IE58403B1 - Intermediates useful for preparing antibacterial agents - Google Patents

Abstract

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(substituted)-iminoacetamido]-3 -[3-(quaternaryammonio)-1 - propen-1-yl]-3-cephem-4-carboxylates of the formula in which R<1> and R<2> are as defined herein and is a quaternary ammonio group as defined herein, and salts, solvates, hydrates and esters thereof, are potent antibacterial agents. Processes for their preparation and intermediates in such processes are described.

Description

2 This application relates to intermediates forpreparing antibacterial agents, and has been dividedout from Patent Specification iio. :36,.6-/ , referred to below as our "primary" Application, Our primary Application has described and claimed 7-(2-( 5-amino-l e, 2,, 4~fchiadiazoi~3~yl)-2- (substituted) iminoa'cet amido 1-3-( 3-(quaternaryammonio)-1-propen-l-yl ]-3-cephesn-4-carboxylates of the formula 10 1 9 m which H* and R are as defined ammonio group as defined „ and It also dealt with the compounds of Formula I# and is a quaternary salts and esters thereof,processes for the preparation ofpharmaceutical compositions containing at least one compound of Formula I, and intermediates15 in their preparation. A) U.S. Patent 4,390,534, issued June 23f 19Q3 to TsutomuTeraji et a 1., discloses cepheni and cepham compounds of the formula 1 2 5 wherein S is amino or protected Anino,· R is hydrogen, acyl,, optionally substituted aryl, substituted alkyl,, alkenyl, alkynyl, I· 4 \ I «u&mt&cuted «$*&<»· 1 Kyi * cycloalkenyl or mn O- or S"Ce»t»-iis3teg SrWMdbered hmrterocyclic ring substituted with oxo3 4 gr»up S «-* J protected carboxy? provided that R is COO when R is optionallysubstituted pyridinioalfcyl &ε optionally substituted thiazolioalkylsand the dashed line indicates either a single or double bond. 10 European Patent Application Mo. 13*762* published August 6f 1980 is concordant thereto and has a similar disclosure. O.S. Patents 4*381*299' (issued April 26* 1983), 4*331*665 (issued Way 25* 1982) and 4*332*798 (issued June 1* 1982) each issued on parent applications of O.S. 4*390*534* and have similar 15 disclosures. B) European Patent Application No. 62*321* published October 13* 1982* discloses cephem compounds of the formula i 2 wherein is amino or protected amino; R is an optionally 20 substituted lower aliphatic hydrocarbon group* or cycloalkenyl; and the group of the formula is «a optionally substituted heterocyclic cation group containingmore than one nitrogen atom? and pharmaceutically acceptablesalts thereof. Also disclosed are intermediates of the formula 12 4 5 wherein R and R are as defined above, R' is a protected carboxyl group and x" is an acid residue. C) European Patent Application No. 74,653» published March 23» 1983» discloses cephem compounds of the formula lO wherein R1 is amino or protected amino; R~ is an optionally substituted lower aliphatic hydrocarbon group, cyclo(lowerJalkyi or cycloilower)alkenyl; R3 is (lower )alkylamino, N-protected(lower )alkylamino, di (lowerJalkylamino, sulfo(lower )alkylamino, hydroxy(lower )~ 15 alkylamino, N-protected hydroxy(lower Jalkylamino, acyloxy(lower)- alkyl, (lower)alkoxy(lower )alkoxy (lower )alkyl, di(lower)alkylamino-(lower)alkyl, (lower)alkylthio(lower )alkyl, (lower)alkylthio, (lewex^al'leceey, (leaver 3*l1ctuey( lover lalfcoxy, feydroxydower lalisoxy# acylOowerJalfcyl, -bydxpxy-tlower )alfcyltbio, di {lower Salkylamino- alfcylthio, R-conteiniag ussaterated S-asesberedlheterocyclic gr©op, R-containing ub,saturated 5-»etab ered 5 heterocyclicthio, or S-ccataising unsaturated S or e-saesaberedfeeterocyclicthioClower>alkyl which »ay .be substituted withsuitable substituent(,s >; and R* is hydrogen or (lowerJalfeyl; or a salt thereof- D) O.S. Patent 4,332,800, isstfed June 1, 1982 to Tsutomu Teraj 10 et »1., discloses inter alia .compounds of the formula 1 ?wherein R~ is amino or protected amino; R" is (lower)alkyl and Xis hydrogen or carbamoyl. E) European Patent Application No. 47,977, published March 24,15 1962, discloses cephem compounds of the formula (0) O wherein mi» G or 1; Am is optionally substituted amino;· T is athiadiazolyl moiety (attached to the other groups by two of itscarbon atoms J; R, is hydrogen# optionally substituted alkyl#cycloa.lkyl or optionally substituted carbamoyl; and R, is optionallysubstituted thiaaolio# optionally substituted pyrasolio# tridowerj-alkylammonio or a pyridinio group of the formula • in which Ra is substituted (lower )alkyl (the substituent beingcycloalkyl# phenyl# hydroxy# alkoxy# halogen# cyano# carbamoyl,carboxyl or sulfo]# (lowerJalkenyl or carboxy-substituted (lower )-alkenyl# (lower)alkylthio or carboxy-substituted (lowerJalkylthio#amino or monosubstituted amino (the substituent being (lower)alkyl#(lowerJalkanoyl or aminobenzenesftulfonyl)# di(lower)alkylamino#substituted carbamoyl (the substituent being (lover )alky 1,.hydroxy(lower )alkyl# (lower)alkoxy# hydroxy or cyano], di(lower )-alkylcarbamoyl# thiocarbamoyl# cycloalkyl# phenyl# hydroxy# (lower)alkoxy# halogen# (lower ,alkoxycarbonyl# (lowerJalkanoyloxy, (lower)alkanoyl# carboxyl# sulfo# cyano, nitro or hydroxysulfo-(lower)alky1; Rb is hydrogen or carbamoyl# or has the samemeaning as Re; and Rc is hydrogen or has the sane meaning as Ra;ano salts thereof.

