Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
66~S
BRIEF SUMMARY OF THE INVENTION
This invention relates to new organic compounds
and, more particularly, is concerned with novel 9,10-di-
hydroanthracene-9,10-dicarboxaldehyde-bis-hydrazones
which may be represented by the following general formula:
N-~ ~
N ~ 1
wherein Rl is hydrogen or alkyl having up to 4 carbon
atoms; R2 is hydrogen, alkyl having up to 4 carbon atoms,
phenyl or a moiety of the formulae:
(C~2 )
- R7 and - C Y :
wherein n is 2, 3, 4, or 5, R7 is amino, anilino, hydra-
zino, monohydroxyalkylamino having from 2 to 4 carbon
atoms and wherein the carbon atom alpha to the nitrogen 35 atom may not bear an hydroxy group, alkylamino having up
to 4 carbon atoms, dialkylamino wherein each alkyl group
`
.
,
~.~.iG6~)5
--2--
has up to 4 carbon atoms, cycloalkylamino having from 3 to
6 carbon atoms, benzylamino, ~-phenethylamino, ~-phenethyl-
amino, 2-furfurylamino, 3-furfurylamino, ~-thenylamino,
~-thenylamino, ~-pyridylmethylamino, ~-pyridylmethylamino,
y-pyridylmethylamino, indanylamino, pyrrolidino, piperi-
dino, morpholino, thiomorpholino, N-methylpierazino, al-
koxy having up to 4 carbon atoms or alkylthio having up to
4 carbon atoms, X is oxo (0=), thioxo (S=) or imino (R-N=
wherein R is hydrogen or alkyl having up to 4 carbom atoms)
and Y is oxy (-O-), thio (-S-) or a divalent group of the
formula:
- N - R8
wherein R8 is hydrogen, alkyl having up to 4 carbom atoms
or monohydroxyalkyl having from 2 to 4 carbon atoms and
wherein the carbon atoms alpha to the nitrogen atom may
not bear an hydroxy group; and R3, R4, Rs and R6 are each
individually selected from the group consisting of hydro-
gen, halogen (F, Cl, Br, I), hydroxy, nitro, amino, sul-
fonamideo, alkyl having up to 4 carbon atoms and alkoxyhaving up to 4 carbon atoms.
The hydrazino substituents pendant from the
anthracene-9,10-bis-carbonyl nuclei may be the same or
different and may be in the syn or anti forms. Addition-
ally, the entire units -CH=N-N Rl at the Cg and
Clo positions may be either cis (both extending out from
the same face of ~he anthracene nucleus) or trans (ex-
tending out from the opposite faces of the anthracene
nucleus).
A preferred embodiment of the present invention
consists of compounds which may be represented by the
following structural formula:
11166~5
N -(CH2)
N-NH-C Y
11
CI~
~CH
N~NI~-C Y
N -(C~2)n
-'
wherein n, Y, R3, R4, Rs and R6 are as hereinabove defined.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention are
obtainable as yellow crystalline materials having charac-
teristic melting points and absorption spectra and whichmay be purified by recrystallization from common or~anic
solvents such as lower alkanols, dimethylformamide, tetra-
hydrofuran, methyl isobutyl ketone, and the like.
The organic bases of this invention form non-
-toxic acid-addition and quaternary ammonium salts with a
variety of pharmacologically acceptable organic and in-
organic salt-forming reagents. Thus, acid-addition salts,
formed by admixture of the organic free base with one or
more equivalents of an acid, suitably in a neutral solvent,
are formed with such acids as sulfuric, phosphoric, hydro-
chloric, bydrobromic, sulfamic, citric, lactic, malic,
succinic, tartaric, acetic, benzoic, gluconic, ascorbic,
and the like. Quaternary ammonium salts may be formed by
reaction of~the free bases with one or more equivalents
of a variety of organic esters of sulfuric, hydrohalic and
and aromatic sulfonic acids. The organic reagents employed
for quaternary ammonium salt formation are preferably lower
alkyl halides. However, other organic reagents are suit-
able for quaternary ammonium salt formation, and may be
selected from among a diverse class of compounds including
benzyl chloride, phenethyl chloride, naphthylmethyl chlo-
. .
