GB1571829A

GB1571829A - Sulphur-containing diaryl compounds and oxygen-containing diaryl compounds

Info

Publication number: GB1571829A
Application number: GB1395076A
Authority: GB
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1976-04-06
Filing date: 1976-04-06
Publication date: 1980-07-23
Also published as: FR2366271B2; BE853235R; DE2715184A1; FR2366271A2; ES457575A2

Description

(54) SULPHUR-CONTAINING DIAKYL COMPOUNDS AND OXYGEN-CONTAINING DIARYL COMPOUNDS (71) We, LABORATOIRE L. LAFON, a French Body (Corporate, of 1, Rue (ieorges Mederic, 947(X) Maisons Alfort, France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to new sulphur-containing diaryl compounds and oxygencontaining diaryl compounds and their therapeutic application, especially in the treatment of cardio-vascular diseases.

In our British Patent Specification No. 1519147, we describe and claim sulphur and oxygen-containing diaryl compounds of the formula:

in which one of A and B is O, S, SO or SO2 and the other is O, Alk is a C1-G hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH GROUP, a carboxylic amide group, OH, O-S02 CH3, NH2, NHR1, NR1R2, NHZOH, NHZNR1R2, C(=NH)NH2, C(=NH)NHOH or 2- A2-imidazolinyl, Z is a C2-C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1-C3 lower alkyl group, or together form, with the nitrogen atom to which they are linked, a N-heterocyclic group of 5 to 7 ring atoms which can be substituted and can comprise a second hetero-atom, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical.

We have now discovered that compounds of the formula (I), in which A and B independently represent S, SO and SO2 and which are consequently newperse and outside the class of compounds described and claimed in our earlier application, may also be used for the treatment of cardio-vascular diseases. Accordingly, the present invention provides diaryl compounds of the formula:

in which A and B independently represent A, SO or SO2, Alk is a C1-G hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxylic amide group, OH, O-SO2CH3, NH2, NHR1, NR1R2, NHZOH, NHZNR1R2, (C=NH)NHOH or 2-A2-imidazolinyl, Z is a C2-C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1-C3 lower alkyl group, or together form, with the nitrogen atom to which they are linked, a N-heterocyclic group of 5 to 7 ring atoms which can be substituted and can comprise a second hetero-atom, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic radical.

'Alk' is preferably, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -C(CH3)2CH2-, CH2CH(CH3)- or -CH2C(Cll3)2- and Z is preferably -CH2CH2-, -CH(CH3)CH2-, - C(CH3)2CH2-, -CH2CH(CH3)- or -CH2C(CH3)2)-.

The term 'esterified COOH group' means any C()()X group where X is either a C1-C'3 alkyl group (such as methyl, ethyl, n-propyl or isopropyl) or a CH2CH2NR1R2 group (in which NR1R2 is as defined above), or an ester radical which rcsults from the esterification ol a bis-[(S-hydroxylalkyl)-thio]-alkane as described in British Patent Specification No. 1,307,227 or No. 1,466,411. The term 'carboxylic amide gniup' Iiirriiis ;I gr()tip of the formula -CONH2, -CONHR1, -CONRi R2, -CONHZOH or -CONlI/N R2 R2 where Ri, R2 cind Z are as defined above, or an amide obtainable by condensing an acid of formula I (R-( ()()H) in the form of its acid chloride, with an amine of formula IX given below. Suitable acid addition salts of the acids of the formula I (R=COOH) are the salts obtained with the usual organic bases and the salts obtained with the bis-[(N-hydroxyalkyl)-amino-alkylthio]-alkanes of the formula: Bo-NRo-Ao-SOx.(CH2)n-SOx-Ao-NRo-Bo IX described in French Patent Specification No. 2258846, wherein Bo is a C2-C4 hydroxyalkyl group or a C2-C4 dihydroxyalkyl group, Ao is a C2-C6 alkylene group, Ro is H, alkyl, acyl or Bo and x is 0, 1 or 2.

It is to be understood that the generic term 'amidine' used in the text which follows includes not only the C(=NH)NH2 group but also the amidoxime group C(=NH)NHOH and the cyclic amidine groups, such as the 2-A2-imidazolinyl group.

The preferred N-heterocyclic groups for NR1 R2 are the morpholino, pyrrolidino, piperidino, 4-methyl-piperidino, 4-methyl-piperazino, 4-p-chlorophenyl-piperazino and azepino groups. The preferred NR1R2 groups are the dimethylamino and diethylamino groups. included Also included within the scope of the present invention are compounds which are within the class of sulphur- and oxygen-containing diaryl compounds disclosed in our British Patent Specification No. 1519147 but which are not specifically disclosed therein. Accordingly, we provide sulphur- and oxygen-containing diaryl compounds of the formula:

in which (a) represents 0 and B represents SO or SO2, Alk is -CH2-, -CH(CH3)- or -C(CH3)2- and R is -COOH, -COOX or -COX where X represents a C1-3 alkyl group, or a -CH2CH2NR1 R2 group where R1 and R2 each independently represents a C13 alkyl group or R1 and R2, together with the nitrogen atom to which they are attached, form an N-heterocyclic group of 5 to 7 ring atoms which can comprise a second hetero-atom such as O or N and can be substituted, and X1 is -NH2, -NHCH2CH20H, -NHCH2CH2N(CH3)2 or NHCH2CH2N(C2Hs)2; or (b) A represents 0 and B represents SO or SO2 Alk is -CH2CH2-, -CH(CH3)CH2-, -C(CH3 2CH2-, -CH2CH(CH3)- or -CH2C(CH3)2- and R is -N(CH3)2, -N(C2H5)2 or NHCH CH3)2; and their addition salts with acids when R is a basic radical; or (c) A represents S and B represents 0, Alk is -CH2- and R is -COOH, and its addition salts with bases other than that of formula (IX) defined above; or (d) one of A and B represents 0 and the other S, or both represent 0, Alk is -CH2-, -CH(CH3)- or -C(CH3)2- and R is

in which n is an integer of from 5 to 15, both T groups are the same and represent H or CH3, and Q is

in which A, B and Alk are as defined immediately above, with the proviso that when N=10, A=S, B=O and Alk=C(CH3)2, then T=CH3.