Although not formally related# European Patent Application Ho. 25,017# published Hatch 11# 1981# has a similar disclosure. F) European Patent Application No. 30,630# published June 24# 1981P discloses 3-vinyl cephem compounds of the formula 8 wherein is an optionally protected amino~substituted heterocyclicgroup which may also haw® halogen, ©sc a group of the formula 3 ’ 5 in which R is (lower)alkyl; R~ is carboxy or protected carboxy;and Λ is lower alkylene which may hfve a substituent selected from amino, protected amino, hydroxy, oxo and a group of the 4 4 formula «N**OR'', wherein R is hydrogen, cyclo C lower )alkenyl, (lower )alkynyl, (lower ) alkenyl [optionally substituted by carboxy 10 or protected carboxy], (lower)alkyl (optionally substituted byone or more of carboxy, protected carboxy, amino, protectedamino, cyano, phosphono, protected phosphono and a heterocyclicgroup which itself may be substituted]; and salts thereof.

This application specifically discloses compounds of theic formula COOH 3 in which OR* 1« methoxy, carboxymethoxy, tert-butoxycarbo«yl-aethoxy or 1-tert-butoxycmrbonylethoxy. G) Θ.Κ. Patent Specification Ko. 1,399,086 published June 25,1975# contains a generic disclosure encompassing a vast number ofcephalosporins of the formula wherein R is hydrogen or an organic group, Ra is an etherifyingmonovalent organic group linked to the oxygen through a carbon atom, B, is^S or and ? is an organic group. In one 0 embodiment, P may be inter alia a vinyl group of the formula R3 / ii *a 4 | in which R and a"* independently may be hydrogen, nitrile, (lower)alkoxvcarbonyl, or substituted or unsubstituted aliphatic,cycloaliphatic, araliphatic or aromatic. However, the 5-amino- 1,2,4-thiadiazol-3-yl group is not identified as a possible R substituent and there is no disclosure or suggestion that P maybe a quaternary ammonio-substituted propenyl group. O.S. Patent 3,971,778 and its divisional Nos. 4,024,133, 4,024,137, 4,064,346,4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have 20 similar disclosures. H) .European Patent Application So. 88,365, published September14, 1983, discloses compounds of the formula in which R~ is (unsubstituted) fehiadxazolyl; R"* is carboxy- Clover) alkyl or protected carboxy(lower)alkyl; R3 is hydrogen, 4 " halogen or (lower) alkenyl? and R" is carboxy or protected carboxy.

Although l-propenyl is listed as one of the possible meanings of 3 3 R , the application only exemplifies compounds where R "ishydrogen, chloro or vinyl. 1) D.S. Patent So, 4,307,233 issued to Daniel Farge et a.l. onDecember 22, 1981, discloses inter a 1 iat, 3-vinylcephalosporinderivatives of the formula 3 in which r inter alia may be alkyl, vinyl, cyanomethyl or a3 4 protective group such as 2-methoxyprορ-2-yl, and R and S are alkvl groups (ODtionally substituted by hydroxy, alkoxy, amino, 3 4 alkylamino or dialkylamino) or phenyl groups, or R and S", takentogether with the nitrogen to which they are attached, may form asaturated heterocyclic ring of 5 or 6 members, optionally containinganother hetero-atom selected from N, 0 and S, and optionallysubstituted by an alkyl group. The compounds are useful asintermediates in the preparation of 3-thiovinyl cephalosporinderivatives. There is no disclosure or suggestion of a 5-amino- 1 1 l,2,4-thiadiazol-3-yl moiety in -place of the 2-a»inothia2ol-4-ylsubstituent ox &S a «guaternety •maonio-subetituted propenylmoiety for the 3«substituent. Published Onited Xincdoa PatentApplication So. 2,051,062 is concordant thereto and has a similar disclosure. J} Suropean Patent Application No. 53,537, published June 9,1982, discloses, iat.er 3-vinylcephalosporin derivatives of the formula 0 in which R® and R^ are the same or different and are hydrogen or alkyl, or taken together, form an alkylene group containing 2 or3 carbon atoms, Rg is an acid protecting group, St, is an acidprotecting group such as an ester, ar© the same or different and are hydrogen, alkyl (optionally substituted by .5 hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R^ and R^, taken together with the nitrogen to whichthey ere attached, may form a saturated heterocyclic ring of 5 or6 members, optionally containing another hetero-atom selectedfrom N, O and S, and optionally substituted by an alkyl group. 20 The compounds are useful as intermediates in the preparation ox 3-thiovinyl cephalosporin derivatives. There is no disclosure orsuggestion of a 5-amino-l,2,4-thiadia2ol-3~yl moiety in place ofthe 2~aminothia2ol-4~yl substituent or of a quaternary ammonio-substituted propenyl group for the 3-substituent. U.S. 4,423,214 is concordant thereto and has a similar 25 disclosure. i 2 Κ!' European Patent Application Ko. 53„©74, published June 2»1982, generically discloses a vast number of 3~vinylcephalosporinderivatives q£ the formula wherein 3eu (in one of several embodiments) may be -C~CO- !l M. *2 OSL in which R5 inter alia may be hydrogen, alkyl, vinyl, cyanomethyl,an oxime-protecting group such as trityl, etc., or a group of theformula C-COOR 10 in which R®5 and are the same or different, and may behydrogen, alkyl or, taken together, an alkylene radical of 2 or 3 carbon atoms, and R is hydrogen or an acid-protecting radical; Se2 is hydrogen or an acid-protecting radical such as methoxymethyl; 15 R° (in one of several embodiments) may be a methyl group substitutedby a S- or 6-membered aromatic heterocyclic ring containing asingle hereto atom, such as 2- or 3-pyridyl, 2- or 3-thienyl or2- or 3-furyl; and 13 Rj is a group of the forssula R4SO2Q- in which R* may he alkyl, trihalomethyl or optionally substituted phenyl .

These compounds are stated to be intermediates in thepreparation of compounds in which the 3-substituent is a group of the formula S’ i -ca«C"SE which are stated to have antibacterial activity.

Although this patent includes the possibility of r· being amethyl group substituted by an ^-containing heterocyclic ring, inboth the intermediates and final products (thus giving a heterocyclsubstituted propenyl moiety), it teaches only that the heterocyclicring is attached via one of its carbon atoms. Thus, there is nosuggestion of a quaternary ammonio-substituted propenyl group.