.
--4--
ride, dimethyl sulfate, methyl benzenesulfonate ethyl to-
luenesulfonate, allyl chloride, methallyl bromide and
crotyl bromide. For purposes of this invention the free
bases are equivalent to their non-toxic acid-addition and
quaternary ammonium salts. The acid-addition and quater-
nary ammonium salts of the organic bases of the presentinvention are, in general, crystalline solids, relatively
soluble in water, methanol and ethanol but relatively in-
soluble in non-polar organic solvents such as diethyl
ether, benzene, toluene, and the like.
The novel compounds of the present invention
possess the property of inhibiting the growth of trans-
planted mouse tumors as established by the following tests.
Lymphocytic leukemia P388 test
The animals used are mice, all of one sex,
weighing a minimum of 18 g. and all within a 3 gram weight
range. There are 5 or 6 animals per test group. The tu-
mor transplant is by intraperitoneal injection of 0:1 ml.
or 0.5 ml. of dilute ascitic fluid containing 106 cells of
lymphocytic leukemia p388. The test compounds are admin-
istered intraperitoneally on days one, S and 9 (relativeto 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 sur-
vival time for treated (T)/control (C) animals are calcu-
lated. The positive control compound is 5-fluorouracil
given as an intraperitoneal injection on days one, 5 and
9. The results of this test with representative compounds
of the present invention appear in Table I below. The
criterion for efficacy is T/C x 100>125%.
, f .,
1166~5
5 ~ .
. ~ . _ ~ U~OI~ ~ ~
c~ ~n,, . ~ ..
'!
.
. ~ .
. . .
.. . ~ . ....... ~ ,
.
-` ~1166~)5i
01 ~ ~ o ~ o o o o u~ n .,
U ~ ~ o ~ In o ~ In O CO ~ 1~ ~
~D.
~ ~ ~ O V~ In Ul U~ O O O O U~ O O O O U U7 ~ U~
~ ~ ~ ~ ~ os~ o a~
U~
V ~ ~ U. ~ ~ U, Ul ., U, U' ,,
E~a e m ~ ~D r~ O O O U~ ~ ~D ~ O O O U~ N ~0 ~ O O
V 1
o r~ I
3 c c
o o s O >I r o
o o 1l o a) o c~
~ ~ c ~ ~ ~ ~ .
t~ ~ ~ _l ~ ~ .,1 ~ ~ ,~
V1 ~ U u~ ~1 U Ul ~ U
~ o 4 ~ ~ .Q ~ ~a L~
LO~ ~ LO ~' LO~ ~ LO LO~ LO~ o ~ L~
'tU L~ ~J 'iJ ~C ~U L~ ~ ~C 'C C L~ 1
O C 1~1 ~ O C 1~ C~rl o c 1
~u u Ln N I ~ U I N I ~a U Ln
a~
11~66~5
Melanotic Melanoma B16
The animals used are C57BC/6 mice, all of the
same sex, weighing a minimum of 17 g. and all within a 3 g.
weight range. There are normally 10 animals per test
gro~p. A one-gram portion of melanotic melanoma B16 tumor
is homogenized in 10 ml. of cold balanced salt solution and
a 0.5 ml. aliquot of the homogenate is implanted intra-
peritoneally into each of the test mice. The test com-
pounds 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 re-
sults of this test with representative compounds of thepresent invention appear in Table II below. The criterion
for efficacy is T/C x 100 > 125%.
- 11166-~5
o~
r I ~ 1~ 1~ N O ~ I O ~ ~ _l 1
~3 N ~C N ~ I
0 ~ U'l O O O 0 11~ O 11~ 0 0 U7 O O O O O
. ~! '~ N ~ N _I N ~'1 N N --I O N U- N ~ O
C) `' It~ U'~
8 ~ N 1'1 ~ O O N ~ O O N ~ _i O O
o ~ o !~` o ~ ~ O ~
~.a ~0 ~.~
N O N O O .
