Note: Descriptions are shown in the official language in which they were submitted.
~SJ~
The present application has been divided out of
Canadian Patent Application Serial No. 470,714 filed
December 20, 198~.
The present invention relates to pharmaceutical
cornposition for the treatment of inflammatory diseases
which contains as the active ingredient 3,4-diacetoxy-
benz~lidene diacetate or 3,5-diacetoxybenzylidene
diacetate.
Dihydroxybenzaldehyde has recently attracted
attention as an antitumour agent (refer to Japanese Patent
Application Laying~Open Mo. 55-51018(1980))and as an anti-
inflammatory agent (refer to Japanese Patent Application
Laying-Open No. 58-83619(1983)).
FIowever, although dihydroxybenzaldehyde shows an
excellent pharmacological activity in suppressing platelet
aggregation and migration of leukocytes at a relatively
low concentration in vitro, owing to the rapid metabolism
thereof in the living body, it is necessary to administer
a large amount thereof for a long tim~ period to obtain
the efEective effects of such pharmacological activity in
vivo, and there are difficulties in administering thereof
due to the stimulus action and the oxidizability of the
aldehyde moiety thereof.
In a first aspect of the present invention, there
is provided a pharmaceutical composition in unit dosage
form, which comprises a dosage effective for the treatment
of inflammation, chronic arthritic rheumatism, systemic lupus
,,.
~ 3~ ~
ery~hematodes or glomerular nephritis of 3,4-diacetoxy-
benzylidene diacetate represented by the formula:
H3C-C-0 ~ C-(O-C-CH3)2
O-C-CH
o
or 3,5-diacetoxybenzylidene diacetate represented by the
formula:
o
H3C-C-0 ~ H 1
~ C-(O-C-CH3)
H3C-C-
and a pharmaceutically acceptable carrier or diluent.
In a second aspect of the present invention,
there is provided a method for the treatment of
inflammatory disease, which comprises administering to a
patient suffering therefrom a pharmaceutically eEfective
10 amount of 3,4-diacetoxybenzylidene diacetate represented
by the formula:
O H O
H3C-C-0 ~ C-(O-C-CH3)2
O-C-CH
~ 3~ ~
or 3,5-diacetoxybenzylidene diacetate represented by the
formula:
H3C-C-O H O
~ C-(O-C-CH3)2
01 >~
H3C-C-~
The compounds 3,4-diacetoxybenzylidene diacetate
and 3,5-diacetoxybenzylidene diacetate are part of a
larger group of compounds of the formula I
~ CH(X )2 (I)
(X')2
whereln Xl and x2 are the same or difPerent and
represent respectively a (Cl_l8) -alkanoyloxy group.
The novel compounds of the Eormula (I) have been described
in Canadian Patent Application Serial No. 470,714 from
10 which the present application has been divided.
The following description will detail the
preparation and activity of all the compounds encompassed
by formula I as defined above.
BRIEF EXPLAN~TION_OF DRAWI~GS.
Of the attached drawing, Figs. 1, 3, 5 and 7 to
19 are the infrared absorption spectra of the present
substances Nos. 1, 2, 3 and 4 to 16 respectively, and
Figs. 2, 4 and 6 are the nuclear magnetic resonance
spectra of the present substances Nos. 1, 2 and 3,
respectively.
The dialkanoylox~benzylidene dialkanoate
represented by the formula ~I) (hereinafter referred to
as the present substance), the process for producing
thereof and the pharmacological composition having an
anti-inflammatory activity comprising the present
substance or containing the present substance as the
active ingredient thereof are explained as follows~
Although the present substance can be
synthesized by reacting an alkanoic acid anhydride
with a dihydroxybenzaldehyde while heating a mixture
of the two reactants in the presence
` :
5~
of a strong alkali such as potassium hydroxide, sodium
hydroxide and sodium acetate, the present substance can be
profitably synthesized in a high yield when the alkanoic acid
anhydride(III) is reacted with a dihydroxybenzaldehyde(II) in
the presence of a strong acid such as sulfuric acid,
hydrochloric acid and nitric acid, as is shown by the following
reaction formula.
(1) In the case where Xl and x2 are the same.
(OH)~ C~O ~ (CmH2m~1CO)2O 2SO4 ~ CH(o-c-cmH2 +1)2
(II) m 2m~1 C )2 (I')
wherein the formula(I') represents the present substance in
which Xl and x2 are the same and represented by CmH2m~l-C-O-,
wherein m is an integer of 1 to 18.
Namely, to one mole of 2,3-; 2,4-; 2,5-; 2,6-; 3,4-
or 3,5-dihydroxybenzaldehyde represented by the formula(II),
more than 3 moles of the alkanoic acid anhydride represented
by the formula(III) wherein m is an integer of from 1 to 18
are added, and after melting the anhydride at a temperature
higher -than the melting polnt of the anhydricle and in a range
of from room temperature to 100C, a catalytic amount of a
strong acid such as concentrated sul~urlc acid, hydrochloric
acid and nitric acid is rapidly addecl to the mixture while
stirring thereof. Then, the reaction exothermically proceeds
to obtain a homogeneous reaction mixture as a solution. The
!
ll
reaction completes within a time period of from one min to
Il 5 hours, preferably from 2 min to one hour.
