Note: Descriptions are shown in the official language in which they were submitted.
114~923
This invention relates to new organic compounds
and, more particularly, is concerned with novel symmetri-
cal l,4-bis(substituted-amino)-5,8-dihydroxyanthraquinones
which may be represented by the following general formula:
OH NH -Q-N ~ 1
OH NH-Q-N
R2
wherein Q is a divalent moiety selected from the group
consisting of those of the formulae:
lCH3 IH3 1CH3lH3
-(CH2)n~ ~ -CH-CH2- , -CH2-CH- , -CH-CH- ,
IC2Hs IC2H5 lCH3
-CH-CH2- ,-CH -CH- -CH-CH2-CH2-
ClH3 ICH3
-cH2-cH-cH2- and
wherein n is an integer from 2 to 4, inclusive; Rl and R2
are each individually selected from the group consisting
of hydrogen, alkyl having from 1 to 4 carbon atoms, mono-
~, -1-
1~4~9Z3
hydroxyalkyl having from 2 to 4 carbon atoms and wherein
the carbon atom alpha to the nitrogen atom may not bear
an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon
atoms and wherein the carbon atom alpha to the nitrogen
atom may not bear an hydroxy group, formyl, alkanoyl
having from 2 to 4 carbon atoms, trifluoroacetyl and
moieties of the formula:
/R3
- (CH2) n-CN , - tCH2) n~O~R and (CH2) n N ~R
wherein n is an integer from 2 to 4, inclusive, R is alkyl
having from 1 to 4 carbon atoms, and R3 and R4 are each
individually selected from the group consisting of hydro-
gen, alkyl having from 1 to 4 carbon atoms, and monohy-
droxyalkyl having from 2 to 4 carbon atoms and wherein the
carbon atom alpha to the nitrogen atom may not bear an hy-
droxy group, and R3 and R4 taken together with their
associated N(itrogen) is morpholino, thiomorpholino, pi-
perazino, 4-methyl-1-piperazino or a moiety of the
formula:
~
-N (CH2)m
J ,
wherein m is an integer from 2 to 6, inclusive; with the
first proviso that the ratio of the total number of car-
bon atoms to the sum of the total number of oxygen atoms
plus the total number of nitrogen atoms in the side
chains at the l-position and the 4-position may not
exceed 4; provided that when Q is -(CH2)n- then:
~'
-2-
3923
a) Rl, and R2 may not simultaneously be hydrogen;
b) when n is 2 then Rl/R2 may not be
CH3/CH3, C4Hg/C4Hg, or -(CH2)s-;n is 3 then
Rl/R2 may not be H/H, CH3/CH3, C3H7/C3H7, or
-(CH2)2-0- (CH2)2-; n is 4 then Rl/R2 may not
be C2H5/C2H5, C4Hg/C4Hg, or -(CH2)4-; and
c) only one of Rl and R2 may be alkanoyl.
The compounds of the above general formula I
wherein A-B is CH2-CH2 are generally stable compounds and
are known as the leuco forms of the corresponding anthra-
quinones. These leuco froms are known to exist in their
respective tautomeric forms, and all such forms are
equivalent for the purposes of the invention. The leuco
forms (herein, leuco bases), and the tautomers thereof
may be represented by the following general formula:
OH C) I~IH - Q- N ~ 1
C (II, leuco bases)
OH (~ NH-Q-N~
11 R2
~ ~ ~ -N~ 1
~ ~ ,Rl (III, tautomeric form)
OH o N-Q-N
-3-
1 ~ 4~ ~ Z3
- The invention also relates to processes for
preparing the novel compounds represented by the above
formulae I, II and III.
Thus, one process contemplated by the instant
invention comprises reacting a compound represented by
the following general formula:
~5 ~ [~ Q~s - X
~A
~ N~ -Q~-S - -X
with a compound of the formula: Y[ Q]T Z
wherein Rs is hydroxy, chloro, or alkanoyloxy
one of X and Y is NRlR2 or NHCOCF3 and the
other is selected from the group consisting of ORlo, Cl,
Br, I, N(R10)2~ NO2, SO3Rlo~ S2R10~ SR10~ SR10~ N3,
ONO, and tetrazolyl, wherein Rlo is selected from the
group consisting of hydrogen, alkyl of from 1 to 6 carbon
atoms, phenyl, para-tolyl and benzyl; S and T are
different and are chosen from 0 to 1;
Z is selected from the group consisting of hydrogen,
alkyl of from 1 to 4 carbon atoms, and NRlR2 or a group
convertible thereto; provided:
a) that only X may be NHCOCF3 and only when S
is O and Z is not hydrogen or alkyl;
b) except as in a), when S is O, then Rl/R2
is H/H and Z is not hydrogen or alkyl of
from 1 to 4 carbon atoms;
--4--
.':
114~Z3
c) when T is O and Y is NRlR2 then Z is hydrogen;
d) when T is O and X is NRlR2 at least one of
Rl/R2 is hydrogen and Z is alkyl of from 1 to
4 carbon atoms;
e) only one of Rl and R2 may be alkanoyl; and
when Rs = chloro or alkanoyloxy converting
them to hydroxy, and when X is NHCOCF3, re-
moving the COCF3 group, and when Z is a group
convertible to NRlR2 effecting its conversion
thereto; and, if desired: converting A-B when
it is CH2-CH2 into CH=CH; and contacting the
product with a pharmacologically acceptable
salt-forming reagent under salt-forming con-
ditions.
The invention also relates to processes for
preparing the novel compounds of the following general
formula:
NH-Q-N ~1
N~l-Q-N ~
and the pharmacologically acceptable acid-addition salts
~hereof; wherein Rl, R2, and Q are as hereinabove defined.
The invention also relates to the acid-addition
salts of the novel compounds of formulae I, II and III.
The invention also relates to pharmaceutical
therapeutic preparations and compositions comprising,
,~
. _5_
ll~V923
compounds of formula I, II and III and their pharmaceu-
tically acceptable acid-addition salts, as well as to
mixtures thereof as the active ingredients.
The invention also relates to methods for using
the compounds and pharmaceutical preparations and compo-
sitions comprising the compounds disclosed herein.
The novel compounds of the instant invention
are represented by the following general formula:
~H ~ N1~-Q~
~N~
the tautomeric forms and the pharmacologically accepta~le
acid-addition salts thereof, wherein A-B is selected from
the group consisting of CH=CH and CH2-CH2;
Q is a divalent moiety selected from the group consisting
of those of the formulae:
~113 fll3 ~113CI~3
(C1]2 )n ~ ~ C~32- , -C112-CII- , , -Cll-C~
~2~15 C2}15 C,,3
25- 11-C112- ; -C112-~ 11-C1l2-c~l2 '
f~l3 - C~3
-CH2-CI1-C1~2- and 2 2
-6-
114(3~Z3
wherein n is an integer from 2 to 4, inclusive; Rl and R2
are each individually selected from the group consisting
of hydrogen, alkyl having from 1 to 4 carbon atoms; mono-
hydroxyalkyl having from 2 to 4 carbon atoms and wherein
the carbon atom alpha to the nitrogen atom may not bear
an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon
atoms and wherein the carbon atom alpha to the nitrogen
atom may not bear an hydroxy group, formyl, alkanoyl
having from 2 to 4 carbon atoms, trifluoroacetyl and
moieties of the formulae:
-~CH2)n-CN , -(CH2)n-O-R and ~(CH2)n- ~ 3
wherein n is an integer from 2 to 4, inclusive, R is
alkyl having from 1 to 4 carbon atoms, and R3 and R4
are each individually selected from the group consisting
of hydrogen, alkyl having from 1 to 4 carbon atoms and
monohydroxyalkyl having from 2 to 4 carbon atoms and
wherein the carbon atom alpha to the nitrogen atom may
not bear an hydroxy group; and Rl and R2 taken together
with their associated N(itrogen) atom is morpholino,
thiomorpholino, piperazino, 4-methyl-1-piperazino or a
moiety of the formula:
-N ~ 2)m
wherein m is an integer from 2 to 6, inclusive, provided
that the ratio of the total number of carbon atoms to the
sum of the total number of oxygen atoms plus the total
number of nitrogen atoms in the side chains at the
-7-
- 114~9Z3
l-position and the 4-position may not exceed 4;
provided that when Q is -(CH2)n- then:
a) Rl and R2 may not simultaneously be hydrogen;
b) when n is 2 then Rl/R2 may not be
CH3/CH3, C4Hg/C4H9, or -(CH2)5; n is 3
then Rl/R2 may not be H/H, CH3/CH3,
C3H7/C3H7, or -(CH2)2-;n is 4 then Rl/R2 may
not be C2Hs/C2Hs, C4Hg/C4Hg, or -(CH2)4-;
and
c) only one of Rl and R2 may be alkanoyl.
