NZ191162A - Carboxy-(phenyl or tolyl)-sulphomium salts and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 91162 1 9116 2 Priori -iV ^ ■ - * c 2f\t 7 *7$\ . . r^-r'^^a-ion Fiisd: ••••••• .-«.!■ coicitfr.;. QkW.?i hj ■■■■■ ■ 3.1. MW.J98A. . ~ .« c ■ [c jy ^ tjy MM w a* &U3 !?$.!§ No.: Date: NX parefr office NEW ZEALAND JUL 1979 PATENTS ACT ,1953 RECEIVED COMPLETE SPECIFICATION CARBOXY (PHENYL OR TOLYL)-SULPHONIUM SALTS, THEIR PREPARATION AND USE AS ANTI-OBESITY AGENTS XK/We, SANDOZ LTD., 35 Lichtstrasse, 4002 Basle, Switzerland, A Swiss Body Corporate hereby declare the invention for which X/ we pray that a patent may be granted toJfHfc/us, and the method by which it is to be performed, / to be particularly described in and by the following statement:- / _ 1 _ (followed by page la) / - \ a. — 191 The invention relates to carboxy-(phenyl or tolyl)-sulphonium salts, their preparation, as well as their use as pharmaceutical agents and to pharmaceutical compositions containing such compounds.

The invention provides compounds of formula I, in which R^ is (Cg_2^)alkyl, R2 is (C^_g)alkyl ^R^) or unsubstituted or substituted phenyl of the formula: Y wherein Y is hydrogen, fluorine, chlorine or bromine, ((C^_^)alkyl or (C-L_4) alkoxy, 15116 Rg is hydrogen, fluorine, chlorine or bromine (C-^_.j) alkyl or (C^_^) alkoxy, R^ is hydrogen, or (C^_g)alkyl (=R^), n is 0 or 1, and » Z®is an anion forming a pharmaceutically acceptable non-toxic salt of the corresponding cation; provided that R2 is alkyl when R^ is hydrogen.

The invention also provides a process for the prep-10 aration of compounds of formula I, characterised by reacting a compound of formula O II in which R is either R, or R~ and R-, R. and n are as 1 2 3' 4 4 defined above, with an alkylating agent transferring an alkyl radical R^ cl a when R is R^,or an alkyl radical R^ defined above, when R is R^, in the presence of an anion . Z® supplying metal salt © y in which Z is as defined above, and, where required, converting the anion Z®in the resulting compound of formula I 0 into a different anion Z by reaction with an acid or.salt containing the anion to'be introduced. 19116 COO G701/X The invention particularly provides a process for the preparation of compounds of formula I, characterised by a) producing a compound of formula la, R, S I R, © 0 "(CH_) -C-O-R' 2. n 4 .© Ia in which R^ is as defined above, by reacting a compound of the formula Ila, O II (CH0)—COR. Ila 2 n 4 R3 wherein n, and R^ are as defined above, and R is either R^ or R2, as defined above, with an alkyl halide of the formula Ilia, X - Rb Ilia wherein X is bromine or iodine, b 3 and R is either R^ when R is Rj, or is RJ!> as defined above, when R is R^, in the presence of a salt of the formula IV, MZ IV G wherein Z is as defined above for 1 , and 19116 COO G791/X1 M is a metal forming with X a salt MX» b) producing a compound of formula lb, O It (CH2>iTC- 0E4 BF © lb in_which R^, R^, R3, n and R^ are as defined above, by reacting an alklythio aromatic acid of the formula lib, 0 <CH2>— C-OR4 lib in which R^, R^, R^ and n are as defined above, with a trialkyl oxonium tetrafluoroborate of the formula Illb, © (R')3 o BF4 © Illb ,© in which R^ is as defined above, and, where required, converting the anion Z^ in the result-10 ing compound of formula I into a different anion Z® by reaction with an acid or salt containing the anion to be introduced.

