CA1061777A

CA1061777A - Terpenes

Info

Publication number: CA1061777A
Application number: CA218,831A
Authority: CA
Inventors: Mustich Giuseppe
Original assignee: Inverni Della Beffa SpA
Current assignee: Inverni Della Beffa SpA
Priority date: 1974-01-29
Filing date: 1975-01-28
Publication date: 1979-09-04
Also published as: DE2503135B2; GB1493926A; ES434246A1; FR2258849A1; AR211381Q; FR2258849B1; DE2503135A1; ZA75403B; JPS5418328B2; DE2503135C3; JPS50111213A

Abstract

ABSTRACT

Pharmaceutically active compounds of the formula II

and III

wherein -OR1, -OR2, -OR3 and -OR4, which may be the same or different, each represents a free or esterified hydroxyl group and -COOR5 represents a free or esterified carboxyl group, are provided together with processes for their production and pharmaceutical compositions containing them. Compounds of formula II and III
possess valuable cicatrising and anti-inflammatory properties.

Description

7~7 This invention relates to novel pharmaceutically active compounds, to processes for their production, to pharmaceutical compositions contain$ng the compounds and to plant extracts fro~
which the compounds may be prepared.
Plants o~ the genus Te~ninalia (of the family Combretaceae) are distributed over regions of Africa, Asia, Australia and troplcal America. We have now discovered that extracts possessing valuable pharmaceutical properties may be obtained from plants of one particular species of this genus, namely Terminalia sericea.
These extracts have a high content of terpenic compounds and, $n addition to the known cornpounds ar~unic acid and ar~unetine, they have been found to contain two hitherto unknown compo~)ds which we have named s~ricic acid and sericoside. These conpounds are respectively 2a,3~ a,24-tetrahydroxy-olean-12-en-28-oic acid and its D-glucopyranoside ester, and may be represented by the formula (I) ., ",~ . : ' HO ~ .

~" CH20H
~:

~herein in the case of sericic acid, R = hydrogen and in the case of 8eriooside, R e glucose.

.

- 2 -' :

:~ ~
j'' '~ ''.

Sericlc acid and sericoside have been found to possess valuable cicatrising and anti-inflammatory properties which render them particularly useful in treating dermatological disorders, for example by being incorporated into cosmetics and in treating stomach ulcers. Sericic acid and sericoside may also be converted into derivatives which have similar valuable pharmacological properties.
Thus in accordance with one aspect of the present lnvention, there are provided compounds of the general formula (II) or (III) R40~ ~

R10 ~ ~ COORc II

R20 . :' -~ `
~' .

:~

wherein -ORl, -0~ , -OR3 and -OR4 each represents a free or I ~:
esterified hydroxyl group and -COOR5 represents a i`ree or esterlfied carboxyl group, and pharmaceutically acceptable 10ti1777 salts of such compounds which are capable of salt formation.
This invention also relates to a process for producing a compound of general formula CII) or (III) R10~ ~ R5 R20 ~" \

H

R1O~

2 CH20R3 :

wherein ~ORl~ -QR2, -OR3 and -OR4, which may be the same or different, each represent a free or esterified hydroxyl group, -CQQR5 represents a free or esterified carboxyl group, or a pha~maceutically acceptable salt thereof, which process compTises extracting tissue of a plant of the species Terminalia se~icea with an organic solvent, isolating sericic acid and/or ~:sericoside from the extract and if desired, converting the isolated sericic acid or sericoside to another compound of general formula (II) or (III) by :
one or more of the following procedures carried out in any appropriate order~
`: ', `~ -4-:

: ~ , - , . , . :

10~177~

(i) oxidation cii) reduction ~iii) hydrolysis (iv) esterification and (v) salification.
Rl, R2, R3 and R4, which may be the same or different, may, for example, be substituted or unsubstituted aliphatic or aromatic mono- or poly-carboxylic acid acyl radicals, particularly such radicals containing up to twelve and preferably up to seven carbon atoms.
The aliphatic mono- or poly-carboxylic acid acyl radicals ~both substituted and unsubstituted) may be straight or branched chained OT cyclic and furthermore may be saturated or unsaturated. Examples of saturated, unsubstituted aliphatic mono-carboxylic acid acyl radicals include acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl and heptanoyl. Particularly preferred are such radicals containing up to four carbon atoms.
Examples of poly-carboxylic acid acyl radicals include hemi-maleyl, hemi-fumaryl and hemi-succinyl.
Examples of aromatic carboxylic acid acyl radicals include benzoyl ~ -and phenylacetyl. -Where such radicals are substituted, the or each substituent may, for example, be selected from halogen (i~e~ fluorine, chlorine, bromine or iodine), nitro, hydroxy, ether, keto and amino groups. The aromatic mono^ or polycarboxylic acid acyl radicals may additionally or alternatively be substituted by one or more aliphatic radicals (optionally substituted, for example by one or re of the substituents referred to above) and preferably containing up to six carbon atoms as in methyl, ethyl, propyl, isopropyl, butyl, isobutyl, valeryl and hexyl.
Particularly preferred acyl radicals for Rl, R2, R3 and R4 are ~cet~l, benzoyl and hemi~succinyl~