~: ~ ~: ~ 4 -I
O N U N O .C ~
-- S ' 0 e U
. --O . 0~1 O O O ~
.~ O 0 4 0 E r~ o
~ 4 o ~ 4 4 4 o . _~ 4 ~1 0 ~1 4
:r .1 0 r r4r_J .~ O r r4 ~ O 1~ :1
N I a ~I ~ 4 O I o I ¦ .
, ' . ~.:
~ ':
11~66~1~
g
The novel compounds of the present invention
exhibit antibacterial activity when tested according to
the following procedure. The antibacterial spectrum, in
terms of the concentration required to inhibit the growth
of various typical bacteria, was determined in a standard
manner by the agar-dilution streak-plate technique. A
Steers multiple inocula replicator was used with incuba-
tion at 37C. for 18 hours in Mueller-Ninton agar. The
results for typical compounds of this invention are set
forth in Table III below as the minimal inhibitory con-
centration in micrograms per milliliter.
66~5
-10-
r
~0 ~01
0~ _ _
~ ~ç ~1~ ~ ~ ~O
r ~ _
l I 0 I 0
N ~ N ~ ~ N ~ S
~ ~ .~ ~ n E ~ .n
o :,. c ~ o ,a ~ o ,a
E C ~1 u~ o~ ~ u) a~
o I ~ n I I
N O r O~ I~ ~ C U
.,.~ ,C ~a r
.,~ .~ X U ~ C 0 ~ C U
I ~ O ~ E ~ O
t~l ~ I 'Q5 o
l~J I :`~ I . I I ~ S
~ ~II
: :~
... .
li~66~5
The novel compounds of formula (I) and their
pharmacologically acceptable acid-addition and quaternary
ammonium salts would be expected to show activity against
a broad range of cancer diseases, and especially blood
cancer diseases such as leukemia, in standard test animals
at doses substantially below toxic levels. The modes con-
templated for administration are essentially parenteral
and intraperitoneal. Solutions of the active ingredient
as a free base or salt can be prepared in water or in water
suitably mixed with, for example, surfactants 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 pre-
vent the growth of microorganisms.
The pharmaceutical compositions can be in forms
suitable for injectable use, which forms include sterile
aqueous solutions or dispersions and sterile powders for
the extemporanous preparation of sterile injectable solu-
tions or dispersions. In all cases the form must be ster-
ile and must be fluid to the extent that easy syringability
exists. It must be stable under the conditions of manufac-
ture and storage and must be preserved against the contam-
inating action of microorganisms such as bacteria and fun-
gi. The carrier can be a solvent or dispersion medium
containing, for example, water ethanol, polyol (for ex-
ample, glycerol, propylene glycol, and liquid polyethylene
glycol, and the like), suitable mixtures thereof, and veg-
etable 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 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 in-
clude isotonic agents, for example, sugars or sodium chlo-
6~ 5
-12-
ride. Prolonged absorption of the injectable compositions
can be brought about by the use in the compositions of
agents delaying absorption, for example, aluminum mono-
stearate and gelatin.
Sterile injectable solutions are prepared by in-
S corporating the active ingredient or ingredients in therequired amount in the appropriate solvent with various of
the other ingredients enumerated above, as required, fol-
lowed by filtered sterilization. Generally, dispersions
are prepared by incorporating the various sterilized active
ingredient into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients 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 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
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 in-
gredient, its use in the present compositions is contem-
plated. Supplementary active ingredients can also be
incorporated into the inventive compositions.
It is especially advantageous to formulate com-
positions in dosage unit form for ease of administra~ion
and uniformity of dosage. Dosage unit form as used in the
specification and claims herein refers to physically dis-
crete units suited as unitary dosages for the animal sub-
jects to be treated, each unit containing a predetermined
quantity of active material calculated to product the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the novel
~`` ~1 16 ~ 5
-13-
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 treat-
ment of disease in living subjects having a diseased con-
dition in which bodily health is impaired as disclosed in
detail in this specification.