(2) In the case where Xl and x2 are different from each
other, for instance, X represents CnH2n~ O-
wherein n is an integer o 1 to 18, x2 represents
Cm~2m+l-C-o- and n ~ m, a derivative represented by the formula:
(Cn~2n+1 C )z CHO
is reacted with an alkanoic acid anhydride represented
by the formula (cmH2m+lco)2o
~ m 2m+lCO)2o ~ CH(o-c-cmH2m+l) ,
n~2nl1 Cll-)2 ( n 2n~1 C )2
From the thus obtained reaction mixture, the present
substance represented by the formula(I') can be isolated by one
of known methods such as recrystallization, extraction and
removal of the by-produced alkanoic acid by extraction,
evaporation of the un-reacted anhydride of the alkanoic acid or
column-chromatography.
The above-mentioned synthetic process only shows
one embodiment for obtaining the present substance and
accordingly, the process for production of the present substance
should not be limited to the above-mentioned process.
~l2~3~
, I .
I,
¦ Each of the present substances showed an activity
of suppressing the migration of leu~ocytes, an activity of
inhibiting the proliferation of granuloma and an activity of
suppressing ad~uvant arthritis as the results of in vivo tests.
In addition, each of the present substances is less toxic than
the known substances such as dihydroxybenzaldehyde and ls
effective at a smaller dose rate than that of the known
substances such as dihydroxybenzaldehyde. Accordingly, each
of the present substances has a pharmacological activity as
an anti-inflammatory agent.
Namely, it is an ordinary anti-inflammatory agent,
an anti-rheumatic agent against chronic arthritic rheumatism
and an agent for treating auto-immune diseases such as
glomerular nephritis and systemic lupus erythematodes.
The mammalian toxicity and pharmacological properties
of the present substances are explained as follows by the
following representative compounds of the present substances.
The other compounds are also useful as the anti-inflammatory
agent although some difference are seen among the activities
thereof.
3,4-diacetoxybenzylidene diacetate, hereinafter
referred to as the present substance No. 1,
2,3 diacetoxybenzylidene diacetate, hereinafter
referred to as the present substance No. 2,
2,5-diacetoxybenzylidene diacetate, hereinafter
referred to as the present substance No. 3,
3~
1 3,4-dipropionyloxybenzylidene dipropionate, herein-
¦, after referred to as the present substance No. 4,
¦ 3,4-di-n-dodecanoyloxybenzylidene di-n-dodecanoate,
hereinafter referred to as the present substance No. 5,
3,4-di-n-octadecanoyloxybenzylidene di-n-octadecanoate,
hereinafter referred to as the present substance Mo. 8 and
2,5-di-n-octadecanoyloxybenzylidene di-n-oc-tadecanoate,
hereinafter referred to as the present substance No. 10.
(1) Acute mammalian toxi~ty
.~_
After dispersing each of the present substances
Nos. 1, 4, 5, 8 and 10 in an aqueous 0O2 % solution of
carboxymethyLcell~lose, the aqueous dispersion was orally
adminlstered to each of male Jcl-ICR mice. As a result,
LD50(acute, oral) of each of the tested substances was larger
than 4,000 mg/lcg. LD50(acute, oral) of the present substances
Nos. 2 and 3 to male Jcl-ICR mice was larger than 2,000 mg/kg.
On the other hand, L~50(acute, oral) of 3,4-
dihydroxybenzaldehyde to male Jcl-ICR mice was 1503 mg/kg and
accordingly, at least the above-mentioned present substances
were found to be extremely low ln acute mammalian toxicity.
(2) Activit ~ ssin~_the miyration of leu]cocytes:
While using groups of male Donryu rats(six rats per
group) and following the carboxymethylcellulose-pouch method
(refer to Xshikawa et al. YAKVGAKU ZASSHI(Journal of the
Pharmaceutical Society of Japan), 88, 1472, 1968), the extent
of inhibition of migration of polymorphonuclear leuckocytes
-a -
il ----` - .... - ..
3 53
Il .
~i to the site of inflammation by the present substance was
examined. The specimen(the present substance) was dispersed
in an aqueous 0.2 ~ solution of carboxymethylcellulose and
the dispexsion was administered to each rat at a predetermined
¦ dose rate, and only the aqueous 0.2 % solution of
carboxymethylcellulose was administered to each rat of control
group. Test was carried out by injecting the aqueous 0.2 %
solution of carboxymethylcellulose int~ the pouch formed in
the body of the rat and after 6 hours of the injection, the
number of polymorphonuclear leukocytes ln the exudate into
the pouch was counted. The results are shown in Table 1, and
as are seen in Table 1, it was confirmed that the present
substance significantly suppressed the migration of
polymorp onuclear leukocytes(PMN~ ts the slte of inilammation.
~ _
I
Table 1
Group o~ Dose Number of Rate of
test rate PMN in exudatel) suppression
animals (mg/kg) (mean ~ SE) of PMN (%)
... ..... ..... _ . ,
Control - 10.2 + 0.64
Group admi-
nistered with
Present Sub- 5 6.0 + lo 00** 41.2
stance No. 1 10 5.3 + 0.47*** 48 0
4.9 + 0.48*** 51 9
. ~
Control - 10.92 + 0.81
Present Sub- 50 5.08 + 0.28*** 53.5
Present Sub- 50 4 55.6
Present Sub-
stance No. 8 50 4.76 + 0.54*** 56.4
Present sub-
stance No. 10 50 6.23 -~ 0.15*** 42.9
Administered with
Prednlsolone 5 6.83 ~ 0.27*** 37.5
Administered with
Indomethacln . 5 7.02 + 0.64** 35.7
Administered with
3,4-dihydroxy- 50 7.9~ ~ 0.36* 27.5
benzaldehyde
_.. _ .. _. . , .... . ... __ . _
Notes: 1) (number of PMN/mm of the exudate) x 10
* : P < 0.05
**: P < 0.01
*** : P ~ 0.005
-10_
3~:~
Il
(3) Activity in su;~ressin~ the proliferation of ~ranulom~:
Il While using groups of male Donryu rats in the fifth
week after birth (5 rats per group), the activity of the
present substance in suppressing the proliferation of granuloma
was tested by the method of Fujimura(refer to OYOYAKURI
(Pharmacometrics), 19(3), 329, 1980).