3~ Where any one of Rl, R2, R3 and R4 represents an acyl radical derived from a polycarboxylic acid, the remaining carboxyl f ~
~ -4a-106177~

(-COO-) group or groups may be in the form of t~le free acid (-COOH) or in the form of a derivative, for example an acid addition salt with a pharmaceutically acceptable cationror an ester with, for example,an aliphatic alcohol containing up to seven carbon atoms, such as, for example, methanol, ethanol, propanol, isopropanol, n-butanol, pentanol, hexanol and heptanol.
R5 may, for example, be hydrogen or a substituted or unsubstltuted straight, branched chain or cyclic aliphatic radical, particularly such radicals containing up to twelve and preferably up to seven carbon atoms. Examples of such radicals include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and heptyl.
Where such radicals are substituted, the or each substituent may, for example, be selected from halogen (i.e.
fluorine, chlorine, bromine or iodine), nitro, hydroxy, ether, Xeto and amino groups. Any amino groups may be further substituted by one or two allphatic radicals (which may be the same or differer,c), for example the radicals specified above.
Particularly preferred examples of radicals represented by R5 include hydrogen; the alkyl radicals referred to above~ ~
aminoalkyl radicals or mono- or dialkylaminoalkyl radicals -(-R'-NRnRn') where -R'- is a straight or branched chain alkylene radical, preferably containing up to seven carbon atoms (for example as in aminomethyl, 1?1- or 1,2-aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl or aminoheptyl and R" and R"', which may be the same or different are selected from hydrogen atoms and alkyl groups (for example the alkyl groups specified above);and -glycosyl residues, particularly D-glucosyl.
Compounds of general formulae (II) and (III) containing _ 5 , 1'7~7'~

carbo~yl groups (for example where R5 = H or where Rl, R2, R3 or R4 contains a free ¢arboxyl group) may be converted to pharmaceut-ically acceptable acid addition salts, for example with metals yielding pharmaceutically acceptable cations, such as, for example, sodium, potassium, calcium, magnesium, aluminium or iron Also, compounds containing substituted or unsubstituted amino groups may be converted to pharmaceutically acceptable acid addition salts with acids yielding pharmaceutically acceptable cations (e.g. hydrochloric or sulphuric acids).
The invention also includes pharmaceutical compositions comprising as active ingredient a compound of the general formula (II) or (III) or a pharmaceutically acceptable salt thereof in combination with a pharmacautically acceptable excipient and processes f~r producing such compositions which comprise admixing the active ingredient with the excipient. Examples of excipients are starch, lactose, propylene~glycol, triethanolamine, water and anti-fermentative agents.
According to a further aspect of the present invention there i~ provided a process for producing a compound of general formula (II) or (III) which comprises extracting tissue of a plant of the species Terminalia sericea, and in particular the roots or the bark of the roots with an organic solvent, isolating sericic acid and/or sericoside from the extract and if desired converting the isolated sericic acid or sericoside to another compound of general formula (II) or (III).
The organic solvent may, for example, be an alcohol (pre~erably a lower alcohol containing up to six carbon atoms nnd most preferably up to four carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, or one of the butanols) , a ketone (preferably a di-lower alkyl ketone wherein the lower alXyl groups contain up to six and preferably up to four carbon ' ~ " ,,'-~ ~ .

1~617 7 ;' atoms as in acetone, methyl ethyl ketone and di-isopropyl ketone) or an ester (preferably an ester formed with a lo~er alcohol containing up to six carbon atoms, and most preferably up to four carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, the butanols and amyl alcohol and a lower alkanoic acid containing up to four carbon atoms, such as formic, acetic, propionic or butyric acids).
Particularly useful solvents are ethanol, acetone and ethyl acetate.
Where the organic solvent is misoible with water, mixtures of the solvent and water may be used.
Pre~erably, prior to isolating seric'c acid and/or sericoside from the extract, fatty and resinous substances are removed, for example by evaporating the organic solvent from the extract and contacting the residue so obtained with a liquid hydrocarbon so as to form a partially puri~ied extract.
Preferably, the residue is diluted with water or -~ith an alcohol/
water mixture before it ls contacted with the hydrocarbon. The ;~`
fatty and resinous substances are pre~erentially dissolved in the hydrocarbon and may therefore be removed by decanting the resulting hydrocarbon solution.
Sericic acid has been found to be generally more soluble ~
in ohlorinated hydrocarbon solvents than in water and sericoside ¦
has been found to be generally more soluble in aqueous solvents ~ i`~ `` `
than chlorinated hydrocarbons. The isolation o~ sericic acid and seri¢oside ~rom the partially purified extract obtained as described above there~ore prePerably includes a fractionation step in which ' the extract is fractionated into a fraction containing sericic a¢id and other non-glucosidated terpenes (Fraction A) and a -~
~raction containing sericoside and other terpenic glucosides ~ 7 -I ~
, . . , : ~
:. . . .~ : . .

