FR2590257A1 - PROCESS FOR THE PREPARATION OF CEPHALOSPORIN TYPE ANTIBIOTICS AND INTERMEDIATES FOR THEIR PREPARATION - Google Patents

Abstract

THE OBJECT OF THE INVENTION IS A PROCESS FOR THE PREPARATION OF KNOWN DERIVATIVES OF CEPHALOSPORIN. THIS PROCESS INCLUDES THE REACTION OF 7-AMINO-CEPHALOSPORANIC ACID DERIVATIVES WITH ACETIC ACID THIOESTERS. THE INVENTION ALSO INCLUDES SUCH THIOESTERS AND THEIR PREPARATION.

Description

The present invention relates to a new preparation process

  cephalosporin-type antibiotics as well as new intermediates for

their preparation.

  The invention relates in particular to a process for the preparation of cephalosporins of formula I R1-CH2-Co-N S

1-2-CO-NH CH2R2

we

R3 (I)

  in which R1 represents a heterocyclic residue. with 5 links containing oxygen, nitrogen and / or sulfur, said heterocyclic residue being. optionally substituted by an amino group, R2 represents hydrogen, a methoxy, acetoxy or carbamoyloxy group, a -S-Y residue in which Y signifies an optionally substituted heterocyclic residue, or a pyridinium residue of formula II

N (II)

  R5 in which R4 and R5 represent, independently of one another, hydrogen, a halogen or an alkyl, hydroxy, carboxamido, alkoxycarbonyl, amino, monoalkylamino or dialkylamino group, or else R4 and R5 together signify a carbocycle with 5 or 6 members optionally substituted and R3 represents a carboxy, carboxylate or ester group

carboxylic acid.

  The compounds of formula I represent a known class of valuable antibiotics of the cephalosporin type. As indicated, the heterocyclic residue represented by R1 contains, as heteroatom or heteroatoms,

  one or more oxygen, sulfur and / or nitrogen atoms.

  Suitable R1 radicals include, for example, pyrazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl and oxadiazolyl radicals. The heterocyclic radical may be substituted or substituted by an amino group. R1 preferably means a group

thienyl or (1H) tetrazolyl.

  R2 can mean hydrogen. It can also mean a carbamoyloxy group. However, it preferably means an acetoxy group, a residue

  -S-Y or an optionally substituted pyridinium residue.

  The suitable heterocyclic residues that Y can represent are known; the preferred heterocyclic radicals include, for example, thiadiazolyl radicals,

  diazolyl, triazolyl, tetrazolyl, thiazolyl, thia-

  triazolyle, oxazolyle, oxadiazolyle, triazolylpyridyle,

  purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyra-

  zolyle and triazinyle. Heterocyclic remains can

  be unsubstituted or substituted, for example mono-

  di- or trisubstituted. As suitable substituents, mention may be made of halogens and C1-C4 alkyl, C1-C4 alkoxy, C1-C4 trihaloalkyl, hydroxy, oxo, mercapto, amino, carboxy, carbamoyl,

  di- (C1-C4 alkyl) amino, carboxymethyl, carbamoyl-

  methyl, sulfomethyl and methoxycarbonylamino. The heterocyclic radicals mentioned in the literature as particularly preferred include the tetrazolyl radicals, in particular 1-methyl-1H-tetrazole-5-yl, thiadiazolyl, in particular 1,2,3-thiadiazole-5-yl and

  2- methyl-1,1,3,4-thiadiazole-5-yl, and triazinyl, special-

  1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine-

  3-yl, 2.5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-

  yle or 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine-

  3-yle. R2 preferably signifies an acetoxy group,

  l-methyl-1H-tetrazole-5-ylthio, pyridinium or 2-methyl-

1,3.4-thiadiazolyle-5-thio.

  As is known in the field of cephalosporins, the compounds can be in the form of free acids (R3 = COOH) or salts,

  for example of alkali or alkaline metal salts

  earthy, preferably of alkali metal salts,

  such as sodium salts. Compounds can also

  ment be in the form of esters, for example in the form of pivaloylexymethyl ester. As examples of other residues forming an ester group, there may be mentioned

  acetoxymethyl, l-acetoxyethyl, l-ethoxy-

  carbonyloxyethyl, 5-indanoyl or preferably hexanoyl-

  methyl, phthalidyl, ethoxycarbonylmethoxymethyl or 3-ethoxycarbonyl-11 acetonyl. When R2 signifies an optionally substituted pyridinium residue, the compounds of formula I can also be in the form

internal salts.