The principal compounds of the invention fall into the following categories: a) acids of the formula:

in which A and B either independently represent S, SO or S02, (a preferred sub-group of compounds are those wherein both A and B are S), or one of A and 23 is () and the other represents SO or SO2, and Y is -CH2-, -CH(CH3;- or -C(CH3)2- and the addition salts obtained by reaction of the said acids with organic bases (other than the bis-[(Nhydroxyalkyl)-amino-alkylthio]-alkanes of the formula IX mentioned above, when Awl()) especially the salts of formula

in which n is an integer from 5 to 15, preferably 10, and T is H or CH; b) esters of the formula:

wllcrcin A and B are as defined in connection with the acids of formula (la) above, Y is -CH2-, -(ll(CH3)- or -C(CH3)2- and X is as defined above, and their addition salts with acids if X contains an amino group; c) alcohols of the formula:

wherein A and B are independently S, SO or SO2, and Y1 is -CH2CH2-, -CH(CH3)CH2-, -C(CHs)2CH2- -CH2CH(CH3)- or -CH2C(CH3)2-, and their derivatives resulting from the converslon of the OH group to an O-SO2CH3 group; d) amides of the formula:

in which A and B are as defined in connection with the acids of formula (lea) above, Y is -CH2-, -CH(CH3)- or -C(CH3)2-, and X1 is -NH2, -NHCH2CH20H, -NHCH2CH2N(CH3)2, or -NHCH2CH2N(C2Hs)2, and their addition salts with acids; e) amines of the formula:

in which A and B are as defined in connection with the acids of formula (Ia) above, Yl is -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH(CH3-- or -CH2C(CH3)2-, and X2 is -NH2, -NHCH2CH20H, -NHCH(CH3)CH20H, NHC(CH3)2CH20H, NHCH2CH2N(CH3)2, -NHCH2CH2N(C2Hs)2, N(CH3)2, -N(C2H5)2 or -NHCH(CH)2, and their addition salts with acids, f) amidines of the formula:

in which A and B are independently S, SO or SO2, Y is -CH2-, -CH(CH3)- or -C(CH3)2- and X3 is -C(=NH)NH2, -C(=NH)NHOH or 2-A2-imidazolinyl, and their addition salts with acids.

The compounds of the invention may be prepared by methods known per se. Suitable such methods are those described in the parent application in connection with the preparation of compounds of formula I in which one of A and B is 0, S, SO or SO2 and the other is 0. These methods may be adapted to prepare the compounds of the invention of formula I in which A and B independently represent S, SO or SO2.

Method A A diphenyl derivative of the formula:

wherein A and B independently represent S, SO and SiO2, is reacted with a halogen denvatlve of the formula: Hal-Alk-R' III wherein Hal is a bromine or chlorine atom and R' is COOC2Hs, OH, NH2, NHR1, NR1R2, NHZOH, NHZNRrR2 and CN, to obtain a compound of the formula:

If necessary, the following conversions are then carried out: a the ester (IV, R' = COOC2H5) is converted to the corresponding acid derivative (I, R = COOH) by hydrolysis, the said acid derivative then being subjected, where necessary, to amidification, e.g. by reaction of said chloride with an amine of formula HX, X1 being as defined above or being an amine radical resulting from a base of formula IX defined above or its addition salts as indicated above; and esterification reactions so as to obtain the amides and the other esters; b) the alcohol (IV, R' = OH) is converted to the corresponding mesylate derivative (I, R = O-SO2CH3) by reaction with methanesulphonyl chloride; c) the cyano derivative (IV, R' = CN) is converted to the corresponding 'amidine' derivative [I, R = C(=NH)NH2, C(=NH)NHOH or 2-A2-imidazolinyl] by reacting the said cyano derivative with NH3, NH20H or H2NCH2CH2NH2 in the presence of an alcohol.

In the reaction to form the compound of formula IV, it is preferred to use a bromine derivative (III, Hal = Br) if R' is COOC2H5. If R' is CN, OH or amino, (including the substituted amino groups of formula Ie), a chlorine or bromine derivative can be used, and in this case the chlorine derivative generally gives better yields than the bromine derivative.

Variants of method A are: i) the preparation of amines by reduction of the corresponding amides; ii) the preparation of amines from alcohols or mesylates (R = O-SOCH3) thereof; iii) the preparation of other esters by transesterification of the compound of formula IV (R' = COOC2Hs); iv) the preparation of amides from the ester of formula IV (R' = COOC2Hs) by reaction with amines; v) the direct preparation of am ides by reaction of the compound of formula II with a bromoalkyl amide of the formula III (R' = carboxamido); vi) the preparation of the alcohol by reduction of the corresponding acid (R = COOH), and vii) the oxidation of the sulphide group S to a sulphinyl group SO or a sulphonyl group S02, by oxidation of the said sulphide by H202 in the presence of acetic acid in a manner known per se. It is recommended to carry out this process at a temperature less than or equal to 50"C to give the sulphinyl derivative and at a temperature above 55"C (55 to 1000C) to give the sulphonyl derivative, with concentrated hydrogen peroxide of at least 110 volumes strength (that is to say water containing at least 33two by weight of hydrogen peroxide). The oxidation with H202 can be carried out at any stage of method A.

Method B Method B, which is less general than the preceding method, comprises the reaction of a copper salt of the formula:

wherein A' is S, with a bromo-compound of the formula:

in which B is S, and Y is CH2, CH(CH3) or C(CH3)2, to give an ester of the formula:

which is subjected to a hydrolysis reaction to give the corresponding acid:

The acid VIII is then, where necessary, subjected to the following reactions: i) reduction of the acid to the corresponding alcohol, followed by treatment of the said alcohol, if necessary, with Cl-O-S02-CH3 to give the corresponding mesylate; ii) esterification of the acid to give the other esters; iii) amidification of the acid to give the amides, followed by reduction of the said amides, if necessary, to give the corresponding amines; and iv) if required, oxidation of the sulphide group S to a sulphinyl group SO or a sulphonyl group SO2 by means of H202, as indicated above.

Amongst the variants of method B, the transesterification and amidification of the ester VII may be mentioned.

The addition salts with acids, which can be prepared from the bases of the formula I, may be obtained by methods known per se, for example by reaction of the free base with an inorganic or organic acid. Suitable acids which can be used are hydrochloric, hydrobromic, hydriodic, sulphuric, formic, maleic, fumaric, oxalic, ascorbic, citric, acetic, methane-sulphonic, ptoluenesulphonic, lactic, succinic, benzoic, salicylic, acetylsalicylic, malic, tartaric, glutamic and aspartic acids.

