IE41574B1 - Antibacterial cephem hydrazones - Google Patents

Description

This invention relates to certain cephalosporin compounds useful as antibacterial compounds or as intermediates.

According to the present invention there is 5 provided a compound of the formula: R C=Z COX (I) wherein A and B are each independently hydrogen or an amino protecting group or represent a single amino protecting group when considered together; X is hydroxy or a carboxy protecting group; Y is hydrogen, halogen, alkyl, alkoxy, or alkylthio; R is hydrogen or alkyl; Z is a group of the formula R' 2 in which either R and R are the same or different and are each hydrogen, an optionally substituted hydrocarbon group (as hereinafter defined), organic acyl, or a group of the formula Μ' ζ in which Μ and Μ' are the same or different and are each oxygen or sulfur and R3 is a hydrocarbon group; 2 or R and R are combined together either directly or through a hetero atom; m is 0 or 1; and the broken line indicates the presence of a double bond at position 2 or position 3.

It should be understood that the term optionally substituted hydrocarbon group as used above and in the claims includes groups in which a ring or rings of carbon atoms is/are interrupted by one or more heteroatoms to give a heterocyclic group, the heteroatom (s) being regarded as substituent(s) .Examples of such groups are given later amongst preferred groups Z.

In the claims, the expression known per se means known to those skilled in the art, in actual use, or described in the literature.

In the above formula (I), the amino protecting group represented by A or B can be acyl, silyl, sulfinyl, hydrocarbyl, or another amino protecting group containing from 1 to 20 carbon atoms (including the corresponding groups in the side chains of natural 1 or synthetic penicillins or cephalosporins).

When A or B in the above formula (I) represent acyl this includes inorganic acyl such as carbonic acyl (e.g. alkoxycarbonyl, haloalkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl) sulfuric acyl or phosphoric acyl (e.g. dialkoxy phosphonyl, dialkoxythiophosphonyl or alkoxyaminophosphonyl); and organic acyl such as alkanoyl, cyclo -alkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl or alkylphosphonyl.

These acyl groups can, where possible, be unsaturated or substituted by halogen (e g. fluorine, chlorine or bromine), a nitrogen function (e.g. amino, hydrazino, azido, alkylamino, arylamino, acylamino, alkylideneamino, acylimino, imino or nitro), an oxygen function (e.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy or oxo), a sulfur function (e.g. mercapto, alkylthio, aralkylthio, arylthio, acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl or aryloxy sulfinyl), a carbon function (e.g. alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aralkanoyl, or cyano) or a phosphorus function (e.g. phospho).

A and B can be considered together as representing a diacyl group of a polybasic acid (e.g. phthalyl, pyridine - 2,3 - dicarbonyl, maleoyl or succinyl).

When A or B represents a hydrocarbon group this can be an easily removable aliphatic hydrocarbon group containing from 1 to 20 carbon atoms (e.g. alkyl, alkenyl, aralkyl or a group chosen from other aliphatic hydrocarbon groups optionally interrupted by a heteroatom in the main nucleus) or an easily removable mono-cyclic aromatic hydrocarbon group (e.g. phenyl or pyrimidyl). Each of these groups can, where possible, be unsaturated or substituted (e.g. by halogen, nitrogen, oxygen, sulfur, carbon or phosphorus func30 tions or by other substituents). A and B can also be considered together as representing a divalent hydrocarbon group (e.g. alkylene, aralkylene, alkylidene, aralkylidene, diarylmethylidene or cycloalkylidene) or another divalent hydrocarbon group which can be interrupted by a hetero atom in its main nucleus, and, where possible, can be unsaturated and/or substituted by a substituent as listed above. When group A is acyl and group B is a hydrocarbon group these can be combined together with a nitrogen bound to position 7 of the cephem ring to form a cyclic group (e.g. a 4-oxo-3-imidazOJidinyl ring).

The silyl (e.g. trialkylsilyl) and sulfenyl (e.g. phenylsulfenyl or o-nitrophenylsulfenyl) groups which may be represented by A or B are conventional amino protecting groups.