  The compounds of formula I which are particularly preferred are those corresponding to the formula Ia Ri '-CH 2-CO-NH-FS R1 N H2R2' (a R3'cH IN_ Y 2 (Ia) R3 'in which Ri represents a group 2- thienyl or 1- (1H) -tetrazolyl, R% represents hydrogen, an acetoxy group or a residue -SY

  in which Y signifies a 2-methyl-1,3,4- group

  thiadiazole-5-yle or 1-methyl-1H-tetrazole-5-yle, and

  R represents a carboxy or carboxylate group.

  As already indicated, the compounds of formula I are known and various methods have been proposed for their preparation. One of these methods includes

  acylation of the corresponding 7-amino acid derivative

  cephalosporanioue possibly protected, with a reactive derivative of an acid of formula A

R - CH2- COOH (A)

I 2

  in which R1 has the meaning given above.

  Such acylations must most of the time be carried out at low temperature (-30 to 0 C)

  and often lead to the formation of secondary products

  daires and colored products, requiring processes

  difficult and complicated to purify the final product.

  Furthermore, when R1 signifies a heterocycle comprising

  as an amino group, another disadvantage of the prior methods lies in the fact that it is necessary

  in practice to protect the amino group before activating

  loss of the acid function, in order to avoid competing reactions which can lead to a sharp drop in the yield of the final product. Introduction of groups

  protectors before the acylation step and eliminating them

  subsequent action is generally accompanied by a decrease in yield and purity of the final product and a considerable increase in reaction time,

  of energy, effort and costs.

  The present invention relates to an improved process for obtaining the compounds of formula I with high purity and yield. Furthermore, it is not necessary in the process of the invention to protect an amino group which may be present.

in the rest heterocyclic R1.

  More particularly, the invention relates to a process for preparing the compounds of formula I and their salts, process according to which a compound of formula IV is reacted R1 "-CH2 - CO - S - C Het '-I

\ N- "(IV)

  and / or of formula! Va S R1 "-CH2 - CO - N Het '(IVa) s- formulas in which R1 represents a 5-membered heterocyclic residue containing oxygen, nitrogen and / or sulfur, said heterocyclic residue being optionally substituted with an amino or protected amino group, and the residues S

/ - ", -.

- C Het and - N Het

NOT-

  represent a 5 or 6-membered heterocyclic residue which may contain, in addition to the nitrogen atom,

  one or two other heteroatoms chosen from oxy-

  gene, nitrogen and sulfur, and which may be substituted or condensed with an optionally substituted benzene ring, with a compound of formula III

R6-NH - .. S

O {(III)

R

  in which R2 has the meaning given above, R6 represents hydrogen or a protecting group for the amino group and R 'represents a carboxy group, a protected carboxy group, a carboxylate group or a carboxylic acid ester group, if necessary, removes the protecting group in

  the resulting product, and, if necessary,

  forms a resulting compound in which R3 signifies

  COOH to a salt of this compound, or vice versa.

  The compounds of formula IV may also

  ment exist in the form indicated by formula IVa, the ratio of the two forms depending on the components

  reaction and reaction conditions.

  For reasons of simplification, the above formula IV is considered to include the compounds

  having the structure indicated by formula IVa.

  The process is suitably carried out in an inert solvent, for example in a lower alcohol, such as ethanol, a chlorinated hydrocarbon, such as dichloromethane, an ester, such as ethyl acetate, or in acetone, dimethylformamide or dimethylsulfoxide, or in a mixture of such solvents

  with water, the reaction temperature is

  suitably between -40 and +60 C, in particular

  between -15 and + 250C. especially between O and 20 C.

  The reaction time can vary between a few minutes and 48 hours. The starting materials of formula III and IV can advantageously be used in stoichiometric quantities. It is also advantageous to use an excess of the compound of formula IV

up to 25%.

  When preparing compounds of formula I in which R3 signifies COOH (as well as the salts of its compounds), the carboxy group can be protected from the starting product of formula III. Suitable protecting groups are known and include

  not only those cited above as significant

  possible ester groups, but also

  protecting silyl ester groups, in particular

  the trimethylsilyl group which can, for example, be introduced by reaction of the free acid with

  N, O-bis-trimethylsilylacetamide.