The preferred compounds of the invention are (a) the acids of the formula:

wherein Alk is -CH2-, -CH(CH3)- or -C(CH2)2- and B is S or Alk is -CH2- and B is 0, and (b) the bis-(hydroxyalkylthio)-alkane esters of the formula:

wherein n is an integer having a value of 5 to 15, preferably 10, A and B, which may be identical or different, each represents 0 or S, Alk is -CH2- -CH(CH3)- or -C(CH3)2- and T is H or CH3.1 14-dithia-1, 16-hexadecyl di 2-[4-(4-chlornphenyfthio)-phenoxy]-2- methylpropionate. [n = 10, A = S, B = O, Alk = C(CH3)2 and T = H] is excluded because it has already been described in the parent application.

Certain specific acids and esters of the invention are listed in Tables I and II below, the melting points given having been measured on a Koflter bench.

The compounds of the present invention are useful in therapy in the treatment of circulatory disturbances, especially cardio-vascular diseases. Some of these compounds, are hypolipidaemic and hypocholesterolaemic agents, some are anti-(blood platelet aggregation) agents, and some are simultaneously hypolipidaemic, hypocholester-olaemic and antiaggregation agents, the property shared by all these compounds being their beneficial action in circulatory disturbances and in particular in cardiovascular diseases.

The invention therefore also provides a therapeutic composition for the treatment of cardio-vascular diseases, said composition containing as active ingredient at least one compound of the invention in association with a physiologically acceptable excipient.

Table I

Example Code No. A B Alk R Melting point 1 CRL 40,351 S S CH(CH3) COOH 71"C 2 CRL 40,356 S S C(CH3)2 COOH 1400C 3 CRL40,363 S S CH2 COOH 110 C 4 CRL40,386 S O CH2 COOH < 50 C Table II

Example Code No. A B Alk T Melting point 5 CRL40,284 O S CH2 H 70-71"C 6 CRL40,368 0 0 C(CH3)2 H (a) 7 CRL40,374 0 0 C(CH3)2 CH3 (a) 8 CRL40,377 0 O CH(CH3) H (a) 9 CRL40,378 0 O CH(CH3) CH3 (a) 10 CRL40,379 0 O CH2 H 59"C 11 CRL40,380 0 O CH2 CH3 45"C 12 CRL40,387 S O C(CH3)2 CH3 (a) 13 CRL40,388 S O CH2 H 72"C 14 CRL40,389 S O CH2 CH3 52"C 15 CRL40,390 S O CH(CH3) H (a) 16 CRL40,391 S O CH(CH3) CH3 (a) 17 CRL40,394 S S CH2 H 55"C 18 CRL40,395 S S CH2 CH3 < 40 C 19 CRL40,398 S S CH(CH3) H (a) 20 CRL40,399 S S CH(C113) CH3 (a) 21 CRL40,402 S S C(CH3)2 H (a) 22 CRL40,403 S S C(CH3)2 CH3 (a) 23 CRL40,405 O S CH2 CH3 (a) 24 CRL40,408 O S CH(CH3) H (a) 25 CRL40,409 O S CH(CH3) CH3 (a) 26 CRL40,413 O S C(CH3)2 H (a) 27 CRL40,414 O S C(CH3)2 CH3 (a) Note (a)= oil Example I (+)-2-lp-(p-Chlorophenylthio)-phenylthio]-propionicacid

a) Preparation of copper p-chlorophenylthiolate (I) A suspension of 115 g (0.760 mol) of p-chlorothiophenol, taken to be 95% strength, and of 35.8 g (0.250 mol) of cuprous oxide in 600 ml of 95% strength ethanol is heated under reflux for 20 hours. After having filtered the precipitate and washed it copiously with alcohol, 103.7 g. of a yellow powder are obtained.

Yield 100% b) Preparation of ethyl (+)-2-(p-bromophenylthio)-propionate A solution of 30 g (0.165 mol) of ethyl 2-bromo-propionate in 30 ml of anhydrous ethanol is run over the course of 30 minutes into a solution of 29 g (0.150 mol) of p-bromothiophenol, taken as 98% strength, and of 6 g (0.150 mol) of sodium hydroxide pellets in 100 ml of anhydrous ethanol, and the mixture is then stirred for 1 hour at ambient temperature. The inorganic salts formed are removed by filtration and the alcohol is evaporated. The residue is taken up in diethyl ether and the organic phase obtained is washed successively with N sodium hydroxide solution and with water. After drying, and evaporating the solvent, 44.6 g of a limpid pale yellow oil are obtained. The purification of this oil by distillation under reduced pressure gives 37.1 g of a limpid colourless oil.

Boiling point/4 mm Hg = 143-145"C.

Yield = 85.3% c) Preparation of ethyl (+)-2-[p-(p-chlorophenylthio)-phenylthio]-propionate A suspension of 29.8 g (0.144 mol) of copper p-chlorophenylthiolate (I) obtained according to a) and of 37 g (0.128 mol) of the ester obtained in b), in 96 ml of quinoline and 26.5 ml of pyridine, is heated for 3 hours at about 1700C. The reaction mixture is then poured onto ice and is acidified with concentrated hydrochloric acid, using Congo Red as the indicator. After extracting the insoluble matter with diethyl ether, drying and evaporating the solvent, 48 g of a brown oil are obtained.

Yield = 100% d) CRL40,351 A solution of 48 g (about 0.128 mol) of the above product and of 12 g (0.216 mol) of KOH pellets in 150 ml of ethanol and 50 ml of water is heated under reflux for 1 hour 30 minutes.

The alcohol is evaporated and the reaction mixture is diluted with water and acidified with concentrated hydrochloric acid. The precipitate is extracted with diethyl ether and the organic phase obtained is in its turn extracted with a solution of potassium bicarbonate. Acidification of the aqueous phase with hydrochloric acid liberates 40 g of an orange oil which is extracted with diethyl ether.

This oil is purified by two successive crystallisations from cyclohexane and one crystallisation from a 50:50 v/v mixture of heptane and benzene, to give 25 g of a white, water-insoluble powder.

