1
AuLCl3 Complexes
.
Empirical Au Analysis (%)
Ex. L Formula *Calculated Found
3 3-Acetylpyridine 7 7 3 46.40 45.58
4 3-Pyridylacetic 7 7 2 3(2 ) 38.37
3-Hydroxypyridine AuC5H5NOC13(4H2O) 41.86 41.97
6 3-Pyridylcarbinol AuC6H7NOC13(1H2O) 45-75 46.69
7 **Pyridine AuC5H5NC13(1H2O) 49.19 49.84
8 Imidazole AUC3H4N2C13 53.03 52.93
* The water of hydration is assumed.
** This product, trichloro(pyridine)gold(III), is
referred to by L. Cattalini et al in "Inorganic
Chemistry", Vol. 5: pages 1145-1150 (1966), though
no utility is suggested for it.
Example 9
Tribromo(N-Methylimidazole)Gold(III)
By repeating the procedure of Example 1 but substituting
potassium tetrabromoaurate and N methylimidazole for the
potassium tetrachloroaurate and nicotinic acid therein des-
cribed there was thus obtained tribromo(N-methylimidazole)-
gold(III) in crystalline form.
Gold Analysis for AuC4H6N2Br3~1H2O
Calculated: 36.69%
Found: 36.54%
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The procedure of example 9 also was used to produce a
variety of trlvalent gold complexes. The following equation
and Table illustrate this procedure, the starting materials
employed and the products obtained thereby:
KAuBr4 + L ~ AuLBr3
TABLE 2
AuLBr3 Complexes
Ex L
Nicotinic Acid
11 3-Pyridylacetic Acid
By following the procedure of Examples 1 and 9 various
other AULX3 complexes are obtained. The following equation and
Table illustrate this method, the starting materials employed
and the gold(III) complexes which may be obtained thereby:
NaAuX4 + L ~ AuLX3
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TABLE 3
AULX3 Complexes
Example L X
12 Methylamine Cl
13 Pyrazine Br
14 3-Methoxypyridine Cl
Pyrazole Cl
1~ Pyrimidine Cl
17 tert.-Butylamine Br
18 Ammonia (NH3) Cl
19 Pyridazine Cl
3-Methylpyrazine Br
21 5-acetylpyrimidine Cl
22 Qulnoline Cl
23 Quinoline Br
24 Isoquinoline Br
NE13 Cl
The products of Examples 22-24 are described by Cattalini
et al in the "Inorganic Chemistry" publication cited above.
The product of example 25 is cited by J. Straehle, J. Gelinek,
and M. Koelmel in Z. Anorg. Allg. Chem., Vol 456: pages 241-260
(1979). There is, however, no disclosure in either publication
relative to the use of said products as anti-tumor agents.
Accordingly, these products share with the novel products of
this invention a common utility and, taken together, they form
the basis for the method of treatment claims which have been
appended to this Specification. In said claims the ligands
which embrace ammonia, quinoline and isoquinoline are identi-
fied as "L ".
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ANTI-TUMOR EVALUATION
The above prepared compounds were evaluated against S180
ascites in female CFW Swiss mice. The mice were weighed
(average weight: 20 g), placed into cages (six mice to a cage)
and on day zero the mice were inoculated with 0.2 ml of a
freshly prepared saline suspension (0.15 M NaCl) containing 1 x
tumor cells/ml or a total of 2 x 106 cells. This inoculum
was freshly prepared using "transfer" mice which had been
injected with tumor cells the previous week; it was obtained
via the following steps: (1) the removal of cells from the
peritoneal cavity of the sacrificed transfer mouse, (2) alter-
nate centrifugation and washing operations (2-3 times with cold
saline) to remove blood and other components, and (3) dilution
of the volume of the packed cell with saline (1:3). A final
centrifugation was carried out at 1000 RPM over a two minute
period. A cell count was made on a 2,000-fold dilution of this
1:3 suspension by means of a Coulter Counter. A final dilution
to 1 x 107 cells/ml was made based on the average count.