  The 7-amino group of the starting material of formula III can also be protected. Suitable protecting groups are known and include, for example, the trimethylsilyl group which may be

  introduced for example simultaneously during protection

tion of the carboxy group.

  When the heterocyclic residue R of the starting product of formula IV is substituted by an amino group, this amino group in the starting product used can be in unprotected form or in protected form. As already indicated, protection of the amino group is not necessary. If protection is however desired, it can be carried out in a known manner using conventional protective groups. After reaction of the compounds of formulas III and IV, any subsequent deprotection step can be

  performed in a conventional manner. Likewise, the transforma-

  tion of free acid (R3 = COOH) in its salts, and reci-

  can also be done according to the

known methods.

  Final products can be isolated

  and purified according to the usual methods.

  In the process of the invention, heterocyclic thioesters of formula IV are used as reactive acid derivatives of formula A. The compounds of formula IV are new and also form part of the invention. These compounds are valuable intermediates which can be used for the acylation of the compounds of formula III, giving cephalosporins of formula I with high yield and purity. Another advantage of the process of the invention lies in the fact that the reactive intermediates of formula IV can be obtained in a pure crystalline form and can be used as they are

  for reaction with the compounds of formula III.

  If necessary, the compound of formula IV can be reacted directly with the compound of formula III, without having to isolate it beforehand. Furthermore, all the operations, that is to say the preparation of the intermediates of formula IV as well as their reaction with the compounds of formula III, can be carried out at normal temperatures,

  without the need to cool.

  Furthermore, it has surprisingly been found that when an amino group is present in the heterocyclic residue of these thioesters, the thioesters are not self-reactive. The protection of this amino group before the subsequent reaction with the compound of formula III is therefore not necessary. It goes without saying that the amino group can nevertheless be protected if such protection proves necessary for any reason. In the compound of formula IV, the nature of the residue -C Het or of the residue S -N Het is not decisive, the preferred compounds being determined by factors such as the ease of

  training and availability of starting materials.

  However, such a residue preferably means a

  2-pyridyl or especially 2-benzothiazolyl group.

  It can however also mean a pyri-

midinyle, triazolyle or thiazolyle.

  The preferred compounds of formula IV are those corresponding to formula IVb R'-CH2-CO-S-C Het (IVb) in which / Ri and - C Het, Ret

  have the meanings given above.

  The compounds of formula IV can be prepared by reaction of a compound of formula V

R '- CH2 - COOH (V)

  in which R has the meaning given above, with a compound of formula VI M Het C-S-S-C Hets (VI) NN 'in which the two residues - C Het, are identical and have the meanings given above. This reaction is preferably carried out

  in the presence of a tri (lower alkyl) - or tri (aryl) -

  phosphine or of a tri- (lower alkyl) or triaryl phosphite, especially triphenylphosphine, and at a temperature between 30 and +50 C, especially between -20 and +250 C, advantageously between 0 and +25 C. The the reaction is suitably carried out in an inert organic solvent free of hydroxy groups, for example a chlorinated hydrocarbon such as dichloromethane. When it is desired to prepare a compound of formula IV in which R 'signifies a heterocyclic residue substituted with a protected amino group, the protecting group for the amino group can be introduced

before or after the reaction.

  The compounds of formula I are valuable antibiotics. They exert an anti-bacterial activity as emerges in vitro from serial dilution tests at a concentration of for example between 0.01 and 50 pg / ml, and in vivo from tests in mice after administration at doses of for example between 0.1 l and 100 mg / kg, against a wide variety of strains such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, E. coli, Proteus vulgaris,

  Proteus mirabilis, Proteus morganii, Shigella dysen-

  teria, Shigella sonnei, Shigella flexneri, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella pneumoniae, Serrata marcescens, Salmonella Heidelberg, Salmonella typhimurium, Salmonella enteritidis and Neisseria gonorrhoae. The compounds are therefore useful as antibiotics with anti-bacterial activity. For this use, the dose to be administered will depend on the compound used, the mode of administration and the

  desired treatment. However, satisfactory results

  sants are generally obtained when the compounds are administered at a daily dose of between 1 and 6 g, advantageously in divided doses two to four times a day in the form of unit doses each containing from approximately 0.25 to approximately 3 g of

  active substance, or in a pro-release form

  longed. The compounds of formula I, in which R3 signifies a COOH group, can be administered

  in the form of free acids or in the form of physiological salts

  logically acceptable, these salts having the same order of activity as the free acids. Suitable salts include the alkali metal and alkaline earth metal salts, particularly the alkali metals such as sodium salts. The compounds can be

  associated with pharmaceutical diluents and conventional vehicles

  ceutically acceptable and possibly other excipients; they can be administered as

  capsules or injections.