Antibacterially preferable acyl groups represented by A or B are: 1) alkanoyl groups containing from 1 to 3 carbon atoms; 2) haloalkanoyl groups containing 2 or 3 carbon atoms; 3) azidoacetyl; 4) cyanoacetyl; ) acyl groups of the formula: Ar—CQ2—Coin which Q is hydrogen or methyl and Ar is thienyl, furyl, pyrrolyl, pyridyl, phenyl,or phenyl substituted by chlorine, bromine, iodine, fluorine, trifluoromethyl, hydroxy, alkyl containing 1 to 3 carbon atoms, alkoxy containing 1 to 3 carbon atoms, cyano or nitro; 6) acyl groups of the formula; 1574 Ax G CH^ wherein G is oxygen or sulfur and Ar is as defined above; 7) acyl groups of the formula: Ar—CHT—CO— wherein Ar is as defined above and T is i) amino, ammonium, amino protected by benzyloxycarbonyl, alkoxycarbonyl containing from 1 to 4 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, triphenylmethyl, 2,2,2-trichloroethoxycarbonyl, guanidylcarbamoyl, sulfo, or amino protected in the forms of phthalimido, or an enamine derived from aceto acetate or acetylacetone, ii) liydroxy or alkanoyloxy containing from 1 to 6 carbon atoms, iii) carboxy or alkoxycarbonyl containing from 2 to 7 carbon atoms, or iv) azido, cyano, carbamoyl or sulfo; 8) 2-sydnon-3-alkanoyl containing from 3 to 5 carbon atoms; 9) (tetrazol-l-yl)alkanoyl containing from 1 to carbon atoms; ) 5-aminoadipoyl, 5-aminoadipoyl protected at the amino group by alkanoyl containing from 1 to 3 carbon atoms or chloroalkanoyl containing from 1 to 3 carbon atoms, or 5-aminoadipoyl protected at the carboxy group by benzhydryl, 2,2,2-trichloroethyl, alkyl containing from 1 to 6 carbon atoms, nitrobenzyl· or methoxybenzyl; and 11) diacyl groups derived from polybasic carboxy lie acids containing from 4 to 12 carbon atoms.

The carboxy protecting group which may be represented by X can contain up to 20 carbon atoms and includes groups such as oxygen functions, e.g. alkoxy containing from 1 to 8 carbon atoms (e.g. methoxy or trichloroethoxy), aralkoxy containing from 7 to 20 carbon atoms [e.g. benzyloxy, methoxybenzyloxy), nitrobenzyloxy, (e.g. p-nitrobenzyloxy), diphenylmethoxy or trityloxy], mono- or bicyclic aryloxy (e.g, phenoxy or naphthyloxy), organometaloxy (e.g. trimethylstannic oxy or trimethylsilyloxy), organic or inorganic acyloxy containing from 1 to 8 carbon atoms, metaloxy wherein the metal is in groups I, Ii or III in the periodic table (e.g. sodiooxy, potassiooxy, magnesiodioxy or aluminiumtrioxy), and other oxygen functions; sulfur functions, such as thiol esters and thiocarboxy groups; nitrogen functions, such as amide, hydrazide or azide groups; and other groups. These groups can, where possible, be unsaturated and/or substituted by a substituent as listed above (e.g. nitrogen, oxygen, sulfur, carbon or phosphorus functions or halogens) of the carboxy protecting groups, those which can be removed without an adverse effect on the other part of the molecule are preferred. Preferred groups are, for example, haloalkyl esters containing from 1 to 3 carbon atoms, acylalkyl esters containing from 2 to 10 carbon atoms, alkoxyalkyl esters containing from 2 to 8 carbon atoms, acyloxy alkyl esters containing from 2 to 8 carbon atoms, carbalkoxyalkyl esters containing from 3 to 8 carbon atoms, phenyl esters, aralkyl esters containing from 7 to 20 carbon atoms, esters with an oxime containing from 2 to 10 carbon atoms, N-alkoxyamide containing - 8 from 1 to 5 carbon atoms, imide with saccharin, imide with phthaliniide, N,N'- diisobutylhydrazide, metal o salts, or alkylamine salts containing from 1 to 6 carbon atoms, or groups equivalent in effect to these groups (in the definitions given above, specified numbers of carbon atoms are for groups X). Antibacterially preferable carboxy protecting groups X include acyloxymethyl esters, phenacyl esters, the benzaldoxime ester, the N,N - dimethylaminoethyl ester, alkali metal salts, alkaline earth metal salts and other groups equivalent in effect to these groups.

