Note: Descriptions are shown in the official language in which they were submitted.
52~:
l3l~lrJl ~lJMM~i~Y 01;`'1'11~ INVEN~ N
_ _____ __ __ ._ __
'l'his inventiorl relates to novel compositions of
matter useful for amel.iorating cancer diseases in mammals.
More particularly, i.t relates to therapeutic compositions
containing certain 1,4-bis(substituted-amino)anthrayuinones
or the non-to~ic acid-addi~ion salts thereof which inhibit
the growth oF transplanted mouse tumors. The invention
includes the new compositions of matter and the method of
inducing the regression and/or palliation of leukemia and
related cancers in mammals therewith. The 1,4-bis(sub-
stituted-amino)-anthraquinones of the present invention may
be represented by the following structural formula:
O Nil-Q-N~ 1
~ R 2
Nll-Q~
~R2
wherein Q is - CH2CH2-r and- ~ 1 is aminor methylamino!
ethylamino, dimethylamino, diethylamino ! piperidino or
morpholino.
-- 1 --
, ~
6~ Z~3
~so include~d within the ~urvi.ew of the present
.i.nvention are the leuco bases and tautomers tihereof which
may be represented by the followillg structural formulae
~/here.ill the coml?lete side chains at the l-l?osition and
the 4-pOSitiOIl are not dep:icted for sake of hrevity:
O Ni3-Q-N'
~ 1~ 1 (III, leuco hases)
O N~l~Q-N'
11
lS ~ I (IV, ~automeric form)
O N-Q-N
-- 2 ---
~ ~ !
~j.,~ 1
In one aspect, the present invention relates to a pharmaceutical
composition in dosage unit form comprising about one to about 400 mg. of a
compound of the fo~nula:
N~l-Q-N
~ R2
~ Q-N ~
R2
the tautomeric forms and the pharmacologically ac oeptable acid-addition
salts thereof~ ~herein Q is -CH2-CH2-; and -N ~ 1 is amino, methylamino,
R2
ethylamino, dimethylamino, diethylamino, piperidino or morpholino; in a~ix-
ture with a non-aqueous phanmaoe utically acceptable carrier.
,~,;
DETAILED DESCRIPTION OF THE INVENTION
-
The active compounds of the present invention are
obtainable as reddish brown to blue black crystalline mater-
ials having characteristic melting points and absorption
spectra and which may be purified by leaching with lower
alkanols since the free bases are insoluble in water and
some of them are insoluble in most organic solvents. The
organic bases of this invention (I, II, III and IV) form
non-toxic acid-addition salts with a variety of pharmaco-
logically acceptable organic and inorganic salt-forming
reagents. Thus, acid-addition salts, formed by admixture
of the organic free base with two or more equival~nts of
an acid~ suitably in a neutral solvent, are formed wi~h
such acids as sulfuric, phosphoric, hydrochloric, hydro-
bromic, sulfamic, citric, lactic, malic, succinic, tartaric,
acetic, benzoic, gluconic, ascorbic, and the like. For pur-
poses of this invention the free bases are equivalent to their
non-toxic acid-addition salts. The acid-addition salts of
the organic bases of the present invention are, in general,
crystalline solids, rela~ively soluble in water, methanol
and ethanol but relatively insoluble in non-polar organic
solvents such as diethyl ether, benzene, toluens, and the
like~
The active compounds of the present invention may
be readily prepared in accordance with the following reaction
scheme:
3~
-- 4 --
~6~Z
0 011
~ ¦ J -~ 1l2~ e~N~
(V~
O NH-Q-
~R
(I)
wherein Rl, R2 and Q are as hereinabove defined. In accor-
dance with this reaction scheme, quinizarin (Yl (o~r leuco-
quinizarin) is condensed with an appropriate alkylene diamine
(VI) in water or N,N,N',N'-te~ramethylethylenediamine as sol-
vent at the reflux temperature for 1-15 hours to produce the
corresponding bases. The leuco bases may be readily oxidized
to the fully aromatic derivatives (I) by a variety of methods
such as air oxidation or treatment with hot nitrobenzene, or
treatment with chloranil, hydrogen peroxide, or sodium per-
borate.