On day 1, solutions of the test compounds were prepared
and each mouse in a set of six were injected with the same test
compound at the same dosage. The doses were based on the
average weight of the animals (cage weight). Also, beginning
on day 1 two controls were employed containing six mice per
control:
(1) Normal Control: This consisted solely of the
carrier or diluent used in combination with the
test compound; and
(2) Positive Control: This consisted solely of the
known anti-tumor agent cis-[Pt(NH3)2C12] (Cisplatin)
in saline (8 mg/kg) to test the response oE the
biological system.
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The effectiveness of a test compound was measured in terms
of the % increase in life span (%ILS) of the test mice relative
to the Normal Control (Calculated from the day of tumor
inoculation, ie., day zero). To standardize the test data and
permit intercomparisons, the day of evaluation was arbitrarily
taken as that day corresponding to twice the mean life span (or
average day of death) of the control. This established a
practical upper limit of 100% on the %ILS attainable. For
calculation purposes the survivors on the day of evaluation
were considered to have died on that day. The %ILS was calcu-
lated as follows:
/mean-life span of test mice
~ mean-life span of control mice -lJ x 100%
ILS values in excess of 50% were interpreted as being indica-
tive of anti-tumor activity, whereas, values in excess of 75%
indicated excellent activity.
The products of Examples l, 4, 10 and 11 were administered
in a freshly prepared 1% sodium bicarbonate solution; the
remaining test compounds were administered as slurries in 0.5%
"Klucel" (hydroxypropylcellulose). All products (I) are insol-
uble in water. The results of this study are summarized in
Table 4.
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TABLE 4
Anti-Tumor Screening Data; S 180 Ascites
Example; Dose Positive Control
(Compound) (m~/kg) %ILS Survivors ~ ILS Survivors
Ex. 1
Au(Nicotinic-10 -3 0 of 6 60 0 of 6
acid)Cl3 20 60 3 of 6
'10 91 3 of 6
98 4 of 6
160 1 0 of 6
320 -69 0 of 6
Ex. 2
Au(N-Methylimi- 5 2 0 of 6 49 Oof 6
dazole)Cl3 10 14 0 of 6
33 1 of 6
91 4 of 6
53 1 of 6
160 -93 0 of 6
Ex. 3
Au(3-Acetyl- 10 -5 0 of 6 52 0 of 6
pyridine)Cl320 42 1 of 6
97 5 of 6
66 4 of 6
160 23 0 of 6
320 -90 0 of 6
Ex. 4
Au(3-Pyridyl-10 6 0 of 6 60 0 of 6
acetic Acid)-20 -15 0 of 6
Cl3 40 63 1 of 6
57 1 of 6
160 -41 0 of 6
320 -90 0 of 6
Ex. 5
Au(3-Hydroxypy- 10 9 0 of 6 96 4 of 6
ridine)Cl3 20 39 20f 6
61 3 of 6
2 of 6
160 -36 0 of 6
320 -85 0 of 6
Ex. 6
Au(3-Pyridyl-10 6 0 of 6 96 4 of 6
carbinol)Cl20 63 1 of 6
340 85 3 of 6
46 0 of 6
160 -70 0 of 6
320 -93 0 of 6
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TABLE 4 (Continued)
Anti-Tumor Screening Data; S 180 Ascites
Example; DosePositive Control
(Compound3(mg/kg)%ILS Survivors % ILS Survivors
Ex. 7
Au(Pyridine)C13 10 45 3 of 6 100 6 of 6
71 2 of 6
~0 66 3 of 6
-6 2 of 6
160 -94 0 of 6
320 -94 0 of 6
Ex. 8
Au(Imidazole)- 5 5 0 of 6 49 0 of 6
C13 10 -7 0 of 6
1 1 of 6
-16 0 of 6
37 1 of 6
160 37 2 of 6
Ex. 9
Au(N-Methylimi- 10 5 0 of 6 52 0 of 6
dazole)Br3 20 76 4 of 6
66 3 of 6
-1 1 of 6
160 -94 0 of 6
320 -94 0 of 6
Ex. 10
Au(Nicotinic-10 -23 0 of 6 40 1 of 6
Acid)Br3 20 26 0 of 6
64 2 of 6
49 0 of 6
160 -19 0 of 6
320 -95 ~ 0 of 6
Ex. 11
Au(3-Pyridyl-10 -16 0 of 6 40 1 of 6
acetic Acid)Br 20 20 0 of 6
3 40 10 0 of 6
31 1 of 6
160 -21 0 of 6
320 -92 0 of 6
Peak activity was observed at 20-80 mg/kg for all of the
test compounds and toxicity occurred within the range of
160-320 mg/kg. The following three compounds exhibited peak
ILS values in excess of 90%: trichloro(nicotinic acid)gold(III)
[Example 1], trichloro(N-methylimidazole)gold(III) [Example 2]
and trichloro(3-acetylpyridine)gold(III) [Example 3].