The alkylation process of the invention, in particular process a), is preferably carried out under essentially 15 anhydrous conditions at moderate temperatures, e.g. from 15°C to 40°C, in an inert solvent, e.g. nitromethane or toluene. The reactants, in particular the compounds Ila 19116 - 5 - 600-6791/X and Ilia, are conveniently mixed in the solvent and the salt, e.g. of the formula IV, may be added thereto exercising suitable caution such as shielding from light. The reaction is also preferably carried out under an inert 5 atmosphere, e.g. dry nitrogen. An excess of the alkylating agent, particularly the alkylhalide of formula Ilia, is preferably employed and in most cases is highly desirable in order to increase the yield of the desired products. The metal in the salt employed, e.g. of formula IV, is 10 chosen such that the resulting salt, e.g. MX is either insoluble or relatively less soluble in the medium than the initial salt employed, e.g. of formula IV. Illustrative of various MZ salts include the salts of noble metals of which silver represents a preferred metal. Other such 15 metals include mercury. Representative anions (Z® ) forming such salts include the tetrafluoroborate, tri-fluoromethylsulphonate and perchlorate ions. Other anions which may be represented by Z include the alkyl and phenyl sulphonates, e.g. methanesulphonate, phenylsulph-20 onate and £-toluenesulphonate. Examples of preferred salts of the formula IV include silver trifluoromethylsulphonate and especially silver tetrafluoroborate. The resulting salt MX is separated by known techniques and the desired product is recovered from the solvent phase by 25 applying conventional procedures. It will be appreciated 19 i U - 6 - 000 0791/X that where a compound la is desired in which is other than alkyl, then a compound Ila is used in which Ra = such R2 radical other than alkyl and a compound Ilia is used in which R is R^.

Process b) is preferably carried out in an inert solvent, especially methylene dichloride, at moderate temperatures, particularly at room temperature.

Using equivalent amounts of Illb, corresponding compounds lb with R^ = hydrogen and with excessive amounts of Illb, corresponding compounds lb are obtained in which R^ has the significance of R|. . .

Conventional anion exchange procedures may be employed to interconvert the anion Z® in the resulting products. For example a compound of the formula I', [ K ] Z® a I" may be converted into a compound of formula I" [ K ] Z® b I" in which n, R^, R2, R^ and R^ are as defined above, K is the cationic portion of compounds I, and Z® a and Z®b are different anions Z® forming end products. 19116 - 7 - 600-0791/X More particularly, the compounds of the formula IM may be prepared by heating a compound I1 in a polar solvent in the presence of an acid of the formula V, H-Z® V b wherein Z® is as above defined, b at temperatures typically of from about 55°C to 120°C, preferably 65°C to 100°C, desirably in the presence of a theoretical excess of the acid of the formula V, and separating the desired compound of the formula I" from any unreacted starting material by taking advantage of 10 its different solubility characteristics.

Preferred compounds of the formula I' include those in which Z® is the tetrafluoroborate ion. The polar solvent may comprise water and a sufficient amount of a water soluble organic solvent, so that the resulting aqueous co-solvent system is capable of dissolving the starting compound of the formula I 1 . Examples of such organic solvents are the lower alkanols, e.g. methanol, propanol and preferably ethanol, and dimethylacetamide and dimethyl- formamide.

The initial isolation of the desired compound I" may be effected by the application of various known procedures depending upon the solubility characteristics of the desired product arid any remaining unreacted starting 19116 - 8 - 'GOO G7Q1/3E material. For example, isolation may be readily effected in certain cases simply by lowering the temperature of the reaction to crystallise the desired product by taking advantage of its reduced solubility in the polar 5 solvent. In other cases the contents of the reaction mixture may be concentrated and redissolved in a solvent from which either the desired product or undesired starting material may be selectively crystallised. In still other cases the contents of the reaction mixture may be 10 subjected to standard chromatography procedures or subjected to the action of ion exchange resins.