- The active compounds of the present invention
possess the property of inhibiting the growth of trans-
planted mouse twnors as established by the following tests.
I.~mphocytic leukemia P388 test (intra~ itoneal)
__
The animals used are BDFl or CDFl~mice all of one
sex, weighing a minimwn of 17 grams and all within a 3-gram
weight range. There are 5 or 6 animals per test group. The
t~lor transplant is by intraperitoneal injection of 0~1 ml.
of dilute ascitic fluid containiny 106 cells of lymphocytic
leukemia P388. The tes-t compounds are administered intra-
peritoneally on days one, 5 and 9; or 1-9 (relative to tumor
inoculation) at various dosesO The animals are weighed and
survivors are recorded on a regular basis for 30 days. The
median survival time and the ratio of survival time for trea-
ted (T~/control (C) animals are calculated. The positive
control compound is 5~-fluorouracil, dosed at 60 mg./kg. of
body weight. The results of this test with typical compounds
of the present invention appear in Table I below. The
criterion for efficacy is T/C x 100~ 125%.
-- 6 --
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. . ~, u~ co ~ o a~
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IH . _
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CO ~ OOO OO OOOOOO
CO E~ O O 111 ~DO O O Irl ~1
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w ~ oR t L
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m ~~ ~ m s~
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1:o I ` t:: o I
r~
_ - -- _
-- 7 --
- -~ - - - -
In ~n In
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U~ ~: U~ ~ U~ ~:
a a a
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r~ r~ ~ r~ ~, ~ r~ r~ ~ ~ r~ r~ r~ ~
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rO _ ___
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u~ r
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~ D ~ ~ O O O ~ ~ ~ O O
D
E~
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a o ~ ~ o
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Lymphocytic leukemia P388 test (oral)
The procedure used i5 the same as for the previ-
ously descri~ed test for lymphocylic leukemia P388 except
that the test compounds are administered orally at various
doses rather than intraperitoneally. The results of this
test with a typical compound of the present invention appear
in ~able II below. The criterion for efficacy is T/C x 100
~ 125%.
-- 10 --
:~ ~
X t~ n ~ ~~
c~ ~
~ -~ u~ ~ o o u-~
~ ~ ~ t~ ~ ~r
O~ h ~ ~ ~ ~~ ,~
.~
.~ ~
.~ ~ oou~ oo
~O ~ U~ o U~ ~ ~
W~v ~-
~ D
~ U~ ~
.,1 ~~)
~ ~0
.U~ ~ o Q
m s~
_
-- 11 --
Lymphocytic leukemia L1210 test
The procedure is the same as fo.r the Lymphocytic
leukemia P388 intraperitoneal test except that the tumor
transplant consists of lymphocytic leukemia L1210 inoculated
at a concentration of 105 cells/mouse with a mean survival
time being calcula~ed. The results with a representative
compound of this invention appear in Table III below.
i5~
a) u~
X ~ ~) N O 1
S~ ~ ~
E~`-
. .. ~ __ _~ ___ _
o o ~r ~ ~
~-~1 ~ ... ..
N
~I r~
--
~q
..
~ _a~
$ a~x~
Ul ~ V~ O In N O O
O O ~>1 11 ) N ~I N
~ _ . .
U O
~ s~
O 'O
CO~ S
.,~
O
I
N r~
~ ~ ~0
,1 ~ O O
m ~ h :~
I
~ O I
I _ -1 11~ C,) U7,_
-- 13 --
Melanotic Melanoma sl6
The animals used are C57BC/6 mice, all of the same
sex, weighing a minimum of 17 grams and all within a 3-gram
weight range. There are normally 10 animals per test group.