Instantaneous melting point (Kofler) = 71 C Yield from stage d) = 61.3% Overall yield = 52.3% Example 2 2-[p-(p-Chlorophenylthio)-phenylthio]-2-methylpropionic acid

Code No.: CRL 40,356 Following the procedure indicated in Example 1b), 47 g of a limpid pale yellow oil are prepared from 29 g (0.150 mol) of p-bromothiophenol and 32.2 g (0.165 mol) of ethyl 2-bromo-2-methylpropionate; subsequent purification of this oil (by distillation under reduced pressure) gives 40.8 g of ethyl 2-(p-bromophenylthio)-2-methylpropionate.

Boiling point/2-3 mm Hg = 142-143"C Yield = 90% Reaction of copper p-chlorophenylthiolate (I) with ethyl 2-(p-bromophenylthio)-2methylpropionate in accordance with the procedure given in Example 1c), gives ethyl 2--(p- chlorophenylthio)-phenylthio]-2-methylpropionate (which is in the form of an orange oil).

This ester is hydrolysed in accordance with the procedure given in Example 1d); subsequent purification (treatment with charcoal and recrystallisation from diisopropyl ether) gives CRL 40,356.

Instantaneous melting point (Kofler) = 140 C.

Example 3 p-(p-Chlornphenylthio)-phenylthioacetic acid

Code No. : CRL 40,363 Following the procedure indicated in Example 1b), ethyl p-bromophenylthio-acetate (boiling point/7 mm Hg = 163-165"C) is prepared and this ester is reacted with copper p-chlorophenylthiolate (I). in accordance with Example 1c) to give ethyl p-(pchlorophenylthio)-phenylthio-acetate which, by hydrolysis followed by purification (charcoal, and recrystallisation from diisopropyl ether) gives CRL 40,363.

Instantaneous melting point (Kofler) = 110 C.

Example 4 p-(p-Chlorophenylthio)-phenoxy-acetic acid

Code No. : CRL40,386 a) Copper p-chlorophenylthiolate (I) A mixture of 265 g (1.83 mols) of p-chlorothiophenol and 80 g (0.55 mol) of cuprous oxide which has been freshly prepared (by reaction of cupric acetate with glucose), in 1,500 ml of anhydrous ethanol, is heated under reflux for 24 hours. After filtering, and washing the precipitate with alcohol, 214 g of a yellow powder are obtained.

b) Ethyl p-bromophenoxy-acetate 2.76 g of sodium are dissolved in 100 ml of anhydrous ethanol and 20.8 g (0.120 mol) of p-bromophenol are added. 22.1 g (0.132 mol) of ethyl bromoacetate are run into this solution over the course of 20 minutes and the mixture is then heated under reflux for 1 hour. The ethanol is driven off under reduced pressure and the residue is dissolved in diethyl ether; after washing with water and then with a potassium carbonate solution, and evaporating the solvent, 30.2 g of a white powder are obtained. After purification of this product by crystallisation from petroleum ether, 23 g of a white, water-insoluble powder are obtained.

Instantaneous melting point = below 50 C Yield = 74% c) Ethyl p(p-chlorophenylthio)-phenoxy-acetate A mixture of 21.9 g (0.0845 mol) of ethyl p-bromo-phenoxy-acetate and 20.7 g (0.1000 mol) of Cu p-chloro-phenylthiolate (I) in 65 mlofquinoline and 21.5 ml of anhydrous pyridine is heated at about 1700C for 6 hours. Thereafter the reaction mixture is poured onto 175 g of ice and 70 ml of concentrated hydrochloric acid. After having stirred the mixture for 2 hours at ambient temperature (15-25"C), the insoluble matter is extracted with diethyl ether, which is washed successively with dilute hydrochloric acid and with water, and after evaporation of the solvent gives 27.3 g of a red-brown oil.

Yield about 100% d) CRL 40,386 A solution of 27.3 g (=0.0845 mol) of the above product and of 7.1 g (0.1270 mol) of KOH pellets in 90 ml of ethanol and 45 ml of water is heated for 2 hours under reflux. The ethanol is then driven off under reduced pressure and the residue is diluted with 100 ml of water. The aqueous phase is acidified with concentrated hydrochloric acid, the insoluble matter is extracted with ethyl acetate and the organic phase obtained is washed with water and then dried over dry sodium sulphate. After evaporating the solvent,24.7 g of a beige powder are obtained, and this is purified by recrystallization from benzene. 19.5 g of CRL 40,386 are obtained.

Instantaneous melting point (Kofler) = 155"C.

Yield of stage d) = 81%.

Overall yield = 60%.

Example 5 3, 14-Dithia-1 , 16-hexadecyl di- [p-(p-chlorophenoxy)-phenyl-thio-acetate]

a) p-(p-Chlorophenoxy)-phenylthio-acetyl chloride A mixture of 17.5 g (0.0595 mol) of p-(p-chloro-phenoxy)-phenylthio-acetic acid (Code No. CRL 40,271) and of 21.6 ml (0.3000 mol) of thionyl chloride is heated under reflux for 30 minutes. After having taken up the reaction mixture in benzene, filtered the solution in the presence of charcoal and evaporated the solvent, 18.5 g of a limpid orange-yellow oil are obtained.

Yield = 99.5% b) CRL40,284 A solution of 9.5 g (0.0303 mol) of the above product in 20 ml of benzene is run, over the course of 40 minutes, into a hot solution of 4 g (0.0136 mol) of 3,14-dithia-1,16hexadecanediol (Code No. LL 1,558) in 25 ml of benzene. The mixture is heated under reflux for 2 hours, the reactants are left in contact at ambient temperature for 48 hours, and the mixture is then evaporated to dryness under reduced pressure. After having dissolved the residue in chloroform, washed the solution with water and potassium carbonate and evaporated the solvent, a crystalline yellowish product is obtained. This product is purified by washing with diethyl ether to give 9.7 g of a white, water-insoluble powder.

Instantaneous melting point (Kofler) = 70-71"C.

Yield of stage b) = 84.4%.

Overall yield = 84%.