After soaking sheets of filter paper of 13 mm in
diameter and 28 mg in wçight into an aqueous 2% solution of
carboxymethylcellulose containing both dihydroxystreptomycin
and penicillin, each of 106 unit at the respective concentration
of 0.1 mg/ml, each of the thus treated sheets was buried
subcu~aneously into the back of each rat under anesthesia by
ether. Each specimen (the present substances) to be tested
was dispersed in an aqueous 0.3 ~ solution of carboxymethyl-
cellulose and the dispersion was administered orally to the
thus treated rat after the rat had been awaken ~rom the
anesthesia once a day for 10 days. After 11 days o the
treatment, granuloma formed in the rat was removed, dried for
24 hours at 70C and weighed. To the rats of control group,
only the aqueous 0.3 % solution of carboxymethylcellulose was
orally admlnistered once a day for 10 days, both results being
shown in Table 2.
As are seen in Table 2 t each of the tested present
substances significantly suppressed the proliferation of
granulating tissue formed.
_ _ .. .. _ .. _._ _ .. .. _ __ ._ _ _ .. ..... _ __ ___. .. .... ... . .
`: ~
3~
Table 2
_ ~
Group of Dose Granuloma
test rate weight suppression
animals (mg/kg/day) (mg) (~)
.. , ~
Control - 88.1+5~0
Present Sub- 5 50.4~8.4** 42.8
stance No. 1 10 39.4+3.0*** 55.3
50 34.0~4.2*** 61.4
._ .... , . _. _ ...... . . ..
Control - 109.4 ~ 7.5
Present Sub- 5 42.4+5.7*** 61.2
stance No. 5 50 39.1+3.4*** 64.7
Present Sub- 36.2+2.6*~* 66.9
Present Sub-
stance No. 10 57.0~6.7*** ~7.9
Administered with 3 66.3~8 4** 39.4
Indomethacin - -
Adminlstered wi-th
Prednlsolone 3 63.2+8.6** 42.2
Administered with
3,4-dihydroxy- 50 70.5~9.7* 35.6
benzaldehyde
. _ . , .. .. ~
Notes: 1) mean value -~ standard error
* p < 0.05
** P < 0.01
*** P ~ 0.005
I _ .
_~i ....
l4) Activit~ in suppressing adjuvant arthritis:
While using groups of female Jcl-SD rats in the 8th
week after birth (6 rats per group), the activity of the
present substance in suppressing the adjuvant arthritis was
tested by the method of Fujihira et al. (refer to OYOYAKURI
(Pharmacometrics), 5(2), 169, 1971).
Namely, Freund's complete adjuvant was irnplanted to
the tail of each rat under anesthesia by ether in an amount of
0.6 mg dissolved in 0.1 ml of mineral oil, and after 2 weeks
of the implantation, each specimen (the present substances)
to be tested was orally administered once a day for 20 days,
and the state of the rat was observed.
As the results of the above-mentioned test, each of
the present substances tested, namely, Nos. 1, 2, 3, 4, 5, 8
and 10 showed an excellent treating effect on the adjuvant
arthritis caused by the implanted Freund's complete adjuvant.
On the other hand, in the rats administered with prednisolone,
the increase of the body weight was significantly suppressed,
and on the autopsv thereof, a significant atrophy of the thymus
thereo was observed. In the rats administered with each of the
present substance, suppression of increase of body weight and
atrophy of the thymus were not observed. The findings confirm
that the present substance has scarcely the side effects.
Accordingly, the present substance is effective as
an agent for treating chronic inflammatory diseases such as
rheumatism, etc.
. l l
As are seen in the above-mentioned test results, it
1 can be recognized that the present substance has the excellent
activities in suppressing the proliferation of granuloma, in
suppressing the adjuvant arthritis and in suppressing -the
miyration of leukocytes and is extremely low in acute
mammalian toxicity.
~ ccordingly, the present substance can be used in the
extremely important uses as an anti-inflammatory agent, an
anti-chronic arthritic rheumatism and an agent for treating
autoimmune diseases such as systemic lu~us erythematodes and
glomerular nephritis, and in addition, it is also effective in
treating cancers accompanying cellular proliferation.
The present substance is possibly administered orally,
~¦ intraintestinally or in the form of injection in one of -the
various forms of pharmaceutical formulation(so-called pharma-
ceutical composition) after being comblned with pharmaceutically
acceptable carrier(s) and/or adjuvant(s). More than two of the
present substances may be used in combination or after being
mixed together, and the present substance may be used after
being combined with any other active ingredient for pharmaceu-
tical use.
Since the present substance can be administered orally
and parenterally, it can take any optional form of pharmaceu-
tical compositions suitable for the route of administration.
In add.ition, the present substance may be offered ln the unit
dose form, and as far as the pharmaceutical composition contains
- ~ .