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 administra-
tion. A daily dose of from about one to about lO0 mg./kg.
of body weight given singly or in divided doses of up to
5 times a day embraces the effective range for the treat-
ment of most conditions for which the novel compounds are
effective and substantially non-toxic. For a 75-kg. sub-
ject, 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
about 2500 mg. of the active ingredient. The preferred
range is from 2 to about 50 mg./kg. of 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 car-
rier in dosage 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 ingre-
dient is generally present in from about 0.1 to about
400 mg./ml. of carrier. In the case of compositions con-
taining supplementary active ingredients, the dosages are
determined by reference to the usual dose and manner of
administration of the said ingredients.
~1166~S
Regression and palliation of cancers are attain-
ed, for example, using intraperitoneal administration. A
single intravenous dosage or repeated daily dosages can be
administered. Daily dosages up to about S 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 administrated is a suffi-
cient amount to aid regression and palliation of the leu-
kemia or the like, in the absence of excessive deleterious
side effects of a cytotoxic nature to the hosts harboring
the cancer. As used herein, cancer means blood malig-
nancies such as leukemia, as well as other solid and non-
-solid malignancies such as the melanocarcinomas, lung
carcinomas and mammary tumors. By regression and pallia-
tion is meant arresting or retarding the growth of thetumor 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 as set forth in the following reaction
scheme:
: ; .
11~66~5
-15-
~) C ¦ C~ 1 R3~ R;
6 ~,~~
( III ) R~ I R6
( IV)
\ ~ ~OI-i
R3 ~
~Vl) (V)
N - N
Il --R2
~ ~L
N-N R2
,~,
11~66QS
16
wherein Rl, R2, R3, R4, R5 and R6 are as hereinabove de-
fined. In accordance with the above reaction scheme, the
anthracene derivative (III) is heated with excess vinylene
carbonate under reflux for about 10-24 hours to give the
cyclic carbonate (IV). Hydrolysis of the cyclic carbonate
(IV) with aqueous-ethanolic potassium hydroxide at 70-
-75C. for about 1-4 hours produces the diol (V) which in
turn is treated with lead tetraacetate in acetic acid at
20-35C. for about 1-2 hours to give the 9,10-dihydro-9,
10-anthracenedicarboxaldehyde (VI). Alternatively, the
diols (V) may be suspended in an aqueous solution of
either sodium or potassium periodate and stirred at room
temperature for 24 hours to provide the dicarboxaldehydes
(VI). Either procedure provides the cis-isomer of the
dicarboxaldehydes (VI) which may be readily converted to
the trans form by standard procedures. Treatment of the
dicarboxaldehydes (VI) with a hydrazine of the formula:
H ~
~ 2~ in ethanol or n-propanol
at the reflux temperature for 1-4 hours provides the 9,10-
-bis-hydrazones (I).
The invention will be described in greater de-
tail in conjunction with the following specific examples.
6~ 5
Example 1
9,10-Dihydro-9,10-anthracenedicarboxaldehyde
A mixture of 21.3 g. of vinylene carbonate (re-
distilled to give a colorless liquid 71-73C., 28 mm.)
and 4.4 g. of dry anthracene is heated at reflux (165G-
-170C.), under nitrogen for 20 hours and then vacuum dis
tilled (62-64C., 17 mm.), leaving 10.2 g. of tan resi-
due. This residue is taken up in 100 ml. of methylene
chloride, treated with charcoal and filtered. The fil-
trate is treated with 100 ml. of methanol and cooled
giving colorless crystals of cis-9,10-dihydro-9,10-ethano-
anthracene-11,12-diol, cyclic carbonate (m.p. 260-262C.).
A mixture of 5.6 g. of cis-9,10-dihydro-9,10-
-ethanoanthracene-11,12-diol, cyclic carbonate, 4.9 g. of
potassium hydroxide, 6.4 ml. of water and 53 ml. of etha-
lS nol is stirred at 70-75C. for 2 hours. The resulting
two layer system is filtered. The filtrate is diluted
with twice i~s volume of water and cooled producing color-
less crystals of cis-9,10-dihydro-9,10-ethanoanthracene- -
-11,12-diol (m.p. 202-204C.).
