IE42404B1 - Process for preparing esters of 7-aminocephalosporanic acid derivatives - Google Patents

Abstract

The use of an iodolactone as esterifying agent in the preparation of lactonyl esters of cephalosporins has the consequence that the tendency of double bonds to migrate during the esterification reaction is markedly reduced.

Description

This invention relates to an improved process for the preparation of certain esters of 7-aminocephalosporanic acid and derivatives. Patent Specification No. 37757 discloses, inter alia a process for the preparation of a class of compounds of formula (I): wherein X and Y are the same or different and each represents oxygen or sulphur; Z represents a straight or branched, saturated or unsaturated divalent hydrocarbon radical having from 1 to 7 carbon atoms in which two adjacent carbon atoms are joined in a carbocyclic ring system which may carry one or more substituents; 43404 - 3 R represents hydrogen or an alkyl, alkenyl, alkynyl, aryl or aralkyl group, or a functional substituent; B represents hydrogen or an acetoxy group; and is an organic acylamino group, a group of formula (II): CH-C (II) NH >N— XCZ / \ CH3 ch3 or a group of formula (III): N-CH=N(III) 3 wherein R and R each represent a C, _ alkyl group, or 3 χ_' R and R taken together with the nitrogen to which they are attached form a monocyclic ring; which process comprises reacting a compound of formula (IV): 43404 or a reactive esterifying derivative thereof, with a compound of formula (V): R HO - C-2 I I (v) X-c Y or a reactive esterifying derivative thereof.

Although such a process, being a conventional esterification process, is simple and efficient, it does suffer from the disadvantage that migration of the double bond occurs during the reaction to a marked extent to produce a proportion of anti-baeterially inactive 2-cephem. Reactive esterifying derivatives of the compound (V) which are known from other cephalosporin esterification procedures to reduce this migration to a minimum include diazo derivatives and the reactive intermediate formed on reaction in situ with a carbodi-imide. However, neither of these procedures may be satisfactorily applied to the case of the particular class of esters described above.

We have now found that the double bond migration during the esterification process can be substantially 43404 - 5 reduced by employing, as the reactive esterifying derivative of the compound (V), the corresponding iodide.

Accordingly, the present invention provides a process for the preparation of a compound of formula (IA), wherein X and Y are as defined with respect to formula I above; Z is a 1,2-phenylene group which may carry one or more substituents selected from nitro, alkoxy, and halogen; R is hydrogen or an alkyl, alkenyl, alkynyl, aryl or aralkyl group; A is hydrogen acetoxy, carbanoyloxy, or a group S-Het wherein Het represents 1,2,3-triazolyl, 1,2,4triazolyl, tetrazolyl, oxazolyl, triazolyl, 1,3,4-oxadiazolyl,.1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl any of which may be substituted with C^g alkyl, C-^g alkenyl, C1_g alkoxy, hydroxyalkyl, alkenoxyalkyl, carboxyalkyl, trifluoromethyl, hydroxy or halogen; and is an amino or acylamino group, or a group of formula II or III as defined with respect to formula I, which process comprises reacting a compound of formula (IVA) or a reactive esterifying derivative thereof with a compound of formula (VA). ,1 S R‘ L CII2A C-OH (IVA) (VA) wherein A, R, R', X, Y and Z are as defined with respect to formula (IA) above. Suitable examples of the groups R, X, Y and Z are disclosed in Patent Specification No. 37757.

Preferably A is Z-methyl-l,3,4-thiadiazolyl-5-thio, 1-methyl-(IH)-tetrazoly1-5-thio, 2-methyl-l,3,4-oxadiazolyl-5-thio or (IH)-1,3,4-triazoly1-5-thio.

The group R1 in formula (1Λ) has been defined as an 10 acylamino group. The vast majority of antimicrobially active ceph-3-ems which have been reported to date in the literature carry a 7-acylamino group. It has been found over the years that by varying the identity of the 7acylamino group, the spectrum and/or level of anti15 bacterial activity of any given ceph-3-em can be modified. Similarly, in the present case a very large number of 7acylamino groups can be introduced producing a range of compounds of widely differing spectra and levels of activity. In general, however, whatever the identity of the acylamino group r\ the compounds of formula (IA) possess some activity and those who are familiar with the cephalosporin art will be aware of the range of acyl groups R1 which may be introduced.