1()f~177~

by contacting a solution of the partially purified extract in water or a mixture of water and an alcohol (for example one of the alcohols specified above) with a chlorinated hydrocarbon solvent such as, for example, chloroform, methylene chloride or dichloroethane, and separating the aqueous and chlorinated hydrocarbon solutions so obtained.
The aqueous solution may then be diluted with alcohol to give an alcohol concentration of not less than 60$ and treated to remove proteinaceous material by adding neutral or basic lead acetate solution and filtering to remove any precipitate which is formed. m e filtrate may then be evaporated to form an aqueous ¢oncentrate by eliminating the alcoholic sol~ent and the terpenic glucosides extracted repeatedly from the concentrate with a mixture of butanol and ben~ene (preferably 3:1 to 4:1)t The solution in the butanol/benzene mixture may then be evaporated to small volume and the residue poured into isopropyl ether. The precipitate so obtained contains a ma~or part of the terpenic glucosides (Fraction B).
Sericic acid and sericoside may be obtained from Fractions A and B respectively by recrystallisation or chromatographic separation.
It will be appreciated that the sericic acid- and sericoside-containing extracts of Terminalia sericea referred to above and in particular the purified fractions referred to as Fractions A and B consitute further aspects of the present invention.
Serlcic acid and sericoside may each be transformed into each of the other compounds of general formulae ~I) and (III)by known methods of esterification, hydrolysis, oxidation and salt formation and such methods form a further aspect of the present invention.

. .

~0~777 Thus, for example, serici¢ acid rnay be oonverted to sericoside by esterifi¢ation with o-bromo-(tetra-a¢etyl~-glucose followed by su¢cessive elimination of the.a¢etyl radi¢als and seri¢oside may be converted to sericic acid by saponifi¢ation.

.
- .: , - ' .....
.......

'' ~ ' : . ~ "' 177'7 The following Examples illustrate the invention:

A - Separation of Fractions A and B
200 kg. of finely ground roots of plants of the species Terminalia sericea are extracted under weak reflux four times using 600 litres of a~ueous alcohol each time. m e reunited extracts are evaporated in vacuo to 100 litres and the aqueous residue extracted three times with ligroin using 100 litres o~
ligroin each time. The ligroin, which oontains fatty acids, resins and ~-sitosterol removed from the residue is decanted and the residue, in ethanol solution, is diluted with 300 litres of water and extr~cted three times with dichloroethane using 100 litres each time.
me dichloroethane solution so obtained is evaporated to dryness in vacuo and 2.5 kg. of residue are obtained containing sericic acid and other ~ree triterpenes (Praction A).
The a~ueous residue remaining after the extraction with dichloroethane is diluted with 500 litres o~ alcohol and 10 kg.
of neutral lead acetate dissolved in 30 litres of alcohol are added. An abundant precipitate is formed and is left to stand overnight to sediment. The precipitate is centrifuged and discarded, and the water-alcohol phase is concentrated in vacuo to about 200 litres. m e a~lueous concentrate is extracted three times with a mixture of t-butanol-benzene in the ratio 3:1 (v/v) using 100 litres each time.
m e organic phase is separated and washed with a 10%
solution of sodium carbonate and then evaporated in vacuo to 20 litres. m e butanolic concentrate so obtained is poured, with vigorous agitation, into 150 litres of diethyl ether. A
precipitate comprising triterpenic glucosides is formed and is -10 -- ' - . . ' , , , 10ti177'7 centrifuged ~nd dried. 5 kg. of product sre obtained, containing sericoside and other trlterpenic glucosides (Fract~on B).
B - Preparation of purified sericic acid by crystallisation 1 kg. of Fraction A is dissolved in 5 litres of alcohol.
The solution is decolourised with carbon, evaporated to 3 litres and left to stand overnight.
300 g. of crude sericic acid crystallise, which by successive recrystallisation from dilute aqueous alcohol or acetic acid enables 200 g. of pure sericic acid having m.p. 278 -82C, [~ ~ 3=+ 37.8 (c = 0.32 EtOH 95) to be obtained.
Additlonal quantities of sericic acid may be obtained by reuniting the mother liquors, which are then evaporated to ~-dryness, to obtain a residue which is acetylat.ed in acetone, using acetic anhydride. 80 g. of sericic acid triacetate are obtalned which after recrystallisation from glacial acetic acid melts at 18~CC and has [ ~ D=+ 4 (c = 2, EtOH 95) rR 3630 cm~l 1745 cm~l and 1705 cm~l.
By saponification with alcoholic potash ~he sericic acld triacetate may be converted to sericic acid~ in a state of purity such that its properties are entirely identical with that obtained by crystallisation, as described above.
C - Preparation of sericic acid by a chromatographic procedure 1 kg. of Fraction A is dissolved in 3 volumes of chloroform and ¢hromatographed on a column containing 15 kg. of silica gel by elutlng with a solvent mixture comprising 95:5 chloroform - ethanol.
qhe fractions containing the individual pure components are collected and reunited a~d after crystallisation from methanol, 250 g. of pure sericic acid having a m.p. 278 - 82 & are obtained along wlth 20 g. of arJunic acid with m.p. 220 - 22& .
D - Preparation of sericoside by crystallisation 1 kg. of Fractlon B is dissolved in 6 litres of alcohol.

