NO760577L - - Google Patents

Description

"Procedure for the preparation of esters

of 7-aminocephalosporanic acid and derivatives thereof"

The invention relates to an improved process for the production of certain esters of 7-aminocephalosporanic acid and derivatives thereof. The applicant's British patent 1,377,817 discloses i.a. a process for the preparation of a class of compounds of formula (I):

where X and Y are the same or different and each represents oxygen or sulfur;

Z represents the residue of a lactone, thiolactone or dithiolactone ring system;

R represents hydrogen or an alkyl, alkenyl, alkynyl, aryl or aralkyl group or a functional substituentj

B represents hydrogen, an acetoxy group or a pyridinium group; and

R"<*>" is an organic acylamino group, a group of formula (II):

or a group of formula (III): where R 2 and R 3 each represent a lower alkyl group, or R 2 and R 3 together with the nitrogen to which they are attached form a monocyclic ring; and the method comprises reacting a compound of formula (IV)s or a reactive esterification derivative thereof, with a compound of formula (V):

or a reactive esterification derivative thereof.

Although such a method, which is a conventional esterification process, is simple and effective, it suffers from the shortcoming that migration of the double bond takes place during the reaction to a considerable extent and yields a certain proportion of antibacterially inactive 2-cephem. Reactive esterification derivatives of compound (V) known from other cephalosporin esterification methods for reducing this migration to a minimum include diazo derivatives and the reactive intermediate formed by in situ reaction with a carbodiimide. However, none of these processes can be satisfactorily applied to the case of the particular class of esters described above.

The applicant has now found that the double bond migration

which takes place during the esterification process, can be substantially reduced by using as the reactive esterification derivative of compound (V) the corresponding iodide.

Accordingly, the invention provides a method

for the preparation of a compound of formula (IA), wherein X, Y, Z and R are as defined with respect to formula (I) above,

A is hydrogen, acetoxy, a carbon, nitrogen or sulfur nucleophile or carbomoyloxy, and R<*>is an amino group or a group as defined for formula I, and the process comprises reacting a compound of formula (IV) or a reactive esterification derivative hence with a compound of formula (VA)„

where R, X, Y and Z are as defined for formula (I) above.

Suitable examples of the groups R, X, Y and Z are disclosed in British patent specification 1377817.

Group A can, among other things, be a strong carbon, nitrogen or sulfur nucleophile. Such nucleophiles displace the acetoxy group from the nucleus of 7-aitiinocephalosporanic acid, and such displacement has been observed in various pyridines (Hale et al., Biochem J. 7jJ, 403 (1961) and Spencer et al., J. Org . Chem. (USA) 32 500, (1967))" other aromatic heterocycles (Hale et al., lo. eit; Kariyone et al., J. Antibiotics, 23, 131 (1970)} and Spencer et al. ., loe. eit.); Xanthates and dithiocarbamates,

Van Heyningen ifi.fl. J. Chem. Soc. (London) 5015 (1965)) and anilines (Bradshawm.fi., J. Chem. Soc. (London) 801 (1968)).

The group A can advantageously be a group of formula

where "Het" is a 5- or 6-membered heterocyclic ring containing 1-4 atoms selected from N, 0 and S unsubstituted or substituted with one or two groups selected from lower alkyl, lower alkenyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, trifluoromethyl, hydroxy or halogen.

Examples of the group "Het" include unsubstituted and substituted 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1, 3,4-thiadiazolyl or 1,2,4-thiadiazolyl.

A is preferably 2-methyl-1,3,4-thiadiazolyl-5-thio, 1-methyl-(1H)-1,2,3,4-tetrazolyl-5-thio, 2-methyl-1,3^5 -oxadiazolyl-5-thio or (1H)-1,3,4-triazolyl-5-thio.

The group R<*>" in formula (IA) is defined as an organic acylamino group. The great majority of antimicrobial active cef-3-em compounds that have been reported up to today in the literature carry a 7-acylamino group. It has in over the years it has been shown that by varying the identity of the 7-acylamino group the spectrum and/or level of antibacterial activity of any given cef-3-em compound can be modified.Also in the present case a very large number of 7-acylamino groups can be introduced which produce a range of compounds with widely differing spectra and levels of activity In general, however, whatever the identity of the acylamino group R<*>'s, the compounds of formula (IA) possess some activity, and those familiar with cephalosporin chemistry ,

will be aware of the range of acyl groups R1 that can be introduced.