In general,therefore, R1 in formula (lA) may be any of the acylamino groups which are present in the reported 25 natural semi-synthetic penicillins and cephalosporins. - 7 Examples include acyl groups of the following general formulae (i), (ii) and (iii): (i) R2(CH2)n-CH-(CH2)m-CO-NH2 wherein R represents hydrogen or an alkyl, cycloalkyl (especially C^ to Cg cycloalkyl), cycloalkenyl (especially cyclohexenyl or cyclohexadienyl), aryl (especially phenyl or substituted phenyl e.g. £-hydroxyphenyl), heterocyclic (e.g. thienyl, pyridyl, substituted isoxazolyl such as 3-0-chlorophenyl-5-raethyl isoxazol-410 yl, sydnonyl, tetrazolyl) or -CH(NH2)CO2H group; 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 ureido, guanidino and substituted guanidino groups), a triazolyl group, a tetrazolyl group, a cyano group, or an acyloxy group (e.g. formyloxy or C^_g alkanoyloxy group); and n and m each represent 0, 1, 2 or 3. wherein p is an integer from 1 to 4 and X^ is as defined in (i) above. - 8 (iii) -C—CO—NH4 wherein R is an alkyl, aralkyl, aryl (especially phenyl or substituted phenyl group), cycloalkyl (especially a C3 to Cg cycloalkyl or substituted cycloalkyl group), cycloalkenyl (especially a cyclohexenyl or cyclohexadienyl group) or heterocyclic (especially a thienyl or 5 6 pyridyl group) group; R and R are each hydrogen or C3_g alkyl, phenyl, benzyl or phenylethyl groups; and Z is oxygen or sulphur.

Specific examples of acylamino groups which may be preeent in the compounds prepared by the process of this invention include 2-thienylacetamido, phenylacetamido, α-hydroxyphenylacetamido, a-aminophenylacetamido, 4-pyridylacetamido, a-amino-£-hydroxyphenylacetamido, 1-tetrazolylacetamido and 4-amino-4-carboxybutanamido.

By the term reactive esterifying derivative in relation to compounds (IV) above, we mean derivatives of (IV) which when reacted with, the iodo compound (VA) take part in a reaction With the consequent formation of an ester linkage; —COO R \ / C / \ X z \ X c II Y 2 4 0 4 - 9 Many methods of esterification using several different reactive esterifying derivatives are known from the literature. For example, the esterification reaction defined above may be achieved by reacting a compound (V A) with a compound of formula (IV A): C0.0(IV A) wherein R^ and A are as defined with reference to formula (lA) above under conditions which cause the elimination of the elements of compound UI with the consequent formation of the ester of formula (IA). Thus, for example, U may represent hydrogen or a saltforming ion such as sodium or potassium, or a trialkyl ammonium ion, particularly triethylammonium.

When the group in compound (IV) contains a free amino group, or when R1 is itself amino, it is preferable that the amino group should be protected prior to the esterification reaction.

Examples of protected amino groups include the + protonated amino group (NH3 ) which after the acylation reaction can be converted to a free amino group by simple neutralisation; the benzyloxycarbonylamino group or substituted benzyloxycarbonylamino groups which are subsequently converted to NH2 by catalytic hydrogenation; and various groups which after the acylation reaction regenerate the amino group on mild acid hydrolysis.

(Alkaline hydrolysis is not generally useful since hydrolysis of the ester group takes place under alkaline conditions). - 10 Examples of a protected amino group which may subsequently be converted to NH2 by mild acid hydrolysis include enamine groups of general formula (VI) or tautomeric modifications thereof, and a-hydroxyarylidene groups of general formula (VII) or tautomeric modifications thereof: R8— XN.CH.

R?_C x zl II ‘N— h ^0' (VI) (VII) In structures (VI) and (VII) the dotted lines 7 represent hydrogen bonds. Xn structure (VX) R is a lower 7 alkyl group, R is a hydrogen atom or Rg together with R completes a carbocyclic ring, and R8 is a C^_g alkyl, aryl or C-j_g alkoxy group. In structure (VII) Z1 represents the residue of a substituted or unsubstituted benzene or naphthalene ring.