Another ion exchange procedure that is particularly convenient involves generally conversion of a compound of formula I,M , [K] Z® , into a compound of formula 15 I, [K] Z®, by reaction with a compound of formula VI, M0Z®, in a polar solvent, K being as defined above, M0 being a metal cation and Z® and Z® being different anions Z®, M0Z® and Z® being such that the salt MCZ® is less > c d c soluble in the medium than the compound of formula I|V , and the compound VI is more soluble in the medium than the salt formed of formula M0Z® . c This process is more particularly carried out in an aqueous solution at temperatures preferably-from 50°C to 120°C, more preferably 80°C to 100°C, preferably with 1 91 16 2 - 9 - GOO G7Q1/X a theoretical excess of the compound VI. An aqueous cosolvent is employed, composed similarly to that used above with ethanol being commonly preferred as the organic component of such solvent system.

By way of illustration, a preferred embodiment of the process involves the use of a compound I"' in which © Z c is the tetrafluoroborate anion and M0 is potassium whereby the insoluble potassium tetrafluoroborate is formed as a result of the reaction and may be separated 10 from the reaction mixture by taking advantage of its insolubility in the aqueous cosolvent system. In such embodiment the desired compound of the formula I remains in the reaction system cosolvent and may be initially separated from any remaining undesired reactants and 15 starting materials by employing conventional procedures.

Other known ion exchange procedures such as those involving ion exchange resins may be employed, especially when representing a convenient method of separating desired products from reactants and starting materials in 20 those procedures specifically detailed above. Typical ion exchange resins for such use are well known, in effecting the initial isolation of the desired products from ion exchange reactions such as process b) by chroma- 1911 - 10 - —600 C7S11/X. tographic procedures both thin layer and column chromatography may of course be employed. Typical chromatography additives for such use are well known, such as silica gel.

Final recovery of the desired compound of the 5 formula I from ion exchange procedures may be also effected by conventional techniques such as crystallisation, precipitation and vacuum distillation.

Starting materials and reagents used in the above described reactions, e.g. compounds Ila, lib, Ilia, Illb, 10 IV and V are either known or may be obtained by known methods.

The compounds of formula I possess pharmacological activity in animals. In particular, the compounds of formula I are indicated for use as 15 anti-obesity agents in the treatment of obesity because they inhibit the passage of glucose into the blood in mammals, indicated by the glucose transport test in which male Wister rats are dosed orally with 0.3-80 mg/kg body weight of the test compound after at least 20 hours of 20 fasting. One hour after receiving the drug, each animal is sacrificed and the upper small intestine is removed 19116 - 11 - 600 -G7P1/X— and washed with glucose-saline. A 5 cm section of the intestine is everted so that the mucosal surface is on the outside. One end of the segment is tied and the centre of the sac so formed is filled with oxygen satur-5 ated with Kreb's bicarbonate buffer. The other end is then closed to form a sac which is then incubated in 10 ml of oxygen saturated bicarbonate buffer for 60 minutes at 37°C. Both the outside and inside solutions contain initially 0.3% of glucose. At the end of the incubation 10 time, the glucose content of the outer (mucosal) and the inner (serosal) solution is determined using the standard Auto Analyser procedure. Similar tests are run simultaneously with control animals receiving only the vehicle. The percent inhibition of glucose transport caused by the 15 . drug is calculated from the formula: rst - Mt ^ 1 " 100 " U - M * 10j c. r. s wherein I = percent inhibition, S = glucose concentration (mg %) of serosal fluid at the end of the experiment in the drug-treated animal, 20 ~ glucose concentration (mg %) of serosal fluid at the end of an experiment in the control animal, 191162 = glucose concentration (mg i) of mucosal fluid at the end of an experiment in the drug-treated animal, and Mc = glucose concentration (mg %) of mucosal 5 fluid at the end of an experiment in the control animal.

For the above-mentioned use, an indicated suitable daily dosage is from about 60 to 3000 mg, suitably administered in divided doses of from 15 to 1500 mg, two to 10 four times daily, or in retard form.