These compounds are generally obtainable as
reddish brown to blue black crystalline materials having
characteristic melting points and absorption spectra and
which may be purified by leaching with lower alkanols
since the free bases are for the most part insoluble in
water and some of them are insoluble in most organic sol-
vents. The organic bases of this invention (I, II and
III), form non-toxic addition salts with a variety of
pharmacologically acceptable organic and inorganic salt-
-forming reagents. Thus, acid-addition salts, formed by
admixture of the organic free base with 1,2 or up to
eight equivalents of an acid, suitably in a neutral sol-
vent, are formed with such acids as sulfuric, phosphoric,
hydrochloric, hydrobromic, sulfamic, citric, lactic,
malic, succinic, tartaric, acetic, benzoic, gluconic,
ascorbic, and the like. The preferred acids are hydro-
chloric and acetic. For purposes 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,
relatively soluble in water, methanol and ethanol but
--8--
~r~
1~4~23
relatively insoluble in non-polar organic solvents such as
diethyl ether, benzene, toluene, and the like.
It will be understood by those skilled in the
art that all such salts may be reconverted to their re-
spective free forms represented by formulae I, II and III
by methods known to those skilled in the art, and all such
salts and free forms are therefore equivalent for purposes
of the invention.
A preferred embodiment of the novel compound
aspect of the present invention may be represented by
the following general formula:
ON O NH-Q-N
and the pharmacologically acceptable acid-addition salts
thereof, wherein A-B and Q are as hereinbefore defined;
Rl is hydrogen, alkyl having from 1 to 4 carbon atoms or
monohydroxyalkyl having from 2 to 4 carbon atoms and
wherein the carbon atoms alpha to the nitrogen from 2 to
4 carbon atoms and wherein the carbon atom alpha to the
nitrogen atom may not bear an hydroxy group, dihydroxy-
alkyl having from 3 to 6 carbon atoms and wherein the
carbon atom alpha to the nitrogen atom may not bear an
hydroxy group or a moiety of the formula:
,_,R3
~ (C1~2 ) n~
_g_
114q~923
wherein n, R3 and R4 are as hereinbefore defined; with
the proviso that the ratio of the total number of carbon
atoms to the sum of the total number of oxygen atoms plus
the total number of nitrogen atoms in each of the side
chains at the l-position and the 4-position may not exceed
four.
A second preferred embodiment of the novel com-
pound aspect of the present invention may be represented
by the following general formula:
01~ ~ Nll-Q- l_ (C112) n 011
~\~ '1
}~ o Nl~-Q-~l- (Cl12) -011
and the pharmacologically acceptable acid-addition salts
thereof, wherein R is hydrogen or alkyl having from 1 to
4 carbon atoms and A-B, n, and Q are as hereinabove
defined with the proviso that the ratio of the total of
number of carbon atoms to the sum of the total number of
oxygen atoms plus the total number of nitrogen atoms in
each of the side chains at the l-position and the 4-posi-
tion may not exceed 4.
A third preferred embodiment of the novel com-
pound aspect of the present invention relates to compounds
of the following formula:
~ ,j
,~ -10-
114~23
~~ 1~ C l2
O NH-(C~ )-N
2 n \R
wherein n, Rl, R2 and A-B are as defined above for the
first preferred embodiment and the pharmacologically
acceptable acid-addition salts thereof.
A fourth preferred embodiment of the novel
compound aspect of the present invention relates to com-
pounds of the following formula:
~ 2CIl2~cl~2cl12O
NllC112C~l2I C112C~21
Rl
wherein Rl is hydrogen or -CH2CH2OH, and the pharmacologi-
cally acceptable acid-addition salts thereof. The pre-
ferred salts are the hydrochloride and the acetate.
The novel compounds of the present invention
represented by formulae I, II and III may be readily
prepared by the following general process.
A compound of the formula:
~
114~Z3
OH O OH
~A
OH OH
is reacted with a compound of the formula
H N-Q-N
R2
wherein A-B, Q, Rl and R2 are as defined above and if
desired converting the product into the tautomer thereof;
and if desired converting A-B when it is CH2-CH2 into
CH-CH and contacting the product with a pharmacologically
acceptable salt-forming reagent under salt-forming condi-
tions.
The reaction is preferably carried out by
heating the reactants at a temperature of from about 40
to 110C. for a period of from about 2 to about 10 hours
in a reaction inert solvent such as water, a lower
alkanol, for example, methanol, ethanol, propanol, i_
-propanol, any of the isomeric butanols and the like, or
in an amide solvent such as formamide, dimethyl formamide
and the like, or in a solvent such as N,N,N',N',-tetra-
methyl ethylenediamine or mixtures thereof. The above
temperatures, times and solvents and combinations thereof
will most normally suffice for carr~ing out the instant
process. ~ther solvents and reaction parameters may at
times be desirable or required and the choice of such
-12-
114~9Z3
additional solvents and reaction parameters is within
the skill of the art and are all considered equivalents
for the purposes of the instant invention.
In most instances, the product will be a solid
and will crystallize spontaneously or upon seeding or
scratching, from the reaction solvent upon cooling and
may be collected by filtration or decantation. In other
instances the reaction mixture may be concentrated, for
example at elevated temperature under vacuum, and upon
cooling the product will crystallize and may be collected
by filtration or decantation as above. In certain other
instances it may be necessary to evaporate the solvent
to dryness in order to collect the product or alterna-
tively to mix or dilute the reaction mixture with another
miscible solvent such as water and proceed to collect the
product by for example filtration or extraction. Those
skilled in the art will be able to choose which procedure
to follow and all such procedures are considered equiva-
lent for the purposes of this invention. The product,
once collected, may be purified by for example, crystal-
lization, chromatography (thin layer or column) or pre-
ferably by leaching with a lower alkanol. Other proce-
dures such as maceration or crushing in a solvent, for
example, an organic solvent such as ethanol may be
utilized and all purification procedures are to be con-
sidered as equivalents for purposes of the invention.
Those skilled in the art will recognize that
when a product in the leuco form is desired, the tricyclic
starting material should be in the leuco form, and care
should be taken to protect such materials, especially
-13-
1~4~23
when at elevated temperatures (i.e. above room tempera-
ture), from oxidizing agents such as, for example oxygen.
Thus, when a leuco product is desired the
reaction is normally and e~ficiently carried out in an
atmosphere to the exclusion of air. Thus, the reaction
S may be carried out in an atmosphere of nitrogen or argon,
for example, and this precaution should also be taken
during purification procedures especially those requiring
elevated temperatures. When an aromatic product is
desired and an aromatic starting material is utilized no
sùch precautions are normally necessary.
It is well known in the art that the leuco form
may be readily converted to the aromatic form when
desired by a variety of methods. Thus, air oxidation is
one such method, other methods are treatment with for
example, hot nitrobenzene, chloranil, hydrogen peroxide,
or sodium perborate. All such methods, and other methods
for conversion of the leuco form to the aromatic form,
are to be considered equivalents for purposes of the
invention.
Those skilled in the art will also understand
that when the substituent Z is a group convertible to
- ~ that the said conversion will be able to be
R2
2S carried out by obvious procedures, well known to those
skilled in the art and within the skill of the art. Con-
version of the group Z to N ~ Rl by all of these
R2
7T
,
~14~23
procedures is therefore contemplated by the instant inven-
tion and all such procedures are to be considered equiva-
lent for purposes of the instant invention. The preferred
procedures contemplated by the instant invention for
converting the group Z into ~ ~1 are exemplified
R2
below. It is to be understood that these are merely
examples of the said conversion, and are not intended to
delimit the scope of the instant invention. Other con-
version procedures will be known to those skilled in the
art and are to be considered full equivalents for the
purposes of the instant invention. Thus, when Z is an
aldehyde or ketone group, i.e. -~-R wherein R is
chosen from hydrogen or alkyl, treatment with an amine
of the formula / Rl wherein Rl and R2 are as herein
IIN
\ ~2
defined under reducing conditions such as hydrogen with
Raney nicket catalyst or sodium borohydride will accom-
plish the desired conversion.