A one-gram portion of melanotic melanoma B16 tumor is homo-
genized in 10 ml. of cold balanced salt solution and implanted
intraperitoneally into each of the test mice as a 0.5-ml~ ali-
quot of the homogenateO The test compounds are administered
intraperitoneally on days one through nine (relative to tumor
inoculation) at various doses. The animals are weighed and
survivors are recorded on a regular basis for 60 days. The
median survival time and the ratio of survival time for treat-
ed (T)/control (C) animals are calculated. The positive con-
trol compound is 5-fluorouracil. The results of this test
with typical compounds of the present invention appear in
Table IV below. The criterion for efficacy is T/C x 100
125%.
- 14 -
~ - - -
a~a~ ~ ~
X o ~ ~ co u~ ~ ~ ~r
E~ ~
-
0 ~ u~ o ~ Ln In u~ O O O O
~ l ~ ~
)
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m ~.
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~In om~ oo oo oo
o ~ U~
~1 ~a ~a ~r~
~3 t,
R ~ ~I C r
~ O
~a~ ~
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O ~ ~,
O .
.~ ~ ~ O
~ ~0 0 ~ ~0 0
~-~ ~ ~
, ~ O , ~ O
r~ ~ O O rJ ~ O O
m s~ m ~ ~ ~
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6~2
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o u~ o ~ oIn oo Lr o L~l O O O
..... .. ..... ..
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O 0 1~ O O ~ C) ~ ~1 0 C~ O
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O ~ ~
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u~ ~ ~ ~ a) ,,
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.q o 111 ,a o ~
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ELI ~ ~ ~ E4
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-- 16 --
5~
1--~r ~ ~ o
co ~ o ~ ~r ~
r l ~ N ,-1 ~1 ~1
_ _
o In o ~ u~ u~ o
..... ..
co
~1
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-
H ~ ~ 1 0 o O
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~ ~ o o
m h s-~ ~
:
~ o l
0 u7
7 -
6S~
The active ingredients of the present invention
inhibit transplanted mouse tumor growth and induce regression
and/or palliation oE leukemia and related cancers in mammals
when administered orally in amounts ranging from about 5 mg.
to about 200 mg. per kilogram of body weight per day. A
preferred dosage regimen for optimum results would be from
about 5 mg. to about 50 mg. per kilogram of body weight per
day, and such dosage units are employed that a total of from
about 350 mg. to about 3.5 grams of the active compound
for a suhject of about 70 kg. of body weight are administered
in a 24-hour period. This dosage regimen may be adjusted
to provide the optimum therapeutic response. For example,
several divided doses may be administered daily or the dose
may be proportionally reduced as indicated by the exi~encies
of the therapeutic situation. A decided practical advantage
of this invention is that the active compound may be admini-
stered in any convenient manner such as the oral or buccal
routes or it may be incorporated directly in the diet.
The active ingredients of the present invention
may be orally administered, ~or example, with an inert diluent
or with an assimilable edible carrier, or they may be enclos2d
in hard or soft shell gelatin capsules, or they may be com-
pressed into tablets, or they may be incorporated directly
with the food of the diet. For oral therapeutic administra-
tion, the active compounds may be incorporated with excipi-
ents and used in the form of ingestible tablets, buccal tablets,
troches, capsules, elixirs, suspension, syrups, wafers, and
the like. Such compositions and preparations should contain
at least 0.1~ of the active compound. The percentage of the
compositions and preparations may, of course, be varied and
- 18 -
;52~
may conveniently be between about 2 to about 60% of the
weight of the unit. The amount of ac~ive ingredient in such
therapeutically useful compositions is such that a suitable
dosage will be obtained. Preferred compositions or prepara-
tions according to the present invention are prepared so
that an oral dosage unit form contains between about 5 and
200 milligrams of active compoundO
The tablets, troches, pills, capsules and the like
may also contain the following: ~ binder such as gum traga-
canth, acacia, corn starch or gelatin; excipients such as
dicalcium phosphate; a disintegrating agent such as corn
starch, po-tato starch, alginic acid and the like; a lubri-
cant such as magnesium stearate; and a sweetening agent sueh
as sucrose, lactose or saccharin may be added or a flavoring
agent such as peppermint, oil of wintergreen, or cherry fla
voring. When the dosage unit foxm is a capsule, it may con~
tain, in addition to materials of the above type, a li~uid
carrier. Various other materials may be present as coatings
or to otherwise modify the physical form of the dosage unit.