Y can be hydrogen, alkoxy containing from 1 to 3 carbon atoms (e.g. methoxy, ethoxy or hydroxymethoxy), alkylthio containing from 1 to 3 carbon atoms (e.g. methylthio or ethylthio), alkyl containing from 1 to 3 carbon atoms (e.g. methyl or ethyl) or halogen (e.g. fluorine, chlorine or bromine), hydrogen and methoxy being preferred groups Y.

The compounds (X) wherein m is 0 are antibacterial compounds. Those wherein m is 1 are useful intermediates for stabilization of the double bond at position 3.

R can represent, e.g. methyl, ethyl, propyl, isopropyl, cyclopropyl, or any other straight chain, branched, or cyclic alkyl groups containing from 1 to 3 carbon atoms. Hydrogen is the most preferred group li from the point of view of antibacterial activity.

A double bond at position 3 is preferred for antibacterial activity, whereas those compounds with a double bond at position 2 are useful as intermediates for preparing the compounds (I) having a double bond at position 3.

It will be apparent that syn- and anti-isomers can be formed around the carbon-nitrogen double bond at position 3 of the cephem nucleus. The ratio of such isomers depends upon the preparative reaction and starting materials. In this specification both isome-'s are intended to be represented by the same structural formula or nomenclature.

Preferred groups Z include the following groups : (1) hydrazono; (2) 2 - (o— or p - carboxyphenyl)hydrazono, 2(p - alkylsulfonylphenyl) - hydrazono in which the alkyl moiety contains from 1 to 3 carbon atoms or 2(p - sulfophenyl)hydrazono which can form a salt with an alkali metal ion; (3) 2 - phenyl - 2 - alkylhydrazono in which the alkyl moiety contains from 1 to 3 carbon atoms; (4) 2-(2- pyridyl)hydrazono, 2 - (thiazol - 2yl)hydrazono, 2-(1- amino -5-- mercapto - 1,3,4triazol - 2 - yl)hydrazono, 2 - (purin - 6 - yljhydrazazono or 2 - (4 - oximidazolin - 2 - yl)hydrazono; (5) 2 - (sulfolan - 3 - yl)hydrazono or 2(carbalkoxymethyl)hydrazono in which the carbalkoxy moiety contains from 2 to 5 carbon atoms; (6) (4 - methyl - 1,4 - dihydro - pyrazin - 1yl)imino or (2- pyridon - 1 - yl) - imino; (7) 2 - (alkanoyl)hydrazono in which the alkanoyl moiety contains from 1 to 4 carbon atoms, 2 - glycylhydrazono 2 - (N - tertiary butoxycarbonyl - glycyl)hydrazono, 2 - (trimethylammoniumacetyl) hydrazono, 241574 (pyridiniumacetyl)hydrazono, 2 - oxalylhydrazono, 2(alkoxyalyl)hydrazono in which the alkoxalyl moiety contains from 3 to 6 carbon atoms, 2 - (amidoxalyl)hydrazono. 2 - (hydrazinodicarbonyl) - hydrazono, 25 (cyanoacetyl) - hydrazono, 2 - (gluconyl) hydrazono, 2(benzoyl) - hydrazono, 2 - (furoyl) - hydrazono, 2(isoxazol - 3 - yl)carbonylhydrazono, 2 -(5 - methylisoxazol - 3 - yl) carbonylhydrazono, 2 - (1,2,5thiadiazol - 3 - yl)carbonylhydrazono or 2 - (510 methyl - 1,2,3 - thiadiazol - 4 - yl)carbonylhydrazono; (8) 2 - (carbalkoxy)hydrazono in which the carbalkoxy moiety contains from 2 to 5 carbon atoms, 2(dithiocarbalkoxy) hydrazono in which the dithiocarbalkoxy moiety contains from 2 to 5 carbon atoms; and other equivalent groups.