In general, therefore, R1 in formula (IA) can be any of the organic acylamino groups present in the described natural and semi-synthetic penicillins and cephalosporins.

Examples include acyl groups of the following general formulas (i), (ii) and (iii)s

where R 2 represents hydrogen or alkyl, cycloalkyl

(especially Cg-Cg cycloalkyl), cycloalkenyl (especially cyclohexenyl or cyclohexadienyl), aryl (especially phenyl or substituted phenyl, e.g. p-hydroxyphenyl), heterocyclic (e.g. thienyl, pyridyl, substituted isoxazolyl, e.g. .

3-0-chlorophenyl-5-methyl-isoxazol-4-yl, sydnonyl, tetrazolyl),

-CH(NH 2 )CO 2 H; X1 represents hydrogen/ a hydroxyl group,

a halogen atom (especially chlorine), a carboxylic acid group or carboxylic acid ester group (e.g. a phenyl or indanyl ester), an azido group, an amino group or substituted amino group

(including ureido, substituted ujreido, guanidino and substituted guanidino groups), a triazolyl group, a tetrazolyl group, a cyano group, an acyloxy group (eg formyloxy or lower alkanoyloxy group) or an esterified hydroxy group; and n and m each separately represent 0, 1, 2 or 3.

where n is an integer from 1 - 4, and X<1> is as defined for (i) above.

4

where R is an alkyl, aralkyl, aryl (especially phenyl or

substituted phenyl group), cycloalkyl-(especially a C-^-C8 cycloalkyl- or substituted cycloalkyl group), cycloalkenyl-(especially a cyclohexenyl or cyclohexadienyl group)

or a heterocyclic group (especially a thienyl or pyridyl group); R^ and R^ are each hydrogen lower alkyl, phenyl, benzyl or phanylethyl groups; and Z is oxygen or sulfur.

Specific examples of organic acylamino groups R^" which may be present in the compounds produced by the method according to the invention include 2-thienylacetamido, phenylacetamido, 2-hydroxyphenylacetamido, 2-aminophenylacetamido, 4-pyridylacetamido, 2-amino-p-hydroxyphenylacetamido and 1-tetrazolylacetamido and co-aminodip-amido.

The term "reactive esterification derivative" in relation to the compounds (IV) above means derivatives of (IV) which, when reacted with the iodine compound (VA), participate in a reaction with subsequent formation of an ester bond:

Many methods of esterification in use

of various reactive esterification derivs. is known from the literature. For example, the esterification reaction defined above can be achieved by reacting a compound (VA)

with a compound of formula (IVA):

where R<1> and A are as defined for formula (IA) above, under conditions which effect removal of the elements of compound Ul with subsequent formation of the ester of formula (IA). Thus, e.g. U represent hydrogen or a salt-forming ion,

e.g. sodium or potassium, or a trialkylammonium ion, especially triethylammonium.

When the group R<1> in compound (IV) contains a free amino group, or when R"<*>" is itself amino, it is preferred that the amino group is protected before the esterification reaction.

Examples of protected amino groups include the protonated amino group (NH^4") which after the acylation reaction can be converted into a free amino group by simple neutralization; the benzyloxycarbonylamino group or the substituted benzyloxycarbonylamino groups which are afterwards converted into NH2 by catalytic hydrogenation; and various groups which after the acylation reaction regenerate the amino group by mild acid hydrolysis.

(Alkaline hydrolysis is not usually applicable, as hydrolysis of the ester group takes place under alkaline conditions).

Examples of a protected amino group which can subsequently be converted to NH2 by mild acid hydrolysis include enamine groups of the general formula (VI) or tautomeric modifications thereof, and α-hydroxyarylidene groups of the general formula (VII) or tautomeric modifications thereof:

In the structural formulas (VI) and (VII), the dashed lines represent hydrogen bonds. In the structural formula (VI)

7 8

is R a lower alkyl group, R is either a hydrogen atom or together with R<7> forms a carbocyclic ring, and R<9> is a lower alkyl, aryl or lower alkoxy group. In structural formula (VII), Z 1 represents the residue of a substituted or unsubstituted benzene or naphthalene ring.

An example of "protected amino" that can be converted to NH2 after the esterification reaction is the azido group. In this case, the final conversion to NH 2 can be accomplished by either catalytic hydrogenation or electrolytic reduction.