For instance, tablets, pills, or capsules may be coated with
shellac t sugar or both. A syrup or elixir may contain the
active compound, sucrose as a sweetening agent, methyl and
propylparabens as preservatives, a dye and flavoring sueh
as cherry or orange flavor. Of course, any material used in
preparing any dosage unit form should be pharmaceutieally
pure and substantially non-toxic in the amounts employed.
In addition, the active ingredients may be incorporated into
sustained-release preparations and formulations.
The active ingredients of the present invention
may also be administered parenterally or intraperitoneally.
-- 19 --
5~
Solutions of the acti~e ingredient as a free base or salt
can be prepared in water suitably mixed wlth a surfactant
such as hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols, and
mixtures thereof and in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative
to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable
use include sterile aqueous solutions or dispersions and
sterile powders for the extemporanous preparation of sterile
injectable solutions or dispersions. In all cases the form
must be sterile and must be fluid to the extent that easy
syringability exists. It must be stable under the conditions
of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and
fungi. ~he carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (for example,
glycerol~ propylene glycol, and liquid polyethylene glycol,
and the like), suitable mixtures thereof, and vege~able oils
The proper fluidity can be maintained, for example, by the
use of a coating such as lecithin, by the maintenance of the
required particle size in the case of dispersion and by the
use of surfactants. The prevention of the action of micro-
organisms can be brought about by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol,
phenol, sorbic acid, thimerosal, and the like. In many cases,
it will be preferable ko include isotonic agents, for example,
sugars or sodium chloride. Prolonged absorption of the in-
jectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
- 20
aluminum monostearate and gelatin.
~terile injectable solutions are prepared by in~
corporating the active ingredient or ingredients in the re-
quired amount in the appropriate solvent with various of the
other ingredients enumerated above, as required, followed by
filtered sterilization. Generally, dispersions are prepared
by incorporatiny the various sterilized active ingredient into
a sterile vehicle which contains the basic dispersion medium
and the re~uired other ingredients from those enumerated
ahove. In the case of sterile powder~ for the preparation of
sterile injectable solutions, the preferred methods of prepar-
ation are vacuum drying and the freeze-drying technique which
yield a powder of the active ingredient plus any additional
desired ingredient from a previously sterile-~iltered solution
thereof.
As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media~ coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use o~ such media and
agents for pharmaceutical active substances is well known in
the art. Except insofar as any conventional media or agent
is incompatable with the active ingredient, its use in the
present compositions is contemplated. Supplementary active
ingredients can also be incorporated into the inventive com-
positions.
It is especially advantageous to formulate paren-
teral compositions in dosage unit form for ease of admini-
stration and uniformity of dosage. Dosage unit form as used
in the specification and claims herein refers to physically
discreet units suited as unitary dosages for the mammalian
- 21 -
subjects to be tre~ted; each unit containing a predetermined
quan-tity of active material calculated to produce the desired
therapeutic effect in associa-tion with the required pharma~
ceutical carrier. The specification for the novel dosage
unit forms of the invention are dictated by and directly
dependent on ~a) the unique characteristics of the active
material and the particular therapeutic effect to be achieved,
and (b) the limitations inherent in the art of compounding
such an active material for the treatment of disease in living
subjects having a diseased condition in which bodily health
is impaired as disclosed in detail in this specificatlon.
The dosage of the principal active ingredient for
the treatment of the indicated conditions depends upon the
age, weight and condition of the subject being treated; the
particular condition and its severity; the particular form of
the active ingredient and the route of administration.
daily dose of from about one to about 100 mg./kg. of body
weight given singly or in divided doses of up to S times
day embraces the effective range for the treatment of most
conditions for which the compound is effective and substantial-
ly non-toxic. For a 75 kilogram subject, this translates into
between about 75 and about 7500 mg./day. If the dosage is
divided, for example, into 3 individual dosages, these will
range from about 25 to aboùt 2500 mg. of the active ingredient.