The compounds of formula I may be admixed with conventional pharmaceutically acceptable diluents and carriers, and optionally other excipients and administered preferably orally, for example in the form of tablets or 15 capsules, Preferred significances of the groups R^-R^ are as follows: R1 ^C10-20^ a^yl / more preferably (Cl2_^g) alkyl, R2 alkyl or unsubstituted phenyl, more preferably alkyl, 20 R^ hydrogen the carboxy moiety being ortho or para to the sulphon-ium ion on the phenyl ring to which both are attached, R^ alkyl, more preferably ethyl.

It is particularly preferred that n = O. 19116 - 13 - nnn nm/" A preferred group of compounds of formula I are those in which all the groups to R^ have the preferred significances indicated above.

Salts of particular interest generally include 5 the tetrafluoroborate, perchlorate, methanesulphonate, phenylsulphonate and p-toluenesulphonate.

Particularly preferred compounds of formula I are t(o-carbethoxy)phenyl]-(n-propyl)-(n-octadecyl)sulphonium tetrafluoroborate; t(o-carbethoxy)-phenyl]-(n-propyl)-(n-octadecyl)sulphonium p-toluenesulphonate; and [p~(a-carbethoxy)-tolyl]-(n-tetradecyl)-(phenyl)sulphonium tetrafluoroborate.

The following Examples illustrate the invention.

All temperatures are in degrees Centigrade and room temperature is 20 to 30°C, unless indicated otherwise. 191162 14 600-6791/X— EXAMPLE 1: [(o- Ca rb ethoxy)phenyl]-(n-propyl)-(n-octa- decyl)sulphonium tetrafluoroborate [Method a)] To a solution of 11.0 g of 2-(n-octadecylthio) benzoic acid ethyl ester and 4.25 g of n-propyl iodide 5 in 50 ml of methylenedichloride and 200 ml of nitromethane is added 4.9 g of silver tetrafluoroborate. The reaction mixture is stirred at room temperature (under exclusion of light) for sixteen hours and is then filtered free of solids. The filtrate is evaporated under vacuum to dry-10 ness. The residue is dissolved in chloroform and chrom-atographed over silica gel with chloroform containing increasing concentrations of ethanol. The desired fractions are collected and evaporated under vacuum to dryness. From the residue is obtained on crystallisation 15 from ethanol the title compound, m.p. 56-58°.

EXAMPLE 2: [(p-Carbethoxymethyl)phenylj-(n-tetradecyl)-(phenyl)sulphonium tetrafluoroborate Following the procedure of Example 1 with 8.2 g of 4-(phenylthio)phenylacetic acid ethyl ester and 9.7 g 20 of n-tetradecyl iodide in 100 ml nitromethane as a solvent and adding 5.8 g of silver tetrafluoroborate, from the reaction mixture is obtained the title compound, m.p. 36-38°. 191162 - 15 - 600-6791/X EXAMPLE 3: Repeating the procedure of Example 1, but using corresponding starting compounds in approximately equivalent amounts there are accordingly obtained: a) [(2-carbethoxy-5-methyl)phenyl]-(n-propyl)-(n-octa-decyl)sulphonium tetrafluoroborate; b) [(2-carbethoxy-6-methyl)phenyl]-(n-propyl)-(n-octa-decyl)sulphonium tetrafluoroborate; c) [(2-carbethoxy-4-chloro-)phenyl]-(n-propyl)-(n-octa-decyl)sulphonium tetrafluoroborate; d) [(2-carbethoxy-5-chloro)-phenyl]-(n-propyl)-(n-octadecyl) sulphonium tetrafluoroborate; e) t(4-carbethoxy-2-methoxy)phenyl]-(n-propyl)-(n-octadecyl) sulphonium tetrafluoroborate; f) [(2-carbethoxy-6-methoxy)phenyl]-(n-propyl)-(n-octadecyl) sulphonium tetrafluoroborate; g) t(o-carbethoxy)phenyl]-(n-propyl)-(n-octadecyl)sulphonium perchlorate; h) t(o-carbethoxy)phenyl]-(n-butyl)-(n-octadecyl)sulphonium tetrafluoroborate; i) t(o-carbethoxy)phenyl]-(methyl)-(n-octadecyl)-sulphonium tetrafluoroborate; and j) [(o-carbethoxy)phenyl]-(isopropyl)-(n-octadecyl)-sulphonium tetrafluoroborate, m.p. 50-52°. 191162 - 16 - COO G7Q1/H EXAMPLE 4: Repeating the procedure of Example 2, and using corresponding starting compounds there are accordingly obtained: a) t (3-chloro-4-carbethoxymethyl) phenyl] - (n-tetradecyl) -i(phenyl) sulphonium tetraf luoroborate; b) [4-carbethoxymethyl-3-methyl)phenyl]-(n-tetradecyl)-(phenyl)sulphonium tetrafluoroborate; c) [4-carbethoxymethyl-3-methoxy)phenyl]-(n-tetradecyl)-$0 (phenyl)sulphonium tetrafluoroborate; d) t(4-carbethoxymethyl-3-methyl)phenyl]-(n-tetradecyl)-(p-tolyl)sulphonium tetrafluoroborate; e) [p-(a-carbethoxy)-tolyl]-(n-dodecyl)-(phenyl)sulphonium tetrafluoroborate; and f) [p-(a-carbethoxy)-tolyl] - (n-octadecyl)-'(phenyl) sulphonium tetrafluoroborate.