The reference exemplifies R® in the intermediates and finalproducts only as methyl. Further, in both the intermediates andfinal product, the propenyl group must contain a second substituentί-O^SE or -SR, respectively). Also there is no disclosure orsuggestion of a 5-amino-l,2,4-thiadiaxol-3-yl moiety in place ofthe 2-aminofchiazol-4~yl substituent. L) European Patent Application No. 53,538, published June 9, 1982, discloses, inter a 1ia, 3-vinylcephalosporin intermediates of the formula 14 S in which n is 0 or b R is hydrogen, alkyls, vinyl, cyanosnethyl3 or an oxime-protecting group, and a is halogen. There is nodisclosure or suggestion of a 5-amino-l,2,4-thiadiazol-3~yl 5 moiety in place of the 2-aminothiazol~4-yl substituent, and nodisclosure or suggestion of a 3-halo-l-propen-l-yl substituent in the 3-position. 1 5 Complete bisclosure Our primary application relates to novel cephalosporin derivetives which are potent antibacterial agents. Sore particularly,it relates to compoeads of the formula J wherein R is hydrogen or a conventional amino-protecting group. 7 H*· is hydrogen, a straight oring from 1 to 4. carboa atoms,containing from 3 to 6 carbon xR4 R4 -C-CH-CB-R^ , It 3 »C-C=C-R i5 As branched chain alkyl group confcain-a eycloalfcyl or cycloalkenyl ringatoms, or a group of the formula I -c-cooa Is 3 in which R is hydrogen, -8SQ i 6 i* a guaternary aaoonio group, and nontoxic pharmaceutically acceptable salts and physiologically hydrolyzable eater» thereof.Also included therein are the solvates and hydrates of the compounds of Formula I, as well as 5 the tautomeric forms of the cempocmds of Formula I, e.g» the 2~iminothiaxolin-4-yl fore of the 2-aminothiasol~4-yl moiety.

Also, our primary application relates to a process for the preparation of the compounds of Formula X - As shown in the structural formula, the compounds ofjo Formula I have the ’syn" or "3" configuration with respect to the alkoxyimino group. Because the compounds are geometric isomers,some of the ’anti" isomer may also be present, e.g. up to 10% of that isomer. Preferably the compounds of Formula I are "syn"isomers which are essentially free of the corresponding "anti" 15 isomers.

In addition to geometric isomers possible with respectto the alkoxyimino group, the compounds of Formula I (and theintermediates of Formulae VIII and IK) also form geometric (cisand trans) isomers about the double bond of the propenyl group. 20 Both the cis (*2") and trans ("S'") isomers of these compounds are specifically contemplated in the case of our primary ApplicationThe numbering system utilized herein for the various reactants, intermediates and final products is as follows: 17 I Roman Numeral ] I Arabic Mosers! |j'(if appropriateJj E- Letter appropriat The Roman Numeral designates whether the compound is a finalproduct (Il or an intermediate or other .reactant (all other RomanNumerals]. The Arabic Numerals and Letters are not used in thoseinstances where the overall class (genus 1 of compounds is meant.

The Arabic Numeral designates the particular meaning of 2 2 substituent R . If the particular R group contains a carboxyl group which is protected by a conventional carboxyl-protecting group* a "prime1* < *) is used after the Arabic Numeral-to indicate this fact. No "prime" is used if the carboxyl group is espro-7 tected- A "prime" also is used with the generic substituent 2’ 2(i,,e. R > when generically referring t© an a group containing aprotected carboxyl group.

The Letter at the end of the compound number refers to the particular meaning of the quaternary ammonio group© ~H=O .

For convenience* the Arabic Numerals and Letters 7 assigned to some of the preferred R groups and quaternary ammonio groups are set forth below.

Arabic Numeral123< 5 methyl ethyl allyl propargyl cyclopentyl Lesley A B C B EPG E 10 Σ «5 K L M S O J? Q © _ 1- jae thy I py e ε ol i d is i o pyc Id in, i© 2- asHissQ-5-fchiazoJl©i 4,5~e Jpyridifii©t r ime thy 1 aasaon i © 3- ass in opy c i <3 i n i © 3~f oxsaylaftinopyx idin io 3-earfoaraoylpyr idiisi© 4~ca rbasioyIpyri δ in i © S-araiaoroethylpyridinio 2- ®ethylthiasoli© 3- hy dr oxvaie fchyl py ci d in i o 4- hydr oxyatethy ipy r idin io 4- C »-a*e fchylcar barney 1) pyx i dinio 4-carboxypycidioxo 2,3-propylenepyridinio 3-ca εboscvmethy 1 py ε id in io4~carboxymethylthiopyxidinio 19 As noted above, our primary Application dealt with ,processes for the preparation of the compounds of Formula I.

The preferred procedures are shown below in Reaction Schemesla, lb and lc9 5 while an alternative procedure is shown in Reaction Scheme 2.

The abbreviation *Ph* represents the phenyl group. Thus, the ~C5(J?b>sodety is the beachydryl group, which is a preferred * 2 carboxyl-protecting group. When R contains a carboxyl group, it is desirable to protect the carboxyl group with a eesveration&I q carboxyl-protecting group such as the t-butyl moiety, X represents chloro, bromo or iodo.