Examples 6 to 27 On proceeding as indicated in Example 5, starting from the following acids: 2[p-(p chlorophenoxy).phenoxy]-2-methylpropionic acid (Code No. : CRL 40,308), (+)-2-[p-(p chlorophenoxy)-phenoxyj-propionic acid (Code No.: CRL 40,299), p-(p-chlorophenoxy) phenoxy-acetic acid (Code No. : CRL 40,333), 2-[p-(p-chlorophenylthio)-phenoxy]-2 methylpropionic acid (Code No. : CRL 40,201), p-(p-chloro-phenylthio)-phenoxy-acetic acid (Code No.: CRL 40,386), (+)-2-[p-(p-chlorophenylthio)-phenoxy]-propionic acid (Code No. : CRL 40,246), p-(p-chlorophenylthio)-phenylthio-acetic acid (Code No. : CRL 40,363), (+)-2-[p-(p-chlorophenylthio)-phenylthio]-propionic acid (Code No. : CRL 40,351), 2-[p-(pchlorophenylthio)-phenyfthio]-2-methylpropionic acid (Code No. : CRL 40,356), p-(pchlorophenoxy)-phenylthio-acetic acid (already used above in the synthesis of the product of Example 5), (+ (+)-2-[p-(p-chlorophenoxy)-phenylthio]-propionic acid (Code No. : CRL 40,281) and 2- p(pchlornphenoxy)-phenylthio]-2-methylpropionic acid acid (Code No. : CRL 40,275), which are reacted, in the form of the acid chlorides, with 3,14-dithia-1,16 hexadecanediol (Code No.: LL 1,558) or (#);2,15-dimethyl-3,14-dithia-1,16-hexadecane- diol (Code No. : CRL 40,122), the esters (shown in Table II) are obtained, namely: Example 6: 3,14-Dithia-1,16-hexadecyl di[2[pp(p-chlorophenoxy)-phenoxyj-2-methylpro- pionate] (Code No. : CRL 40,368); Example 7: (+)-2-,15-Dimethyi-3,14-dithia-1,16-hexadecyl di- [2- [p-(p-chlorophenoxy)- phenoxyj-2-methylpropionate] (Code No. : CRL 40,374); Example 8 3, 3,14-Dithia-l, 16-hexadecyl di-( + )-(2- [p-(p-chlorophenoxy)-phenoxyj- propionate) (Code No. : CRL 40,377); Example 9 : )-2, 15-Dimethyl-3, 14-dithia-1, 16-hexadecyl di-(f )-(2-[p-chlorophenoxy)- phenoxy]-propionate) (Code No. : CRL 40,378); Example 10 : 3,14-Dithia-1,16-hexadecyl di-[p-(p-chlorophenoxy)-phenoxy-acetate] (Code No. : CRL 40,379); Example 11 : (+)-2,15-Dimethyl-3,14-dithia-1,16-hexadecyl di-[-(p-chlorophenoxy)phenoxy-acetate] (Code No. : CRL 40,380); Example 12 : (f)-2, 15-Dimethyl-3,14-dithia-l, 16-hexadecyl di-(2-[p-(p-chlorophenylthio)phenoxy]-2-methylpropionate) (Code No as a hypolipidaemic and hypocholesterolaemic agent; at these doses, the reduction in the lipids is respectively 17, 21 and 29%, and that in the cholesterol respectively 32, 43 and 42%, after 3 days' treatment.

The anti-aggregation action was studied in accordance with two tests. At a dose of 100 mg/kg given orally for 4 days, it is found that according to the collagen test, the latency time is +40 and the speed is -, whilst, according to the ADP test, the inhibition of transmission is 19%.

CRL 40,394 (product of Example 17) The reduction in the cholesterol is 16 (?%) and that in the lipids is 33% after 5 days' treatment at a dose of 50 mg/kg.

CRL 40,395 (product of Example 18) At a dose of 100 mg/kg given orally, the reduction in the cholesterol is 27% and that in the lipids is 18%, after 4 days' treatment.

CRL 40,398 (product of Example 19) At a dose of 100 mg/kg given orally, the reduction in the lipids is 17% after 4 days' treatment. On the other hand, it is found that there is no change in the cholesterol content.

CRL 40,402 (product of Example 21) At doses of 10 mg/kg, 20 mg/kg and 50 mg/kg given orally, a reduction in the cholesterol content and lipids content is observed after 3 to 5 days' treatment, in particular a reduction of 14% in the cholesterol and of 17% in the lipids at a dose of 20 mg/kg after 3 days' treatment.

Furthermore, it is found that the product has an anti-aggregation action according to the ADP test at a dose of 100 mg/kg given orally, the inhibition of transmission being 25% after 4 days' treatment.

CRL 40,403 (product of Example 22) At a dose of 100 mg/kg given orally, a reduction of 32% in the cholesterol and of 10% in the lipids is observed after 4 days' treatment.

CRL 40,405 (product of Example 23) At a dose of 100 mg/kg given orally, a reduction of 44% in the cholesterol and of 35% in the liPids is observed after 4 days' treatment. At a dose of 20 mg/kg the reduction in the cholesterol is 30% and that in the lipids is 12% after 5 days' treatment.

The product modifies the platelet aggregation according to the collagen test (latency time: + 10; speed: - 17; % transmission: - 10%) at a dose of 100 mg/kg given for 4 days.

CRL 40,408 (product of Example 24) At a dose of 100 mg/kg given orally, a reduction of 20% in the cholesterol and of 17% in the lipids is observed after 4 days' treatment.

CRL 40,409 (product of Example 25) At a dose of 100 mg/kg given orally, a reduction of 9-10% in the lipids is observed after 4 days' treatment.

CRL 40,414 (product of Example 27) At a dose of 100 mg/kg given orally, a reduction of 12% in the lipids is observed after 4 days' treatment.

The conclusions obtained from clinical trials are that the compounds of the present invention can be used therapeutically for the treatment of cardio-vascular diseases, and in particular in the treatment of hyperlipidaemia.

The compounds of the invention can be administered orally in the form of capsules or gelules containing from 200 to 600 mg of active ingredient. Compound CRL 40,389 was administered successfully to patients as a hypolipidaemic agent by way of 2 to 4 capsules or gelules (each containing 500 mg of active ingredient) per day. Compound CRL 40,386 was also successfully administered to patients as a hypolipidaemic agent at a dosage of 2 to 6 gelules (each containing 300 mg of active ingredient) per day. Compound CRL 40,414 was similarly administered successfully by way of 3 gelules (each containing 300 mg of active ingredient) per day.