An example of a protected amino which can be converted to NH2 after the esterification reaction is the azido group. In this case, the final conversion into NH2 may be brought about by either catalytic hydrogenation or electrolytic reduction.

The advantage of the process of this invention is that double bonded migration during the reaction is minimi· sed. It is likely that the speed of the reaction is an important factor in this reduced isomerisation, which may be caused by the carboxylate of the starting material.

The speed process also allows a convenient synthesis of the compounds of formula (I) wherein R^ is amino, which - 11 are often difficult to prepare by previously known methods.

The following examples illustrate the process of the invention. Xn these examples, the following abbreviations are used: Cephalothin 2-thienylacetamidocephalosporanic acid BOC t-Butyloxycarbonyl DMSO Dimethylsulphoxide Cephaloglycin D-a-aminophenylacetamidocephalosporanic acid ACA 7-aminocephalosporanic acid Example 1 Phthalidyl 2-thienylacetamidocephalosporanate Iodophthalide was prepared immediately prior to use by mixing acetonitrile solutions of sodium iodide (1.5 mmole) and bromophthalide (1.5mmole) and stirring for 3 minutes. This solution was filtered (to remove precipitated sodium bromide) into an ice cooled DMSO solution of cephalothin (lmmole), stirred 10 minutes and poured into ice water to precipitate the required ester. Yield, of crude, neutral product after work up-90%. TLC and NMR indicate >90% ceph-3-em ester, fi (CDCl^/trace DMSO)= 2.08 (d, 3H, -OCOCH3), 3.61 (broad s, 2H, C2-H), 3.88 (s, 2H, 2), 4.6-5.4 (ABg+d, 3H, -CH2O-+C6), 5.6-6.0 (m, IH, Cg) 6.9-7.4 (d, + t, 3H, thienyl aromatics), 7.5-8.2 (m, ca. 5H, phthalidyl aromatics and -OCHO-), 8.2-8.6 (2d, IH, amide N-H). „ (CHC1,) 3370, 2960, lUclX - «5 1793, 1743, 1682, 1505, 1230, 982 cm-1; (EtOH) 275 max nm (ε, 7000). - 12 Example 2 Phthalidyl N-t-Butyloxycarbonylcephaloglycinate N-t-BOC cephaloglycin (l.lmmole) in DMSO was treated with Et^N (lmmole) at room temperature and a solution- of iodophthalide (l.Smmole) in acetonitrile was filtered into this. The mixture was stirred 15 minutes at room temperature and poured into ice water to precipitate the phthalidyl ester. Yield 77%. tic and NMR indicate >90% pure ceph-3-em ester, δ (CDCl^) 1.40 (s, 9H, Bu-H) , 2.10 (d, 3H, -OCOCH3), 3.48 (broad s, 2H, C2-H), 4.6-5.6 (m, 4h, C6+-CH-0-+C ), 5.7-61 (m, 2H, C7+NHB0C), 7.2-8.2 Z (X ' "" (m, 11H, α-phenyl+phthalidyl aromatics and -0CH0-+amido NH). (CHC1,), 3400, 2960, 1792, 1693, 1495, 1230, ITIsItC ό 981 cm-±; (EtOH) 270 nm (e, 7400).