Also contemplated for Z are moieties of the
formula ,~
-N O
(~C1~2) )
wherein m is 2 or 3. Treatment of this group with acid,
for example aqeuous-ethanolic hydrogen chloride at 40-
-80C. for from 1 to 6 hours will convert it to
-NH-(CH2)m-OH which is a moiety contemplated by the
group N,-Rl
R2
-15-
1~4V~Z3
Also contemplated for Z are efficient leaving
groups, such as Cl, Br, I, para-tosyl, OSO2CH3 and the
like. When Z is an above disclosed leaving group or an
equivalent, treatment with an amine of the formula
Rl in for example a lower alkanol solvent
~ R2
will effect the desired conversion.
In addition, when Z is a primary or secondary
amine, i.e. -NH2 or -NHRl, then further alkylation will
convert it to the desired group ~ Rl . Well known
1~2
alkylating agents are known which will readily effect
this conversion. Such agents as alkyl halides, alkyl
sulfates, substituted and unsubstituted acrylonitriles,
and the like are contemplated. Aldehydes and ketones
condensed under reducing conditions may also be utilized.
All such conversions and other conversion
procedures are considered equivalents for the purposes
of the invention.
A preferred embodiment of the primary process
aspect of the present invention may be represented by
the following reaction scheme:
-16-
Z3
o fH
S/~ + H N ,- R
R5 ~H (V ) \
lIV) ~
~ / ~ Q-N
R5 NH-Q-N
(II)
~~~
R5 O NH-Q-N~
~I)
wherein Rl, R2, Rs, and Q are as hereinabove defined.
In accordance with this reaction scheme, leuco 1,4-di-
hydroxyanthraquinone (IV) is condensed with an appropri-
ate alkylene diamine (V) in a solvent such as N,N,N',N'-
-tetramethylethylenediamine, ethanol, water, dimethyl-
formamide, or mixtures thereof at from about 40C. to
about 60C. under an atmosphere of nitrogen for several
hours to produce the corresponding leuco bases (II).
7,- ~ 30
-17-
114~23
The leuco bases (II) 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
perborate. The product may then be contacted with a
pharmacologically acceptable quaternizing or salt-forming
reagent under quaternizing or salt-forming conditions.
A preferred subgeneric embodiment of the
primary process aspect of the invention may be repre-
sented by the following reaction scheme A:
OH O OH
H r 2 Q ~R ~ ,R
OH O NH-Q-N
' ~ ~ ~r ~ ~`
I OH O NH-Q-N
OH O NH-Q-N~ 1
~, ' r~ `~
OH O NH-Q-N
~R2
Scheme A
wherein Rl, R2 and Q are as hereinabove defined.
A more preferred subgeneric embodiment of the
primary process aspect of the invention is represented
~30
-18-
4~9Z3
by the above reaction scheme A wherein Q is as herein-
before defined; Rl hydrogen or alkyl having from l to 4
carbon atoms; R2 is monohydroxyalkyl having from 2 to 4
carbon atoms and wherein the carbon atoms alpha to the
nitrogen atom may not bear an hydroxy group, dihydroxy-
alkyl having from 3 to 6 carbon atoms and wherein the
carbon atom alpha to the nitrogen atom may not bear an
hydroxy group or a moiety of the formula:-(cll2)n-N 3
~R4
wherein n, R3 and R4 are as hereinbefore defined; with
the proviso that the ratio of the total number of carbon
atoms to the sum of the total number of oxygen atoms plus
the total number of nitrogen atoms in each of the side
chains at the l-position and the 4-position may not
exceed four, and contacting the product with a pharma-
cologically acceptable acid, preferably acetic or hydro-
chloric, to prepare the pharmacologically acceptable
acid addition salts thereof.
A second more preferred subgeneric embodiment
of the primary process aspect of the invention is
represented by the above reaction scheme A wherein R
is hydrogen or alkyl having from 1 to 4 carbon atoms
and R2 is -(CH2)nOH and n and Q are as hereinabove
defined with the proviso that the ratio of the total
number of carbon atoms to the sum of total number of
oxygen atoms plus the total number of nitrogen atoms in
each of the side chains at the l-position and the
4-position may not exceed four, and contacting the
product with a pharmacologically acceptable acid, pre-
ferably acetic or hydrochloric, to prepare the pharma-
E -19-
114t3~23
cologically acceptable acid addition salts thereof.
The most preferred subgeneric embodiment of the
primary process aspect of the invention is represented by
the above reaction scheme A wherein Q is -(CH2)n- wherein
n is an integer of from 2 to 4, preferably 2, and Rl is
hydrogen or -CH2CH2OH and R2 is -CH2CH2OH, and contacting
the product with a pharmacologically acceptable acid,
preferably acetic or hydrochloric to prepare the pharma-
cologically acceptable acid addition salts thereof.
The invention also contemplates conversion of
the products into acid-addition salts. Many methods for
salt formation are known to those skilled in the art and
are to be considered equivalent for purposes of the in-
vention. Thus, for example, the product may be dissolved
or suspended in a solvent such as a lower alkanol
(e.g. methanl, ethanol, i-propanol) and treated with the
salt forming reagent, itself in solution in the same or
in a different solvent. Thus, a suspension or solution
of the product in ethanol for example may be treated with
dilute or concentrated acetic acid, hydrochloric acid
or the like, or ethanolic-HCl and the corresponding salt
may be collected by for example filtration. The salt
forming reagent may also be added in pure form. Thus,
the solution or suspension of the product may be treated
with glacial acetic acid or gaseous HCl and the corres-
ponding acid addition salt collected.
The instant invention also contemplates the
use of the compounds of formulae I, II and III and the
pharmacologically acceptable acid-addition salts thereof,
as well as mixtures thereof, as the active ingredients
-20-
. _ _
1~4~9Z3
in pharmaceutical therapeutic preparations and composi-
tions.
The therapeutic compositions of this invention
inhibit transplanted mouse tumor growth and induce
regression and/or palliation of leukemia and related
cancers in mammals when administered 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 ranging from about 5 mg. to about 200 mg. per kilo-
gram 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
subject of abount 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 exigencies of the therapeutic situation. A
decided practical advantage is that the active compound
may be administered in any convenient manner such as by
the oral, intravenous, intramuscular, or subcutaneous
routes.
The active compounds may be orally admin-
istered, for example, with an inert diluent or with an
assimilable edible carrier, or they may be enclosed
in hard or soft shell gelatin capsules, or they may be
-21-
~l~V923
compressed into tablets, or they may be incorporated
directly with the food of the diet. For oral therapeutic
administration, the active compounds may be incorporated
with excipients and used in the form of ingestible tab-
lets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, and the like. Such compo-
sitions and preparations should contain at least 0.1%
of active compound. The percentage of the compositions
and preparations may, of course, be varied and may con-
veniently be between about 2 to about 60% of the weight
of the unit. The amount of active compound in such
therapuetically useful compositions is such that a
suitable dosage will be obtained. Preferred compositions
or preparations according to the present invention are
prepared so that an oral dosage unit form contains be-
tween about 5 and 200 milligrams of active compound.
The tablets, troches, pills, capsules and the
like may also contain the following: A binder such as
gum tragacanth, acacia, corn starch or gelatin; excip-
ients such as dicalcium phosphate; a disintegrating
agent such as corn starch, potato starch, alginic acid
and the like; a lubricant such as magnesium stearate;
and a sweetening agent such as sucrose, lactose or sac-
charin may be added or a flavoring agent such as
peppermlnt, oil of wintergreen, or cherry flavoring.
When the dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid
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 shellec, sugar or both. A syrup or
-22-
1141~)923
elixir may contain the active compound, sucrose as a
sweetening agent, methyl and propylparabens as preserva-
tives, a dye and flavoring such as cherry or orange
flavor. Of course, any material used in preparing any
dosage unit form should be pharmaceutically pure and
substantially non-toxic in the amounts employed. In
addition, the active compounds may be incorporated into
sustained-release preparations and formulations.