WHAT WE CLAIM IS: 1. Diarvl compounds of the formula:

in which A and B independently represent S, SO or S02, Alk is a C1-Cs hydrocarbon radical with a straight or branched chain, R represents COOH, an esterified COOH group, a carboxylic amide group, OH, O-SO2CH3,NH2, NHRi, NRtR2, NHZOH, NHZNR1R2, C(=NH)NH2, C(=NH)NHOH or 2-A2-imidazolinyl, Zis a C2-C4 hydrocarbon radical with a straight or branched chain, and R1 and R2 each represent a C1-C3 lower alkyl group or together form, with the nitrogen atom to which they are linked, a N-heterocyclic group of 5 to 7 ring atoms which can be substituted and can comprise a second hetero-atom, and their addition salts with bases when R is COOH, and their addition salts with acids when R is a basic

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. as a hypolipidaemic and hypocholesterolaemic agent; at these doses, the reduction in the lipids is respectively 17, 21 and 29%, and that in the cholesterol respectively 32, 43 and 42%, after 3 days' treatment. The anti-aggregation action was studied in accordance with two tests. At a dose of 100 mg/kg given orally for 4 days, it is found that according to the collagen test, the latency time is +40 and the speed is -, whilst, according to the ADP test, the inhibition of transmission is 19%. CRL 40,394 (product of Example 17) The reduction in the cholesterol is 16 (?%) and that in the lipids is 33% after 5 days' treatment at a dose of 50 mg/kg. CRL 40,395 (product of Example 18) At a dose of 100 mg/kg given orally, the reduction in the cholesterol is 27% and that in the lipids is 18%, after 4 days' treatment. CRL 40,398 (product of Example 19) At a dose of 100 mg/kg given orally, the reduction in the lipids is 17% after 4 days' treatment. On the other hand, it is found that there is no change in the cholesterol content. CRL 40,402 (product of Example 21) At doses of 10 mg/kg, 20 mg/kg and 50 mg/kg given orally, a reduction in the cholesterol content and lipids content is observed after 3 to 5 days' treatment, in particular a reduction of 14% in the cholesterol and of 17% in the lipids at a dose of 20 mg/kg after 3 days' treatment. Furthermore, it is found that the product has an anti-aggregation action according to the ADP test at a dose of 100 mg/kg given orally, the inhibition of transmission being 25% after 4 days' treatment. CRL 40,403 (product of Example 22) At a dose of 100 mg/kg given orally, a reduction of 32% in the cholesterol and of 10% in the lipids is observed after 4 days' treatment. CRL 40,405 (product of Example 23) At a dose of 100 mg/kg given orally, a reduction of 44% in the cholesterol and of 35% in the liPids is observed after 4 days' treatment. At a dose of 20 mg/kg the reduction in the cholesterol is 30% and that in the lipids is 12% after 5 days' treatment. The product modifies the platelet aggregation according to the collagen test (latency time: + 10; speed: - 17; % transmission: - 10%) at a dose of 100 mg/kg given for 4 days. CRL 40,408 (product of Example 24) At a dose of 100 mg/kg given orally, a reduction of 20% in the cholesterol and of 17% in the lipids is observed after 4 days' treatment. CRL 40,409 (product of Example 25) At a dose of 100 mg/kg given orally, a reduction of 9-10% in the lipids is observed after 4 days' treatment. CRL 40,414 (product of Example 27) At a dose of 100 mg/kg given orally, a reduction of 12% in the lipids is observed after 4 days' treatment. The conclusions obtained from clinical trials are that the compounds of the present invention can be used therapeutically for the treatment of cardio-vascular diseases, and in particular in the treatment of hyperlipidaemia. The compounds of the invention can be administered orally in the form of capsules or gelules containing from 200 to 600 mg of active ingredient. Compound CRL 40,389 was administered successfully to patients as a hypolipidaemic agent by way of 2 to 4 capsules or gelules (each containing 500 mg of active ingredient) per day. Compound CRL 40,386 was also successfully administered to patients as a hypolipidaemic agent at a dosage of 2 to 6 gelules (each containing 300 mg of active ingredient) per day. Compound CRL 40,414 was similarly administered successfully by way of 3 gelules (each containing 300 mg of active ingredient) per day. WHAT WE CLAIM IS:

1. Diarvl compounds of the formula:

radical.

2. A compound according to claim 1, in which Alk represents -CH2-,-CH(CH3)-, C(CH3)2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH(CH3)- or -CH2C(CH3)2-.

3. A compound according to claim 1 or 2, in which NR1R2 is N(CH3)2, N(CH2CH3)2, morpholino, pyrrolidino, piperidino, 4-methyl-piperidino, 4-methyl-piperazino, 4-pchlorophenyl-piperazino or azepino.

4. A compound according to claim 1 or 2, in which the esterified COOH group is a group of the formula COOX, wherei X is a C1 -C3 alkyl group, a CH2CH2NRr R2 group where R1 and R2 are as defined in claim 1 or 3, or an esterified bis- (s-hydroxyalkyl)-thio]-alkane group.

5. A compound according to claim 1 or 2, in which the carboxylic amide group is a group of the formula -CONH2, -CONHR1, -CONRIR2, -CONZOH or -CONHZNRiRi in which Z is as defined in claim 1 and R1 and R2 are as defined in claim 1 or 3, or an amide obtainable by condensing an acid chloride of formula:

in which A, B and Alk are as defined in claim 1, with an amino of formula: BO-NRo-Ao-Sox-(CH2)n-SOx-Ao-NRo-Bo (IX) in which Bo is a C2-C6 hydroxy alkyl group or a C2-C4 dihydroxyalkyl group, Ao is a C2-C6 alkylene group, Ro is H, alkyl, acyl or Bo and x is 0, 1 or 2.

6. A compound according to claim 1 of the formula:

in which A and B are as defined in claim 1 and Y is -CH2-, -CH(CH3)- or -C(CH3)2-, and its addition salts with organic bases.

7. A salt according to claim 6, in which the base is a bis-[(N-hydroxyalkyl)-aminoalkylthio]-alkane of the formula: BO-NRo-Ao-Sox-(CH2)n-SOx-Ao-NRo-Bo (IX) in which Bo, Ao, Ro and x are as defined in claim 5.

8. A compound according to claim 6 of the formula:

in which Y is as defined in claim 6.