The advantage of the method according to the invention is that double bond migration during the reaction is reduced to a minimum. It is likely that the rate of reaction is an important factor in this reduced isomerization, which may be caused by the carboxylate of the starting material.

The speed of the process also allows a convenient synthesis of the compounds of formula (I) where R 1 is amino, which is often difficult to prepare by previously known methods.

The following examples illustrate the method according to the invention. In these examples, the following abbreviations are used;

Cephalothin : 2-thienylacetamidocephalosporanic acid

BOC : t-butyloxycarbonyl

DMSO: dimethyl sulfoxide

Cephaloglycin : D-ct-aminophenylacetamidocephalosporanic acid ACA : 7-aminocephalosporanic acid

Example 1

Phthalidyl- 2- thienylacetamidocephalosporanate

Iodophthalide was prepared immediately before use by mixing acetonitrile solutions of sodium iodide (1.5 mmol)

and bromophthalide (1.5 mmol) and stirring for 3 minutes. This solution was filtered (to remove precipitated sodium bromide) into an ice-cold DMSO solution of cephalothin (1 mmol), stirred for 10 minutes and poured into ice water to precipitate the desired ester. The yield of crude, neutral product after work-up: 90%.

TLC and NMR indicate >90% cef-3-em ester. 6 (CDCl3/trace DMSO) = 2.08 (d, 3H, -OCCH3), 3.61 (broad s, 2H, C2-H), 3.88 (s, 2H, a-CH2), 4.6-5 ,4 (ABq + d, 3H,"CH20- + C6), 5.6 - 6.0 (m, 1H, C?) 6.9 - 7.4 (d, + t, 3H, thienyl aromatics), 7.5 -8.2 (m, ca. 5H, phthalidyl aromatics and -0CH0-), 8.2 - 8.6 (2d, 1H, amide-NH),<V>max <CHC13> 3370'2960, 1793, 1743, 1682, 1505, 1230, 982 cm"<1>»<X>max <Et0H) 275 n" 1 <e 7000).

Example 2

Phthalidy1- N- t- butyloxycarbonyl& ce phaloglycinate

N-t-BOC-cephaloglycine (1.1 mmol) in DMSO was treated with Et^N (1 mmol) at room temperature, and a solution of iodophthalide

(1.5 mmol) in acetonitrile was filtered into this. The mixture was stirred for 15 minutes at room temperature and poured into ice water

for precipitation of the phthalidyl ester. Yield 77%. TLC and NMR indicate >90% cef-3-em ester. 6 (CDClg) 1.40 (s, 9H, Bu-H), 2.10 (d, 3H, -OCCH3), 3.48 (broad s, 2H, C2-H), 4.6-5.6 (m, 4H, C6 + -CH2O- + Ca), 5.7 - 6.1 (m, 2H, C7 + NHBOC), 7.2 - 8.2

(m, 11H, a-phenyl + phthalidyl aromatics and -0CH0- + amido-NH).<V>max (CHC13), 3400, 2960, 1792, 1693, 1495, 1230, 981 cm"<1>?Amax (EtOH) 270 nm <e 74°°).

Example 3

Phthalidyl-7-aminocephalosporanate

(a) Sodium 7-N-(3- methoxycarbonyl- prop- 2- en- 2- yl)- aminocephalosporanate

ACA (3.68 mmol) was suspended in dry methanol, and a solution of sodium (13.68 mmol) in dry methanol was added dropwise. On completion of the addition, methyl acetoacetate (4 mmol) was added and the solution stirred for 5 hours with a molecular sieve (4A), filtered and evaporated. The evaporation residue was ether-washed. Yield 69%. 6 (DMSO) 2.03 (s, 6H, CH3-C=CH + -OCOCHg), 3.56 (bs, 5H, -C00CH3+ C2 -H), 4.67 (s, 1H, a=CH-) , 4.7 - 5.3.

(m, 3H, -0CH20- + C6), 5.5 - 5.9 (m, 1H, C7, 9.00 (d, 1H, NH) ,<V>max <nu3ol> 1762'1665'1620, 1280 cm"<1>.