  The following examples illustrate the present invention without in any way limiting its scope In these examples, all the temperatures are indicated

in degrees Celsius.

Example 1

  Sodium salt of acid 7- (2Z-thi'nylacetamido) -cepha-

  losporanic (cefalotin) a) S-2-benzothiazolyl 2-thienyl-tnioacetate

  To a suspension of 14.3 g of 2-thienyl acid

  acetic acid and 30 g of triphenylphosphine in 100 ml of dichloromethane, added with stirring and

  room temperature 33 g of 2,2'-dithio-bis-

  Cbenzothiazole] .After a short time, a reddish precipitate forms. The mixture is stirred for 3 hours at approximately 200. The end of the reaction

  is determined by thin layer chromatography.

  The resulting reaction mixture can be used

  directly for the next reaction. We can also

  cool the resulting reaction mixture to 0 and filter it, giving 27 g of the title compound (yield: 93%). b) Sodium salt of 7-j2-thienylacetamidolceeaha acid: leseerani-gu

  To a suspension of 22 g of 7-amino acid

  cephalosporanic in 200 ml of dichloromethane, 22 g of N, Obis (trimethylsilyl) acetamide are added and the reaction mixture is heated for 2 hours to 25, which gives a clear solution. To this solution, to about 20 is added either the suspension obtained under a) above, or the isolated product.

  under a) above; the temperature increases slightly.

  The reaction mixture is then stirred for another 80 minutes at about 20 and 100 ml of acetone and 2 ml of water are added. With stirring, add

  dropwise a solution of 20 g of 2-ethyl-

  sodium hexanoate in 50 ml of acetone, which causes the title compound to precipitate in the form of easily filterable crystals. After cooling to 0, the crystals are filtered, washed with acetone and dried. This gives 31 g

  of the title compound in the pure state (yield: 91.5%).

Example 2

  Acid 7- [1- (1H) -tetrazolylacetamido) -3- [5- (2-methyl-

  1,3,4-thiadiazalyl] --3-cephem-4-carboxylic [cefazolin] a) 1: 1!) S-2-benzothiazolyl tetrazolyl-thioacetate

  12.8 g of l- (1H) - acid are suspended

  tetrazolylacetic in 120 ml of dichloromethane and 30 g of triphenylphosphine are added. With good stirring, add at a temperature included

  between 18 and 23 33 g of 2,2'-dithiobis- [benzothiazole].

  The reaction mixture is then stirred for 4 hours at about 20, which causes the formation

  a pale yellow crystalline precipitate.

  The resulting suspension can be used directly.

  ment for the next step. We can also isolate

  the title compound by cooling the suspension to 0

  resulting ion and filtering the precipitate which has formed; the precipitate is then washed with cold dichloromethane and dried under vacuum, this

  which gives 25 g of the title compound (yield = 90%).

  b) Acid 7- [1: l: l-tetrazollacetamido] -3 -: [5: 5-: 2-methyl: _ 1,3,4thiadiazolylthiom thyl]: 3: ce2heme-4-carboxy-_ ligue

  To a suspension of 27.8 g of acid 7-

  amino-3- [5- (2-methyl-1,3,4-thiadiazolyl) -thiomethyl] -

  3-cephem-4-carboxylic in 250 ml of dichloro-

  methane, 26 g of N, O-bis (trimethylsilyl) acetamide are added. The reaction mixture is stirred for

  2 hours to 25 and then added to a temperature-

  ture between 18 and 23 either the suspension obtained under a) above, or the product isolated under a) above, which causes a slightly exothermic reaction. The reaction mixture is stirred for another 120 minutes at about 20, 100 ml of methanol is added and the mixture is stirred for 5 hours at room temperature; the title compound precipitates as

  colorless crystals. The reaction mixture is maintained

  tional for 2 hours at 00, the crystals are separated by filtration and washed with cold methanol and then with acetone. After drying under vacuum, 32 g of the title compound are obtained

(yield = 87%).