One embodiment of the invention is a compound as defined above wherein A and R are each hydrogen; Y is methoxy; li is thienylacetyl; X is hydroxy; m is zero; the broke i line represents a double bond at position 3; and Z’is -in acetylhydrazono or 2 - (p - carboxyphenyl) hydrazono group, and alkali metal salts thereof.

A further embodiment is a compound as defined above wherein A, Y and R are each hydrogen; X is hydroxy; m is zero; the broken line represents a double bond at position 3; and B and Z are selected from the following pairs; furoyl and acetylhydrazono; phenylacetyl and acetylhydrazono; 2,2,2 - trichloroethoxycarbonyl and acetylhydrazono; (1H - tetrazol - 1 - yl)acetyl and formylhydrazono; phenylglycyl and ethox30 alylhydrazono; phenylmalonyl and cyanoacetylhydrazono; mandeloyl and butyrylhydrazono; and hydrogen and acetyl- 11 41574 hydrazone, respectively and alkali metal salts thereof.

Yet a further embodiment provides a compound as defined above wherein Y and R are each hydrogen; X is hydroxy; m is zero; the broken line represents a double bond at position 3; A and B are phthalyl or benzal; and Z is an acetylhydrazono or 2 - pyridylhydrazono group and alkali metal salts thereof.

The present compounds can be prepared by the reactions set out in the following paragraphs (1) The reaction of an oxo compound (II), or its reactive derivatives, with a hydrazine compound (III), or its reactive derivatives, as in the following scheme: (II) (III) (j) wherein A, Β, X, Y, Z, R, m and the broken line are as defined above. The compound (II) can be prepared from the corresponding 3-hydroxyalkyl compound by e.g. oxidation with chromium trioxide. Its reactive derivatives include acetals (e.g. the dialkylacetal, diacyl acetal, hemiacetal or the hemiacetal lactone with the carboxy group at position 4) and other derivatives which form hydrazones upon reaction with hydrazines. The hydrazine compounds (III) are easily available compounds. 4157 4 - 12 The reactive derivatives of the hydrazine compounds (III) include salts thereof with an acid, N-acyl derivatives (e.g. alkanoyl derivatives or carbonic acyl derivatives), alkylidene derivatives, aralkyli5 dene derivatives, or like reactive derivatives which form hydrazones upon reaction with the oxo compounds (II) or their reactive derivatives.

The reaction can be carried out by contacting the reactants, preferably in a solvent, to give the desired products. The solvent can be a hydrocarbon, a halohydrocarbon, an ether, an ester,an alcohol, a carboxylic acid, a base, an amide, a nitrile, a nitrohydrocarbon, a sulfoxide, or an aqueous solvent, or a mixture thereof. Preferred solvents are tetrahydrofuran, tetrahydropyran, ethyleneglycol dimethyl ether, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water or a mixture thereof. The reaction can be carried out at room temperature (preferably), or at an elevated or cooled temperature. The pH of the reaction medium can be ad20 justed to neutral or to a weakly acid pH for fast reaction. Stirring and protection of the reaction mixture from moisture with an inert gas are preferred.

This reaction proceeds through 3 - (a - hydroxy - ahydrazinylalkyl)cephem compounds as intermediates.

The products can be recovered by conventional methods (e.g. by extraction, precipitation, adsorption, recrystallization, reprecipitation and/or chromatography).