The solution is decolourised with carbon and evaporated to litres.

. .

10~i177'7 1 litre of hot uater (at about 50C~ is added snd the liquid is left to stand overnight. ~00 g. of crude sericoside crystallise which, after repeated crystallisations from dilute alcohol, furnish 250 g. of pure sericoside having the following characteristics:
m.p. 206 - 208& and [a ~ D = + 5-4 (c = 2~ pyridine)-E - Preparation of sericoside by chromatography -1 Xg. of fraction B is dissolved in 3 litres of an 8:2 (v/v) chloroform - ethanol mixture and chromatographed on 30 kg. of silica gel by eluting with the said solvent mixture.
The fractions containing the individual pure products are reunited and`concentrated to dryness. After crystallisation from methanol there are obtained respectlvely 320 g. of sericoside having an m.p. of 206 - 208& and 210 g. of ar3unetine.

BAMPiE 2 Preparation of methyl sericate 10 g. of sericic acid are dissolved in 50 ml. o~ chloroform and treated with a solution of diazomethane in methylene chloride until complete reaction. The solution is concentrated in vacuo to dryness and the residue is crystallised from acetone.

'" ~

Preparation of tribenzoyl methyl sericate 10 g. of methyl sericate are dissolved in 50 ml. of anhydrous pyridine and 9.24 g. of benzoyl chloride are added. The reaction mixture is left to stand for one night, then poured into water.
Tribenzoyl methyl sericate precipitates, and after crystallisation from methanol has a melting point of 199C.

.
- 12 - ~

.:

;177~

Preparation of triacetyl l9-keto methyl sericate 10 g. of methyl triacetylsericatç (prepared in an analogous manner to methyl tribenzoyl sericate) are dissolved ln 500 ml. of anhydrous acetone and Jones's reagent is added until the reaction is complete.
m e acetone solution is diluted with 1,500 ml. of water whereupon the product precipitates in amorphous form.
The product is collected by filtration, and recrystallised from aqueous methanol. After drying, there are obtained g g.
of triacetyl l9-keto methyl sericate having an m.p. of 200 and L ]D ' + 33 (c = 0.5, EtOH).

Preparation of diethylaminoethyl sericate ~ -10 g~ of po;:assium sericate are dissolved in 50 ml. of dimethyl formamide and treated with 3 g. of diethylaminoethyl chloride. The reaction mixture is kept at 50C for 5 hours, then poured into 600 ml. of water. An abundant precipitate forms which is filtered, washed with water and recrystallised from aqueous isopropanol. The product melts at 105 - 8& and [ ~D ' +19-7 (c = 1, EtOH).

' '; .
, " ' Preparation of methyl tetracetyl sericate 20 g. of methyl triacetylsericate are dissolved in 30 ml. of acetic anhydride and 1 ml. of concentrated perchloric acid is added. The reaction mixture is left to stand for 1 hour, ;

~ . .

~(3~77'7 then poured into 500 ml. of water.
There is precipitation of the product which, a~ter filtration, is crystallised from ethanol The product melts at 223 C.

Preparation of methyl tetracetyI 18o-sericate 10 g. of methyl triacetyl sericate are dissolved in 50 ml.
of 40~ hydrobromic acid in acetic acid and left at room temperature ~or 30 hours. The reaction mixture is poured into water. The product is filtered and precipitates, and after drying it is ¢rystallised from hexane. 6 g. of methyl tetracetyl 18X-*ericate are obtained having an m.p. o~ 194C and [~] D =+12.6 (c = 0.4 in EtOH).