! an effective amount of the present substance, the composition
! can take the various forms such as powder, granule, tablet,
sugar-coated tablet, capsule, suppository, suspension, solution,
emulsion, ampoule and injection.
Accordingly, it should be recognlzed that the pharmaceu-
tical composition comprising the present substance can be formu-
lated by application of any known means for formulation of
a pharmacologically active agent.
In addition, the content of the present substance
as an active ingredient in the above mentioned pharmaceutical
composition can be adjusted in a broad range of from 0.01 to 100
by weight, preferably in a range of from 0.1 to 70~ by weight.
As has been stated, although the phaxmaceutical compo~
sition comprising the present substance is orall~ or parenterally
administered to human or mammals, the oral administration
including sublingual administration is particularly preferable.
The parenteral administration includes subcutaneous-,
. intramuscular and intravenous injection and instillation.
Since the dose rate of the present substance depends .
on the specles, the sex, the age~ the individual difference and
the state of the disease of the patient to be administered
therewith, there may be cases where an amount outside the
following range is administered, however, in the cases where
human being is the object of administration, the oral daily
dose rate of one of the present substances is in a range of
from 0.1 to 500 mg/kg body weight, preferably in a range of
~ ~5~3 ~
from 0.5 to 200 mg/kg body weight, more preferably in the
range of from 3 to 100 mg/kg body weight, and the
parenteral daily dose rate is in a range of Erom 0.01 to 200
mg/kg body weight, preferably in a range of from 0.1 to 100 mg/kg
body weight, more preferably in the range of from 1.5 to 50
mg/kg body weight. The above-mentioned daily amount is divided
equally into 1 to 4 portions, and the thus divided portion is
administered at a time ~one to four times per day).
nhe invention oE the present appli.cation and that of
Canadian Patent Application Serial No. 470,714 from which the
present application has been divided will be explained in more
detail with reference to the following non-limitative examples.
EXAMPLE 1:
,. . ~
Synthesis of 3!4 diacetoxybenzylidene diacetate
(the present substance No. l?
After introducing 30 g of protocatechualdehyde(3,4-
dihydroxybenzaldehyde) and 92.4 g of acetic anhydride into a
200 ml-flask and adding one drop of concentrated sulfuric acid
to the content of the flask, the flask was shaken to rapidly
induce a beginning of an exothermic reaction, thereby obtaining
a uniform liquid reaction mixture of red in colour. After
shaking the Elask for 3 min, the liquid reaction mixture was
poured into 500 ml of water to form a colourless, powdery crude
product as a precipitate. The amount of the crude product
after collecting the precipitate by filtration and drying thereof
was 68.0 g (the yield: 96.6~). By subjecting the dried, crude
product to recrystallization from a 2:1 mixed solvent of ethanol
~! ~ - -
1,
and ethyl acetate, 59.9 g of colourless prisms (the yield: 85.0~)
were obtained as the above named product, the physical
¦ properties thereof being shown as follows.
! (1) Melting point 126.0 to 127.0C (by capillary method)
(2) Elementary analytical data:
C(%) H(%)
Found : 55.70 4.90
CalCd- as C15~l68
(3) Infrared absorption spectrum (by KBr-tablet method)
The spectrum is shown in Fig. l.
(4) Nuclear magnetic resonance spectrum of H:
The spectrum is shown in Fig. 2 with the following
peaks:
~ (DMSO-d6) ppm,
2.12(s) : [Ar-C(OCOC~3)2, (6H)],
2.28(s) : [Ar-OCOCH3, (6H)],
7.37 to 7.42(m) : [Ar-H, (3H)],
7.55(a) : [Ar-CH ~0 , (lH)]
EXAMPLE 2:
Synthesis of 2,3-diacetox benz lidene diacetate
, .. , .,, .,Y _, Y , _. ,
(the present substance No. 2)
,__, _ _
In the same procedures as in Example 1 except for
using 2,3-dihydroxybenzaldehyde instead of protocatechualdehyde
.
in Example 1~ the crude product of the objective substance was
!, obtained, and by recrystallizing thereof from ethyl acetate,
a colourless ppwdery substance was obtained as the present
substance No. 2 in a yield of 78.7%. The physical properties
¦ of the product are shown as follows.
(l) Melting point: 10800 to 109.0C (by capillary method)
(2) Elementary analytical data:
Ct%) H(%)
Found : 55.70 4.80
CalCd- as Cl5Hl68
(3) Infrared absorption spectrum(by KBr-tablet method~:
The spectrum is shown in Fig. 3.
~4) Nuclear magnetic resonance spectrum of H:
The spectrum is shown in Fig. 4 with the following
peaks.
~ ( DMSO-d6 )
2.09(s): [Ar-C(OCOCH3)2, (6H)],
2.27(S)1
2.30(s~ [Ar OCOCH3, (6H)~,
7.37 to 7.59(m) : [Ar-H, (3H)],
7.70(s) : [Ar-CH ~ O , (lH)]
EX~MPLE 3:
....
Synthesis of 2~$-diacetoxybenzylidene diacetate
(the present suostance No. 3)
In the same procedures as in Example 1 except for
- 18 -
i
" using 2,5-dihydroxybenzaldehyde instead of protocatechualdehyde
in Example l, the crude product of the objective substance
was obtained, and by recrystallizing the crude product from
ethyl acetate, colourless prisms were obtained
in a yield of 81.3~. The physical properties of the thus
recrystallized product are shown as follows:
(l) Melting point: 125.5 to 126.5C (by capillary method)
(2) Elementary analytical data:
10 1 C(%) H(~)
¦ Found : 55.70 4.90 .