\ EXAMPLE 5 : [ (o-Carbethoxy) phenyl] - (n-propyl) - (n-octadecyl) -sulphonium p-toluene sulphonate To a solution of 5.0 g of [(o-carbethoxy)phenyl]-20 (n-propyl) - (n-octadecyl) sulphonium tetraf luoroborate in 20 ml of ethanol is added 20.0 g of potassium tosylate dissolved in a mixture of 200 ml ethanol and 10 ml water. The reaction mixture is maintained at 80-90° while being 1 91 1 f.

COO G701/X stirred vigorously for 2 hours. The reaction mixture is then cooled and filtered, and the filtrate then evaporated under vacuum to dryness to obtain a residue. The residue is taken up in methylene chloride; the organic phase 5 washed several times with water, dried over sodium sulphate, filtered and evaporated under vacuum to dryness. The residue is chromatographed over silica gel three times dsing methylene chloride and increasing amounts of methanol to obtain the title product, m.p. 65-67° EXAMPLE 6: Repeating the procedure of Example 5, but using corresponding starting compounds in approximately equivalent amounts there are accordingly obtained: a) [ (o-carbethoxy) phenyl].- (n -propyl) - (n-octadecyl) sulphon-15 ium bromide; and b) [(o-carbethoxy)phenyl]-(n-propyl)-(n-octadecyl)sulphonium trifluoromethylsulphonate.

EXAMPLE 7 : [ (o-Carbethoxy) phenyl] - (ethyl) - (n-octadecyl) -sulphonium tetrafluoroborate [Method b)] To a suspension of 2.0 g 2-(n-octadecylthio)- benzoic acid in 150 ml methylene dichloride is added an excess of freshly prepared triethyloxonium tetrafluoro-borate. The reaction mixture is stirred at room temperat- 1 91 1 6 - 18 - - GOO G7Q1/X - ure for 48 hours. Thereafter the methylene~d.ichloride layer^is washed extensively with water, dried over anhydrous sodium sulphate, filtered and evaporated in vacuum to dryness. The crude residue is then chromato-5 graphed over silica gel: eluting first with methylene dichloride and then with methylene dichloride containing increasing amounts of methanol. The desired fractions are collected and evaporated in vacuum to dryness thereby giving the title product.