(*>) Phthalidyl- 7- N - ( 3- methoxycarbonylprop- 2- en- 2- yl) amino-cephalosporanate

The above sodium salt was esterified by the same method as in Example 1 using DMSO/acetonitrile solvent at 0-5°C. Yield 83% of pure cef-3-em ester. 6 (CDCl 3 ) 2.05 (s, 3H, -0C0CH3), 3.2 - 4.0 (s at 3.68 + m,

5H, 0CH3+ C2-H), 4.6 - 5.8 (m, 5H >C=CH- + C6 + C7'* -CH20-), 7.4-8.2 (m approx. 5H, phthalidyl- aromatics and -0CH0-), 9.30 (d, 1H, NH). V k (CHC13), 3540, 3020, 1800, 1750, 1667, 1630, 1230, 995 cm in *max (EtOH) 279 nm (e 14800). The above crude product was deprotected (HCl/acetone) to form ACA phthalidyl ester in 70% yield. Impurities in the N-protected compound were washed out after deprotection.

Example 4

(a) Sodium- 7- N-(3- methoxycarbonylprop- 2-en- 2- yl)-amino-3-( 1-methyl- tetrazol- 5'- yl- thiomethyl)- cef- 3- em- 4- carboxylate Prepared in the same way as in example 3(a) from tetrazole ACA. Yield 74%. 6 (DMSO) 2.02 (s, 3H, CH3-C + CH), 3.60 (s, 3H, -C00CH3), 4.00 (s, 3H, -NCH-j) , 3.2 - 4 .9 (m, 4H,

C2-H + CH2S), 4.68 (s, 1H, C=CH), 5.16 (d, 1H, C6, 5.4 - 5.8

(m, 1H, C7), 9.01 (d, 1H, NH), Vmakg (nujol) 3300, 1757, 1650 (shoulder), 1610, 1275 cm"<1>.

(b) Phthalidyl-7-N-(3-methoxycarbonylprop-2-en-2-yl)amino-3-1'-methyltetrazol-51-yl-thiomethyl)-cef-3-em-4-carboxylate Esterification was carried out as indicated in Example 3(b) i

57% yield of pure cef-3-em ester. 6 (CDCl1) 1.98 (s, 3H,

CH3-C + CH), 3.68 (s, 3H, 0CH_3) , 4.02 (d, 3H, N-CH_3) 3.3 - 5.0

(m, 5H, C2-H + 3 -CH2- + >OCH-) , 5.10 (d, 1H, Cg) 5.40

(q, 1H, C?), 7.3 - 8.2 (m, 8H, phthalidyl-aromfcfcfee and -0CH0- + impurity), 9.28 (d, 1H,NH), vmakg (CHC13) 3540, 3000 , 1780,

1740, 1653, 1610, 1260, 1210, 1155, 970. *max (EtOH) 283 nm (e 17500). This crude product was deprotected with HCl/acetone to give tetrazole-ACA-phthalidyl ester hydrochloride (52%).

Example 5

Phthalidyl- 7- ( D- a- t-- butyloxycarbonylaminophenylacetamido) - 3-( 11- methyl- tetrazol- 5'- yltlomethyl) °cef°3- em- 4- carboxylate

Esterification of the cephalosporin triethylammonium salt was carried out in the same way as in example 2 with 78% yield.

6 (CDCl3/sporDMSO) ■ 1.40 (s, 9H, Bu-H), 3.59 and 3.70 (2 broad s, 2H, C2-H), 3.90 and 3.96 (2s, 3H , N-CH3), 4.0 - 4.7 (m, 2H, 3-SCH2-), 4.87 (d, 1H, C6), 5.38 (d, 1H, Cot-H), 5, 5 - 5.9

(m, 1H, C7), 6.04 (d, 1H, NHBOC), 7.2 - 8.0 (m, 10H, ot-phenyl-

+ phthalidyl aromatics and -0CH0-), 8.4 - 8.7 (m, 1H, amide-NH).

<V>max (CHC13> = 3420, 3010, 1785, 1690, 1490, 1230, 1160, 977 cm"<1>.<X>max <Et0H>'268 nm <* = 8300).