T'ne trichloro(imidazole)gold(III) of Example 8 and the
tribromo(3-pyridylacetic acid)gold(III) of ~xample 11 failed to
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meet the 50% ILS criterion for anti-tumor activity and, there-
fore, they are considered to be inactive in this study.
The therapeutic indices for the present compour.ds (I),
their effective dose (ED90) and lethal dose (LD50) were deter-
mined according to the method of Miller and Tainter (Reported
by R. A. Turner, "Screening Methods in Pharmacology", Academic
Press, New York, pages 61 62 (1976)). This study was conducted
with implanted Sarcoma 180 tumors in Swiss white mice and the
results of this study are set forth in Table 5; ED90 represents
the dose which resulted in a 50% increase in life span (ILS)
for 90% of the animals tested, determined graphically, and LD50
represents the lethal dose to 50% of said animals (Therapeutic
index LD50/ED90)
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Case 2021
TABLE 5
Therapeutic Indices; S 180 Ascites
Example Maximum Therapeutic
(Compound) ~ ILS (Dosage) ED90 LD50 - Index
Ex. 1
Au(Nicotinic 98(8Omg/kg) 31 180 5.8
Acid)Cl3
~x. 2
Au(N-Methylimi- 91(40mg/kg) 31 90 2.8
dazole)C13
Ex. 3
Au(3-Acetyl- 97(40mg/kg) 31 140 4.5
pyridine)Cl3
Ex. 4
Au(3-Pyridyl- 63(40mg/kg) 84 150 1.8
acetic Acid)Cl3
Ex. 5
Au(3-Hydroxy- 61(40mg/kg) 87 120 1.4
pyridlne)C13
Ex. 6
Au(3-Pyridyl- 85(40mg/kg) 43 90 2.1
carbinol)Cl3
*Ex. 7
Au(Pyridine)Cl3 71(20mg/kg) 35 80 2.3
Ex. 9
Au(N-Methylimi- 76(20mg/kg) 42 85 2.0
dazole)Br3
* This product is described by Cattalini et al in the
publication entitled "Inorganic Chemistry" cited above.
All of the test compounds exhibited indices which exceed
the 1.0 threshold limit. The trichloro(nicotinic acid)-
gold(III) of Example 1 and the trichloro(3-acetylpyridine)-
gold(III) of Example 3 afforded indices of 5.8 and 4.5 respec-
tively, figures which compare favorably with the 2.2-2.5 value
attributed to commercially available Cisplatin.
On the basis of the foregoing the complexes of this
invention have been determined to be effective anti-tumor
agents; however, the products herein-described are merely
illustrative of the invention and it is to be understood that
alterations in structure are within the skill of the artisan to
24
~255673 Case 2021
effect. Accordingly, any deriva-tives of the herein-described
compounds which prove useful in the treatment of tumors are to
be considered as being within the scope of this invention.