EXAMPLE 8: [ (o-Carboxyethoxy)phenyl]-(n-propyl)-(n-octadecyl) sulphonium tetrafluoroborate [Method a)] To a vessel equipped with a stirrer and maintained under a dry nitrogen gas atmosphere there is added, 150 g of n-octadecy1-ethylthio salicylicate, 105 ml of 15 n-propyliodide and 3.0 1 of toluene and stirred until dissolved. To the stirred solution is added, in one portion, 75 g of silver tetrafluoroborate. The reaction mixture is then stirred for 22 hours under the nitrogen atmosphere and protected from light. The resulting mixture 20 is filtered through a Celite pad (50g) to remove the solids, which are then washed with 250 ml of toluene. The filtrate and washings are combined and evaporated (at 45°/20 mm) to obtain a residue. The residue is then dissolved in 1.5 1 19116 - 19 - ' 00 0 C7Q1/X of diethyl ether, and the solution stirred at 5° for 18 hours, resulting in the precipitation of the title product as a white solid (at lower-temperatures unreacted starting material co-precipitates). The solid product is washed with 200 ml of cold diethyl ether, then dried (under vacuum at 25°/10 mm) to obtain the refined title product, m.p. 60-63°. 191

Claims (34)

WHAT WE CLAIM IS:

1. A process for the production of compounds of formula I, R, © • S- R, O (CH_) —C-OR. 2 n 4 ,© 10 in which R^ is (Cg-C24)alkyl, Rj is (C^-Cg)alkyl (=R^ or unsubstituted or substituted phenyl of the formula: . Y wherein Y is hydrogen, fluorine, chlorine - or bromine, alkyl or (C1_4)alkoxy, R3 is hydrogen, fluorine, chlorine or bromine, (Cj_3)alkyl or (C1_3)alkoxy, R4 is hydrogen, or (C1-6)alkyl (=R^), n is 0 or 1, and *^PATE?rromcg 23 OCT 1981 1 fciS RECEIVED 191162 21 Z®i3 an anion forming a pharmaceutical^ acceptable non-toxic salt of the corresponding cation; provided that R2 is alkyl when is hydrogen, 5 characterised by reacting a compound of formula II, Ra - S 4 0 ~(CH2)n"C~°"R4 11 in which Ra is either R^ or R£ and R^ , R^ and n are as defined above, with an alkylating agent transferring an alkyl radical R^ •when Ra is R2,or an alkyl radical R^ defined above, when Ra 10 is in the presence of an anion Z® supplying metal salt in which Z® is as defined above, and, where required, converting the anion Z®in the resulting compound of formula I <r) into a different anion 1 by reaction with an acid or salt containing the anion to be introduced. 15 2. A process for the production of compounds of formula I, stated in Claim 1, characterised by a) producing a compound of formula la, 19116 - 22 - 600 -6 701/X R, © O II "(GH0) -C-O-R' 2 n 4 ,© la in which R!, is as defined above, by reacting a compound of the formula Ila, (CH0) COR. Ila

2 n 4 r3 wherein n, and R^ are as defined above, and R is either R^ or R2, as defined above, 5 with an alkyl halide of the formula Ilia, X - Rb Ilia wherein X is bromine or iodine, and Rb is either when Ra is R2, or is R2 as defined above, when R is R^» . in the presence of a salt of the formula IV, MZ IV © 10 wherein Z is as defined above for Z , and 19116 - 23 - 600 G791/X M is a metal forming with X a salt MXj b) producing a compound of formula lb, 0 <CH2)n-C- OR4 BF® lb by reacting an alkylthio aromatic acid of the formula lib, 0 II (CH2>n—<=-°R4 lib © Illb in which R^, R^, and n are as defined above, 5 with a trialkyl oxonium tetrafluoroborate of the formula IIIb< © (RJ)3 O L*4 in which R^ is as defined above, .and where. ..required,. converting the anion .7.® in the resulting compound of formula I into a different, anion Z 10 by reaction with an acid or salt containing the anion .to. be introduced. ©

3. A process for the production of a compound of formula I, stated in Claim 1, substantially as described in any one of the Examples. 15

4. A compound of formula I, stated in Claim 1, whenever prepared by a process as claimed in Claim 1, 2 or 3. 191162 - 24

5. A compound of formula I, stated in Claim 1.

6. A compound as claimed in Claim 4 or 5 in which R1 is (C10_2q)alkyl.

7. A compound as claimed in Claim 4 or 5 in 5 which R_ is (c r) alkyl or unsubstituted phenyl. ^ 1-6

8. A compound as claimed in Claim 4 or 5 in which is hydrogen.

9. A compound as claimed in Claim 4 or 5, in which the carboxy moiety is ortho or para to the sulph- 10 onium ion on the phenyl ring.