Example 3

  Sodium salt of acid 7- (2-thienylacetamido) -3-

  [5- (2-methyl-1,3,4-thiadiazolyl) -thiomethyl] -3-cephème-

  4-carboxylic A suspension of 27.6 g of acid

  7-amino-3- [5- (2-methyl-1,3,4-thiadiazolyl) -thiomethyl] -

  3-cepheme-4-carboxylic in 300 ml of dichloromethane,

  26 g of N, O-bis (trimethylsilyl) acetamide are added.

  The reaction mixture is stirred for 2 hours at -30, it is cooled to 18 and then either the suspension obtained in Example 1a or the product isolated in Example 1a is added, which causes a slightly exothermic reaction. The reaction mixture is stirred for another 100 minutes at about 20 and 150 ml of acetone and 3 ml of water are added. Under

-------- - - - - - - - - __

  stirring, a solution of 20 g of 2-ethyl- is added

  sodium hexanoate in 50 ml of acetone, which precipitates the title compound. We separate the

  precipitated by filtration and washed with acetate

  tone, which gives 36 g of the title compound (yield = 93%). To purify the product, it is dissolved in ml of water, treated with activated carbon, filtered and 750 ml of ethanol are added to the pale yellow filtrate, which crystallizes the title compound in the state pure in the form of colorless needles. NMR spectra (D20): 7.3 and 7.0 (3H, 2m; thienyl protons); , 60 (1H, d, J = 5 Hz, C7-H); 5.02 (1H, d, J = 5 Hz, C6-H); 4, 42 and 4.00 (2H, ABq, J = 14 Hz, C3-CH2); 3.88 (2H, S, thienyl-CH2); 3.66 and 3.30 (2H, ABq, J = 18 Hz-, C2-CH2);

2.72 (3H, S, thiadiazolyl-CH3).

Example 4

  Sodium salt of acid 7- (2-thienylacetamido) -3- [5-

  (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-

4-carboxylic

  To a suspension of 26.2 g of 7-amino acid

  3-E5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-

  4-carboxylic in 300 ml of dichloromethane, 26 g of N, Obis (trimethylsilyl) acetamide are added. The reaction mixture is stirred for 2 hours at 25-30, the clear solution thus obtained is cooled to approximately 18 and either the suspension obtained is added to it

  in example la, or the isolated product in example la.

  The mixture is then stirred for 1 hour at room temperature.

  ambient rature. To the clear reddish solution thus obtained, a solution of 20 g of sodium 2-ethylhexanoate and 3 g of water in 200 ml of ethanol is added, which causes the title compound to precipitate. After filtration, washing with ethanol and drying, 33.7 g of the title compound are obtained

(yield = 88%).

  NMR spectra (D20): 7.3 and 7.0 (3H, 2m, thienyl protons); , 45 (1H, d, J = 5 Hz, C7-H); 5.02 (1H, d, J = 5 Hz, C6-H); 4.30 and 4.07 (2H, ABq, J = 14 Hz, C3-CH2); 4.00 (3H, S, N-CH3); 3.86 (2H, S, thienyl-CH2); 3.68 and 3.36 (2H, ABq, J =

18 Hz, C2-CH2).

Example 5

  Sodium salt of 7- (2-thienylacetamido) -3-methyl- acid

3-cephem-4-carboxylic

  To a suspension of 17.2 g of 7-amino acid

  3-deacetoxycephalosporanic in 250 ml of dichloro-

  methane, 26 g of N, O-bis (trimethylsilyl) acetamide are added. After stirring the mixture for 2 hours at 25-30, the resulting almost clear solution is cooled to 18 and either the suspension obtained in Example la or the compound isolated in Example la is added. The reaction mixture is stirred for 2 hours at room temperature, 100 ml of acetone and 3 g of water are added thereto and the mixture is evaporated in vacuo. The residue is taken up in 100 ml of a 1: 1 mixture of acetone and water, treated with 3 g of activated carbon and filtered. 300 ml of water and 100 ml of a 20% solution of sodium 2-ethylhexanoate in acetone are added to the filtrate, which causes the title compound to precipitate. 22 g of product are thus obtained

(yield = 76%).