A mixture of 2.38 g. of cis-9,10-dihydro-9,10-
-ethanoanthracene-11,12-diol in 40 ml. of glacial acetic
acid at room temperature is treated portionwise with 4.8
g. of lead tetracetate, with stirring over a period of
10 minutes. The mixture is cooled to 15C. and the solid
which forms is collected by filtration, washed once with
glacial acetic acid, then thoroughly with water giving
the desired product as colorless grains, m.p. 144-146C.
~ .
1~6~
-18-
Example 2
Cis-1,4-Dimethoxy-9,10-dihydro-9,10-anthracene-
dicarboxaldehyde
One gram of 1,4-dimethoxy-9,10-dihydro-9,10-
-ethanoanthracene-11,12-diol, is suspended in 30 ml. of an
aqueous solution containing 0.77 g. of potassium periodate
and one ml. of ethanol. After stirring at room tempera-
ture for 24 hours the insoluble material is removed by
filtration, washed well with water and dried leaving a
yellow product, m.p. 129-132C.
ïO Example 3
Bis(2-imidazolin-2-ylhydrazone)=9,10-
-dihydro-9,10-anthracenedicarboxaldehyde
A mixture of 2.36 g. of 9,10-dihydro-9,10-
-anthracenedicarboxaldehyde and 3.46 g. of 2-hydrazino-
imidazoline dihydrochloride in 200 ml. of n-propanol is
boiled on a hot plate for 1 1/2 hours, concentrating the
volume to 100 ml. The mixture is cooled and allowed to
stand overnight, giving a solid which is collected by
filtration, washed with n-propanol and dried. A 0.4 g.
portion of this solid is recrystallized from water giving
the desired dihydrochloride product as colorless flakes,
m.p. 258-262C.
Example 4
2-Chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde
A solution of 15.0 g. of 2-chloroanthracene in
60.8 g. of vinylene carbonate is refluxed for 20 hours
and then vacuum distilled. The residue is recrystalllized
from methylene chloride-methanol giving cis-2-chloro-9,10-
-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic car-
bonate as gray crystals, m.p. 200-230C.
A mixture of 12.0 g. if cis-2-chloro-9,10-dihy-
dro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate,
9.2 g. potassium hydroxide, 12 ml. of water and 100 ml.
of ethanol is heated at 75C. for 2 hours and then evapo-
rated _ vacuo to 50 ml. The concentrate is diluted with
400 ml. of water and the resulting solid is collected by
,
li~66~S
-19-
filtration. This solid is recrystallized from toluene,
decolorizing with a small amount of charcoal, giving color-
less crystals of cis-2-chloro-9,10-dihydro-9,10-ethano-
anthracene-11,12-diol, m.p. 195-210C.
To a solution of 2.7 g. of cis-2-chloro-9,10-
S -dihydro-9,10-ethanonanthracene-11,12-diol in 20 ml. of
acetic acid at room temperature is added 5.0 g. of lead
tetraacetate (containing 10% acetic acid) portionwise.
The mixture is stirred for 10 minutes, cooled in an ice-
-water bath and the crystals which form are collected by
filtration and washed with cold acetic acid, giving the
desired product as off-white crystals, m.p. 113-115C.
Example 5
2-Chloro-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-
9,10-anthracenedicarboxaldehyde dihydrochloride
A reaction mixture comprising 0.7 g. of 2-chlo-
ro-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 0.88
g. of 2-hydrazinoimidazoline dihydrochloride in 20 ml. of
n-propanol is refluxed for one hour, during which time
about 10 ml. of n-propanol is removed through a reflux
condenser. The mixture is cooled and ether is added
giving the desired product as yellow crystals, m.p. 190C.
(dec.).
Example 6
l-Chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde
A mixture of 29.5 g. of l-chloroanthracene and
126 g. of vinylcarbonate is reacted as described in
Example 4, giving tan crystals of cis-1-chloro-9,10-di-
hydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate,
m.p. 242-250C.