EXAM Æ 8 `
Preparation o~ 2,~,24-trihemisuccinyl derivative of sericic acid 10 g. o~ sericic acid are dissolved in 50 ml. of anhydrous pyridine and 10 g of succinic anhydride are added.
The reaction mixture is rehèated to 80C for 6 hours, then cooled and diluted with 800 ml. of chloroform.
m e solution is counter-washed with 10% aqueous HCl until the pyridine is eliminated and then-concentràted to dryness and dehydrated over Na2S04.
The residue is crystallised from glacial acetic acid and 11 g. of trihemisuccinyl sericic acid with m.p. of 105 - 108 C

and [ ]D=~2.65 (c = 2, EtOH) is obtainéd. ~;

By following the general procedures of the above Examples 2 - ``
to 8, but using appropriate alternative reactants, other compounds ~ -of general formulae (II) or (III) may be prepared.

lU61777 i The following pharma¢euti¢al data i8 glven to illustrate the anti-inflammatory and ¢i¢atrising properties of the compounds of the invention:
Anti-ulcer activity - Gastric Ulcer in the rats indu¢ed by Shay's method The anti-ulcer a¢tivity of sericic acid and sericoside was determined by administering the compounds to rats in which gastric ulcers were induced by Shay's method. The ¢ompounds were administered at the dose of 200 mg./kg. orally five times, at 42, 30, 25 and 6 hours before tying of the pylorus and immediately after the operation and as shown in Table 1 diminished the ulcer index by 48 and 45 per cent respectively, compared with the controls.

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s~,l o 0p~ ~ ~
~ ~ o ~ ~ ~ ~ , . ~C+, l l l ~ ~ ~
~g~ ~ ~ .

h ~ ~ ~ ~ .
:~ H ~ ~. ~ ~
~ r8 ~ X
CU ~ $ ~ .
o~p ~ O ~ ~ h 0 H cr~O OC~l ~ ~ ~ 0 r~ O _ _ .~
~1 ~ H 8 ^ ~ ~ ~ o .0 ~ H O _I O 1~ ~ g 1:~ ~ O ~ ~ N
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1()61~ 'i' LD 50 in Mice . .

The LD~o in mice (as determined with intraperitoneal administration) for sericic acid and sericoside was as follows:

Sericic acid > 1,000 mg./kg.

Sericoside > 1,000 mg./kg.

Anti-inflammatory Activity Against Carragenin-induced Oedema in Rats .
The anti-inflammatory activities of sericoside and sericic acid were determined by measuring the extent to which the oedema caused by sub-plantar administration of carragenin to rats could be inhibited by prior oral and intraperitoneal administration of the substances.
The following resuits were obtained:

1. Oral Administration Treatment Doses Number of Volume of oedema Percentage mg/kg (1) animals in ml. (Average + inhibition - -S.D) (2) of the oedema .
Controls - 10 0.30~0.005 Sericoside 200 10 ~ 0.22+0.010 26 Seri¢ic acid 200 10 ~ 0.23+0.009 23 . .

Significantly different (P < 0.05) from the average obtained with the controls according to Student's "t" test.
(1) Doses administered orally for 3 days; on the third day the administration was effected two hours before the subplantar in~ection of carragenin.
(2) Maximum volume of the oedema measured 3 hours after the subplantar in3ection of carragenin.

~ 17 7~

2. Intraperitonea] Adminlstration .

.
Treatment Doses Number of Volume of the Percentage mg/kg animals oedema in ml. inhibition of (1) (Average + S.D.) the oedema . _ . .

Controls - 10 0.31~0.010 Sericoside 100 10 0.10~0.008 (*) 67 Sericio Acld 100 10 0.11~0.006 t*) 64 Controls - 10 0~31+0.006 Sericoside 50 10 0.20+0.005 (*) 35 Sericic acid 50 10 0 2~+ 0.008 (*) 25 t*) Significantly different (P< 0.05) from the average obtained with the controls acoording to Student's "t" test.
(1) Administration endoperitoneally 30 minutes prior to the ln~ection of carragenin.
(2) Maximum volume me~sured after 3 hours.

Cicatrising Activity Upon Experimental Wounds in Rats ~ -The cicatrising activity of sericic acid and sericoside upon experlmental wounds was determined on rats in accordance with the method of Morton ~ Malone (Arch. Int. Pharmacodyn. Ther. 196, 117, 1972).
The treatment of the wounds was effected with a 10~ suspension o~ the active prlnciples in water oontaining 2% carboxymethyl cellulose (CMC). The suspensions were used in doses of 0.1 ml.
for each application, one treatment being effected per day.
From the data shown in the following Table 2 it can be seen that sericic acid and sericoside possess significant healing activlty, compared with the controls, especially in the first days of treatment.

l()t~

H ~1 ~ ~
~ ~ + ~ +, N

+1 r~0 ~ ,,:~' ~0 ~ ~ ~ O H

~ ~ H

.,~ L 1 ~. N N _ -~i ~ N ~ ~ ~ L

_i . - i N
o L N ~ ~ ~ d N I ' + I +

o ~

la ~o ;~
C ~ ~ ~ C g O O

.~ ~ ~ 1 ~0, :
O C~ O +o ~ : .