The active compounds may also be administered
parenterally or intraperitoneally. Solutions of the
active compound as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed
with a surfactant such as hydroxypropylcellulose. Dis-
persions 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 inject-
able 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 micro-
organisms such as bacteria and fungi. The 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 vegetable oils.
'?~ '?L
~J -23-
114{)~23
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 microorganisms 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 to
include isotonic agents, for example, sugars or sodium
chloride. Prolonged absorption of the injectable
compositons can be brought about by the use in the compo-
sitions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by
incorporating the active compound in the required amount
in the appropriate solvent with various of the other
ingredients enumerated above, as required, followed by
filtered sterilization. Generally, dispersions are
prepared by incorporating the various sterilized active
ingredient into a sterile vehicle which contains the
ba~ic dispersion medium and the required other ingredi-
dents from those enumerated above. In the case of
sterile powders for the preparation of sterile injectable
solutions, the preferred methods of preparation are
vacuum drying and the freeze-drying technique which yield
2S a powder of the active ingredient plus any additional
desired ingredient from a previously sterile-filtered
solution thereof.
As used herein, "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic
-24-
~ 2 3
and absorption delaying agents and the like. The use of
such media and agents for pharmaceutical active substances
is well known in the art. Except insofar as any conven-
tional media or agent is incompatable with the active
ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also
be incorporated into the compositions.
It is especially advantageous to formulate
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit
form as used herein refers to physically discrete units
suited as unitary dosages for the mammalian subjects to
be treated; each unit containing a predetermined quantity
of active material calculated to produce the desired
therapeutic effect in association with the required
pharmaceutical 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 compoundng such an active material for the treat-
meot of disease in living subjects having a diseased
condition in which bodily health is impaired as herein
disclosed in detail.
Regression and palliation of cancers are
attained, for example, using intraperitoneal administra-
tion. A single intravenous dosage or repeated daily
dosages can be administered. 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
';~~~
~ -25-
114~9Z3
less frequent days. As can be seen from the dosage
regimens, the amount of principal active ingredient
administered is a sufficient amount to aid regression
and palliation of the leukemia or the like, in the
absence of excessive deleterious side effects of a cyto-
toxic nature to the hosts harboring the cancer. As used
herein, cancer disease means blood malignancies such as
leukemia, as well as other solid and non-solid malig-
nancies such as the melanocarcinomas, lung carcinomas,
and mammary tumors. By regression 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 novel compounds of the present invention
may be readily prepared in accordance with the following
reaction scheme:
-26-
il409Z3
OH O OH
~ J H 2 N Q N 1 ~
OH OH (V)
(IV) OH O NH-Q~
(II) ~R2
OH O NH_Q_N~ l
NH-Q-~
(I) _ _
wherein Rl, R2 and Q are as hereinabove defined. In
accordance with this reaction scheme, leuco 1,4,5,8-
-totrahydroxyanthraquinone (IY) is condensed with an
appropriate alkylene diamine (V) in a solvent such as
N,N,N',N'-tetramethylethylenediamine, methanol, ethanol,
water, dimethylformamide, or mixtures thereof at from
about 40C. to about 60C. under an atmosphere of nitro-
gen for several hours to produce the corresponding
leuco bases (II). The leuco bases (II) 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 perborate.
-27-
~14V923
The novel compounds described herein are useful
as chelating, complexing or sequestering agents. The
complexes formed with polyvalent metal ions are partic-
ular~y stable and usually soluble in various organic
solvents. These properties, or course, render them
useful for a variety of purposes wherein metal ion con-
tamination presents a problem; e.g., as stabilizers in
various organic systems such as saturated and unsaturated
lubricating oils and hydrocarbons, fatty acids and waxes,
wherein transition metal ion contamination accelerates
oxidative deterioration and color formation. They are
further useful in analyses of polyvalent metal ions
which may be complexed or extracted by these materials
and as metal carriers. Other uses common to sequestering
agents are also apparent for these compounds. In addi-
tion, the leuco bases (II) are useful as intermediates
in the preparation of the fully aromatic derivatives (I).
The novel compounds of the present invention
also possess the property of inhibiting the growth of
transplanted mouse tumors as established by the following
tests.
Lymphocytic leukemia P388 test
The ar.imals used are DBA/2 mice all of one
sex, weighing a minimum of 17 g. and all within a 3 gram
weight range. There are 5 or 6 animals per test group.
The tumor transplant is by intraperitoneal injection of
0.1 ml. of dilute ascitic fluid containing 106 cells of
lymphocytic leukemia P388. The test compounds are ad-
ministered intraperitoneally on days one, 5 and 9
(relative to tumor inoculation) at various doses. The
aminals are weighed and survivors are recorded on a
-28-
~ 2 3
regular basis for 30 days. The median survival time
and the ratio of survival time for treated (T)/control
(C) animals are calculated. The positive control com-
pound is 5-fluorouracil given as a 60-mg./kg. injection.
The results of this test with representative compounds
of the present invention appear in Table I. The
criterion for efficacy is T/C x 100 > 125%.
-29-
... ..
1140~23
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-- 30. --
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114~923
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114~3Z3
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-- 36 --
114~9Z3
~ I ~ ,~ _~ N~ N ~r 1~l NO O O n
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- 37 `
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11409Z3
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- 38 -
114t~Z3
o l .. . ..
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~'
114~;)9Z3
LymphocYtic leukemia P388 test
The procedure used is the same as for the previously
described test for lymphocytic leukemia P388 except that the
test compounds are administered orally at various doses rather
than intraperitoneally. The results of this test with typi-
cal compounds of the present invention appear in Table II.
The criterion for efficacy is T/C x 100 ~ 125%.
,~, 15
;
~'
~ 20
,,."
;',
42 -
~,'
114~9Z3
o ~ o u~ u~ O ~ O~ o ~r
X~ ~ ~
o ,, . , ~
C C
~ a o u u o o o o o ~ o
~ ~ U~ ~ o U~ _l o
a x
o ~ . ~ .
~¦ v a ~ o oo D ~ o o 3
-- 43 --
~?l ~l
9Z3
Melanotic Melanoma sl6
The animals used are C57BC/6 mice, all of the
same sex, weighing a minimum of 17 g. and all with a 3 g.
weight range. There are normally lO animals per test group.
A one-gram portion of melanotic melanoma B16 tumor is
homogenized in 10 ml. of cold balanced salt solution and
and 0~.5 ml. aliquot of the homogenate is implanted
intraperitoneally into each of the test mice. The test
; compounds are administered intraperitoneally on days one
through 9 (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 treated (T)/control (C)
animals are calculated. The positive control compound is
5-fluorouracil given as a 20~mg./kg. injection. The
results of this test with representative compounds of the
present invention appear in Table III. The criterion for
efficacy is T/C x 100 ~ 125%
- 44 -
923
oou)o U~O ~U~OU~ oo o U O
N r~ , r c~ o
- 45 -
. ~ .
~ 114V~Z3
, ¦ ~ ~ U~ ~ O O O O O U- ~ O O O ~
I ~ ~ ~ ~ ~ N .--/ ~ ~ D
a a~,lC ~ --- I
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-- 46 --
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9Z3
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mo ~ oo ~ o
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-- 47 --
~ .,
`"~ 114q~23
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::,, ~-I ~` O ') ~ 1~ O 1` 11') ~ ~ 1` U') ~ ~ ~ ~O
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I ~ O O I ~ 0 0 ~ O O
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U ~ ~ ~ ~ ~ I
~ 4 ~ S ~ ,
al ~ ~ I O ~) ~ o I " ~ ~ o
~J ,.~U 11- a) ~_ C~u ~
-- 48 --
~ ~ .
114~;g9Z3
'o
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a:, ~ ~t ~ ~1 ~1 N N N ~1
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-- 49 --
~" .,;,
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923
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-- 50 --
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1~4~23
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1~4~23
Ridgway Osteogenic Sarcoma
The animals used are AKD2Fl/J mice, all of the
same sex, weighing a minimum of 17 g, and all within a
three-gram weight range. There are normally 8 animals
per test group. The tumor is administered subcutaneously
by trocar as five 2 mm. fragments per mouse. The test
compounds are administered intraperitoneally every 4 days
for a total of 6 inoculations beginning on day 15
(relative to tumor inoculation) at various doses. The
animals are weighed and survivors are recorded on a
regular ~asis for 90 days. ~The regression of tumors is
recorded in all test animals. Table IV gives the result
o~ thi& test with a representative compound of this
invent;on in terms of the percentage of animals showing
tumor regression.