Example 3 Phthalidyl 7-aminocephalosporanate (a) Sodium 7-N-(l-methoxycarbonyl-prop-l-en-2-yl)aminocephalosporanate ACA (3.68mmole) was suspended iri dry methanol and a solution of sodium (3.68mmole) in dry methanol added dropwise. On completion of the addition, methyl acetoacetate (4mmole) was added and the solution stirred 5 hours with molecular sieve (4A), filtered and evaporated. The residue was washed with diethyl ether. Yield 69%. δ (DMSO) 2.03 (s, 6H, CH3-C=CH+-OCOCH3), 3.56 (bs, 5H, -COOCH3+C2-H) , 4.67 (s, IH, ct=CH-) , 4,7-5.3 (nt, 3H, -OCH2O-+C6), 5.5-5.9 (m, IH, C7, 9.00 (d, IH, NH), /nujol (Registered Trade Mark)/ 1762, 1665, 1620, 1280 cm · (b) Phthalidyl 7-N-(l-methoxycarbonylprop-l-en-2-yl)aminocephalosporanate The above sodium salt was esterified by the same method as Example 1 using DMSO/acetonitrile solvent at 0-5°C. Yield 83% of pure ceph-3-em ester, δ (CDC13) 2,05 - 13 (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+-CH2O-), 7.4-8.2 (m ca 5H, phthalidyl aromatics and -0CH0-), 9.30 (d, 1H, NH). v " IilclX (CHC13), 3540, 3020, 1800, 1750, 1667, 1630, 1230, 995 cm 1; λ (EtOH) 279 nm (ε, 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 - (1 - methoxycarbonylprop - 1 - en 2 - yl) - amino -3-(1- methyl - tetrazol - 5' - yl - thiomethyl) - ceph - 3 - em - 4 carboxylate Prepared similarly to Example 3(a) from 7-amino-3(l-methyl-tetrazol-5-yl-thiomethyl)-ceph-3-em-4-carboxylic acid. Yield 74%. δ (DMSO) 2.02 (s, 3H, CH3~C+CH), 3.60 (s, 3H, -COOCH3), 4.00 (s, 3H, -NCH3), 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/lH, NH), υ „ /nujol (Trade mark)/ 3300, 1757, 1650 (shoulder), 1610, 1275 cm-1. (b) Phthalidyl 7 - N - (3 - methoxycarbonylprop - 2 en - 2 - yl)amino - 3 - 1' - methyltetrazol - 5' - yl - thiomethyl) - ceph - 3 - em - 4 carboxylate Esterification was carried out as in Example 3(b) in 57% yield of pure ceph-3-em ester, δ (CDClj) 1.98 (s, 3H, CH3C+CH) , 3.68 (s, 3H, OCHj), 4.02 (d, 3H, N-CH-j) 3.3-5.0 (m, 5H, C2-H+3 -CH2S-+>C=CH-), 5.10 (d, 1H, Cg) 5.40 (q, 1H, Cy), 7.3-8.2 (m, 8H, phthalidyl aromatics and -0CH0-+impurity), 9.28 (d, 1H, NH), (CHC13) 3540, 3000, 1780, 1740, 1653, 1610, 1260, 1210, 1155, 970. λ (EtOH) 283 nm (ε, 17500). This crude product was max , _ deprotected with HCl/acetone to yield the hydrochloride of the title compound (52%). 43404 - 14 Example 5 Phthalidyl 7-(D-a-t-butyloxycarbonylaminophenylacetamido)-3-(11-methyltetrazol-5'-ylthiomethyl)ceph-3-em-4-carboxylate Esterification of the cephalosporin triethylantmonium salt was carried out similarly to example 2 in 78% yield. 5 (CDClg/trace DMSO)=1.4O 2~H), 3.90 and 3.96 (2s, 3H, N-CH3), 4.0-4.7 (m, 2H, 3-SCH2-), 4.87 (d, IB, C6) , 5.38 (d, IH, Οθ,-Η) , 5.5-5.9 (m, IB, C?) 6.04 (d, 1H, NHBOC), 7.2- 8.O(m, 10H, α-phenyl+phthalidyl aromatics and -OCHO-), 8.4-8.7 (m, IH, amide NH). (CHCl,)=3420, 3010, 1785, 1690, 1490, 1230, 1160, 997 cm . (EtOH), 268 nm HlaX (£=8,300).

Example 6 Phthalidyl 7-(D-a-t-butyloxycarbonyl aminOphenyiacetamido)-3-(2'-methyl-1',3',4'-thiadiazol5'-ylthiomethyl)ceph-3-em-4-carboxylate Esterification was carried out similarly to example 20 2 in 67.1% yield, δ (CDClg/ trace DMS0)=1.40 (s, 9H, Bull) , 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, IH, Ca), 5.5-5.9 (m, IH, C?), 6,04 (d, IB, NHBOC), 7.2- 8.0 (10H, a-phenyl+phthalidyl aromatics and -OCHO-), 8.5-8.8 (m, IH, amide NH). (CHC13)=333O, 2930, 1785, 1733, 1690, 1492, 1220, 1160, 978 cm~l. (EtOH) 274 nm (£=11300).