The preferred range is from 2 to about 50 mg./kg. o~ body
weight/day with about 2 to about 30 mg./kg./day being more
preferred.
The principal active ingredient is compounded for
convenient and effective administration in effective amounts
with a suitable pharmaceutically-acceptable carrier in dosage
- 22 -
unit form as hereinbefore disclosed. A unit dosage form can~
for example, contain the principal active ingredient in amounts
ranging from about 0.1 to about 400 mg., with from about one
to about 30 mg. being preferred~ Expressed in proportions,
the active ingredient is generally present in from about 0.1
to about 400 mg./ml. of carrier. In the case of compositions
containing supplementary active ingredients, the dosages are
determined by reference to the usual dose and manner of ad-
ministration of the said ingredientsO
Regression and palliation of cancers are attained,
for example, using intraperitoneal administration. A single
intravenous dosage or repeated daily dosages can be admini-
stered. Daily dosages up to about 5 or 10 days are often
sufficient. It is also possible to dispense one daily dosage
or one dose on alternate or less frequent days. As can be
seen from the dosage regimens, the amount of principal active
ingredient administered is a sufficient amount to aid regres-
sion and palliation of the leukemia or the like, in the ab-
sence of excessive deleterious side effects of a cytotoxic
nature to the hosts harboring the cancer~ As used herein,
cancer means blood malignancies such as leukemia, as well as
other solid and non-solid malignancies such as the melano-
carcinomas, lung carcinomas, and mammary tumors. By regres-
sion and palliation is meant arresting or retarding the growth
of the tumor or other manifestation of the disease compared to
the course of the disease in the absence of treatment.
The invention will be described in greater detail
in conjunction with the following specific examples.
- 23 -
Exam~le 1
Preparation of 1,4-bis(2- imeth~laminoethylamino)-
anthra~uinone
A mixture of 3 g. of quini7arin, 10 g. of N,N-di-
methylethylenediamine and 17.5 ml. of ~ater is stirred and
heated under reflux for 3.5 hours. The mixture is cooled
and the solid is collected and washed with water giving 2.96
g. of the desired product as a dark blue solid, mp. 170~
-172C .
Alternatively, the above product may be prepared
by stirring and heating under reflux for 5 hours a mixture
of 2.4 g. of quinizarin, 2.82 g. of N,N-dimethylethylene-
diamine and 9 ml. of N,N,N',N'-tetramethylethylenediamine.
The product is recovered as described above.
Example 2
Preparation of 1,4-bis(2-morpholinoethylamino)-
anthraquinone
A 9.60 g. portion of quinizarin, 46.90 g. of N-
- -(2-aminoethyl)morpholine and 56 ml. of water are reacted
as described in Example 1 giving 9.92 g. of the desired
product as a blue-black solid, mp. 15~-159C.
Example 3
P e aration of 1 4-bis(2-dieth~laminoethylamino)-
r p
anthraq~linone
A mixture of 42 ml. of N,N,N',N'-tetramethylene-
diamine, 17.43 g. of N,N-diethylethylenediamine and 12.01 g.
of quinizarin is stirred and heated under reflux for 15 hours.
The resulting solution is evaporated to dryness and a chloro-
form solution of the residue is filtered through 300 g. of
alumina. The blue filtrate is chromatographed on silica
- 2~ -
gel in a Nylon~ll) film column, developing with a chloroform:-
methanol (6:]) mixture. The major blue band is cut out and
then eluted with a chloroform:methanol:triethylamine (6:2:1)
mixture. The elua-te is evaporated. The residue is crystal-
lized from hexane and washed with petroleum ether, giving
1.43 g. of the desired product as blue-black plates, mp.
109C
Example 4
-
Preparation of leuco-1,4-bis(2-aminoethylamino)-
.
