CA1252391A - Dialkanoyloxybenzylidene dialkanoate - Google Patents

Abstract

Abstract:
The present invention is directed to a pharmaceutical composition for the treatment of inflammatory diseases which comprises as the active ingredient 3,4-diacetoxybenzylidene diacetate of the formula:

or, 3,5-diacetoxybenzylidene diacetate of the formula:

Description

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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 ,,.

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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) 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:

~ 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 ` :

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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.

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, 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 ----` - .... - ..

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.

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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.

_ _ .. .. _ .. _._ _ .. .. _ __ ._ _ _ .. ..... _ __ ___. .. .... ... . .

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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 _ .

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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 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) ~'`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 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.

Claims (2)

Claims:

1. A pharmaceutical composition in unit dosage form, which comprises:
a dosage effective for the treatment of inflammation, chronic arthritic rheumatism, systemic lupus erythematodes or glomerular nephritis of 3,4-diacetoxybenzyl-idene diacetate represented by the formula:

and a pharmaceutically acceptable carrier or diluent.

2. A pharmaceutical composition in unit dosage form, which comprises:
A dosage effective for the treatment of inflammation, chronic arthritic rheumatism, systemic lupus erythematodes or glomerular nephritis of 3,5-diacetoxybenzyl-idene diacetate represented by the formula:

and a pharmaceutically acceptable carrier or diluent.