  NMR spectra (D20): 7.30 and 7.00 (3H, 2m; thienyl proton); 5.56 (1H, d, J = 5 Hz, C7-H); 5.00 (1H, d, J = 5 Hz, C6-H); 3.85 (2H, S, thienyl-CH2); 3.47 and 3.10 (2H, ABq, J =

18 Hz, C1-CH2); 1.93 (3H, S, C3-CH3).

Example 6

  Sodium salt of acid 7- (2-thienylacetamido) -3-

  methoxymethyl-3-cephem-4-carboxylic Proceeding in a manner analogous to that described in example 5, but using 19.5 g of 7-amino-3methoxymethyl-3-cephem-4-carboxylic acid

  instead of 7-amino-3-deacetoxycephalospora acid

  nique, we obtain 26.5 g of the title compound under

  form of colorless crystals (yield = 83%).

  NMR spectra (D20): 7.30 and 7.00 (3H, 2m, thienyl proton); , 64 (1H, d, J = 5 Hz, C7-H); 5.10 (1H, d, J = 5Hz, C6-H); 4.25 (2H, S, C3-CH2); 3.88 (2H, S, thienyl-CH2); 3.55 and

  3.35 (2H, ABq, J = 18 Hz, C2-CH2); 3.38 (3H, S, OCH3).

1.8

Claims (8)

  1.- Process for the preparation of the compounds of formula I R1 CH2-CO-N S __ LCH2R2 ()   R3 in which R1 represents a heterocyclic residue. with 5 links containing oxygen, nitrogen and / or sulfur, said heterocyclic residue being. optionally substituted with 1S an amino group, R2 represents hydrogen, a methoxy, acetoxy or carbamoyloxy group, a residue -S-Y in which Y signifies an optionally substituted heterocyclic residue, or a pyridinium residue of formula II R4 (II)   R5 in which R4 and R5 represent, independently of one another, hydrogen, a halogen or an alkyl, hydroxy, carboxamido, alkoxycarbonyl, amino, monoalkylamino or dialkylamino group, or else R4 and R5 together signify a carbocycle with 5 or 6 links: optionally substituted and R3 represents a carboxy, carboxylate or ester of carboxylic acid, and of their pharmaceutically acceptable salts, characterized in that a compound of formula IV Ri "-CH2 - CO - S is reacted - C Het, (IV) N. and / or of formula IVa S (IVa) R "-CH2 - CO - N Het 'formulas in which R'R represents a 5-membered heterocyclic residue containing oxygen, l 'nitrogen and / or sulfur, said heterocyclic residue being optionally substituted by an amino or amino protected group, and the residues S - C Het and - N Het À' represent a 5 or 6-membered heterocyclic residue which may additionally contain of the nitrogen atom,   one or two other heteroatoms chosen from oxy-   gene, nitrogen and sulfur, and which may be substituted or condensed with an optionally substituted benzene nucleus, compound of formula III with -a R6-NH - - -S C 0 N C2-R2 R3 (1.II)   wherein R2 has the meaning given above, R6 represents hydrogen or an amino group protecting group and R represents a carboxy group, a protected carboxy group, a carboxylate group or a carboxylic acid ester group, if necessary, it is eliminated the protecting group in   the resulting product, and, if necessary,   forms a resulting compound in which R3 signifies   COOH to a salt of this compound, or vice versa.   2. A process according to claim 1 for the preparation of compounds of formula Ia R1 '-CH2-C0-NH S)   rH2R28 (Ia) R3 'in which Ri represents a 2-thienyl group or l- (1H) -tetrazolyl, R2 represents hydrogen, an acetoxy group or a residue -SY   in which Y signifies a 2-methyl-1,3,4- group   thiadiazole-5-yle or 1-methyl-1H-tetrazole-5-yl, and R% represents a carboxy or carboxylate group,   and their pharmaceutically acceptable salts.   3.- A process according to claim 1, characterized in that / "- C Het, signifies a 2-benzothiazolyl group in the compound of formula IV.   4.- Process for the preparation of a compound of formula IV specified in claim 1, characterized in that a compound of formula V is reacted R "- CH2 COOH (V)   in which R'1 has the meaning given in claim 1, with a compound of formula VI \ HetC - S - S - C Het (VI)   in which the two -C Het remains are identical NOT-"   ticks and the meanings given to the claim tion 1.   5.- The compounds of formula IV specified in claim 1.   6.- The compounds of formula IVb RI '- CH2 - CO - S - C Het' (IVb) N "'in which Ri represents a 2-thienyl group or l- (1H) -tetrazolyl and / - C Heta. NOT   has the meaning given to claim 1.   7.- The 2-thienylthioacetate of S-2-benzo-   thiazolyl. 8.- S-2-Benzothiazolyl 1- (1H) -tetrazolylthioacetate.