~'
A 125-ml. portion of ethylenediamine is de-aerated
by bub~ling nitrogen through it for 15 minutes. A 12~0-gO
portion of leucoquinizarin is added and the mixture is heated
with stirring under nitrogen at 50C. for one hour. The mix-
ture is allowed to cool. The solid is collected and washed
successively with ethyl acetate, acetonitrile and petroleum
ether, giving 8.07 g. of the desired product as green-gold
crystals, mp. 162-165C. (dec.) at a heating rate of 9 per
minute.
Example 5
Preparation of 1,4-bis(2-aminoethylamino)-
anthraquinone
_
Air is bubbled into a mixture of 7.0 g. of leuco-
-1,4-bis(2-aminoethylamino)anthraquinone and 87.5 ml. of
ethylenediamine while heating at 50C. for one hour. The
mixture is diluted with 87.5 ml. of acetonitrile, allowed to
cool and the solid is collected and washed with acetonitrile
giving 5.43 g. of the desired product as a dark blue solid,
mp. 170-171C.
- 25 -
Example 6
Preparation of 1,4-bis[2-(methylamino)ethylamino]-
anthraquinone
A mixture of 2.4 g. of leucoquiniæarin and 25 g. of
de-aerated N-me~hylethylenediamine is heated at 50C. with
stirring under nitrogen for one hour. Heating at 50C. is
continued as air is bubbled into the mixture for 40 minutes.
The mixture is evaporated to dryness, then re-evaporated
twice from 25 ml. portions of ethanol. Crystallization of
the residue from ethanol-ether at -70C. gives 2.32 g. of
crude solid which is recrystallized twice from carbon tetra-
chloride giving 1.92 g. of the desired product as dark blue
crystals, mp. 131-132C.
EXample
Preparation of 1,4-bis(2-piperidinoethylamino)-
anthraquinone
.. _ _ ~
A mixture o 4~07 g. of quinizarin, 21.74 g~ of
N-(2-aminoethyl)piperidine and 26 ml. of water is stirred
under reflux for 2 hours and then allowed to stand overnight.
The gummy solid is collected and washed with water by centri-
fugation, giving 1.99 g. of blue-black solid. This solid is
dissolved in 15 ml. of chloroform and chromatographed by an
abbreviated wet-column procedure on 100 g. of alumina, eluting
with chloroform. A total of 180 ml~ of eluate is collected
in eight separate cuts from the time the eluate turns blue
until a black band nears the bottom of the column. Cuts 1-6
are combined and evaporated giving 1.42 g. of blue-black
crystals which are recrystallized from ethanol giving 1.35 g.
of the desired product as blue-black needles, mp. 140U-141C.
Product dried in vacuo at 78C. melted at 156~157C.
-
- 26 -
65'~
xample 8
Preparation of leuco-1,4-bis(2-dimethylamino-
____ __ _ _
ethylamino)anthraquinone
A solution of 26.44 g. of N,N-dimethylethylene-
diamine in 75 ml. of N,N,N',N'-tetramethylethylenediamine
is de-aerated by bubbling through N2 for 15 minutes. Then,
12.11 g. of leucoquinizarin is added and the resulting
mixture is stirred under N2 while heating at 48-50C.
for 21 hours. After cooling overnight under nitrogen~
the solid is collected by filtration and washed three times
by slurrying with acetonitrile and then twice with petroleum
ether. There is thus obtained 12.52 g. of dark green crystals,
mp. 150-157C.; or on the hot stage miscroscope, mp. 153-
-154C.
Example_~
Preparation of 50 mg. Tablets
Per Tablet Per 10,000 Tablets
-
0.050 gm. 1,4-bis~Z (methylamino)- ~ O 500 gm~
ethylamino]anthraquinone
0.080 gm. Lactose ~ OO~O~O~ O 800 gm.
O.010 gm. Corn Starch (for mix) .O~.O~O~100 gm.
0.008 gm. Corn Starch (for paste1................ 75 gm.
0.148 gm. ~7~ gm.