A reaction mixture comprising 27.9 g. of cis-l-
-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol,
cyclic carbonate, 21.4 g. of potassium hydroxide, 28 ml.
of water and 230 ml. of ethanol is heated at 75C. for 2
hours and then evaporated ln vacuo to 80 ml. The residue
is dissolved in 500 ml. of chloroform. The chloroform
solution is washed with three 70 ml. portions of water
1~
1~66~5
-20-
and decolorized with charcoal. The chloroform is removed
and the yellow residue is dissolved in 150 ml. of toluene.
On cooling the product cis-l-chloro-9,10-dihydro-9,10-
-ethanoanthracene-11,12-diol is collected as colorless
crystals, m.p. 180-182C.
To a solution of 0.54 g. of cis-1-chloro-9,10-
-dihydro-9,10-ethanoanthracene-11,12-diol in 5 ml. of
acetic acid at 35C. is added 1.0 g. of lead tetraacetate,
portionwise. The mixture is stirred for 10 minutes,
cooled in an ice-water bath and the crystals which form
are collected by filtration and washed with cold acetic
acid, giving the desired product as colorless crystals,
m.p. 144-146C.
Example 7
l-Chloro-bis(2-imidazolin-2-ylhydrazone)-9,10-
-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride
A reaction mixture comprising 3.7 g. of l-chlo-
ro-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 4.64
g. of 2-hydrazinoimidazoline dihydrochloride in 100 ml. of
n-propanol is refluxed for one hour, during which time
about 50 ml. of n-propanol is removed through a relfux
condenser. The mixture is cooled and ether is added giv-
ing the desired product as yellow crystals, m.p. 200C.
(dec.j.
Example 8
2-Methyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde
A 10 g. portion of 2-methylanthracene in 50 ml.
of vinylene carbonate is heated to reflux under nitrogen
for 20 hours. The excess vinylene carbonate is removed
by vacuum distillation (55C., 11-12 mm.) and the residue
is taken up in 100 ml. of methylene chloride, filtered
and triturated with three times its volume of methanol.
The product, cis-2-methyl-9,10-dihydro-9,10-ethanoanthra-
cene-11,12-diol, cyclic carbonate is recovered in its syn
and anti forms as cream colored crystals, (m.p. 225-227C~
and 183-185C.).
,i'~
1 116 6~ ~
A 2.8 g. portion of one of the syn and anti
forms of cis-2-methyl-9,10-dihyclro-9,10-ethanoanthracene-
-11,12-diol, cyclic carbonate (m.p. 225-227C.) in a mix-
ture of 2.5 g. of potassium carbonate, 2.3 ml. of water
and 27 ml. of ethanol is stirred at 70C. for 2 hours. The
mixture is treated with three times its volume of water
giving the corresponding syn or anti form of cis-2-methyl-
-9,10-dihydro-9,10-ethanoanthracene-11,12-diol as pale
yellow crystals, (m.p. 227-228C.).
A 7.4 g. portion of the other syn or anti form
of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-
-diol cyclic carbonate (m.p. 183-185C.) in a mixture of
6.15 g. of potassium hydroxide, 8.1 ml. of water and 70 ml.
of ethanol is reacted as described immediately above giv-
ing the corresponding syn or anti form of cis-2-methyl-9,
10-ethanoanthracene-11,12-diol as a cream colored solid,
(m.p. 153-156C.)
A 2~5 g. portion of cis-2-methyl-9,10-dihydro-
-9,10-ethanoanthracene-11,12-diol [obtained above as yel-
low crystals (m.p. 227-228C.)] is suspended in 100 ml.
of an aqueous solution containing 2.14 g. of sodium perio-
date and one ml. of ethanol. The mixture is stirred at
room temperature for 2 hours and the solid is collected
by filtration, washed with water and dried giving the de-
sired product as a pale yellow solid, m.p. 125-126C.