Reactiga Scheroe la N--s-C· -COOH III H2*s ^οϊΓ 2.0 ϊί 2 oase ra ι /· O5T "CONI h) NL C0CCH(?h5„ *3 β**1 '5·*? I lHh'*-’ »4»1« ;CHO 2 1 Bal or XX Λ «ία eta deblock //μ ίί \, 2«C3CH-,»^SZD Reaction Scheme la ows two alternate means of going from Compound IS to Compound XII. "Ph A OW> W· direct route, e Til 'ΐ.Λ A ·«»«£] l^|rtrffh t£a 3 fl Vg tertiary amine C3CX5«· is appli .cable for* the preparation Vi. all 5 compounds of Formula I» The indirect route, via Compound X, utilises a secondary amine as reactaat, and is quateraised in thefollowing step. The secondary amine HR’HH may be acyclic ie.g.dimethylamine) or cyclic (e.g. pyrrolidine), and this indirectprocedure therefore is suitable for the preparation of compounds 10 of Formula I in which the quaternary ammonio group is acyclic or"mixed" acvciic/cvclie. This indirect route is not suitable forthe preparation of compounds of Formula X wherein the quaternarynitrogen is in a fully unsaturated heterocyclic ring (e.g.pyridinio, thiazolio, 2-amino-S-thiazoloi4,5-cIpyridinio ). 15 Reaction Scheme lb <ξ> "3 «Μ» 24 CXCH^CK© XVIX XVJII SIX VIIX as in Scheme la Reaction Scheme lb is a variation of Reaction Scheme Is,in that the 7-amino group of the starting material (III isprotected as a Schiff base during most of the reaction steps, and 5 the desired 7-side chain acid is added later in the synthesis.Otherwise* the general procedure is similar. '2 5 Reaction Scb«ae lg vty 4*js, ZF yxx Λϋ-Sii» A I X sow X. (secon Cc x x> Q5S v =CSCH-, .M==Q **- — © 26 acylation with III I Reaction Scheme 1c is a further variation of-Reaction Schemelb. in Reaction Schemes la and lb, quaternization of the 3-sidechain is the last step, but in Reaction Scheme lc the last step 5 is acylation of the 7-amino group. The relationship betweenReaction Schemes la, lb and lc is shown in the followingflowchart. ·> "3 XV χχχχ ,Χ" dib COOCB (i'to). I . ,Asx IS 55 \ 2OB ^s~\ ,d cooca (?h) 2 1« Ito Qu*te ra x=»t Ice Deblocking Cestpowaffi X 1^3V Xc r _nf 1 Z' ^^^csf-scsxi XV21 GXOJCfe]-, !Qua€e=nix*tie»Deblocking XXJ2 as In Reaction Schemes la, lb and le, the benzhydryl groupwas shown as the preferred carboxyl-protecting group, it will beappreciated by those skilled! in the art that other carboxyl-protecting groups# well-known in the art# siay be used- Theacylating acid in may be used Sft ttte form of a derivative suchas its acid halide# activated ester# mixed acid anhydride#all of which are well-known in the art. We prefer to utilize itin the form of its acid chloride. Acylating acid III also mayhave its amino group protected By any of the common amino-protecting groups# e.g. K-trityl, ^-formyl. The base used to convert the phosphonium iodide (Vi or XV) to givethe phosphorylide {vii or xvi) may be BaOH, »a2CO3, IRA-<10 C0H~3resin, IKAiCO^’j resin, or the like, or a mixture thereof. Thechloroacetaldehyde used to convert the phosphorylide VI1 to the 3-chloropropenyl-3-cephe® compound VIII (or Compound XVI to Com-pound XVIIJ may be the commercially available 40-50% aqueoussolution# a distilled solution (e.g. JOt) or the anhydrousaldehyde .

We have found that Compound VIII prepared from CompoundVII {scheme la, typically had a Z:E ratio of about 2:1 at thepropenyl double bond. Compound vm prepared from Compound XVIII{Scheme lb), on the other hand, typically 'was almost exclusivelythe Z isomer. The difference may not be in the route used# butin the conditions utilized in the Wittig reaction (VII to vm orXVI to XVII), We have also found that the use of an appropriatesilyl reagent such as Ν,Ο-bis(trimethylsilyl)acetamide in theWittig reaction (Vii to VIII In Scheme la. and XVI to XVII inScheme lb) caused improvement of the yields and purity of Vllland XVII. The reaction is preferably carried out with 2-5equivalents of the silyl reagent. When the chloropropenyl cephem(VIII) was reacted with Bal in acetone to give the iodopropenylcephem CIX), the double bond in the propenyl group was isomerizedfrom z to e during the iodination. A short reaction periodretained the configuration of the parent Compound VIII to a largeextent, while a long reaction period gave primarily the 2 isomerof Compound IX. However, an excessive reaction time at high 29 temperature gives « lower parity compound XX. We find that eboat10 minutes at 25*C and 2 boar· at 5*C gives pure XX in goodyield. When utilizing fteactioa scheme 2c f we have found that,when iodinating cosspownd XIV with i«al, a purer compound is 5 obtained if the acetone solution is diluted with when iodination is essentially completed? and the isomerizationportion of the reaction is conducted in the acetone-CCl^ mixture.When iodination of the chlocopropenyl cephem ξχνχΐ) to theiodopropenyl cephem (XIX? was performed with K2 in BMF, the 10 isomerization of the double bond from s to £ proceeded as fast asthe iodination did. The whole reaction completed within 45 .minutes at room temperature to give pure XXX without dilutionwith CCI^ is the course of the reaction.

Compound XII normally was deblocked without purifica-X5 tion, and the fiaal product (1} was purified by reverse phase column chromatography utilizing a glass column containing thepacking removed from a Waters’ Associates PrepPAK-500/c,8 car-tridge. xx: ,1 -asi Scb "GR XXXV 1 H XXV Reduction •/s,% CONH M '\^ί>ίχ CH«CE~Ci ©" ΐ,ΗΞβ <«u COOCH(Ph)^ XXVI 31 Reaction Scheme 2r shown in brief outline form above,is similar to Reaction Scheme la except that Compound XXXII(equivalent to Compound IX of Reaction Scheme la) is converted toits s-oxide prior to quaternisation. Compound XXV is subsequentlyreduced, and the remainder of Reaction Scheme 2 is as ReactionScheme la. In Reaction Scheme 2, it is preferred to protect theamino group of the 7-side chain with a known amino-protectinggroup such as the trityl group.

The acylating acid© of Formula III herein are either known compounds or are readily prepared by published procedures.

European Patent Specification 7,470 published October 12, 1983(application published February 6, 19805 exemplifies the preparatioiof compounds of Formula III wherein R is methyl, ethyl, propyland isopropyl. 'O.S. Patent 4,39Q,534, referred to in the PriorArt.section, above, exemplifies the preparation of a wide varietyof compounds of Formula III wherein R2 is, for example, cyclopentyl 2-cyclopenten-l-yl, allyl, 2-propvnyl, 1-tert. butyloxycarbonyl-1-methylethyl, 1-tert. butyloxycarbonyl-l-cyclopentyl, l-ethoxy-carbonyl-I-methylefchyl, tert, butyloxycarbonylmethyl, 1-tert.butyloxycarbonyl-2-methylpropyl, trityl .

Compound II herein (7-amino-3-chloromethyl-3-cephem-4~ 32 « e»*d a· · material in Reaction Schemes la, lib e®3 is » fcaown scRpoasd·.