10. A compound as claimed in Claim 4 or 5 in which R4 is (ci_6)alkyl.

11. A compound as claimed in Claim 4 or 5 in tetrafluoroborate, perchlorate, methanesulphonate, phenyl- 15 sulphonate or p-toluenesulphonate salt form.

12. [(o-Carbethoxy)phenyl]-(n-propyl)-(n-octadecyl)sulphonium tetrafluoroborate.

13. t(o-Carbethoxy)-phenyl]-(n-propyl)-(n-octadecyl)sulphonium p-toluenesulphonate. 20

14. [p-(a-Carbethoxy)-tolyl]-(n-tetradecyl)- (phenyl)sulphonium tetrafluoroborate.

15. [(2-Carbethoxy-5-methyl)phenyl]-(n-propyl)- 23 OCT octadecyl)sulphonium tetrafluoroborate, - 25 - 1 91 1 COO G791/X—

16. [(2-Carbethoxy-6-methyl)phenyl]-(n-propyl)-(n-octadecyl)sulphonium tetrafluoroborate.

17 . [ (2-Carbethoxy-4-chloro-) phenyl] - (n-propyl)* -(n-octadecyl)sulphonium tetrafluoroborate.

18 . t (2-Carbethoxy-5-chloro) -phenyl] - (n-propyl) -(n-octadecyl)sulphonium tetrafluoroborate.

19. t(4-Carbethoxy-2-methoxy)phenyl]-(n-propyl)-(n-octadecyl)sulphonium tetrafluoroborate.

20. t(2-Carbethoxy-6-methoxy)-phenyl]-(n-propyl) (n-octadecyl)sulphonium tetrafluoroborate.

21. t (o-Carbethoxy) -phenyl] - (n-propyl) - (n-octadecy1)sulphonium perchlorate.

22. '[(o-Carbethoxy)phenyl]-(n-butyl)-(n-octadecyl) sulphonium tetrafluoroborate.

23. [(o-Carbethoxy)-phenyl]-(methyl)-(n-octadecyl) -sulphonium tetrafluoroborate.

24. [(3-Chloro-4-carbethoxymethyl)-phenyl!-(n-tetradecyl)-(phenyl)sulphonium tetrafluoroborate.

25. [4-Carbethoxymethyl-3-methyl)phenyl]-(n-tetradecyl)-(phenyl)sulphonium tetrafluoroborate.

26. [4-Carbethoxymethyl-3-methoxy)-phenyl]-(n-tetradecyl)-(phenyl)sulphonium tetrafluoroborate.

27. [(4-Carbethoxymethyl-3-methyl)phenyl]-(n- - 26 ~ 191162 tetradecy1)-(p-toly1)sulphonium tetrafluoroborate.

28. [p-(a-carbethoxy)-tolyl]-(n-dodecyl)-(phenyl)sulphonium tetrafluoroborate.

29 . [p- (o.-Carbethoxy) - tolyl] - (n-octadecyl) -(phenyl)sulphonium tetrafluoroborate.

30. [(o-Carbethoxy)phenyl]-(n-propyl)-(n-octadecyl)sulphonium bromide.

31. [(o-Carbethoxy)phenyl]-(n-propyl)-(n-octadecyl) sulphonium trifluoromethyIsulphonate.

32. [ (o-Carbe'thoxy) phenyl] - (ethyl) - (n-octadecyl) -sulphonium tetrafluoroborate.

33. [(o-Carbethoxy)phenyl]-(isopropyl)-(n-octadecyl) -sulphonium tetrafluoroboratey m.p. 50-52°.

34. A pharmaceutical composition; comprising a compound according to any one of Claims' 4 to 33, in association with a pharmaceutical^ acceptable diluent or carrier. HAT^O THIS <2^ DAY OF &<- ^ A . J . IP X K & SON Pc.n Ji -\ ^ agentg'fcr the applicants