Example 9
2-Methyl-bis(2-imidazolin-2-ylhydrazone)-9,10
-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride
A mixture of 1.9 g. of 2-methyl-9,10-dihydro-
9,10-anthracenedicarboxaldehyde and 2.63 g. of 2-hydrazino-
imidazoline dihydrochloride in 150 ml. of n-propanol is
heated to boiling and concentrated to about 50 ml. over
the course of 1-2 hours, filtered while hot and then
cooled. A 2-3 ml. portion of acetone and 200 ml. of ether
are added giving a precipitate which is collected by fil-
tration giving the desired product as a yellow solid, m.p.
210-22QC. (dec.j.
;r
111~6~5
-22-
Example 10
2,3-Dimethyl-9,10-dihydro-9,10-anthracene dicar-
boxaldehyde
A mixture of 35.4 g. of vinylene carbonate and
8.5 g. of 2,3-dimethylanthracene(a) is heated at reflux
under nitrogen for 20 hours. The cooled solution is
treated with 100 ml. of methanol, warmed, decolorized with
charcoal, filtered and cooled giving 7.1 g. of colorless
crystals (m.p. 207-212C.) of 2,3-dimethyl-9,10-dihydro-
-9,10-ethanoanthracene-11,12-diol, cyclic carbonate.
A mixture of 6.4 g. of 2,3-dimethyl-9,10-dihy-
dro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate,
5 g. of potassium hydroxide, 6.6 ml. of water and 60 ml.
of ethanol is stirred at room temperature for 56 hours.
The formed precipitate is filtered, dissolved in glacial
acetic acid and precipitated with excess water giving 4.0
g. of colorless 2,3-dimethyl-9,10-dihydro-9,10-ethano-
anthracene-11,12-diol, (m.p. 240-245C.).
A suspension of 0.3 g. of 2,3-dimethyl-9,10-
dihydro-9,10-ethanoanthracene-11,12-diol in 10 ml. water
and 0.1 ml. of ethanol is treated with 0.243 g. of sodium
periodate and stirred at 20 for 2.5 hours. The formed
solid is filtered, washed with water and dried giving 0.2
g. of 2,3-dimethyl-9,10-dihydro-9,10-anthracene dicarbox-
aldehyde, (m.p. 113-117C.).
(a)Jaylord, N. G., Stepan, V., Collect. Czeck, Chem. Comm.
39,1700(1974).
~1~66~5
-23
Example ll
2,3-Dimethyl-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-
. . _ _ . _ _ _ . . .
-9,10-anthracenedicarboxaldehyde dihydrochloride
A mixture of 0.2 g. of 2,3-dimethyl-9,10-dihy-
dro-9,10-anthracenedicarboxaldehyde and 0.3 g. of 2-hy-
drazinoimidazoline dihydrochloride in 30 ml. of n-propanol
is boiled for 2 hours while concentrating to 10 ml. The
yellow solution is treated with 0.5 ml. of acetone and 20
ml. of ether giving a yellow precipitate which was fil-
tered, washed with acetone and dried leaving 0.15 g. of
product (m.p. 285-290C.).
Example 12
1,4-~imetbyl-9,10-dihydro-9,10-anthracene-
dicarboxaldehyde
A mixture of 4.12 g. of 1,4-dimethylanthracene
and 17.2 g. of vinylene carbonate is refluxed under nitro-
gen for 18 hours, cooled, treated with four volumes of
methanol, stirred and cooled. The formed crystals are
filtered, washed with methanol and dried leaving 5.45 g.
of colorless l,4-dimethyl-9,10-dihydro-9,10-ethanoanthra-
cene-11,12-diol, cyclic carbonate (m.p. 225-245C.).
A mixture of 4.4 g. of 1,4-dimethyl-9,10-dihy-
dro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate,
3.45 g. of potassium hydroxide, 4.5 ml. of water and 40 ml.
of ethanol is stirred at 20 for 16 hours. The two layered
mixture is filtered through Celite and treated with four
volumes of water giving 3.8 g. of colorless 1,4-dimethyl-
-9,10-dihydro-9,10-ethanoanthracene-11,12-diol (m.p. 158-
-160C.).