Calcd. as Cl5Hl6O8 : 55.56 4.97
(3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is shown in Fig. 5.
(4) Nuclear magnetic resonance spectrum of 1H
The spectrum is shown in Fig. 6 with the following
pea~s.
~(in DMSO-d5), ppm
2.10(s) : [Ar-C(OCOCH3)2, (6H)],
2.26(s)l
2~28(s)J : [Ar-OcocH3~ (6H)],
7.27 to 7.38(m) : [Ar-H, (3H)],
7.70(s) : [Ar-CH ~ OO , ~lH)].
EXAMPLE 4: .
Synthesis of 3,4-di~ropionyl_x ~ zylidene
nate (the present substance No. 4)
23~
After introducing 20.0 g of protocatechualdehyde
(3,4-dihydroxybenzaldehyde) and 76.3 g of propionic acid
anhydride into a 200 ml-flask and adding one drop of concentrated
sulfuric acid to the mixture in the flask, the flask was shaken
to rapidly induce the beginning of an exothermlc reaction,
thereby obtaining a nearly uniform liquid reaction mixture of
red in colour. After shaking the flask for 5 min, the liquid
reaction mixture was poured into 300 g of water to obtain a
crude powdery product of whitish yellow in colour. By recrystal-
lizing the thus obtained crude product from a mixed solvent of
methanol and water, 45.9 g of colourless prisms product were
obtained in a yield of 83.2 ~, the physical properties thereof
being shown as follows.
(1) Melting point : 64.0 to 65.0C (by capillary method)
(2) Elementary analytical data:
C(~) H(%)
Found : 60.00 6.30
Calcd- as C19H24~8 6.36
(3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is sho~m .tn Fig. 7.
(4) Nuclear magnetic resonance spectrum of H:
~ (in ~MSO-d6) ppm:
0.97 to 1.20~m) : [O-e-¢-CH3, (12H)],
2.32 to 2.71(m) : ~-OCOCH2-, ~8H)],
7.29 to 7.50(m) : [Ar-H, (3H)],
7.59(s) : [Ar-CH C O , (lH)].
;l
EXAMPLE 5:
Synthesis ~f 3~4-didodecanoyloxybenzy-lidene
didodecanoa-te(the present substance No. 5)
After introducing 11.4 g of protocatechualdehyde and
127.8 g of dodecanoic acid anhydride into a 500 ml-flask, the
mixture was heated to 80 to 85C to obtain a heterogeneous
solution consisting of solid protocatechualdehyde and liquefied .
dodecanoic acid anhydride. Ater adding one drop of concentratec .
sulfuric acid to the mixture, the thus formed mixture was shaken
to rapidly induce an exothermic reaction, thereby obtaining
a nearly homogeneous reac~ion mixture of reddish brown
in colour. After heating the liquid reaction mixture for
40 min at 80 to 85C, a mixPd solvent of 500 ml of ethanol and
50 ml of ethyl acetate was added to the reaction mixture, and
the thus formed mixture was cooled to room temperature and left
for while to form scaly crystals of white in colour as a
precipitate. After collecting the crystals by filtration,
the crystals were dried to be 56.0 g o the white scaly product
in a yield of 76.7 ~, the physical properties of the thus
obtained white scaly crystals being shown as follows.
(1) Melting point: 52.0 to 53.0C (by capillary method) .
(2) Elementary analytical data:
C(~) H(~)
Found : 74.80 11.20
CalCd~ as C55H968 : 74.61 10.93
(3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is shown in Fig. 8.
(4) Nuclear magnetic resonance spectrum of H:
~(in DMSO-d6) ppm:
0.79 to 0.98(m) : ~-C-CH3, (12H)],
1.17 to 1.54(m) : 1_¢_CH2_C_, (72H)],
2.1 to 2.26 (m) : [Ar- C(OCOCH2R)2, (4H)],
2.46 to 2.66(m) : [Ax-OCOCH2R, (4H)]I
7.47 to 7.94(m) : [Ar-H and Ar-CH C O ~ (4H)]
EXAMP~E 6:
SYnthesis of 3,4-di-n-tetradecano loxvbenz lidene
, ,.. ~_ ~ ~ . . . , . Y..~ Y,
di-n-tetradecanoate (the present substance No. 6)
-- . . --' --- . -- . -- ~ - --'T
In the same procedures as in Example 5 except for
using n-tetradecanoic acid anhydride instead of dodecanoic
acid anhydride in Example 5, crystals were obtained, and the
crystals were recrystalllzed from a mixed solvent (5:1) of
ethanol and ethyl acetate to obtain a powdery white product
in a yield of 69.7 %. The physical properties of the thus
obtalned prod~ct are shown as follows.
(1) Melting point: 60.0 to 61.0C~by capillary method)
(2) Elementary analytical data:
C (%) H (%)
Found : 76.00 11.60
CalCd- as C63H1128 11.32
(3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is shown in Fig. 9.
.
i
Il. .
(4) Nuclear magnetic resonance spectrum of H:
,l ~(in,C~C13) ppm
0.87 to 0.93(m) : ~ -C~CH3, (12H)~,
1.25 to 1.61(m) : [ -C-CH2-¢- , (88H)],
2.29 to 2.59(m) : [ -O-C-CH2-, (8H)],
O
7.14 to 7.42(m) : [ Ar-H, (3H)],
7.67(s) : [ Ar-CH O ~ (lH)~.