When the free acid is obtained it can be converted to a salt by neutralization or by cation exchange with a suitable metal salt. (2) When A or B of a compound (I) is hydrogen - 13 the amino group can be protected by conventional metho is to give the corresponding compound (I) wherein A or B is an amino protecting group. Among amino protecting groups, acyl groups can be introduced by the use of an acylating reagent having the desired acyl moiety e.g. halides, anhydrides, reactive esters, reactive amides and azides, or like acylating reagents; silyl, sulfenyl or hydrocarbon groups can be introduced by the use of e.g. silyl halide compounds, silazanes, sulfenyl halides, halohydrocarbons, aldehydes, ketones or like reagents. In these cases, the group —NAB can be prior activated in the form of e.g. an iminohalide, an iminoether, an isocyanate or like forms. (3) Compounds (I) wherein A or B is an amino protecting group can be deprotected to give compounds (I) wherein A or B is hydrogen. The methods which can be used for the deprotection include, for acyl groups, the action of carbonium ion-forming reagents, acid, acid halides, toluene-p-sulfonic acid, hydrazine, or phosphorus pentachloride followed by alcohols and acids; for benzyloxycarbonyl or haloalkoxy carbonyl groups, catalytic hydrogenation or reducing metals with acid; for silyl or sulfenyl groups, acids or bases; for aralkyl, 1-alkylene, alkylidene or aralkylidene groups, acids, catalytic hydrogenation or hydrogenolytic reducing reagents all according to conventional methods . (4) Compounds (I) wherein X is hydroxy can be protected to give compounds (I) wherein X is a carboxy protecting group. Such protection methods include esterification with alcohols or phenols or their reactive derivatives, with diazo compounds, halogenated compounds, reactive esters, reactive amides or like 574 - 14 esterifying reagents; amide formation with amine compounds, hydrazine compounds, reactive amides or like amidating reagents; salt formation from a free acid with a base or by cation exchange with other suitable salts; and silyl or tin ester formation with silyl halides, disilazanes, tin halides or like reactive organic silyl or organic tin derivatives. Prior to these protection methods the carboxy group can be activated by the use of halide forming reagents (e.g. thionyl halides, phosphorous trihalides and oxalyl halides), acylating reagents (e.g. alkoxycarbonyl halides for anhydride formation), amidating reagents (e.g. carbonyl diimidazole for reactive amide formation), esterifying reagents (e.g. p-nitrophenol for reactive ester formation) or like reagents. (5) Compounds (I) wherein X is a carboxy protecting group can be deprotected to give compounds (I) wherein X is hydroxy. Such deprotection methods include the use of acids (e.g. inorganic acids, sulfonic acids, trifluoroE'cetic acid or other organic acids), water or bases ior esters, amides or anhydrides; the use of reducing reagents (e.g. zinc or tin) for haloalkyl esters; the use of alkali metal thiophenoxides for phenacyl esters, and other conventional deprotection methods which give the free carboxy group. Salts can be converted to free acids by the action of an acid, including cation exchange resins (H+-form) (6) Compounds (I) wherein m is 0 can be treated with an oxidizing reagent to give compounds (I) wherein m is 1. Such oxidizing reagents include oxidizing inorganic salts (e.g. periodates or permanganates) inorganic or organic peracids or their salts (e.g. periodic acid, chromic acid, peralkanoic acids, aromatic percarboxylic acids or their salts), salts, esters, or amides of hypohalogenous acids, iodobenzene salts, metal peroxides (e.g. nickel peroxide), hydrogen peroxide, oxygen, ozone and other reagents capable of oxidizing sulfide to sulfoxide. If desired, regulators, e.g. isopropanol, can be added to the reaction mixture. (7) Compounds (I) wherein m is 1 can be treated with reducing reagents to give compounds (I) wherein m is 0. Suitable reducing reagents include reducing inorganic salts (e.g. thiosulfate, iodides, divalent tin or iron salts), phosphorous trihalides, phosphines, hydrides (e.g. sodium borohydride), hydrogen or other reducing reagents capable of reducing sulfoxides to sulfides. Conventional methods known in the art may be used. (8) Compounds (I) wherein any of the groups A, Β, X, or 'Δ has a functional group can be protected by a suitable protecting group to give compounds (I) wherein A, Β, X, or Z have protected functional groups. The methods used are conventional in the art. Thus, for example, amino groups may be protected by acyl groups by means of acylating reagents (e.g. acid halides, acid anhydrides, acid azides, reactive amides or reactive esters), by silyl or sulfenyl groups by means of silyl halide compounds, disilazane compounds, sulfenyl halides or like reagents, or by hydrocarbon groups by means of unsaturated compounds, halohydrocarbons, oxo compounds, or by other methods listed above in paragraph (2); hydroxy groups can be protected by the use of acylating reagents as described above, by the use of etherifying reagents (e.g. dihydropyran , 1,1-dialkoxy41574 alkanes or oxo compounds) or by other reagents to protect them in the form of esters, ethers, acetals, or other protected forms; oxo groups can be protected by the use of alcohols, hydroxylamine, acylating rea5 gents or other reagents to protect them in the form of acetals, oxides, enol ethers, enol esters or other protected forms; carboxy groups can be protected by the use of alcohols, diazo compounds or like reagents to protect them in the form of esters, or by other methods described above in paragraph (4); basic groups and acid groups can be protected with acids or bases, respectively, in the form of salts; or other conventional methods in the art may be used. (9) Compounds (I) wherein the groups A, Β, X, or Z have protected functional groups can be deprotected to give compounds (I) wherein the groups have free functional groups. The deprotecting methods which may be used are conventional in the art. Thus, for example, amino protecting groups, namely acyl, silyl, sulfenyl, hydrocarbon groups and like amino protecting groups, can be removed by hydrolysis, hydrogenolysis, reducing reagents, ultraviolet irradiation or by other methods e.g. those described in paragraph (3) above; hydroxy protecting groups, namely acyl, silyl, ether or acetal groups, or like groups can be removed by hydro)ysis, hydrogenolysis, reduction with zinc or tin or by other methods; carboxy protecting groups can be removed by hydrolysis with an acid or a base, hydrogenolysis, reductive fission, ultraviolet irradiation or by other methods e.g. those described in paragraph (5) above; enol ethers, enol esters or acetals can be hydrolyzed with acids or bases; and the salts of basic or acidic groups can be neutralized.