9. A salt according to claim 6, of the formula:

in which n is an integer of from 5 to 15, Y is as defined in claim 6 and T is H or CH3.

10. A salt according to claim 9, in which n is 10.

11. A compound according to claim 1 of the formula:

in which A and B are as defined in claim 1, Y is -CH2-, -CH(CH3)- or -C(CH3)2- and X is as define din claim 4, and its addition salts with acids if X contains an amino group.

12. A compound according to claim 1 of the formula:

m which A and B are as defined in claim 1, Y1 is -CH2CH2- -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH(CH3), or -CH2C(CH3)2- or its derivatives resulting from the conversion of the OH group to an O-SO2CH3 group.

13. A compound according to claim 1 of the formula:

in which A and B are as defined in claim 1, Y is -CH2- -CH(CH3)- or -C(CH3)2-, and X1 is -NH2, -NHCH2CH20H, -NHCH2CH2N(CH3)2 or -NHCH2CH2N(C2Hs)2, and their addition salts with acids.

14. A compound according to claim 1 of the formula:

in which A and B are as defined in claim 1, Y1 is -CH2CH2-,-CH(CH3)CH2-,-C(CH3)2CH2-, -CH2CH(CH3)- or -CH2C(CH3)2- and X2 is -NHi, -NHCH2ClI2OH, -NMCH(CH3)CH2OH, -NHC(CH3)2CH20H, -NHCH2CH2N(CH3)2, -NHCH2CH2N(C2Hg)2, -N(CH3)2, -N(C2H5)2 or -NHCH(tH3)2, and their addition salts with acids.

15. A compound according to claim 1 of the formula:

in which A and B are as defined in claim 1, Y is -CH2-, -CH(CH3)- or -C(CH3)2- and X3 is -C(=NH)NH2, -C(=NH)NHOH or 2-A2-imidazolinyl, and their addition salts with acids.

16. (+)-2-lp-(p-Chlorophenylthio)-phenylthiol-propionic acid and its addition salts with bases.

17. 2-[p-(p-Chlorophenylthio)-phenylthio]-2-methylpropionic acid and its addition salts with bases.

18. p-(p-Chlorophenylthio)-phenylthioacetic acid and its addition salts with bases.

19. 3, 14-Dithia- 1, lOhexadecyl di-[p-(p-chlorophenylthio)-phenylthio-ac di- [p-(p-chlorophenylthio)-phenylthio-acetate].

20. (+)-2,15-Dimethyl-3,14-dithia-1,16-hexadecyl di-[p-(p-chlorophenylthio)phenylthio-acetate] .

21. 3,14-Dithia-1,16-hexadecyl di-(1)-(2-[p-(p-chlorophenylth 0 )-phenylthio]-pro- pionate).

22. (+)-2,15-Dimethyl-3, 1Cdithia-l ,16-hexadecyl di-(+)-(2-[p-(p-chlorophenylthio)- phenylthio]-propionate).

23. 3, 14-Dithia- 1, 16-hexadecyl di-(2-[p-(p-chlorophenylthio)-phenylthio]-2-methylpro- pionate).

24. 1-2, 15-Dimethyl-3, 14-dithia-1 16-hexadecyl di-(2-[p-(p-chlorophenylthio)-phenyl- thioj-2-methyl-propionate).

25. A sulphur- and oxygen-containing diaryl compound of the formula:

in which: (a) A represents 0 and B represents SO or SO2, Alk is -CH2-, -CH(CH3)- or -C(CH3)2and R is -COOH, -COOX or -COX1 where X represents a Ci alkyl group, or a -CH2CH2NR1R2 group where R1 and R2 each independently represents a C1~3 alkyl group or R1 and R2, together with the nitrogen atom to which they are attached, form an N-heterocyclic group of 5 to 7 ring atoms which can comprise a second hetero-atom such as O or N and can be substituted, and X1 is -NH2, -NHCH2CH20H, -NHCH2CH2N(CH3)2 or -NHCH2CH2N (C2H5)2; or (b) A represents 0 and B represents SO or SO2 Alk is -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2CH(CH3)- or -CH2C(CH3)2- and R is -N(CH3)2, -N(C2Hs)2 or -NHCH(CH3)2; and their addition salts with acids when R is a basic radical; or (c) A represents S and B represents 0, Alk is -CH2- and R is -COOH, and its addition salts with bases other than that of formula (IX) defined in claim 5; or (d) one of A and B represents 0 and the other S, or both represent 0, Alk is -CH2, -CH(CH3)- or -C(CH3)2- and R is

m which A, B and Alk are as defined immediately above, with the proviso that when n = 1O,A=S, B=O and Alk=C(CH3)2, then T=CH3

26. A compound according to claim 25 of the formula:

in which A represents 0 and B represents SO or S02, Y is -CH2-, -CH(CH3)- or -C(CH3)2-, and its addition salts with organic bases other than that of formula IX defined in claim 5.

27. A compound according to claim 25 of the formula:

in which A represents 0 and B represents SO or SO2, Y is -CH2-, -CH(CH3)- or -C(CH3)2 and Xis as defined in claim 25, and its addition salts with acids if X contains an amino group.

28. A compound according to claim 25 of the formula:

in which A represents 0 and B represents SO or SO2, Y is -CH2-, -CH(CH3)- or -C(CH3)2-, and X1 is -NH2, -NHCH2CH20H, -NHCH2CH2N(CH3)2 or -NHCH2CH2N(C2Hs)2, and their addition salts with acids.

29. A compound according to claim 25 of the formula:

in which A represents 0 and B represents SO or S02, Y1 is -CH2CH2-, -CH(CH3)CH2)-, -C(CH3)2CH2-, -CH2CH(CH3)- or -CH2C(CH3)2- and X2 is -N(CH3)2, -N(C2Hs)2 or -NHCH(CH3)2 and their addition salts with acids.

30. A compound according to claim 25 of the formula:

and its addition salts with bases other than that of formula (IX) defined in claim 5.

31. A compound according to claim 25 of the formula:

in which one of A and B represents S and the other 0, or both represent 0, Alk is -CH2-, -CH(CH3)- or -C(CH3)2-, or n is an integer of from 5 to 15, and T is H or CH3, with the proviso that when n = 10, A = S, B = O and Alk = C(CH3)2, then T = CH3.