0.002 gm. Magnesium Stearate (1%) ~O~ 15 gm.
0.150 gm. 1490 gm.
The 1,4-bis~2-(methylamino)ethylamino]anthraquinone,
lactose and corn starch (for mix) are blended together. The
corn starch (for paste) is suspended in 600 ml~ of water and5
heated with stirring to form a paste. This paste is then used
to granula~e the mixed powders. Additional water is used if
necessary. The wet granules are passed through a No~ 8 hand
screen and dried at 120F. The dry granules are then passed
through a No. 16 screen. The mixture is lubricated with 1%
0
magnesium stearate and compr~ssed into tablets in a suitable
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tableting machine~
Example 10
Preparation of Oral Suspension
Ingredient Amount
Leuco-1,4 bis(2-aminoethylamino~anthraquinone.~..... 500 mg.
Sorbitol solution (70% N.F.) .......................... ~.~ 40 ml~
Sodium banzoate .~.............. ~..... ~...... ~.~....... ...150 mg.
Saccharin ...... ~.............. ~...................... ....10 mg.
Red dye ........ ~.............. 0.~..................... ....10 mg.
Cherry flavor ............ ........................ ..... ....50 mg.
Distilled water.~.gs... ad....... ~.... ~... ~............. ....100 ml.
The sorbitol solution is added to 40 ml. of dis-
tilled water and the leuco-1,4-bis(2-aminoethylamino)-
anthraquinone is suspended therein. The saccharin, sodium
benzoate, flavor and dye are added and dissolved. The volume
is adjusted to 100 ml. with distilled water. Each ml. of
syrup contains S mg. of leuco-1,4-bis(2-aminoethyl-
amino)anthraquinone.
Example 11
Preparation of Parenteral Solution
.
In a solution of 700 ml. of propylene glycol and
200 ml. of water for injection is suspended 20~0 grams of
1,4-bis~4-aminobutylamino)anthraquinone with stirring.
After suspension is complete, the pH is adjusted to 5~5 with
hydrochloric acid and the volume is made up to 1000 ml. with
water for injection. The formulation is sterilized, filled
into 5.0 ml. ampoules each containing 2.0 ml. (representing
40 mg. of drug) and sealed under nitrogen.
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~L6~
Exampl.e 12
Preparation of leuco-1,4-bis(3-aminopropylamino)-
anthraquinone
When 1,3-propanediamine is used instead of ethyl-
enediamine in the procedure of Example 4 the product is the
title compound.
Example 13
Preparation of leuco-1,4-bis[2-dimethylaminopropyl~
amino]anthraquinone
Using 15.32 g. of 2-dimethylaminopropyl amine
instead of N,N-dimethylethylenediamine in the procedure of
Example 8 gives the title compound after a reaction time of
one hour at 50.
Example 14
Leuco-1,4-bis[2-(2-methylaminoethylamino)ethyl-
amino]anthraquinone
A solution of 14.10 g. (0 12 mole) of l-methyl-
-diethylenetriamine in 100 ml. of ethanol is de-aerated by
bubbling nitrogen through it for 15 minutes; then 9.69 g.
(0.04 mole) of leucoqu.inizarin is added gradually with stir~
ring. The mixture is stirred under nitrogen and heated with
an oil bath at 50C. for 21 hours. The mixture is allowed
to cool, the product is collected by filtration and washed
with acetonitrile and then with petroleum ether to give the
title compound as a dark green solid.
Example 15
Preparation of leuco~l,4,bis(2-methylaminoethylamino)-
anthraquinone
To a de-aerated (See Example 8) solution of 8.89 g.
of N-methylethylenediamine in 80 ml. of N,N,N',N'-tetra-
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methylethylenediamine is added 9.68 g. of leucoquinizarin.
The mixture is stirred and heated at 50C. under nitrogen
for one hour, then allowed ~o cool. The solid is collected,
washed with toluene and then with ether, giving 9.0 g. of a
green-black solid, m.p. 105-109~C.
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