The tertiary amines of Formula XI (and the secondary aminesRSTKB) utilized in preparing the quaternary ammonio compounds of 5 formula I ate either known compounds or are· readily prepared by those of ordinary skill in the art. Many of the amines are commercially available. ©us? primary Application identified a process for thepreparation of compounds of the formula wherein R" is hydrogen or a conventional amino-protecting group,,R4 is hydrogen, a straight or branched chain alkyl group contain-ing from 1 co 4 carbon atoms, a cycloalkyl or cycloalkenyl ringcontaining from 3 co € carbon atoms, or a group of the formula R' • 3 is -e-ca=CH-R R ί 7j -C"C~C"R~ • 5 COOH or R ‘i-COOH *5 R 3 in which R is hydrogen, (lower)alkyl or carboxyl, X is halogen, 4 5 hydroxy or (lower)alkoxy, and R' and R are each independently 4 5 hydrogen* methyl or ethyl* or a and H * taken together with the 33 carbon atom to which they ace attached* «ay be a cycloalkyliden«ring containing frees 3 to 5 carbon atoms* and is a quaternary ammonio -group* and nontoxic pharmaceutically 5 acceptable salts and physiologically hydrolyzable esters thereof*which process comprises reacting a compound of the formula 2 - wherein R is the same as R** or is a group of the formula λ κ 1 10 in which X* R and S’* are as defined above, 3' is a conventional carboxyl-protecting group* B" is hydrogen or a conventionalamino-~protecting group* Z is chloro* bromo or iodo* and m is zeroor one, with a tertiary amine QSSM (or sequentially with asecondary amine RR'KS and a compound of the formula R*Z), and, if 15 m is 1* reducing the sulfoxide by conventional meass, and subsequently removing all blocking groups by conventional means.

Our- primary Application also identified a process for thepreparation of compounds of the formula 34 1 wherein S. is hydrogen or a conventional amino-protecting group,R* is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring 5 containing from 3 to 6 carbon atoms, or a group of the formula H4 a4 COOH 3 i-n which R is hydrogen, (lowerSalkyl or carboxyl, X is halogen, 4 5 hydroxy or (lower)alkoxy, and R" and R' are each independently4 5 10 hydrogen, methyl or ethyl, or R" and R , taken together with thecarbon atom to which they are attached, may be a cycloalkylidenering containing from 3 to '5 carbon atosis, and © ~N=Q is a quaternary ammonio group, and nontoxic pharmaceutically !5 acceptable salts and physiologically hydrolyzable esters thereof, which process comprises acylating a compound of the formula ΧΧΪ with an acid! of the formula 10 3 3N .

(«· I os with a?, acylating derivative of said acid,» wherein H** is the - 2 sasne as H or a group of toe formula €008 or -C—C003 R* in which X, R and R-1 are as defined above, B* is a conventional carbozyl-protecting group and 3amino-protecting group» hyarogen or a conventional The present invention relates to novel intermediates O«- «a X <- he formula aWk a»to! CH=CH-CHΌ-N—Q COO xxi: wherein -5^=0 is a quaternary anwnonio group; or a salt, ester,solvate or hvdrate thereof - As used herein, the terms acylamino and acyloxy refer to an5 acylated amino or acylated hydroxy group in which the acyl moiety is (lower)alkanoyl (e.g. formyl, acetyl, propionyl, butyryl,isobutyryl, isovaleryl), aroyl (e.g. benzoyl), (lower)alkanesulfonyl (e.g. mesyl, ethanesulfonyl)> or arylsulfonyl (e.g. benzenesulfonyl, tosyl).

As used herein, the tetiras *-(lc«er> alkyl", "(lower 1 alkoxy’g, 8(lowerJalkylthio" mean straight or branched chain Klfcvl, alkoxy, alkyltfei© groups containing from 1 ro 6 carbon atoms, Lusive. Similarly, the terms (lower>alkenyl and (lower}alkynyl mean alkenyl or alkynyl groupscontaining from 2 to 6 carbon atoms.

In addition to the above-mentioned intermediates of theformula XXII per se, the present invention includes a processfor the preparation cf these compounds. This process comprises 10 those steps mentioned in the foregoing description for Schemeslb and 1c wherein compound XXII is obtained by way of compounds II, XIII, XIV, XV, XVI, XVII , XIX , XX and XXI ( cf. Scheme lb for compounds II, XIII , XIV., XV, XVI and XVII, and Scheme 1c for compounds XVII 9 XIX , XX, XXI and XXII).

Preparation &3q. 1 BenzhyeSryi 7~-Asnino-~3-iI 3-chioro-l-pgopen-l-yl l-3-cephem-4-- carboxylat® gz-isamer? (XVIII) Compound 2CVI1T is the cannon intermediate utilized in 5 Besetion Schemes lb and lc. A. Benzhydryl 7-Benzylideneamino-3-triphenylphosphonioroethyl-3~ cephem-4-carboxylate chloride (XV) 3 9 To « scepeneion of benxfcydryl ?-e»iBo-S-cfalororaetfayi^j»cephera-4-carboxylate hydrochloride <21 hydrochloride} <200 g, 0.44 mole) is CB^Cl^ <940 ml) was added 1 M KaOB <440 ®X> at rooratemperature. The mixture was shaken for 1Θ minutes *adi theorganic layer was separated, To the organic layer were addedRigSO* OS gl and benzaldehyde <51 g, 0..46 mole) and the mixturewas allowed to stand for 3 hours. The reaction mixture wasfiltered asd the insolubles were.washed with 'Cs^CjL· <200 ml>. To ufe <£> the combined filtrate and washings was added triphenylphosphine <126 g, 0.48 mole).. The mixture was concentrated to about 400 mland allowed to stand for 4 days. The resulting viscous oil'was .'diluted with ethyl acetate <1 L) and triturated to separate thetitle compound an. pale yellow crystalline powder which was .5 collected by filtration and dried in vacuo. M.p. 185-190*C idee.5.