EXAMPI,~ 7:
Synthesis of 3,4-di-n-hexadecan~yloxybenz~lidene
di-n-hexadecanoate (the present substance No. 7)
In the same procedures as in Example 5 except for
using n-hexadecanoic acid anhydride instead of dodecanoic acid
anhydride in Example 5, crystals were obtained and by
recrystallizing thereof from a mixed solvent (2:1) of ethanol
and ethyl acetate, a powdery white product was ohtained in
a yield of 72.9 ~. ~
The physical properties of the thus obtained product
are shown as follows.
(1) Melting point: 70.0 to 71.0C (by capillary method)
(2) Elementary analytical data:
C(~) H(~)
Found : 76.90 11.70
CalCd- as C71H1288 76.84 11.63
(3) Inrared absorptlon spectrum (by KBr-t~blet method)
- 23 -
~'`523')~
. I
,i The spectrum is shown in Fig. 10.
(4) Nuclear magnetic resonance spectrum of 1
~(in CDC13) ppm
0.81 to 0.94(m) : [-¢-CH3, (12H)],
1.25 to 1.62(m) : [- C - OE[2 - C - , (104H)],
2.28 to 2.60(m) [~ ~ a ~ CH2-' (8H)~
7.13 to 7.43(m) : [Ar-H, (3~)],
7.67(s) : [Ar-CH ~ O I (lH)]
EXAMPLE 8:
Synthesis o 3, ~ lidene
di-n-Qctadecanoate (the present substance No. 8)
In the same procedures as in Example 5 except for
using n-octadecanoic acid anhydride instead of dodecanoic acid
anhydride in ~xample 5, crystals were obtained, and by
recrystallizing the crystals from a mixed solvent (2:1) of
ethanol and ethyl acetate, a white powdery product was obtalned
in a yield of 73.4 %. The physical properties of the thus
obtained product are shown as follows.
(1) Melting point: 77.0 to 78.0C (by capillary method)
(2) Elementary analytical data:
C(~) H(~)
Found : 77.40 12.10
CalCd. as C79H1448 77.65 11.89
(3) Infrared absorption spectrum(by KBr-tablet method):
.5~3~
The spectxum is shown in Fig. 11.
(4J Nuclear magnetic resonance spectrum of 1H:
~(in CDC13) ppm,
0.82 to 0.88(m): [-C-CH3, (12H)],
1.25 to 1.61(m): [-IC-CH2-C~- , (120H)],
2.28 to 2.60(m): [-O-C~-CH2-, (8H)],
7.15 to 7.44(m): [Ar-H, (3H)],
7.67(s) : [Ar-CH = O ~ (lH)] .
~XAMPLE 9:
~ 4
Synthesis of 2,5 di ~-d~decan ~ benzylidene
di-n-dodecanoate (the present substance No. 9)
In the same procedures as in Example 5 except for
using 2,5-dihydroxybenzaldehyde lnstead of protocatechualdehyde
in Example 5, crystals were obtained, and by recrystallizing
the crystals from a mixed solvent ~2:1) of ethanol and ethyl
acetate, a white powdery product was obtained in a yield of
76.9 %. The physical properties of the thus obtained produc~
are shown as follows.
(1) Melting polnt: 62.0 to 63.0C(by capillary method)
(2) Elementary analytical data:
C(%) H(%)
Found : 74.50 11.00
CalCd- as C55H968 74.61 10.93
~3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is shown in Fig. 12.
_ 25_
li ~ . .
- ll
I
(4) Nuclear magnetic resonance spectrum:
(in CDC13) ppm,
0.82 to 0.87(m) : [-,C-C~13 , (12~)],
1.25 to 1.56(m) : [-C-CH2-C-, (72H)],
2.25 to 2.67(rn) : [-O-,C,-CH2~, (8H)],
7.11 to 7.33(m) : ~Ar-H, (3H)],
7.85~s) ~Ar-CH = O ~ (lH)]
EX~MPLE 10:
Synthesis of 2,5-di-n-octadecanoyloxybenzylidene
. _~,
di-n-octadecanoate (the present substance No. 10)
, ... . . . .
In the same procedure as in Example 5 except for using
2,5-dihydroxybenzaldehyde instead of protocatechualdehyde in
Example 5 and further using n-octadecanoic acid anhydride
instead of dodecanoic acid anhydride in Example 5, crystals
were obtained and by recrystallizing the thus obtained crystals
from a mixed solvent (2:1) o~ ethanol and ethyl acetate, a
white powdery produck was obtained in a yield of 82.8 %.
The physical properties of the thus obtained product are ~hown
as follows.
(1) Melting polnt : 84.0 to 85.0C (by capillary method)
(2) E]ementary analytical data:
C(%) H(~)
Found : 77.40 12.00
Calcd. as C79H1~48 77.65 11.89
-
l! '. '' .` ~ ........ : ,
(3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is shown in Fig. 13.
(4) Nuclear magnetic resonance spectrum of 1H:
~(in CVC13), ppm,
0.81 to 0.92(m) : [-C-CH3, (12H)],
1.25 to 1.66(m) : [-C-CH2-C- , (120H)],
2.24 to 2.59(m) : [-0-C-CH2-, (8H)],
7.11 to 7.33(m) : [Ar-H, (3H)~,
7.85(s) : [Ar-CH = , (lH)].