~ ~a ,~ ~c , 3 ~ o ~ ~ z; -` - 19 .,~

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Act)vity Against Ultra-Viole-t Ray Erythema Ultra-violet ray erythema in guinea pigs was effected in accordance with the method Or Winder et al. (Arch, Int. Pharm-acodyn. 106, 261, 1968).
Sericoside and sericic acid were applied to the depilated skin of male albino guinea pigs (average weight 300 - 400 g) in the form of a 5% gel (using 200 mg. thereof) one hour prior to irradiation.
~he animals were depilated 18 hours prior to the irradiation and irradiated for 3 minutes with a 500 W. mercury vapour lamp at a distance of 18 cms.
The controls were treated with a similar gel which did not contain the active ingredients, sericoside or sericic acid.
m e compounds under examination were able to reduce the erythema with a most pronouncea activity at 8 hours, as shown by the results set forth in ~he following Table ~;

;~

:
~ ::

l(~ f~7 S +O +O ~,~ +O ~
,, o ~ o~ ~g o~

1~ l~o~
~ ~ .

~ ~o, +~"~ +o,~c, ~ ~ Z

a ~ +ol+o~+o ' ~o ~ ~

+~ ~ ~ d ~ J
. .C -i O ~\ O '~ E ,~
~ E ~ :

I I -.. .

~ ~ ~ 6 I ~ ~ o U ~ 21 -,.
. : . , , : , 1~ti177~ 1 Pharmaceutical Preparations The following examples of pharmaceutical preparations were prepared by admixing the active inderedi~ents with the excipients referred to and illustrate the manner in which the compounds o~ the invention may be brought into forms suitable for topical and oral administration.
1 % Gel for Topical Application 13 Sericoside 1 g.
Excipients (propylene glycol, Carbopol 9~4, ethyl alcohol, triethanolamine, water, antifermentative) q.s. 100 g.
2) Sericic acid 1 g.
Excipients (propylene glycol, Carbopol 934, ethyl alcohol, triethsno.Lamine, water, antifermentative~ q.s. 100 g.
1_~ Ointment for ~`opic 1 Application Sericoside 1 g.
Excipients (glycerine, cetyl alcohol, saturated vegetable triglycerides, lanoline oil, propylene glycol, water) q.s. 100 g.
Suspension for Oral Administration Sericic acid 1 g.
Excipients (sodium alginate, corn starch, saccarose, ~ :
water, antifermentative) q.s. 100 g. ~ ` -Powder for Topical Application 1) Sericoside . 2 g. ~ `
Excipients (Microlan, corn starch, magnesium stearate, talc) q.s. ~ 100 g.
2) Sericic acid 2 g. -~
Excipients (Microlan~ corn starch, magnesium stearate, talc) q.s. . 100 g. ~ ~ `
Ampoule for InJection .~
1) Sericic acid 10 mg. ~ `
Excipients (propylene glycol, ethyl alcohol, sterile pyrogen free water) q.s. 1 ml.
~, Q~r~ - 22 - :

~(~61'~

2) Sericoside 20 rng.
Excipients (propylene glycol, ethyl alcohol, sterile pyrogen-free water) q.s. 2 ml.
Confections 1) Sericoside 20 mg.
Excipients (corn starch, lactose, talc, magnesium stearate, sodium alginate, sugar, gum arabic, magnesium carbonate) q.s. 250 mg.
2) Sericic acid 10 mg.
EXcipients (corn starch, lactose, talc, magnesium stearate, sodium alginate, sugar, gum arabic, magnesium carbonate) q.s. 200 mg.
~ransparent gel Sericic acid 10 g.
Excipients (propylene glycol, triethanolamine, watér, antifermentative) q.s to 200 g.
Transparent gel Sericoside 5 g Excipients (propylene glycol, triethanolamine, water, antifermentative) Q.S. to 200 g.
T_blets Sericoside ` 100 mg.
Excipients (starch, lactose) q.s. to 500 mg.

- 2~ -

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a compound of general formula (II) or (III) (II) (III) wherein -OR1 , -OR2, -OR3 and -OR4, which may be the same or different, each represent a free or esterified hydroxyl group, -COOR5 represents a free or esterified carboxyl group, or a pharmaceutically acceptable salt thereof, which process comprises extracting tissue of a plant of the species Terminalia sericea with an organic solvent, isolating sericic acid and/or sericoside from the extract and if desired, converting the isolated sericic acid or sericoside to another compound of general formula (II) or (III) by one or more of the following procedures carried out in any appropriate order:

(i) oxidation (ii) reduction (iii) hydrolysis (iv) esterification and (v) salification.

2. A process according to claim 1 in which the organic solvent com-prises an alcohol, a ketone or an ester.

3. A process according to claim 2 in which the organic solvent com-prises ethanol, acetone or ethyl acetate.

4. A process according to claim 1 in which prior to isolating sericic acid and/or sericoside from the extract, the organic solvent is evaporated and the resulting residue contacted with a liquid hydrocarbon so as to remove fatty and resinous substances.