2Q
3Q
r~
~ - 52 -
114V923
_ ._ . COO~ ~,~
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V C~ ~ ~ ~ ~ 1
ul u~ -
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~ ~ ~ ~ ~ er ~ ~ ~ ~ ~ ~ a~ ~ cL Ln ~
a ~r ~ u~ ~O ~ x
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-- 53 --
Z3
This invention will be described in greater
detail in conjunction with the following specific
examples.
Example 1
Leuco-1,4-bis~(2-dimethylaminoethyl)animo~-5,8-
-dihydroxy-anthraquinone
A reaction mixture comprising 10.58 g. of N,N-
-dimethylethylenediamine, 60 ml. of N,N,N',N'-tetramethyl-
ethylenediamine and 10.96 g. of leuco-1,4,5,8-tetra-
hydroxyanthraquinone is flushed with nitrogen and stirred
under nitrogen for 2 hours while heating with an oil bath
kept at 49-51C. The mixture is allowed to cool under
nitrogen. The solid is collected and washed with ethanol
giving 14.78 g. of the desired product as a dark red-
brown solid.
Example 2
1~4-Bis~(2-dimethylaminoethylLamino]~5-r8 dihydroxy-
anthraquinone
A 12.00-g. portion of leuco-1,4-bis[(2-dimethyl-
aminethyl)amino-5,8-dihydroxy-anthraquinone in 100 ml. of
nitrobenzene is heated under reflux for 15 minutes and
then filtered while hot. The filtrate is reheated to
boiling, allowed to cool, and the solid is collected and
washed with ethanol giving 8.44 g. of the desired product
as blue-black crystals, mp. 236-238C.
Example 3
Leuco-1,4-bis(2-morpholinoethylamino)-5,8-dihydroxy-
anthraquinone
A solution of 15.62 g. of N-(2-aminoethyl)-
morpholine in 40 ml. of N,N,NI,N'-tetramethylethylenedi-
amine is de-aerated by bubbling nitrogen through it
'" ? 3 - 54 -
11~0923
for 15 minutes. A lQ,~7~g. portion of leuco-1,4,5,8-
-tetrahydroxyanthraquinone is added slowly and the
suspension is treated as described in Example 1, giving
18.07 g. of the desired product as an olive solid, mp,
223 227C.
Example 4
1,4-Bis(2-morpholinoethylamino~-5,8-dihydroxy-
anthraquinone
A 13.90-g. portion of leuco-,4-bis(2-morpholino-
ethylamino)~5,8-dihydroxy-anthraquinone in 100 ml. of
nitrobenzene is oxidized as described in Example 2 giving
lQ.3Q g. of the desired product as black rods, mp. 241-
243C.
Example 5
Leuco-1,4-bic~(2-diethylaminoethyllamino]-5,8-
-dih.ydroxyanthraquinone
The procedure of Example 3 is repeated using
13.qS g. of N,N-diethylethylenediamine in place of the
N-(2-a~inoethyl)-morpholine, giving 13.97 g. of the
2~ desired product as a red-brown solid, mp. 182~185C.
Exam~le 6
1!4~Bis L (2-diethylaminoethyl)amino]-5,8-dihydroxy-
anthraquinone
A 10.90 g. portion of leuco-1,4-bisl(2-diethyl-
aminoethyl)amino]-5,8-dihydroxyanthraquinone is oxidized
as described in Example 2 giving 6.35 g. of the desired
product as blue-black needles, mp. 202-204C.
Example 7
Leuco-1,4-bis[2-(1-pyrrolidinyl)ethylamino~-
-5,8-dihydroxyanthraquinone
- 55 -
114~Z3
The procedure of Example 3 is repeated using
12.Q5 g, of N-2-pyrrolidinoethylamine, in place of the
N~(2-aminoethyll-morpholine, and 90 ml. of the N,N,N',N'-
-tetramethylethylenediamine, giving 13.24 g. of the
desired product as a red-brown solid, mp. 180-185C.
Example 8
1!4 Bisf ?- ~l-pyrrolidinyl)ethylamino]-5,8-
-dihydroxyanthraquinone
An 8.61 g. portion of leuco-1,4-bis~2-1(1-
lQ -pyrrolidinyllethyl]amino]-5,8-dihydroxyanthraquinone is
oxidized as described in Example 2. The reaction mixture
is eYaporated to dryness and the residue recrystallized
from toluene, giving 5.12 g. of the desired product as
~lue-hlack crystals, mp. 193-196C.
Example 9
Leuco-1,4-bisl2-(methylamino ethylamino~-5j8-
-dihydroxyanthraquinone
The procedure of Example 7 is repeated using
8,QQ g. of N-methylethylenediamine in place of the N-2-
2Q ~pyrrolidinoet~ylamine, giving 13.73 g. of the desired
product a~ a dark green solid, mp. 157-160C.
Example 10
Leuco-1l4-bis[(3-dimethylaminopropyl)amino]-5~8
-dihydroxyan hraquinone
Nitrogen is bubbled through an 80-ml. portion
of dimethylaminopropylamine for 15 minutes. A 10.97 g.
portion of leuco-1,4,5,8-tetrahydroanthraquinone is
added slowly with stirring. The mixture is heated under
nitrogen at 50-52C. for 2 hours and then allowed to
cool. The solid is collected and washed with cold
Ei ethanol giYing 5,59 g. of dark~ orange-red crystals,
- 56 -
1~4U~Z3
mp. 115-118C.
Example 11
1~4-BisL(~3-dimethylaminopropyl~amino3-5 ! 8 -dihydrox~-
anthraquinone
A suspension of 6ØQ g. of leuco~l,4-bis~3~di
methylaminopropyl)amino~-5,8-dihydroxyanthraquinone in 60
ml. of N, N',N'-_etramethylethylenediamine is heated on a
steam bath.under reflux while air is bubbled in for 12
hours. The solution is cooled, producing a solid which
is collected and washed twice with.heptane and once with
petroleum ether. This solid is recrystallized by extrac-
tlng wi.th 35Q ml. of hot heptane, filtering and concentra-
ting to 3Q0. ml. Crystallization and washing with petro-
le~m ether gives 3.72 g. of the desire product as black
lS needle~ mp. 154`157C,
Exam~le 12
Leuco-1,4-bis~2-aminoethylamino)-5~8~dih~droxy~
anthraquinone
A reaction mixture comprising 10..97 g. of
2Q leuco-1,4,5,8-tetrahydroxyanthraquinone in 80 ml. of de-
aerated ~,N,N'N'-tetramethylethylenediamine containing
7.22 g. of ethylenediamine is heated and stirred under
nitrogen at 8Q-SQC. for one hour. The mixture is
allowed to stand under a slow flow of nitrogen, pro-
ducing a solid which is collected and washed with ethyl
acetate, acetonitrile and petroleum ether giving 13.8 g.
of t~e desired product as a red-black solid.
Example 13
Leuco-1~4~bis(3-aminopropylamino~5f8-dihydroxy
30. anthraquinone
57 -
,. J
il4~923
A suspension of 10.97 g. of leuco l,4,5,8-
-tetrahydroxyanthraquinone in a de-aerated solution of
8.9 g. of 1,3-diaminopropane in 80 ml. of N,N,N',N'-
-tetramethylethylenediamine is stirred and heated at 49C.
for one hour under nitrogen, then allowed to cool. The
resulting solid is collected and washed with cold ethanol
giving 14.21 g. of the desired product as a black solid.
Example 14
Leuco-1,4-bis~ ~ rox~ethyla no)ethylamino~
lQ -5~8-dihydroxyanthraquinone
A suspenion of 12.5 g. of 2-(2-aminoethyl-
animo)ethanol in 40 ml. of N,N,N',N'-tetramethylethylene-
diamine is stirred and de-aerated by bubbling nitrogen in
for 15 minutes. A 10.97-g. protion of leuco-1,4,5,8-
tetrahydroxyanthraquinone is gradually added with stir-
ring. The suspension is heated and stirred under nitro-
gen in an oil bath at 5Q-52C. for 5 hours. The mixture
is allo~ed to stand and cool under nitrogen for 12 hours.