EXAMPLE 11:
Synthesis of 2,3-di-n-octadecanoylox~enzylidene
di-n-octad _anoate (the p_esent substance No. 11)
In the same procedures as in Example 5 except for
using 2,3-dihydroxybenzaldehyde instead o~ protocatechualdehyde
in Example 5, and further using n-octadecanoic acid anhydride
instead of dodecanoic acid anhydride in Example 5, crystals
were obtained, and by recrystallizing the thus obtained crude
crystals from a mixed solvent (5:1) of ethanol and ethyl
acetate, a white powdery product was obtained in a yield of
90.0 %. The physical properties of khe thus obtained product,
the present substance No. 11, are shown as follows.
(1) Meltlng point: 64.0 to 65.0C(by capillary method)
(2) Elementaxy analytical data:
C(~) H(%)
Eound : 77.80 12.10
Calcd. as C79H14408 77.65 11.89
l! ~; -
(3) Infrared absorption spectrum(by KBr-tablet method):
The spectrum is shown in Fig. 14.
(4) Nuclear magnetic resonance spectrum oE 1H:
~ (in C~C13), ppm
0.82 to 0.93(m) : [-¢-CH3, (12H)],
1.26 to 1.62(m) : [-¢~CH2-C-, (120H)],
2.24 to 2.67(m) : [-O-~CH2-, (8H)],
7.24 to 7.53(m) : [Ar-H, (3H)],
7.86(s) : [Ar-CH = O ~ (lH)].
10¦ EXAMPLE 12:
l Synthesis of 3,4-di-n-butyrylo-xybenz~lidene
l ~ r
l di-n-butyrate (the ~resent substance No 12)
~ ~ r--~ ~ -- . ------ ., ---- -
In a 300 ml-flask, 10 g of protocatechualdehyde and
46.3 g of butyric acid anhydride were introduced, and after
adding one drop of concentrated sulfuric acid to the resultant
mixture, the flask was shaken for 10 min at room temperature
to obtain a liquid reaction mlxture of reddish brown in colour.
After adding 200 ml of ethyl acetate to the liquid reaction
mixture, the system was extracted five times with each 80 ml
of an aqueous lN solution of sodium hydrogen carbonate for the
removal of butyric acid contained ln the liquid reaction mixture.
After washing the organic layer with an aqueous saturated
solution of sodium chloride, the thus washed organic layer was
dried on anhydrous sodium sulfate and decolorized by treatment
with activated carbon and subjected to evaporatlon under a
jl
reduced pressure to remove the solvent. The residue was sub-
jected further to dis~illation under a reduced pressure by
heating for the removal of still remaining butyric acid anhydrid ,
thereby obtaining a pale yellow oily product in a yield of
¦ 97.4 %. The physical properties of the thus obtained oily
product are shown as follows.
(1) Elementary analytical data:
C (~6) H (9~)
Found : 63.10 7.40
CalCd- as C23H328 63.29 7.39
(2) Infrared absorption spectrum (by NaCl plate method):
The spectrum is shown in Fig. 15.
(3) Nuclear magnetic resonance spectrum
~(in CDC13), ppm,
0.87 to l.ll(m) : [-¢-CH3, (12H)],
1.48 to 1.96(m) : [-¢-CH2-C-, (8H)],
2.27 to 2.60(m) : [-O-~-CH2-, (8H)],
7.15 to 7.46(m) : ~Ar~H, (3H)],
7.69(s) : ~Ar-CH C o , (lH)].
EXAMPLE 13:
. ._
Synthesis of 2~5-di-n~butyryloxybenzylidene
di-n-butyrate (the present substance No. 13)
.. ,_.
In the same procedures as in Example 12 except for
using 2,5-dihydroxybenzaldehyde in.stead of protocatechualdehyde
! ----
Il
5~
I in Example 12, a pale yellow oily product, the present substance
I' No. 13 was ob-tained in a yield of 97.5 ~. The physical
properties of the product are shown as follows.
! (1) Elementary analytical da-ta:
C~%) H(%)
¦ Found : 63.50 7.10
Calcd. as C23H3~O8 63.29 7.39
(2) Inrared absorption spectrum (by NaCl plate method):
The spectr~n is shown in Fig. 16.
(3) Nuclear magnetic resonance spectrum of H:
(in CDC13), ppm,
0.86 to l.ll(m) : [-C-CH3, (12H)],
1.47 to 1.97(m) : ~-¢-CH2-C- , (8H)],
2.25 to 2.67(m) : [-O-~-CH2-, (8H~],
7.12 to 7.37(m) : [Ar-H, (3H)],
7.87(s) : [Ar-CH = O , (lH)].
EXAMPLE 14:
........ ........
Synthesis of 2!3-di-n- ~ xybenzylidene .
di-n-but rate (the present substance No. 14)
In the same procedures as in Example 12 except for
using 2,3-dihydroxybenzaldehyde instead o~ protocatechualdehyde
in Example 12, a pale yellow oily product, the present substance
No. 14, was obtained in a yield of 98.4 %. The physical
properties of the t.hus obtained oily product are shown as
~ollows.
l,
(1) Elementary analytical data:
. C (%) H (%)
Found 63.50 7.20
CalCd- as C23H328 63.~29 7.39
(2) Infrared absorptlon spectrum (by NaCl plate method):
The spectrum is shown in Fig. 17.