32. A compound according to claim 31 in which n is 10.

33. p-(p-Chlorophenylthio)-phenoxy-acetic acid and its addition salts with bases other than that of formula IX defined in claim 5.

34. 3,14-Dithia-1,16-hexadecyl di-[p-(p-chlorophenoxy)-phenylthio-acetate].

35. 3,14-Dithia-1,16-hexadecyl di-(2-[p-(p-chlorophenoxy)-phenoxy]-2-methylpro- pionate).

36. (#-2,15-Dimethyl-3,14-dithia-1,16-hexadecyl di-(2-[p-(p-chlorophenoxy)-phenoxy]- 2-methylpropionate).

37. 3, 14-Dithia- 1, 16-hexadecyl di-(+)-(2-[p-(p-chlorophenoxy)-phenoxy3-propionate).

38. (#)-2,15-Dimethyl-3,14-dithia-1,16-hexadecyl-di-(#)-(2-[p-(p-chlorophenoxy)- phenoxy] -propionate).

39. J,14-Dithia-1,16-hexadecyl di-[p-(p-chlorophenoxy)-phenoxy-acetate]

40. (f)-2, 15-Dimethyl-3, 14-dithia-l, 16-hexadecyl di- [p-(p-chlorophenoxy)-phenoxyacetate].

41. (#)-2,15-Dimethyl-3,14-dithia-1,16-hexadecyl di-(2-[p-(p-chlorophenylthio)-phen oxy] -2-methylpropionate

42. 3,14-Dithia-1, 16-hexadecyl di- [p-(p-chlorophenylthio)-phenoxy-acetate].

43. (+ )2,15-Dimethyl-3,14-dithia-1,16-hexadecyl di-[p-(p-chlorophenylthio)-phenoxyacetate].

44. 3,14-Dithia,1,16-hexadecyl di-(+)-(2-[p-(p-chlorophenylthio)-phenoxy]-pro- pionate).

45. (+ )-2,15-Dimethyl-3,14-dithia-1,16-hexadecyl di-(#)-(2-[p-(p-chlorophenylthio)- phenoxy]- -propionate) .

46. (+)-2, 15-Dimethyl-3, 14-dithia-l, 16-hexadecyl di-[p-(p-chlorophenoxy)-phenylthioacetate].

47. 3,14-Dithia-1,16-hexadecyl di-(+)-(2- [p-(p-chlorophenoxy)-phenylthio]-pro- pionate).

48. (#)-2, 15-Dimethyl-3,14-dithia-1,16-hexadecyl di-(#)-(2-[p-(p-chlorophenoxy)- phenylthio] -propionate).

49. 3, 14-Dithia-1, 16-hexadecyl di-(2-[p-(p-chlorophenoxy)-phenylthio]-2-methylpro pionate).

50. (::::)-2, 15-Dimethyl-3, 14-dithia- 1, 16-hexadecyl di-(2-[p-(p-chlorophenoxy)-phenyl- thio]-2-methylpropionate).

51. Process for the preparation of diaryl compounds of the formula (I), and salts thereof with acids and bases, as defined in claim 1, which comprise reacting a diphenyl derivative of tne tormula:

in which A and B are as defined above, with a halogen compound of the formula: Hal-Alk-R' III in which Alk is as defined above, Hal represents bromine or chlorine and R' is COOC2H5, OH, NH2, NHRt, NR1R2, NHZOH, NHZNR1R2, or CN to produce a compound of the formula:

(a) hydrolysing a carboxylate (IV, R' = COOC2Hs) to the corresponding acid (R = COOH) which may then be converted by methods known per se into an amide or other ester; (b) converting an alcohol (IV, R' = OH) into the corresponding mesylate (R = OSO2CH3) by reaction with methane-sulphonyl chloride; or (c) reacting a cyanide (IV, R' = CN) with NH3, NH20H or H2NCH2CH2NH2 in the presence of an alcohol to produce an amidino compound in which R is C(:NH)NH2, C(:NH)NHOH, or 2-A2-imidazolinyl respectively.

52. Process according to claim 51 in which NRr R2 is as defined in claim 3.

53. Process according to claim 51 in which the esterified COOH group is a group of formula COOX as defined in claim 4.

54. Process according to claim 51 for the preparation of a compound of the formula I(a), and salts thereof with bases, as defined in claim 6, which comprises reacting the said compound of the formula (II) with the said compound of formula (III) wherein Hal is bromine, R' is 0OC2Hs, and Alk is -CH2-, -CH(CH3)-, or -C(CH3)2-, and hydrolysing the ester obtained.

55. Process according to claim 51 for the preparation of a compound of the formula I(d), and salts thereof with acids, as defined in claim 13, with the additional possibility of X1 being an amine radical resulting from a base of formula IX hereinbefore defined or its addition salts with acids when X1 is NHCH2CH2N(CH3)2 or NHCH2CH2N(C2Hs)2, which comprises reacting an acid obtained by the process of claim 54, as its acid chloride, with an amine HX where X1 is as defined in this claim.

56. Process according to claim 51 for the preparation of an amine of the formula I(e), and salts thereof with acids, as defined in claim 14, which comprises reacting the said diphenyl derivative of the formula (II) with the said compound of formula (III) wherein Hal is chlorine, Alk is Y1 as defined in claim 14, and R' is X2 as defined in claim 14.

57. Process for the preparation of diaryl compounds of the formula (I) and salts thereof with acids and bases, as defined in claim 1, which comprises reacting a copper salt of formula:

where A' is S, with a bromo-compound of formula:

in which B is S, and Y is CH2, CH(CH3) or C(CH3)2, to produce an ester of the formula:

hydrolysing this ester to produce the corresponding acid and then, if desired, reducing this aid to the corresponding alcohol, with or without converting the said alcohol into the mesylate by reaction with CH30SO2CI, esterifying the said acid to give an ester, amidifyingthe said acid to produce an amide, with or without reducing the amide to give an amine, and/or oxidizing a sulphide atom to a sulphinyl or sulphonyl group with H202.

58. Process for the production of a compound as claimed in claim 1 substantially as described in Examples 1, 2, 3 or 17 to 22.

59. A compound as claimed in any one of claims 1 to 24 when produced by a process claimed in any one of claims 51 to 58.

60. A therapeutic composition comprising, as active ingredient, at least one compound according to any one of claims 1 to 24, 25 to 50 or 59 in association with a physiologically acceptable excipient.