Example 7 Phthalidyl 7-p-nitrobenzyloxycarbonylamino 30 cephalosporanate Sodium 7-p-nitrobenzyloxycarbonylamino cephalosporanate was esterified by the method of example 1 in 48% yield, δ (CDC13)=2.O7 and 2.12 (2s, 3H, COCHj), 3.63 - 15 (broad, s, 2H, C2-H), 4.7-5.5 (m, 3H, Cg+CH2O-), 5.30 (s, 2H, N02 .5-6.0 (m, 2H, Cy+NH), 7.3-8.4 (m, 9H, aromaticst phthalidyl -0CH0-), υ v (CHClo)=3400, 1785, 1740, 1520, ITlciX o 1350, 1230, 1050, 980 cm-1.

Example 8 Phthalidyl N-(l-methoxycarbonylprop-l-en-2-yl)cephaloglycinate (a) Sodium N-(l-methoxycarbonylprop-l-en-2-yl)cephaloglycinate This was prepared by two methods: (i) Analogously to example 3(a) with cephaloglycin replacing ACA. Yield 89%. (ii) By acylation of ACA sodium salt with an activated derivative of D-α-Ν-(3-methoxycarbonylprop-2-en-2-yl)aminophenylacetic acid (see J. Med. Chem. 9 749, 1966). The aqueous solution was freeze dried-yield 50%. (b) Phthalidyl N-(l-methoxycarbonylprop-l-en-2-yl) cephaloglycinate The above sodium salt was esterified according to example 1 in 53% yield.

Example 9 Phthalidyl 7(1'-methoxycarbonylprop-11en-21-yl)aminophenylaoetamid2/-3-/l'1methyltetrazole-5''-ylthiomethyl7ceph-3-em-442404 - 16 carboxylate Sodium 7-/p-a-N-(l - methoxycarbonylprop 1' - en - 2* - yl)aminophenylacetamido7 - 3 - /P ’ methyltetrazol - 511 - ylthiomethyl/ceph - 3 - em - 4 5 carboxylate was prepared and esterified as for example 8.

Example 10 Phthalidyl 7-/^-a-N-(11-methoxycarbonylprop-11en-21-yl)aminophenylacetamidg7"3-/21'-methyl1'', 3'', 41' -thiadiazol-5'' -ylthiomethyl/ceph10 3-em-4-carboxylate Sodium 7-Zp-a-H- (1' - methoxycarbonylprop 1* - en - 2’ - yl) - aminophenylacetamido7 - 2 - /2'1 methyl - 1 ’', 3' ’, 4 - thiadiazol - 5'’ - ylthiomethyl/ ceph - 3 - em - 4 - carboxylate was prepared and esteri15 fied as for example 8.

Example 11 Phthalidyl 7-/Ff- (1'-methoxycarbonylprop-11-en2 '-yl) aming7-3-/21 '-methy1-1'' ,31',4' thiaziazol-51'-ylthiomethyl7ceph-3-em-420 carboxylate Sodium 7 - $3 ~ (1' - methoxycarbonylprop - 1' en-2' - yl)aming7 - 3 - /2'' - methyl - 1^,3^,411 thiadiazol - 5'' - ylthiomethyl7ceph - 3 - em - 4 carboxylate was prepared and esterified analogously to example 3.

Example 12 Phthalidyl 7-/N-(1'-methoxycarbonylprop-1'-en21-yl)amino7-3-carbamoyloxy-methylceph-3-em4-carboxylate Sodium 7 -/5 - (1* - methoxycarbonylprop - 1' en-2' - yl)amino/ - 3 - carbamoyloxy - methylceph 3 - em - 4 ~ carboxylate was prepared and esterified - 17 analogously to example 3.