The solid is collected by decantation, macerated in etha-
2Q nol, collected and wash with ethanol giving 15.06 g. of
the de~ired product as a green-gray solid, mp. 129-131C.
~xam~le 15
Leuco~1,4-his~2-~di(~hydr
no]-5~8-dihydroxyanthraquinone
A solution of 17.8 g. of N,N-di~hydroxyethyl)-
ethylenediamine in 100 ml. of methanol is cooled with an
ice ~ath, stirred, and de-aerated by bubbling in nitrogen
for 15 minutes. A 10.97-gram portion of leuco-1,4,5,8-
-tetrahydro~yanthraquinone is gradually added with stir-
ring and continued cooling. The suspension is heated
- 58 -
~t~ ~
923
and stirred under nitrogen in an oil bath at 50-52C.
for one hour and the mixture is then allowed to stand and
cool under nitrogen overnight. The solid is collected
and washed with ethanol giving 14.8 g. of a red-brown
solid, m.p. 165-168C.
Example 16
1,4-Bis[2-methylamino)ethylamino]-5,8-dihydroxy-
anthraquinone_dihydrochloride
To a suspension of 11.60 g. (0.03 mole) of
lQ leuco-1,4-bisL2-(methylamino)ethamino]-5,8-dihydroxy-
anthraquinone in 200 ml. of 2-methoxyethanol was added
gradually with stirring 15 ml. of 8N ethanolic hydrogen
chloride, The system was chilled with an ice bath and
gtirred as 7.50 g. (0.0305 mole) of chloranil powder
was ~radually added. The mixture was stirred overnight
at room temperature and diluted with 600 ml. of ether.
The solid was collected and washed with tetrahydrofuran.
The product (14.16 g.) was recrystallized by dissolving
it in 13Q ml. of water and adding 650 ml. of acetone to
2Q giYe 13.15 g. of a blue-black solid.
Example 17
1,4-Bis~2-(2-aminoethylamino)ethylamino]-
5 ! 8 dihydroxyanthraq-uinone
Following the general procedure of Example 3,
a mixture of 10.97 g. of leuco-1,4,5,8-tetrahydroxyanth-
raquinone, 80 ml. of N,N,N',N'-tetramethylethylene-
diamine and 21.84 g. (0.24 mole) of diethylenetriamine
soon gave a thick, congealed mass which prevented effec-
tive stirring so the reaction time was extended to 24
hours. The mixture was allowed to cool and the superna-
tent liquid was decanted and discarded. A solution of
E~q - 59 -
1~4~923
~he congealed mass in 100 ml. of methanol was filtered,
then allowed to oxidize in the air for four days in a
partially covered flask. The gelantinous mass which had
separated became solid when the oxidation mixture was
agitated with 20n ml. of acetonitrile and then allowed
to stand for one hour. After the solid was collected
and ~ashed first with acetonitrile, then with ether, it
amounted to 10.88 g. of blue-black powder.
Example 18
Leuco-1,4-bis(4-aminobutylamino)-5,8-dihydroxy
_nthraquinone
Following the general procedure of Example 3
hut u8ing 45 ml. of 1,4~diaminobutane as the primary
amine component, there was obtained 12.20 g. of product
a~ a dull grey-green solid.
Example 19
Leuco~lr4~bis~2-dimethylaminopropylamino]-5~8-di~
h.ydroxyanthraquinone
The reaction of 12.26 g. of 2-dimethylamino-
2a propylamine ~ith 10.97 g. of leuco-1~4,5,8-tetrahydroxy-
anthraquinone is 100 ml. of ethanol for one hour by the
procedure of Example 1 gives 7.29 g. of red-brown crys-
tal~.
Example 20-
Leuco-1,4-bis[2-(2-methylaminoethylamino)ethyl-
amino-5,8-dihydroxyanthraquinone
To a solution of 14,10 g. of l-methyl diethy~
lenetrimaine in 50 ml. of ethanol and 40 mol. of
N,N,N',N'-tetramethylethylenediamine is added 10.97 g.
3Q of leuco-,4,5,8-tetrahydroxyanthraquinone as in Example
1. The mixture is heated at 50 and stirred under nitro-
gen for one hour, chilled with an ice bath, the solid
- 60 -
114~5~3Z3
collected and wash with.cold ethanol to give 7.23 g.
of green-black crystals, m.p. 108-111C.
Example 21
Leuco-1~4-his~2-(2-dimethylaminoethylamino)ethyl-
amino,l-5 ! 8-dihydroxyanthraquinone
The reaction of N-(dimethylaminoethyl)ethy-
lenedia~ine with.leuco-1,4,5,8-tetrahydroxyanthraquinone
by the procedure o Example 20 gives the title comp,ound.
Bxample 22
Leuco-lL4~bis~?~ piperazinyl)-ethylamino]~5r8
-dihydroxyanthraquinone-
The procedure of Example 20 applied to 15.50
g. of N~ aminoethyl).piperazine gives 3.92 g. of a
hlack.powder which does not melt by 35QC. and is dis-
ca~ded. The mother liquor and ethanol washes, on stan-
ding and partly evaporating during two weeks in an un-
atoppered flask, deposit a solid which is collected
and was.hed with.ethanol to giYe 6.19 g. of the title
cQmpound as a black soli.d, m.p. 200-203C.
2Q Bxample 23
1,4~is.(2-aminoethylamino?,-5r8-dihydroxyanthraqui-
none dihydrochloride
Oxidation with chloranil of 28.25 g. of the
product of. Bxample 12 hy the procedure of Bxample 16
giYes 29.66. g. of a crude, hlue.-black solid which is then
extracted hy stirring for 14 hours with 800 ml. of water.
Soli.d& are remoYed by centrifugation and the supernatent
~oluti.on freeze.dried, leaYing 16.38 g. of a blue-black
&oli,d which is unmelted by 350C.
- 61 -
11~4~923
Example 24
lt4~is~2~-~2~hydrQxyeth~aminoLethylamino~5~8;dihydroxy
anthraqui e Di~ydrochloride
Chloranil oxidation of 17.86 g. of the product
of Example 14 by the procedure of Example 16 gives ~with-
out recrystallizationl 21.34 g. of blue-black solid, m.p.
2Q3-205C.
Example 25
lr 4~B~s~2~(2 meth~laminoethylamino)~ethylamino~-5~8-dihyd
10roxyanthraquinone Tetrahydrochloride
The product of Example 20 (11.70 g.) is oxi-
dized with chloranil by the procedure of Example 16, gi-
ving 18.03 g. of hlue-black solid, m.p. l9Q-203C.
Example 26
15lt4~Bi~2~ hydroxyeth~lamino)-ethylamino~-5~8
dihydroxyanthraquinone
In a modification of the synthesis of Example
14 the solYent used is lQQ ml. of ethanol. The mother
liquor from the leuco product is allowed to stand for two
2Q week~ in an unstoppered flask, whereupon the oxidized
product separates. It is collected and washed with etha-
nol, giving ~lue-black crystals, m.p. 175-177C.
Example 27
Leuco-1,4-bis~3-(?-hydroxyethylamino)-l-propyl-a-ml-no]
255 ! 8 ~ dihydroxyanthraquinone
The procedure of Example 15 is used with a
solution of 14.18 g. of 2-(3-aminopropylamino)ethanol in
lQQ ml. of ethanol. The resulting solution is filtered
and the filtrate diluted with 300 ml. of ether, preci-
3Qpitating the product as a goo. After decantation of the
62 _
~'
114~923
supernatent solution the goo is caused to crystallize
by agita,ting it with lQQ ml. of tetrahydrofuran. Wash-
in~g ~ith,ethanol giYe~ 12.56 g. of green hlack solid,
m.p. lQ1C~lQ4C.
Example 28
1,4~is~3 ~2~h~droxyethylaminoL~ ropylamino]
5,,8 dihydrQ~yanthraqu~none dih;y rochloride
Oxidation of q.~S g. of leuco-1,4-bis~3-
~('2-hydro~yethylamino)propylamino~ 5,8 dihydroxyanthra-
quinone with chloranil as in Example 16 gives 11.70 g.
o,f a blue solid which does not melt by 350C.