5. A process according to claim 1 in which the isolation of the sericic acid and/or sericoside includes a fractionation step in which a solution of the extract in water or a mixture of water and an alcohol is contacted with a chlorinated hydrocarbon solvent and separating the aqueous and chlorinated hydrocarbon solutions so obtained.

6. A process according to claim 4 or 5 in which the isolation of the sericic acid and/or sericoside includes the step of fractional recrystalliza-tion or chromatographic separation.

7. A process according to claim 1, 2 or 3 in which an 18.alpha.-epimer of a compound of formula (II) or (III) is produced.

8. A compound of the general formula (II) or (III) (II) (III) wherein -OR1, -OR2, -OR3 and -OR4, which may be the same or different, each represents a free or esterified hydroxyl group, -COOR5 represents a free or esterified carboxyl group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

9. A process according to claim 1 in which a compound is produced wherein R1, R2, R3 and R4, which may be the same or different, each represents a hydrogen atom, or a substituted or unsubstituted aliphatic or aromatic mono-or poly-carboxylic acid acyl radical.

10. A compound as claimed in claim 8 in which R1, R2, R3 and R4, which may be the same or different, each represents a hydrogen atom or a substituted or unsubstituted aliphatic or aromatic mono- or poly-carboxylic acid acyl radical, whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.

11. A process according to claim 1 in which a compound of formula (II) is produced wherein R1, R2, R3 and R4 all represent hydrogen.

12. A compound of formula (II) as claimed in claim 8 wherein R1, R2, R3 and R4 all represent hydrogen whenever prepared by the process of claim 11, or by an obvious chemical equivalent thereof.

13. A process according to claim 1 in which a compound of formula (II) is produced wherein R1, R2, R3 and R4 all represent acetyl.

14. A compound of formula (II) as claimed in claim 8 wherein R1, R2, R3 and R4 all represent acetyl, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.

15. A process according to claim 1 in which a compound of formula (II) is produced wherein R1, R2, R3 and R4 all represent benzoyl.

16. A compound of formula (II) as claimed in claim 8 wherein R1, R2, R3 and R4 all represent benzoyl, whenever prepared by the process of claim 15, or by an obvious chemical equivalent thereof.

17. A process according to claim 1 in which a compound of formula (II) is produced wherein R1, R2 R3 and R4 all represent hemisuccinyl.

18. A compound of formula (II) as claimed in claim 8 wherein R1, R2, R3 and R4 all represent hemisuccinyl, whenever prepared by the process of claim 17, or by an obvious chemical equivalent thereof.

19. A process according to claim 1 in which a compound of formula (III) is produced wherein each of R1, R2 and R3 represents hydrogen.

20. A compound of formula (III) as claimed in claim 8 wherein each of R1, R2 and R3 represents hydrogen whenever prepared by the process of claim 19, or by an obvious chemical equivalent thereof.

21. A process according to claim 1 in which a compound of formula (III) is produced wherein each of R1, R2 and R3 represents acetyl.

22. A compound of formula (III) as claimed in claim 8 wherein each of R1, R2 and R3 represents acetyl, whenever prepared by the process of claim 21, or by an obvious chemical equivalent thereof.

23. A process according to claim 1 in which a compound of formula (III) is produced wherein each of R1, R2 and R3 represents benzoyl.

24. A compound of formula (III) as claimed in claim 8 wherein each of R1, R2 and R3 represents benzoyl, whenever prepared by the process of claim 23, or by an obvious chemical equivalent thereof.

25. A process according to claim 1 in which a compound of formula (III) is produced wherein each of R1, R2 and R3 represents hemisuccinyl.

26. A compound of formula (III) as claimed in claim 8 wherein each of R1, R2 and R3 represents hemisuccinyl, whenever prepared by the process of claim 25, or by an obvious chemical equivalent thereof.

27. A process as claimed in claim 1 in which a compound is produced wherein R5 represents hydrogen, a substituted or unsubstituted aliphatic radical, or a glycosyl group.

28. A compound according to claim 8 wherein R5 represents hydrogen, a substituted or unsubstituted aliphatic radical, or a glycosyl group, when-ever prepared by the process of claim 27, or by an obvious chemical equivalent thereof.

29. A process as claimed in claim 1 in which a compound is produced wherein R5 represents an alkyl group.

30. A compound according to claim 8 wherein R5 represents an alkyl group, whenever prepared by the process of claim 29, or by an obvious chemical equivalent thereof.

31. A process as claimed in claim 1 in which a compound is produced wherein R5 represents an aminoalkyl, a monoalkylaminoalkyl, or a dialkylamino-alkyl group.

32. A compound according to claim 8 wherein R5 represents an amino-alkyl, a monoalkylaminoalkyl, or a dialkylaminoalkyl group, whenever pre-pared by the process of claim 31, or by an obvious chemical equivalent thereof.