A mixture of 1.5 g. of 1,4-dimethyl-9,10-dihy-
dro-9,10-ethanoanthracene-11,12-diol and 1.22 g. of sodium
periodate in 50 ml. of water and one ml. of ethanol is
stirred for two hours at 20. The formed solid is fil-
tered, washed with water and dried leaving 1.45 g. of 1,4-
-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde
(m.p. 159-l60oc )
11~66~5
-24-
Example 13
1,4-Dimethyl-bis(2-imidazolin-2-ylhydrazone)-9,10-
-dihydro-9,10-anthracenedicarboxaldehyde
dihydrochloride
A mixture of 1.15 g. of 1,4-dimethyl-9,10-dihy-
dro-9,10-anthracenedicarboxaldehyde and 1.53 g. of 2-hydra-
zinoimidazoline dihydrochloride in 50 ml. of n-propanol is
boiled and concentrated to 20 ml. over the course of two
hours. The resulting solution was treated with one ml. of
ace~one and 75 ml. of ether giving a pale yellow precipi-
tate which was filtered off, washed with acetone and dried
leaving 1.8 g. of product, m.p. 230-235C. dec.
Example 14
Cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-
-11,12-diol, cyclic carbonate, syn and anti isomers
Fifteen grams of 1,4-dimethoxyanthracene is re-
fluxed under nitrogen with 55 g. of vinylene carbonate for
16 hours. The excess vinylene carbonate is removed under
vacuum (55C./12 mm.) and the residue is slurried in chlo-
roform and filtered retaining 13 g. of a mixture of yellow
and colorless crystals. On boiling this mix-~ure with
methylene chloride and filtering there is left 10.5 g. of
colorless crystals, m.p. 283-285C. of one syn or anti
isomer of the product.
The other syn or anti isomer is obtained from the
original chloroform filtrate by precipitation with methanol
and recrystallizing from a mixture of methylene chloride
and methanol giving 5 g. of colorless crystals, m.p. 255-
-260C. Both isomers show the same infra-red spectrum,
analyze correctly and show a depressed mixed melting point
(238o-245oc.).
Example 15
Cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanonanthracene-
-11,12-diol, syn and anti isomers
A mixture of 10.5 g. of cis-1,4-dimethoxy-9,10-
-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbo-
1~66~5
nate, m.p. 283-285C., and 8.5 g. of potassium hydroxide,
12 ml. of water and 85 ml. of ethanol is stirred at room
temperature for 16 hours. The formed solid is filtered,
washed with water and dried leaving 5.0 g. of one of the
isomers of the product m.p. 187-188C.
The other syn/anti isomer is obtained in the
same manner from 4.0 g. of the corresponding cyclic car-
bonate, m.p. 238-245C., giving 2.1 g. of product, m.p.
183-185C. Both isomeric diols show the same infra-red
spectrum, analyze correctly and show a depressed mixed
meïting point, m.p. 155-158C.
Example 16
Bis-(2-imidazolin-2-ylhydrazone)-1,4-dimethoxy-9,10-
-dihydro-9,10-anthracenedicarboxaldehyde
dihydrochloride
A mixture of 1.5 g. of 1,4-dimethoxy-9,10-dihy-
dro-9,10-anthracenedicarboxaldehyde and 1.8 g. of 2-hydra-
zino-2-imidazoline dihydrochloride in lO0 ml. of n-propa-
nol is boiled and concentrated to 50 ml. over the course
of two hours. The cloudy solution is clarified by filtra-
tion and then is basified with saturated sodium bicarbo-
nate solution and diluted with three volumes of water
yielding 1.5 g. of the free base as a yellow solid, m.p.
235-240C. The dihydrochloride salt of the product is
obtained by dissolving l g. of the free base in 40 ml. oE
n-propanol and treating with l ml. of 7N anhydrous hydro-
chloric acid in ethanol. The solution is concentrated to
an oil and recrystallized from n-propanol giving 0.3 g. of
a colorless dihydrochloride salt m.p. 250-255C.