Example 13 Phthalidyl 7-(p-nitrobenzyloxycarbonylamino)-3carbamoyloxymethylceph-3-em-4-carboxylate - (p - nitrobenzyloxycarbonylamino) - 3 - carbamoyloxymethylceph - 3 - em - 4 - carboxylic acid was esterified according to example 2.

Example 14 N-phthaloylcephalosporin C bis-phthalidyl ester N-phthaloylcephalosporin C as the di-sodium salt (5mmole) was esterified as in example 1 using iodophthalide (from 15mmole of bromophthalide). After 10 minutes the bis phthalidyl ester (2.3g) precipitated on the addition of ice-water.

Example 15 (a) Phthalidyl 7-D-a-t- butyloxycarbanylaminophenylacetamido - 3 - carbamoyloxy - methyl 3 - cephem - 4 - carboxylate A solution of 7-D-a-t-butyloxycarbonylaminophenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxyllc acid (l.Q2g., 2mmole) in dimethyl sulphoxide (16 ml) is treated with triethylamine (0.28 ml., 2mmole) and a freshly prepared solution of iodophthalide (Smmole) in acetonitrile (8 mis) is added. After 15 mins, at 20° icewater is added and the solid 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-petrol ether gives the desired ester (1.5g.). (b) Phthalidyl 7-D-a-aminophenylacetamido-3-carbamoyloxymethy1-3-cephem-4-carboxy1ate The foregoing crude ester (1.6g.). is treated with - 18 chilled trlfluoracetic acid (15 mis) over 40 mins. Evaporation and trituration with diethyl ether gives the title compound as its trifluoracetate (1.5g.). This shows one major zone on biochromatography R^=0.75 in n-Butanolethanol-water.

Claims (9)

1. CLAIMS;1. A process for the preparation of a compound of formula (IA) X-C I Y 5 wherein X and Y are the same or different and each represents oxygen or sulphur; Z represents a 1,2-phenylene group which may carry one or more substituents selected from alkoxy, 10 nitro and halogen; R represents hydrogen or an alkyl, alkenyl, alkynyl, aryl or aralkyl group; A is hydrogen, acetoxy, carbamoyloxy or a group S-Het wherein Het represents 1,2,3-triazolyl, 1,2,415 triazolyl, ΙΗ-tetrazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiaZolyl, 1,3,4-thiadiazolyl, or 1,2,4thiadiazolyl, any of which may be substituted with Cj_ 6 alkyl, Cj_ 6 alkenyl, 0 1-6 alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, trifluoromethyl, hydroxy 20 or halogen. - 20 is an amino group, an acylamino group, or a group of formula or a group of formula: \ ,z N—CH=N2 3 wherein R and R each represent a C._ 7 alkyl group, or 2. 3 . ~ R and R taken together with the nitrogen to which they are attached form a monocyclic ring; which process comprises reacting a compound of formula or a reactive esterifying derivative thereof, with a compound of formula: - 21 R I X-c-z I I X—c II Y

2. A process as claimed in claim 1 wherein Z is 1,2-phenylene.

3. A process as claimed in claim 1 or 2 wherein 5 X and Y are both oxygen.

4. A process as claimed in any one of claims 1 to 3 wherein the group R is hydrogen, methyl or phenyl.

5. A process as claimed in any one of claims 1 to 4 wherein the group A is 2-methyl-l,3,4-thiadiazolyl-510 thio, 1-methyl-(IH)-tetrazolyl-5-thio, 2-methyl-1,3,4oxadiazolyl-5-thio or (lH)-l,3,4-triazolyl-5-thio.

6. A process as claimed in any one of claims 1 to 5 wherein R^ is an acylamino group.

7. A process as claimed in claim 6 wherein R^ is 215 thienylacetamido, phenylacetamido, a-hydroxyphenylacetamido, α-aminophenylacetamido, 4-pyridylacetamido, aamino-£-hydroxyphenylacetamido, 1-tetrazolylacetamido or 4-carboxy-4-aminobutyramido.

8. A process as claimed in claim 1 substantially as 20 described in any one of Examples 1 to 15.

9. A compound of formula (IA) wherein R 1 , A, R, X, Y and Z are as defined in claim 1, whenever prepared by the process as claimed in claim 1.