Tield 522 g C9< vKBr cm"1 1780, 1720, 1630.'tax OV : XCg2Cl2 an 260 <241005max 20 3 » 3en2hydr_yl 7-Bena:ylideneamino-3~£ (triphenylphosphoran- vlidene imethvl )-3~cephero-4-carboxylate «Ζ room. temperature. The organic layer was separated, dried overKcSO, and concentrated to about 500 ml of volume. Theconcentrate was added to acetone <1 14, with stirring, ail) in GS. <1.6 w&i :ec for mnutes ai •a ? to give a ght yellow crystalline powder which was collected by filtration to yield 237 g (78%) of melting at 195-198*0 (dec. 25 4 0 XR ον c»"1 nr©, ie»e. max ACfi2Cl2 is® 254 (23000), 389 (22000). max 6CBC13 2,56 J. 3el6 (2fii 5,0Q ilBr j.4 5,23 ppm (IS, d, J· 4 Hz), 5.47 (IS, <3, J-22 Sz), 6.95 (IS, e), 7.2-7.8 (30a, m), 8.55 (IS, s). C. Benzhydryl 7-amino-3-|[ehloro-i-propen-l-.yl)-3~cePhem~4- carboxylafce hydrochloride (2 isomer>_(XVIII Hydrochloride) To a refluxing solution of XVI (214 g, 0.294 stole) andN,O-bis-(ferimethylsilyl,acetamide (40 »1, 0.15 stole) in dryC3^£l? (2.9 L) was added dropwise, with stirring, a 50% solutionof chloroacetaldehyde ¢93 g, 0.59 stole) in CHC1, over a period of15 ainutes. After standing for 30 minutes, the mixture wasconcentrated to dryness. To the residufel oil were added ca7Cl?(1.5 I,), Girard Reagent T (99 0.59 mole) end 10% aqueous SCI (300 al>, and the mixture was stirred for 1 hour at room tempera-ture. The organic layer was washed with water (200 ml) and asaturated SSeCI solution (200 ml},,, dried over MgSO^, treated withcharcoal (5 g) and filtered. The filtrate was cooled to -10ecand treated with 1 H HC1 in ea^OB <300 ml). The mixture wasstirred for 30 minutes at room temperature and concentrated toabout 300 ml. The concentrate was diluted with ethyl acetate(400 ml) and seeded with a few crystals of XVIII hydrochloride.After 2 sours the separated crystals were collected byfiltration, washed with ethyl acetate (200 ml) and dried in vacuoto give 74 g (53%)'of the title compound XVIII as itshydrochloride, melting at »1S5'®€ (dec.). Pale yellow needles. 4 1 10 IR : νΚΒε ca’1 2830, 1780,, 1720.max ps-fts gv : x--^· nsn 286 (8800J., max N MR : 6 OKSO-d ΡΡίη £ s #?(«’ Η’’ κ '3 (9 / w’ £> ά>3 S’ far di» ifi fat £ (13, a, Jf-4.5 32, 6-HS ώ 437 (7Π — fs? rl ) S "i") 9 »* · «j (?’ ffA* jfi λ^ι v dfe / $ θ , 5.37 (13, d, J«4.5 32, 7-3), 5.77 (IB, a, 3-C3-C3), δ.«5 (IB, d, J-ll H ·? ·3 _P B &> dM i? *&<' <*» ¢: g> s, Ph-3)- Anal, Calc'd for 6.88 (1Ξ, s, CsPh-J, 7.33 CIO M , *f|T AuTL ill lu—il a * a >3 Ο 5P1 . 9 m wt ftrfl «Β 1« 1 0* —i 'W oite> ItuA ra^ ufe. a) Λί a& efe d» A> *** Found; :, 57.87; 3» 4.65?8, 5.87? 5, 6.72;Cl, 14.85. C, 57.62; S, 4.53?8, 5.70; S, 6.64;Cl, 14.89. 15 Preparation Ko. 2 Benzhydryl 7-3entylideneamino-3-l3-chloro-i-propen-l-yl1-3- To an ice-cooled mixture of the crystalline 7-amino- 5 cephem intermediate XVIII (Z isomer) (13.4 g, 28 mmole) andbenzaldehyde (3.3 g, 31 mmole) in ethyl acetate (150 ml) wasadded dropwise 0.5 N sodium hydroxide (55 ml, 28 mmole) over aperiod of 20 minutes* to maintain the temperature of the reactionmixture below lOeC. The mixture was stirred with cooling for 10 another 15 minutes* and the organic layer was separated* washedwith saturated aqueous sodium bicarbonate (100 ml x 2) and driedover magnesium sulfate. To the dried solution was added a smallamount of charcoal and the mixture was filtered. The filtratewas concentrated to dryness. The residual oil was dissolved in 15 carbon tetrachloride (50 ml), and concentrated again. This procedure was repeated 3 tines, and the mixture was monitored byreverse phase tic to confirm that ail of the starting 7-amino- 4 3 cepbalosporia was converted to the Schiff*· base. Removing tfceadvent in vac ο ·ο gave 16,, <5 g ©f tfe* title compound XVII (2isomer! as * pale yellow powder (estimated parity 85%; M„p. 7<*c(dec.)# which was esed for the next step without purification. IS : vKBr ts’1 1780# 1725# 1635.max 0V ; .C5 —Cl« λ 2 2 nm (S1% ) 257 (400). sax 1 cm 8 ME : 6CDC13 6.18 (Is# d# J-ll as’ ppm Pr e pa r a fc i on So 3 Sen_zhydryl 7-Sengylideneamino-3-E3T4<-cagkamoyl-l-pyrldinio_)-l- propen-l-ylp3-cepfaem-4~earhoxylafce Iodide . (XXI-S,).