The above types o£ reaction (2) to (9), can generally be carried out at temperatures of from -50°C to 100°C, in the presence, if desired, of an acid, a base or a condensing reagent and preferably in conventional solvents.

The products of the reaction can be isolated and purified by extraction, concentration, precipitation, adsorption, washing, reprecipitation, recrystallization, chromatography, lyophillization and/or countercurrent distribution, or by the use of other conventional methods.

The compounds (I) of this invention are useful as antibacterial compounds or as their intermediates. Thus, for example, the compounds (I) wherein A is arylacetyl, B is hydrogen, X is hydroxy, Y and R are both hydrogen, m is 0, the broken line represents the presence of a double bond at position 3 and Z is a 4 4 group =N—NHR (in which R is an acyl group containing from 1 to 6 carbon atoms, e.g. alkanoyl, oxalyl, alkoxalyl or cyanoacetyl; or a carboxyphenyl group), and their alkali metal salts, show stronger antibacterial activity in vitro against Proteus mirabilis or other Gram negative bacteria than commercial cefalotin, cefaloridin, cefalexin and cefazolin. Furthermore, compounds (I) wherein R is formyl, acetyl, cyanoacetyL, oxalyl, or like groups, show stronger antibacterial activity in vivo than cefalotin, cefaloridin, cefalexin, cefaloglycin or cefazolin against Streptococcus pyogenes by an anti-infection test The present antibacterial compounds can be used for the treatment or prevention of human, veterinary or plant diseases; or for disinfection (e.g. of an article or building structure) or for the prevention of decay. For human use, they may be administered as powders, solutions, vials, injections, capsules, tablets, ointments or like preparations containing, for example, from 0.01 to 100% of the compound or compounds (I) at a daily dose of from 1 mg to 1 g per kilogram body weight. 3-0 The present invention provides a pharmaceutical formulation which comprises as an active ingredient a compound in accordance with the invention or salt thereof, provided that the double bond is at position 3 of the six-membered ring, said compound or salt being formulated for pharmaceutical use.

In one embodiment of the formulation, suitable for parenteral administration said formulation contains from 0.1 to 10 g of said compound or salt and is in the form of powder, lyophilizate or crystals in a vial.

The invention also includes a pharmaceutical composition which comprises a compound in accordance with the invention or salt thereof, provided that the double bond is at position. 3 of the six-membered ring, and a pharmaceutically acceptable diluent, carrier or excipient.

The present pharmaceutical formulation and compositions may be in unit dosage form.

The invention further provides a method for inhibiting the growth of bacteria in an environment, which method comprises administering to the environment an effective amount of a compound in accordance with the invention or salt thereof, provided that the double bond is at position 3 of the six-membered ring, of a pharmaceutical formulation in accordance with the invention, or of a pharmaceutical composition in accordance with the invention. Such a method may be used in the treatment or prevention of disease in a non-human animal or a plant, in the prevention of decay in a perishable substance or in the disinfection of an article or building structure.