33. A process as claimed in claim 1 in which a compound is produced wherein R5 represents hydrogen.

34. A compound according to claim 8 wherein R5 represents hydrogen, whenever prepared by the process of claim 33, or by an obvious chemical equivalent thereof.

35. A process as claimed in claim 1 in which a compound is produced wherein R5 represents a methyl group.

36. A compound according to claim 8 wherein R5 represents a methyl group, whenever prepared by the process of claim 35, or by an obvious chemical equivalent thereof.

37. A process as claimed in claim 1 in which a compound is produced wherein R5 represents a diethylaminoethyl group.

38. A compound according to claim 8 wherein R5 represents a diethyl-aminoethyl group, whenever prepared by the process of claim 37, or by an obvious chemical equivalent thereof.

39. A process as claimed in claim 1 in which a compound is produced wherein R5 represents a D-glucosyl group.

40. A compound according to claim 8 wherein R5 represents a D-glucosyl group, whenever prepared by the process of claim 39, or by an obvious chemical equivalent thereof.

41. A process as claimed in claim 1 for the preparation of sericoside which comprises extracting tissue of a plant of the species Terminalia sericae with an organic solvent comprising aqueous ethanol, and isolating sericoside from the thus obtained extract.

42. Sericoside whenever prepared by the process of claim 41, or by an obvious chemical equivalent thereof.

43. A process as claimed in claim 1 for the preparation of sericic acid which comprises extracting tissue of a plant of the species Terminalia sericae with an organic solvent comprising aqueous ethanol, and isolating sericic acid from the thus obtained extract.

44. Sericic acid whenever prepared by the process of claim 43, or by an obvious chemical equivalent thereof.

45. A process as claimed in claim 1 for the preparation of methyl sericate which comprises reacting the thus-obtained sericic acid with diazomethane in a solvent.

46. Methyl serlcate whenever prepared by the process of claim 45, or by an obvious chemical equivalent thereof.

47. A process as claimed in claim 1 for the preparation of tribenzoyl methyl sericate which comprises reacting the thus-obtained sericic acid with diazomethane in a solvent to provide methyl sericate and thereafter reacting the thus obtained ester with benzoyl chloride in an organic solvent.

48. Tribenzoyl methyl sericate whenever prepared by the process of clain 47, or by an obvious chemical equivalent thereof.

49. A process as claimed in claim 1 for the preparation of triacetyl 19-keto methyl sericate which comprises reacting the thus-obtained sericic acid in sequence with diazomethane in an organic solvent to provide methyl sericate; acetylating the thus obtained ester with acetyl chloride in a sol-vent to provide triacetyl methyl sericate and subjecting the thus obtained compound to reaction with Jones's reagent.

50. Triacetyl 19-keto methyl sericate whenever prepared by the pro-cess of claim 49, or by an obvious chemical equivalent thereof.

51. A process as claimed in claim 1 for the preparation of diethyl-aminoethyl sericate which comprises converting the obtained sericic acid to its potassium salt, and reacting the salt with diethylaminoethyl chloride.

52. Diethylaminoethyl sericate whenever prepared by the process of claim 51, or by an obvious chemical equivalent thereof.

53. A process as claimed in claim 1 for the preparation of methyl tetracetyl sericate which comprises reacting the thus-obtained sericic acid with diazomethane in an organic solvent to provide methyl sericate; acetylat-ing the thus obtained ester with acetyl chloride to provide triacetyl methyl sericate and further acetylating this compound with acetic anhydride in the presence of perchloric acid.

54. Methyl tetracetyl sericate whenever prepared by the process of claim 53, or by an obvious chemical equivalent thereof.

55. A process as claimed in claim 1 for the preparation of methyl tetracetyl 18.alpha.-sericate which comprises reacting the thus obtained sericic acid with diazomethane in an organic solvent to provide methyl sericate;
acetylating the thus obtained ester with acetyl chloride to provide triacetyl methyl sericate and further acetylating this compound with acetic acid in the presence of hydrobromic acid.

56. Methyl tetracetyl 18.alpha.-sericate whenever prepared by the process of claim 55, or by an obvious chemical equivalent thereof.

57. A process as claimed in claim 1 for the preparation of 2,3,24-trihemisuccinyl sericic acid which comprises reacting the thus obtained sericic acid with succinic anhydride in an organic solvent.

58. 2,3,24-Trihemisuccinyl sericic acid whenever prepared by the process of claim 57, or by an obvious chemical equivalent thereof.

59. A process according to claim 1 in which R5 represents a group of the formula -R'-NR"R'" wherein -R'- represents a straight or branched chain alkylene radical, and R" and R"', which are the same or different, are selected from hydrogen atoms and alkyl groups.

60. A compound of the general formula II or III given in claim 1 wherein -OR1,-OR2, -OR3 and -OR4 are as defined in claim 1 and R5 is as defined in claim 59 whenever prepared by the process of claim 59 or by an obvious chemical equivalent thereof.