(3) Nuclear magnetic resonance spectrum of lH:
~(in CDC13), ppm,
0.85 to 1.12(m) : [-~-CH3, (12H)],
1~46 to 1.96(m) : [-C-CH2-C-, (8H)],
2.23 to 2.67(m) : [_O_,C,_CH2_, (8H)],
7.12 to 7.54(m) : [Ar-H, (3H)],
7.87(s) : [Ar-CH = ~ , (lH)].
EXAMPLE 15:
. ~
Synthesis o ~ diacetox ~
dioctadecanoate (th~ p~resent substance No. 15)
In 100 ml-flask, 11.11 g of 3,4-diacetoxybenzaldehyde
and 27.55 g of stearic acid anhydride were introduced, and
after heating the mixture at 80 to 85C to obtain a homogenous
solution, one drop of concentrated sulfuric acid was added to
the solution and the mixture was reacted at 80 to 85C for
20 min under agitation. After the reaction was over, the
reaction mixture was dissolved in 150 ml of ethyl acetate while
heating the reaction nixture. The white powdery crystals were
- 31 -
3~9~
~¦ separated from the reaction mixtllre after leaving the reaction
mixture to cool, collected by iltration and dried to obtain
27.64 g of a product in a yield of 71.50 %.
The thus obtained product showed the following
¦ properties.
(1) Melting point: 75.0 to 76.0C (by capillary method)
(2) ~lementary Analytical Data:
C(%) H(%)
Found : 73.30 10.70
Calcd. as C47H868 : 73.01 10.43
(3) Infrared absorption specrum (by KBr-tablet method):
The spectrum is shown in Fig. lB.
¦4) Nuclear magnetic resonance spectrum o H:
~(in CDC13), ppm,
0.81 to 0.93(m) : [-~~CH3, (6H)],
1.25 to 1.64(m) : [-¢-C~2-¢- , (60H)],
2.29 to 2.43(m) : [-0ll-CH2 , and Ar-OIl-CH3, tlOH)],
O
7.16 to 7.44(m) : [Ar-H, (3H)],
7.67(s) : [~r-CI = O_ , (lH)].
EXAMPLE 16:
~y_thesis of 3 4-dioctadecanoyloxybenzylidene
_, ...... . .
diacetate (the present substance No. 16)
, . , ... , ,, -
In a 50 ml-flask, 10.2 g of 3,4-dioctadecanoyl-
benzaldehyde and 15.5 g of acetic anhydride
were introduced, and after dissolving the
5~
Il
3,4-dioctadecanoylbenzaldehyde in acetic anhydride by
Il heating the mixture to 60 to 70C, one drop of concentrated
¦I sulfuric aci~ was added to the thus obtained solution, and
¦I the flask was shaken to initiate the reaction. A reaction
¦ exo~hermically proceeded to form a reaction mixture uniform
and pale brcwn in colour. After shaking the reaction mixture
for 2 min, the reactlon mixture was cooled to room temperature
and 100 ml of purified water were added to the reaction mixture.
The thus separated white powdery crystals were collected by
filtration and dried to obtain 11.73 g of a white powdery
product in a y`ield of 99.8 %. The product showed the following
properties.
(1) Melting point: 81.0 to 82.0C (by capillary method)
(2) Elementary analytical data:
C(%) H(%)
Found : 73.00 10.60
Calcd. as C~7H86O8 73.01 10.43
(3) Infrared absorption spectrum (by KBr~tablet method):
. The spectrum is shown in Fig. 19.
(4) Nuclear magnetic resonance spectrum of H:
~ (in CDC13), ppm,
0.82 to 0.94(m) : [-¢-CH3, (6H)],
. 1.26 to 1.93(m) : [-¢-CH2-¢-, (60~1)],
2.12(s) : [ ~ C-0-~-CH3, (6H)],
2.46 to 2.60(m) : [ ~ O-,C,-CH2-, (4H)],
-
'I __.......................................... ...
~1
7.16 to 7.46(m) : [ ~ H, (3H)~,
7.65(s) : [ ~ C C O , (lH)].
FORMULATION EX~MPLl~
Preparation of powdery composition and capsular
composition
Ten parts by weight of 3,4-dipropionyloxybenzylidene
dipropionate(the present substance No. 4), 15 parts by weight
of heavy magnesium oxide and 75 parts by weight of lactose were
uniformly mixed and the mixture was pulverized to obtain a
powdery composition, and by capsulating the thus formed powdery
composition into capsules, a capsular composition was obtained.
FORMULATION ~:XAMPLE 2:
.... -.- ... -.-
Preparation o ~ sition
Fortv-five parts by weight of 3,4-didodecanoyloxy-
benzylidene didodecanoate (the present substance No. 5),
15 parts by weight of starch, 16 parts by weight of lactose,
21 parts by weight of crystalline cellulose, 3 parts by weight
of polyvinyl alcohol and 30 part~ by weight of water were
uniformly mixed, and the mixture was well kneaded.
Thereafter, the kneaded mixture was pulverized,
shaped into granular form and dried. The thus dried material
was sifted to obtain a granular composition.
3~
FORMUI.ATION EXA~PL~ 3:
Pre~aration of an injection
Ten parts by weight of 3,4-diacetoxybenzylidene
diacetate (the present substance No. 1), 3 parts by weight
of benzyl alcohol and 87 parts by weight of an aqueous
physiological saline solution were mixed under heating, and
the thus heated uniform mixture was sterilized to obtain an
injection.