Example 23
Le~co 1~4 bis~2-(,3~hydroxy-l-propylamino ?- ethylamino~-
5,8~dihydroxyanthraquinone
lS The procedure of Example lS is paralleled with
14.18 g, of N-(3-hydroxypropyl)ethylenediamine in 100 ml.
of ethanol to give 14.63 g. ~f red-brown crystals, m.p.
58-60,C.
Example 30
2 Q 1 ! 4-Bis~2-(3-hydroxy-l-propylamino)ethylamino]
5r8-dih,ydroxy'anthraquinone dihydrochloride
Choranil oxidation of 10.77 g. of the product
of Example 2~. by the procedure of Example 16 yielded
11.64 g. of a dark hlue solid, m.p. 210-216C.
Example 31
Leuco-1,4-bis[2-(,2-hydroxy-l-propylaminolethylamino]
5 ! 8-dih~droxyanthraquinone
With 14.18 g. of 1-(2-aminoethylamino)-2-
propanol in lQ0 ml. of ethanol the procedue of Example 17
3Q yields 17.61 g. of green-black crystals, m.p. 50-60C.
- 63 -
~ .
923
Exa~ple 32
1!4-~ia~2-(2~h~droxy-1-propylamino)ethylamino~
5~8-dihydroxyanthraquinone dihydrochloride
A filtered solution of 14,44 g. of leuco-,4-
~isl2-(2-hydroxy-1-propylaminto),ethylamino~-4-dihydroxy-
anthraquinone in 215 ml. of 2-methoxyethanol is oxidized
with,7.65 g. of chloranil by the procedure of Example 16,
affording 16.75 g. of purple solid, m.p. 177-185C.
Example 33
Leuco-1!4-his~2-(,2-h~droxyethylamino)ethylamino]
eth~lamino~ ~ 8-dihydroxyanthraquinone
The procedure of Example 15 used with a solu
tion of 17,67 ~. of 2-~2 (2-aminoethylaminolethylamino]~
e,thanol in lOQ ml. of methanol gives a solution which is
filtered, then diluted with 300 ml. of ether, precipi-
tating a goo which,hardens on standing overnight. Har-
dening is completed by thorough maceration of the solid
in the solYent. The &olid is collected and washed with
ether! yielding 16.82 g. of a green-black solid. This
20, solid remains, granular if stored at -25C., but coales-
cea into a solid cake if stored at 25C.
Example 34
1,4-Bis~2-(,2-hydroxyethylami~olethylamin
ethylamlno] 5t8-dihydr-o-xxanthraquinone
tetrahydrochloride
Chloranil oxidation of 12.lQ g. of the product
of Example 33 hy the method of Example 16, including
three additional washings of the solid with methanol,
~ives 12.46 g. of dark, bluet solid product.
~ 64 -
- `` 1141rJ9Z3
Exam~le 35
1!4~Bis~2 (2/3~dlhydroxy~ropylamino?ethy~amlno]~
5,.8-di.h~droxyanthraquinone dih~drochloride
By the procedure of Example 15 a solution of
16..... 10. g. of 3 (2-aminoethylaminol~1,2-propanediol
~A. R. ~urrey, C. M. Sutter and J, S. Buck, J. Am. Chem.
Soc.! 74~ 41Q2 U9,52).~ in lQ0. ml. of methanol gives a goo
which.is separated from solvent b.y chilling with an ice
bath.~ then decanting. The goo is washed four times by
lQ. stirring 1,5 hours at 25 with.lQQ-ml. portions of
me.thanol, chilling with.an ice bath., then decanting. A
fi.ltered s.olution of the goo in 280. ml. of 2-methoxyetha-
nol is oxidized with.10..01 g, of chloranil by the method
of Example 16. The product is additionally washed with
e,thanol! giving 15.25 g. of blue-hlack solid, m.p. 191-
-19.3C.
Example 36
Leuco-1!4~bis~2 (l~aziridino?.ethylamino~-
5,8-dih ~ oxyanthraqu_~one
2Q ~ith.lQ,33 g. of N-(,2-aminoethyl).aziridine in
8Q ml. of N!N,NIrN'-tetramethylethylenediamine the
procedure.of Example 15 gives. a stiff gum. The next day
the, aupernatent solution is discarded, 100 ml. of ether
is added and the,gum periodically macerated therein for
another day, when the gum is mostly hardened. Hardening
is completed by maceration during three washings of the
solid with.ether, giYing 17.66 g. of blue-black, granu-
lar powder.
3Q
- 65 -
114V9Z3
Example 37
1,4-Bis~2~ aziridino)ethylamino~-5,8-dihydroxy-
anthraquinone
To a suspension of 4.10 g. of the product of
Example 36 in 40 ml. of chloroform is added a solution of
1.74 g. of diethyl azddicarboxylate in 25 ml, of chloro-
form, The mixture is stirred for 20 minutes, the resul-
ting dark blue solution is filtered, and the filtrate is
eYaporated at ~ 30. A solution of the residue in 40 ml.
of chloroform is stirred five minutes with 2 g. of
lQ decolorizing carbon, filtered and washed through with
another 25 ml. of chloroform. Addition of 100 ml. of
ether to the filtratefi precipitates a gum which is
eliminated by decantation-filtration. The filtrates
depoait crystals which are washed sparingly with acetone.
The chloroform-ether mother liquor, chilled at -60C.,
deposits a second crop of crystals which is washed with
ethe~r and with methanol. A solution of both crops of
crystals in 2Q ml. of chloroform is stirred with decolo-
rizing carbon, filtered, evaporated at ~ 25C. to a
2Q Yolume of 5 ml., diluted with 20 ml. of ether, then
chilled at -60C. The resulting blue-black crystals,
washed ~ith ether, amount to 0.64 g., m.p. 168-170C.
In thin-layer chromatography on silica gel the product
is mo~ed as a blue spot by chloroform-triethylamine-
5 methanol, 27/3/1 (xatios by volumel.Example 38
1!4-B.iS[2-~2-(l-morph41ino).ethylamino]ethylamino]-
5!8 dihydroxyanthraquinone tetrahydrochloride
A solution of 20.80 g. of N-(morpholinoethyl)-
Q eth~lene diamine in lOQ ml. of ethanol is used in the
- 66 -
114~923
procedure of Example lS to give a solution which isfiltered and diluted with 90.0 ml. of ether, precipating
a goo. The supernatent solution is dec~ted, the goo
dis.solved in 175 ml. of 2-methoxyethanol and oxidized
~ith 5.2~ g. of chloranil by the method of Example 16,
giYing 17.7 g. of dark blue solid.
Example 39
Leuco-1,4-Bis~2-(acetamido).ethylamino.]-
5,8-dihydroxyanthraquinone
A solution of 12.26 g. of N~acetylethylene
di.a~ine in lOQ ml. of ethanol in the procedure of
Example 15 giYes 15.27 g, of dark, red-brown solid,
m,p. 125C.
Example 40.
1,4-~isi2-(acetamido)ethylamino.]~
5~8-dih.ydrQxyanthraquinone
A suspension of ll.9S g. of leuco-1,4-bis[2-
~acetami.do)-ethylamino~-5,8-dihydroxyanthraquinone is
oxidized with.6.76 g. of chloranil during 61 hours by
2~ the.~ethod of Example 61, giving a very acidic hydro-
chloride. salt which.is converted to the free base by
four ~ashings with water. Crystallization from 110 ml.
of dimethyl sulfoxide (~oiling only 2 minutes and not
attempting a hot filtration), then washing with dimethyl
sulfQxide.and with.ethanol gives 7.76 g. of blue-black
solid, m.p. 273-274C.
Example 41
1, 4-~is f 2-~N-(2-hydroxyethyl triflouracetamido]-
ethylamino]-5~8-dihydroxyanthraquinone
3Q A suspension of 1.50 g. of 1,4-bis[2-(2-
- 67 -
114~923
-hydrQxyethylamino)ethylamino]-5,8 dihydroxyanthra-
quinone in 75 ml. of ethyl triflouroacetate and 75 ml.
of methanol is stirred for 10 minutes. Evaportation of
the resulting solution ln vacuo at 30C. leaves a
residue which is washed and macerated with methylene
chloride, giYing 2.11 g. of blue-black solid, m.p.
162C.