To a chilled mixture of the 3-chloropropenylcephem xvu(2 isomer) (16.4 g! in acetone (5 ml), was added dropwise asolution of ©odium iodide (6.3 g# 42 mmole) in acetone (30 ail I over 10 minutes under nitrogen atmosphere? and the mixture was stirred at room temperature. The reaction was monitored by the ratio of uv absorption (E^ *' (255 nmi/E* * <320 nm>J. When 1 cm 1 cm the ratio reached below 1.30 (after 45 minutes), the mixture wasdiluted with carbon tetrachloride (400 ml), and allowed to standat room temperature. When the ratio came to below 1.10 (after 3 hours J,, the mixture was concentrated to a half its volume. Theconcentrate was treated with a small amount of charcoal anddiatomaceous earth# and filtered. The filter cake was washedwith a 1:1 mixture (100 ml) of methylene chloride and carbontetrachloride. To the combined solution of the filtrate andwashings# was added a solution of isonicotinamide (3.5 g# 28.7mmole) in dimethylformamide (20 ml) and the mixture was concen-trated under reduced pressure. Tse concentrate was allowed to I stand at room temperature for 1.5 hours and washed with isopropyl ether lS,d was dissolvedin methylene chloride <50 ml) end fc.be solution was addeddropwise* with stirring* to ethyl tc«ute Cl.5 i.). The resultingprecipitate was collected by filtration and washed with ethylacetate <200 sill. After drying over phosphorous pentoxide .invacuo* 17 g of the title compound XMI-B Preparation ^o._4 7~3imino-3-13-( 4-carbamoyl-l-pyridinio)-l-propen-l-yl)-3-cephem—4_-carboxylate (XXII-S) (a is_omer) To a suspension of the guaternized cephem XXI*3 ¢17 -g)in 85* formic acid (25 ml) was added dropwise concentratedhydrochloric acid (5 ml}* and the fixture was stirred at roomtemperature for 1.5 hours and treated with a small amount ofcharcoal. The mixture was filtered and washed with 851 formicacid (5 ml). The filtrate was combined with the wash and pouredinto acetone ¢1 L), with stirring. The resulting precipitate wascollected by filtration to give 9.52 g of yellow-colored crudeproduct. To a suspension of the crude material (9.5 g) in water(50 ml) was added a small amount of charcoal* and the mixture wasfiltered. The filtrate was added dropwise* with stirring* toisopropyl alcohol ¢700 ml). The resulting precipitate was collec(30 ml i ssnerpurity IR : a»w w w „ u v : NKR : ted by f i It ratios», washed -with a email amount of methane ί as «dried to give 7„58 g e, e c ©bi pound XX3 H fur he hydrochloride. Light yellow powder. Estimated85* by UV. M.p. 173-188^0 (decU. KBr CKI 1795, 1680, 1620, 1575» 1540. max ^Phosphate buffer (pH 7) nm ^1 % j 2 4 δ Χχΐ-Ε iodide *Ξ Diphenylmethyl 7~Benzylidfeneamino~3—(CSS — 3--C4-carbamoyl-pyridinio)-l-propenyl)-3~ce_phem-4~carboxylate (XXI-H iodide) (_s isomer I To a chilled solution of the 3-chloropropenylcephem(XVII, x isomer* 42.8 g, 90 mmoles) (frcm Preparation Ho- 16)-indry DM? <80 ml), was added XI <20 g, 120 mmoles) in one portion*and the mixture was stirred at room temperature. The .reaction "3 ft 10 was monitored by the ratio ©f OV absorption (£"" {255 aaO/ 1 cm 11' S (320 ism)). When the ratio became below i„iq (after <51 cm minutesK the mixture was diluted with 800 ml of methylenechloride* treated with active carbon <4 g), and filtered. The 15 filter cake was washed with 100 ml of CB^Cl,. To the combinedfiltrate and washings was added isonicotinamide <14.64 g), andthe mixture was concentrated under reduced pressure. Theconcentrate was Kept at room temperature for 1.5 hours and washedwith a mixture of toluene and η-heptane (1:1, 600 ml). The 20 residual brown semi-solid was dissolved in CB^Cl? (100 ml) andthe solution was added dropwise to ethyl acetate (3D withvigorous stirring. After drying over ?2°5 *n ya9uo» 57.37 g(88%) of the guaternixed title product XXI-8 was obtained as theiodide. 'fellow amorphous powder. Mp. 150*-155°C (dec.). This 25 product was identical to that obtained by iodination with Hal(Preparation No. 3). lora So. 6 SCI* EEj» XVXXI *S Piphenylzaethyl 7"Amino^3-;< 3-chloro-l«*propenyl)-3-cephem-<- carboxylate hydrochloride (2 isomer) (XVIIIf Hydrochloride) 5 A 25«, solution of chloroacetaldehyde (69 g, 0.22 mmoles} in CHCl^ was added fco a solution of XVI <80 g, 0.11 mole)la CB2C19 (1.1 X.) containing S,O~bis(triaiethylsilyl)acetamide(13.2 ml, 0..OS mole) at ~10®C in one portion, and the mixture wasallowed to stand overnight at 5*C. The mixture was concentrated 10 to ca. 0.3 I,,# diluted with a mixed solvent of ethyl acetate andisopropyl ether (1/2, 0.6 L), treated with silica gel (WakogelC-100, 60 g) and filtered through a dicalite pad. The filtercake was washed with the same solvent system (0.2 14. Thecombined filtrate and washing were -concentrated to ca. 0.2 L„ 15 treated with Girard Beagent T (60 g, 0.26 mole) and 4N 3Cl (220ml), and seeded with a few crystals of XVIII hydrochloride.

After stirring for 3 hours, the resulting crystals were collectedby filtration,, washed with water <0.5 L> and ethyl acetate (0.514 and dried in vacuo to give 37 g (70%) of the title compound 20 XVIII hydrochloride^ melting at >185°C (dec.K Pale yellowneedles. This product was identical to that obtained inPreparation „ 1- 4 S XVI1I *2 Piphenylmethyl I-Amino-j- ( 3-chloro-l-propenyl)~3-cephem-4- carboxylate hydrochloride (2 isomer) (XVIII, Hydrochloride) 5 io a solution of chloroacetaldehyde (25% solution in CHCl,^ 628 mg, 2 mmoles) in CH^Cl^ (10 ml) were added bbO-bis-(trimethyIsilyl)acetamide ¢0.135 ml,,. 0.5 mmole) and XVI {728 mg, 1 mmole), successively, at 5*C. The mixture was allowed to standovernight at 5eC. The mixture was evaporated and diluted with a io mixture of ethyl acetate and isopropyl ether (1/2, 10 ml).Insolubles were removed by filtration and the filtrate wasconcentrated to ca. 5 ml- The concentrate was treated withSCI (2 ml), seeded with XVIII hydrochloride and stirred for 1hour at room temperature. The crystals were collected by 15 filtration, washed with ethyl acetate (10 ml) and water (10 ml)end dried in vacuo to give 384 mg (80%) of the title compoundXVIII hydrochloride, melting at >185*C (dec.). Pale yellowneedles. This product was identical to that obtained byPreparation No. 1.