Example 6

Phthalidyl-7-(D-g-t-butyloxycarbonylaminophenylacetamldo)-3-(2'-methyl-1',3',4'-thiadiazol-5'-ylthiomethyl)ceph-3-em-4-carboxylate esterification was carried out similarly to that indicated in Example 2, with 67.1% yield. 6 (CDCl 3 /trace DMSO) = 1.40

(s, 9H, Bu-H), 2.70 (s, 3H, 2'-CH3), 3.60 and 3.67 (2 broad s,

2H, C2-H), 3.9 - 4.8 (m, 2H, 3-SCH2~), 4.85 (d, 1H, Cg) 5.40

(d, 1H, Ca), 5.5 - 5.9 (m, 1H, C?), 6.04 (d, 1H, NHBOC),

7.2 - 8.0 (10H, α-phenyl + phthalidyl aromatics and -OCH0-), 8.5 - 8.8 (m, 1H, amide-NH). vmax (CHCl 3 )=3330, 2930, 1785, 1733, 1690, 1492, 1220, 1160, 978 cm"<1>.*max (EtOH) 274 nm (e = 11300).

Example 7

Phthalidyl- 7- p- nltrobenzyloxycarbonylamlnocephalosporanate

Sodium 7-p-nitrobenzyloxycarbonylaminocephalosporanate was esterified by the method indicated in Example 1, in 48% yield- 6 (CDCl3) = 2.07 and 2.12 (2s, 3H, COCHg), 3.63 (broad s , 2H, C2~H), 4.7 - 5.5 (m, 3H, Cg + CH2O-), 5.30 (s, 2 H,

5.5 - 6.0 (m, 2H, C? + NH), 7.3 - 8.4 (m, 9H,

aromatics + phthalidyl -OCHO-), v . (CHC1-) = 3400, 1785, 1740, 1520, 1350, 1230, 1050, 980 cm .

Example 8

Phthalidyl- N - ( 3- methoxycarbonylpropyl- 2- en- 2- yl) cephaloglycinate

(a) Sodium N-(3-methoxycarbonylpropyl-2-en-2-yl) cephaloglycinate This was prepared by two methods: (I) Analogous to Example 3(a) with cephaloglycin as a substitute for ACA. Yield 89%.. (II) By acylation of ACA sodium salt with an activated derivative of D-a-N-(3-methoxycarbonylprop-2-en-2-yl)-aminophenylacetic acid (see J. Med. Chem. 9_, 749, 1966) . The aqueous solution was freeze-dried, with a yield of 50%. (b) Phthalidyl-N-(3-methoxycarbonylpropyl-2-en-2-yl)cephaloglycinate The above sodium salt was esterified as indicated in Example 1 in 53% yield.

Example 9

Phthalyldyl-7-[D-a-N-(3'-methoxycarbonylprop-2'-en-2 1-yl)-aminophenylacetamido3-3-| ?1"- methyltetrazol- 5"- ylthiomethyl] cef- 3- em- 4- carboxylate

Sodium 7-[D-α-N-(3•-methoxycarbonylprop-2*-en-2'-yl)-aminophenylacetamido]-3-[1"-methyltetrazol-5"-ylthiomethyl]cef-3-em-4-carboxylate was prepared and esterified as indicated in Example 8.

Example 10

Phthalidyl- 7-[ D- a- N-( 31- methoxycarbonylprop- 2'- en- 2'- yl) aminophenylacetamido3- 3-[ 2"- methyl- 1", 3", 4"- thiadiazole- 5"- ylthiomethyl] cef-3-em-4-carboxylate

Sodium 7-1D-α-N-(3*-methoxycarbonylprop-2'-ery-2'-yl)-aminophenylacetamido]-2-[2"-methyl-1",3",4"-thiadiazole-5"- ylthiomethyl]cef-3-em-4-carboxylate was prepared and esterified as indicated in Example 8.

Example 11

Phthalyldyl- 7-[ N-( 3'- methoxycarbonylpropyl- 2'- en- 2'- yl) amino3- 3-[ 2"- methyl- 1"/ 3'\ 4"- tladia2ol- 5"- ylthiomethyl] cef - 3- em- 4- carboxylate Sodium 7-[N-(3'-methoxycarbonylprop-2'-yl)amino]-3-[2"-methyl-1",3<H>/4"-thiadiazole- 5,,-ylthiomethyl]cef-2-em-4-carboxylate was prepared and esterified analogously to example 3.

Example 12

Phthalidyl- 7-[ N-(3'- methoxycarbonylprop- 2'- en- 2'- yl) amino]- 3-carbamoyloxy- methylcef- 3- en°4- carboxylate

Sodium 7-[N-(3'-methoxycarbonylprop-2'-yl)amino]-3-carbamoyloxy-methylcef-3-em-4-carboxylate was prepared and esterified analogously to Example 3.