Example 42
1!4-Bis~2-amino-2-carboxyethylamino]-5r8-dihydr
anthraquinone . 3/4 HCl
To a solution of 6.23 g. of dl-a,~-diaminopro-
pionic acid in 3Q ml. of warm water is added 1.078 g. of
lithium hydroxide and 60 ml. of dimethyl sulfoxide. The
system is flushed with nitrogen and 4.12 g. of leuco-1,4,-
lS 8-tetrahydroxyanthraquinone is added gradually with stir-
ring, The mixture is stirred and heated with an oil bath
at 5Q, first for 15 hours under nitrogen, then for 21
hours as the initial product is oxidizéd by bubbling in
a stream of air. Thin-layer chromatography on silica gel
with methanol~water-concentrated ammonia (25/5/11 by
volume) shows all the product spots to be blue when the
oxidation is complete. After the mixture is cool the
solids are removed by filtration and washed once with
dimethyl sulfoxide -water (2/1). Addition of 400 ml.
of methanol to the filtrates precipitates a solid which
is collected and washed with methanol. Further washing
with a total of 13. ml. of 0.01 N aqueous acetic acid
dissolYes virtually all of the solid. Addition of 3 ml.
of concentrated h~drochloric acid to the acetic acid
filtrates precipitates a blue-black solid which is washed
- 68 -
923
with acetone to giye 0.24 g. of the product.
Example 43
Leuco-1!4-bisI2-(2-methoxyethylamino ethylamino]-
5,8-dihydroxyanthraquinone
An ethanol solution of N-(2-methoxyethyl)-
ethylenediamine (U.S. Pat. 3,454,640) reacts in the
procedure of Example 51 to give the title compound.
Example 44
1,4-Bis[2 (1,3-oxazolidin-1-yl)ethylamino]-5,8-dihydroxy-
anthraquinone
A solution of 1.62 g. of 37% aqueous formal-
dehyde solution in 50 ml. of water is stirred overnight
with 4~44 g. of 1,4-bis~2-(2-hydroxyethylamino)ethylaminoI-
-5,8-dihydroxyanthraquinone. The resulting solid is
washed with water to give the product.
Example 45
1,4-Bis[2-(tetrahydro-1,3-oxazin-1-yl)ethylamino]-
5,8-dihydroxyanthraquinone
A solution of 1.62 ml. of 37~ aqueous formal-
dehyde in 50 ml. of 0.4N aqueous sodium hydroxide is
stirred overnight with 5.45 g. of 1,4-bis[2-(30hydroxy-1-
~propylaminolethylamino]-5,8-dihydroxyanthraquinone di-
hydrochloride. The product is obtained by washing the
resulting solid with water
Example 46
1,4-Bis[2-(1,3-oxazolidin-2-one-1-yl)ethylamino]-
5,8-dihydroxyanthraquinone
A solution of 0.020 g. of sodium in 25 ml. of
methanol is stirred and heated under reflux overnight
with 75 ml. of diethyl carbonate and 4.44 g. of 1,4-bis-
- 69 -
114~9Z3
~2~(2~h~droxyethylamino)~ethylamino]-5,8edihydrQxyanth-
raquinone. The mixture is allowed to cool. It is stirred
with Q.l ml. of acetic acid, the solid is collected by
filtration and washed with methanol to give the product.
Example 47
1!4-Bis~2-(1,3-oxazin-2-one-1-yl?,ethylamino~-
5,8-dihydrQxyanth-raquinone
A solution o o.48 g. of sodium in 25 ml. of
me*hanol is stirred and heated overnight with 75 ml. of
diethyl carbonate and 5.45 g. of 1,4-bis~2 (3-hydroxy-1-
~propylamino)ethylamino~-5~8-dihydroxyanthraquinone di-
hydrochloride. After the mixture cools it is stirred with
Q.l ml. of acetic acid. The solid product is collected
by filtration and washed with ~ethanol and then with
water.
Example 48
1!4-Bls[2-.[di (,~-h~droxyethyl)amino~ethylamino]
5 ! 8rdihydroxyanthraquinone dihydrochloride
Chloranil oxidation of 10.77 g. of the product
2Q o~ Example 15 by the method of Example 16 gives 11.64 g.
of a dark blue solid, m.p. 216C.
Example 49
Preparation of 50 mg. Tablets
Per Tablet Per 10 ! Tablets
250,Q50 gm. 1~4-bis(~-aminopropyalamino)-
5,8-dihydroxyanthraquinone ................ 500 gm.
0,.0,80 gm. Lactose ... ,....................... 800 gm.
Q,010 gm. Corn Starch (for mix)........................ 100 gm.
0.008 gm. Corn Starch ~for paste) ....... ,............. .75 gm.
Q`.~4'8 gm 1475 gm.
Q.Q02 gm Magnesium Stearate (1%) ................. ..... .15 gm
0`.150'gm 1490 gm
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~'
923
The 1,4-bis(3~aminopropylamino)~5 ! 8-dihydroxy-
anthraquinone ! lactose and corn starch (for mix2 are
~lended together. The corn starch (for paste~ is sus-
pended in 6~0 ml. of water and heared with stirring to
form a paste. This paste is then used to granulate the
mixed powders. Additional water is used if necessary.
The wet ~ranules 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
lQ 1% magnesium stearate and compressed into tablets in a
suitable tableting machine.
Example 5Q
Preparation of Oral Sus~ension
Ingredient Amount
Leuco-1~4-bis~3-aminopropylaminol~5,8-dihydroxy-
anthraquinone ....,................................ 500 mg.
Sorbitol solution (70~ N.F.) ....................... 40 ml.
Sodium benzoate ..,................................ 150 mg.
Saccharin ........................................ , 10 mg.
Red dye ............................................ 50 mg.
Cherry flavor ....,................................. 50 ml.
Distilled water... qs...ad.......................... 100 ml.
The sorbitol solution is added ta 40 ml. of
distilled water and the leuco-1,4-bis(3-aminopropylamino)-
-5~8-dihydroxyanthraquinone is suspended therein. The
saccharin, sodium benzoate, flavor and dye are added and
dissolved. The volume is adjusted to 100 ml. with dis-
tilled water. Each ml. of syrup contains 5 mg. of leuco-
-1,4-b (3-aminopropylamino)-5,8-dihydroxyanthraquinone.
Example 51
Preparation of Parenteral solution
In a solution of 700 ml. of propylene glycol
3Q and 200 ml. of water for injection is suspended 20.0
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114V9Z3
~ grams of 1,4~bis~3-(dime.thylamino propylamino.l -5,8~di-
: hydroxyanthraqui.none.dihydrochloride.with.stirring.
After suspension is complete, th.e pH. is adjusted to 5.5
with hydrochloric acid and the volume is made up to 1000
ml with.water for injecti.on. The formulation is steri.
li.zed, filled into 5.Q ml. ampoules each.containing 2 0
ml CrePresenting 40 mg. of drug). and sealed under
nitrogen
Exam~le 52
10. 1!4-Bis~2 (2-hydroxyethylamino)ethylamino~-5l8
-dihydroxyanthraquinone disuccinate salt
.
A mixture of 222 mg. of 1,4 bis~2-(.2 hydroxy-
ethylaminoLethylamino.]-5,8.dihydroxyanthraquinone, 118
mg. of s.uccinic acid, and 5Q ml. of ethanol is heated
under reflux for 3Q minutes to give the title compound.
Example 53
.
1,4-Bis~2~q3~hydroxypropylamino)ethylamino~5~8
-dihydr~xyanthaquinone dimalate.salt
A mixture of 228 mg. of 1,4-bis~2;(.3-hydroxy-
20. propylamino)ethylamino.~5,8-dihydroxyanthraquinone, 134
mg, of DL-~alic acid~ and 50. ml. of ethanol is heated
under re.flux for 3Q minutes to give the title compound.
Example 5~
1!4-Bis~2-(.2-hydroxypropylamino)ethylamino~-5,8-
dihydroxyanthraquinone dilactate salt
A mixture of 228 mg. of 1,4-bis[2-(2-hydroxy-
propylaminolethylamino)-5,8-dihydroxyanthraquinone, 120
mg. of 80% DL-lactic acid, and L0 ml. of ethanol is
heated on a steam bath for lO.minutes, cooled, treated
with.50.ml. of acetone and cooled to obtain the title
compound.
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