In the claims which now follow the word "solvate"is to be understood as not including a hydrate. 20

Claims (6)

1. A compound of the formula < img-format="tif" img-content="drawing" /> N X^C^CH-CH^-NSQ wherein 5 solvate -N=Q is aor hydrate quaternary ammonio group?thereofor a saltteste A compound of Claim* U h o r a ί n -- ai >=ur» me Θ ~N=jQ is selected from 5 0 < img-format="tif" img-content="drawing" /> 13 1 4 15 wherein R , S* and R* are the same or difrerent and are (lower)alkyl, (lower)alkenyl, amino(lower)alkyl with the pro-5 vision that the amino may not be on an e-carbon,, or hydroxy- dower )alkyl with the provision that the hydroxy group, may not be on an a-carbon? 16 R is hydrogen, (lowerJalkyl, (lower)alkoxy, (lower )-alkylthio, amino, (lower )alkylamino, di (lower ) alkylamino, formvl- 10 amino, (lowerJalkanoylamino, carboxy, hydroxy, carboxyl lower)-alkyl, carboxy(lower)alkylthio, hydroxy(lower)alkyl,halo(lower)alkyl, amino{lower )alkyl , (lower)alkoxy(lower )alkyl,carbamoyl or ^-(lower)alkylcarbamoyl, or R16 may represent adivalent alkylene group having 3 to 5 carbon atoms? 17 15 R is (lower)alkyl, (lowerJalkoxy(lowerJalkyl, halo- dower )alkyl, allyl, hydroxydower )alkvl with the provision thatthe hydroxy group is not on the e-carbon, amino(lower )alkyl withthe provision that the amino group is not on the e-carbon, orphenyl(lower )alkyl? Ί 8 2Q R“ is hydrogen, (lower)alkyl, (lower )alkoxy, (lower)- alkoxy dower Jalkyl, (lower ) alkyIthio, amino, (lower )alkylamino,di(lowerJalkylamino, carboxy, hydroxy, carboxyilower)alkyl,hydroxy(lower ) alkyl, aminodower Jalkyl, f ormylamino, (lower)-alkanoylamino, carbamoyl or M-(lowerJalkylcarbamoyl? 51 n is an integer of from 1 to 3, inclusive; Z is CH, or, when n is 2» Z also way be s, O or N-ax5, i a in which R* is hydrogen or (lower>alkyl; and •>n 21 R“ and R “ are the same or different and are hydrogen,(lower) alkyl, (lower) alkoxy, (lower,alkylthio, amino, (lower )-alkylamino, di(lower)alkylamino, carboxy, hydroxy, hydroxy-(lower ) alkyl, amino(lower>alkyl, dower ) alkoxy (lower ) alkyl, carboxy (lower )alkyl, carboxy(lower )alkylamino, (lower)alkanoyl- amino, carboxydower) alkanoylamino, carbamoyl or N-(lower ) alkyl-carbamoyl; or a salt, ester, solvate or hydrate thereof©.

2. 3, A pyrrol idinio compound of Claim 1 A compound of Claim 1 5. A thiasolol4,5 compound of-cIpyridinio Claim 1 ® X δ. A ammonio. compound of claim X 7. A pyridinio. compound of Claim 1 3- A py ridinio. compound of Claim 1 9. A py ridinio. compound of Claim 1 10. A pyridinio. compound of Claim 1 11. A pyridinio. compound of Claim 1 wherexn is 1-methyl- wherein © B=Q is pyridinio. wherein Θ is 2-amino-5- wherein © is trimethyl- wherein © H=Q is 3-amino- wherein © N=Q is 3-formylamino- wherein © ΝΞβ is 3-carbamoyl- wherein © ΝΞ0 is 4-carbamoyl- wherein © is 3-aminomethy1- 5 a

3. 12. A thiazolio , compound of Clair 13. A pyridinio. compound of Claim. 5 14, A pyridinio. compound of Claim 15. A compound carbamoyl)pyridinio. of Claim 10 16. A pyridinio. compound of Claim 17. A pyridinio. compound of Claim 18. A pyridinio. compound ox Claim 15 19. A compound thiopyridinio. of Claim 1 wherein © N"Q is 2-methyl- 1 wherein © N=0 is 3-hydr oxyrethyl 1 wherein © N=Q is 4-hydroxymethyl 1 wherein © is 4-(N-methyl- 1 wherein © is 4-carboxy- 1 wherein © ΝΞΞΌ is 2S3-propylene- 1 wherein © N=Q is 3-carboxymethyl 1 wh® r e in © is 4-carboxymethyl 53

4. 20. A process for the preparation of compounds of the formala XXII < img-format="tif" img-content="drawing" /> ©' wherein -£3»Q is a quaternary aaaoaio group; c»r a salt, ester„solvate or hydrate thereof· which comprises reacting a coapound offormula with a coapound of < img-format="tif" img-content="drawing" /> formula II < img-format="tif" img-content="drawing" /> 54 to give a compound of forscla XIII,, < img-format="tif" img-content="drawing" /> then reacting a ccapouad of formula XIII with sodium iodide orpotassium iodide to give a compound of formula XIV. < img-format="tif" img-content="drawing" /> then reacting compound of formula with triphenylphosphine, orreacting compound of formula XHIwith triphenylphosphine, to givecompound of formula XV„ < img-format="tif" img-content="drawing" /> < img-format="tif" img-content="drawing" /> B2P«Pfa>. COOGH(Ph>^ & XV 5 5- then reacting compound of foraula V with a base to give coapouKjdof formala X2I < img-format="tif" img-content="drawing" /> farther reacting compound of formula Χ&Ϊ with CICS^CEO to give5 coapocad of formula zyTL. < img-format="tif" img-content="drawing" /> then reacting coapound of formulaXVII with sodiun iodide orpotassium iodide to give coapound of formula XDL < img-format="tif" img-content="drawing" /> COOCS (PM 2 10 then further reacting coapound of formula XIX, with a secondary 5 6 < img-format="tif" img-content="drawing" /> «herein Rit R3· are each aethyl or together for®. pyrrolidine to give a c&apound of the formula XX. < img-format="tif" img-content="drawing" /> then reacting compound XX with R"Y, wherein R" is a tertiaryaaine 5 and T is chloro, bromo or iodo, to give a compound of the formula XXI, < img-format="tif" img-content="drawing" /> -&=0 XXI or reacting compound XIX with a tertiary aaine QBS, wherein Q isas defined above to give compound XXI, then treating eoapound XXIwithGirard Reagent T or SCI to give compound XXII» and if desiredconverting the free acid to a. salt, ester, solvate or hydratethereof» 10

5. 21. A process as claimed in claim 20 wherein one ormore of the steps performed are substantially asdescribed in the foregoing Preparations section.

6. 22. A compound as claimed in claim 1 prepared by5 a process as claimed in claim 20 or 21. Dated this the 14th day of April,1989.F. R. KELLY & CO. . BY: EXECUTIVE. -1----pi-/— 27 Clyde Road,. Ballsbridge^ Dublin 4.AGENTS FOR THE APPLICANTS. Page 1 at ERRATUM Patent Specification No. 58403(54) date of filing should read "04 APR 1985". Patents Dublin Office November 1993