Example 13

Phthalidyl- 7-( p- nitrobenzyloxycarbonylamino)- 3- carbamoyloxy-methylcef- 3- em- 4- carboxylate

7-(p-nitrobenzyloxycarbonylamino)-3-fearbamoyloxymethyl-cef-3-em-4-carboxylic acid was esterified as indicated in Example 2.

Example 14

N- phthaloylcephalosporin- C- bis- phthalidyl ester

N-phthaloylcephalosporin C in the form of the disodium salt

(5 mmol) was esterified as indicated in Example 1 using iodophthalide (from 15 mmol of bromophthalide). After 10 minutes, the bis-phthalidyl ester (2.3 g) precipitated on addition of ice water.

Example 15

(a) Phthalidyl- 7- D- a- t- butyloxycarbonylaminophenylacetamido-3- carbamoyloxy- methyl- 3- cephem- 4- carboxylate

A solution of 7-D-α-t-butyloxycarbonylaminophenyl-acetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.02 g,

2 mmol) in dimethyl sulfoxide (16 mL) is treated with triethylamine (0.28 mL, 2 mmol), and a freshly prepared solution of iodophthalide (3 mmol)

in acetonitrile (8 ml) is added. After 15 minutes at 20°, ice water is added, and the solid is collected. A solution of the latter in ethyl acetate is washed with dilute sodium bicarbonate, water, dried and evaporated. Precipitation of the residue from ethyl acetate/petroleum ether gives the desired ester (1.5 g).

(b) Phthalidyl- 7- D- a- amlnophenylacetamido- 3- carbamoyloxy- methyl-3- cephem- 4- carboxylate

The crude ester described above (1.6 g) is treated with 15 ml of cooled trifluoroacetic acid for 40 minutes. Evaporation and trituration with ether gives the title compound as its trifluoroacetate (1.5 g). This shows one main zone by bio-chromatography, R^=0.75 in n-butanol/ethanol/water.

Claims (2)

1. Method of making a compound of formula (IA) where X and Y are the same or different and each represents oxygen or sulfur; Z represents the residue of a lactone, thiolactone or dithiolactone ring systemj R represents hydrogen or an alkyl, alkenyl, alkynyl, aryl or aralkyl group or a functional substituent; A is hydrogen, acetoxy, a carbon, nitrogen or sulfur nucleophile or carbamoyloxy; R 1 is an amino group, an organic acylamino group or a group of formula or a group of formula: where R 2 and R 3 each represent a lower alkyl group, or 2 3 R and R together with the nitrogen to which they are attached form a monocyclic ring; characterized by turnover of a compound of formula or a reactive esterification derivative thereof, with a compound of formula 2. Method as set forth in claim 1, characterized in that Z is 1,2-phenylene which can carry one or more substituents selected from alkoxy, nitro or halogen. 3. Procedure as stated in claim 2, characterized in that Z is 1,2-phenylene. 4o Process as stated in any of claims 1-3, characterized in that X and Y are both oxygen" 5. Method as stated in any of claims 1-4, characterized in that the group R is hydrogen, methyl or phenyl. 6. Method as stated in any of claims 1-5, characterized in that the group A is hydrogen, acetoxy, carbamoyloxy or a group - S - Hot, where "Het" is a 5- or 6-membered heterocyclic ring containing 1-4 atoms selected from N, 0 and S which is unsubstituted or substituted with one or two groups selected from lower alkyl, lower alkenyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, trifluoromethyl, hydroxy or halogen. 7. Procedure as specified in claim 6, characterized in that the group A is 2-methyl-1,3,4-thiadiazolyl-5-thio, 1-methyl-(1H)-*1,2,3,4-tetrazolyl-5-thio, 2-methyl-1 ,3,4-oxadiazolyl-5-thio or (1H)-1,3,4-triazolyl-5-thio. 8. Method as stated in any one of claims 1-7, characterized in that R1 is an organic acylamino group. 9o Procedure as stated in claim 8, characterized in that R1 is 2-thienylacetamido, phenylacetamido, 2-hydroxyphenylacetamido, 2-aminophenylacetamido, 4-pyridylacetamido, 2-amino-p-hydroxyphenylacetamido-1-tetrazolylacetamido or "staminoadipamido.