Among the coinpounds (I), the 1-oxides, 2-cephems and the usual esters are weak antibiotics rather more useful as intermediates for the synthesis of compounds having stronger antibacterial properties. Furthermore, compounds (I) wherein A or B is an organic acyl, inorganic acyl or phenylthio group are strongly antibacterial with respect to Gram positive bacteria.

The invention will now be further illustrated and described by way of the following Examples.

The elemental analyses of the compounds as prepared show good agreement with the calculated values. DMSO stands for dimethyl sulfoxide and EtOH stands for ethanol.

Example I—1.

A solution of 3 - formyl - 7 - acylamino - 3cephem - 4 - carboxylic acid hemiacetal lactone (II) in an organic solvent is mixed with a solution of a hydrazine compound (III) and acid, or a salt or a hydrazine compound (III) in water, and allowed to react at room temperature. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with water and ethyl acetate or - 2 Ο ether, and dried to give the objective cephalosporin compound (I). When little or no solid is formed upon concentration, the concentrated reaction mixture or filtrate is extracted with ethyl acetate, washed with water, dried and evaporated to dryness to give a residue which is triturated in ether or petroleum ether to obtain the desired cephalosporin compound (I).

The Tables which follow after Examples I—2 to IX—2 show examples of the reaction, the reaction conditions and physical constants of the products THF stands for tetrahydrofuran and on stands for standing overnight.

Example I—2.

By procedures similar to those of Example I—1, the following compounds are prepared: (1) 3-(2- acetylhydrazono)methyl - 7 - (2furylamino) - 3 - cephem - 4 - carboxylic acid. (2) 3-(2- acetylhydrazono)methyl - 7 - pheny]acetamido - 3 - cephem - 4 - carboxylic acid, (3) 3-(2- acetylhydrazono)methyl -7-. phthalimido - 3 cephem - 4 - carboxylic acid, (4) 3-(2- acetylhydrazono)methyl - 7 - (2,2,2trichloroethoxycarbonyl)amino - 3 - cephem - 4carboxylic acid, (5) 3 - (2 - acetylhydrazono)methyl - 7benzalamino - 3 - cephem - 4 - carboxylic acid, (6) 3-(2- formylhydrazono)methyl - 7 - (1 tetrazolyl)acetamido - 3 - cephem - 4 - carboxylic acid, 41S74 (7) 3 - (2 - eChoxalylhydrazono)methyl - 7phenylglycylamino - 3 - cephem? - 4 - carboxylic acid, (8) 3-(2- cyanoacetylhydrazono)methyl - 7(u - carboxyphenylacetamido) - 3 - cephem - 45 carboxylic acid, (9) 3-(2- cyanoacetylhydrazono)methyl - 7mandeloylamino - 3 - cephem - 4 - carboxylic acid, and (10) 3-(2- propylhydrazono)methyl - 710 mandeloylamino - 3 cephem - 4 - carboxylic acid.

Example I—3 To a solution of diphenylmethyl 3 - formyl - 7(2 - thienylacetamido) - 3 - cephem - 4 - carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solu15 tion of carbethoxymethylhydrazine hydrochloride (69 mg) in water (2.5 ml), and the mixture is kept at room temperature for 2 days. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 7-(2- thienylacetamido) - 3(2 - carbethoxymethylhydrazono)methyl - 3 - cephem.4 - carboxylate (129 mg.) m.p. 70—75°C.

Yield. 69%. Ir: (registered Trade Mark) 3270, max 1780, 1745, 1670; 1540cm1, NMR: 6d6DMS° (60MHz) 1-435 (6Hz) 3H, 3.52ABq (24; 17Hz) 2H, 3.48s2H, 3.60S2H, 4.17 quintet (6Hz) 2H, 4.95d(5Hz)1H, 5.70dd(8;4Hz)1H, 6.67—7.63ml6H, 8.03slH. [α]β24'5 -144° (c=O.34O, chci3).

Example I—4.

To a solution of diphenylmethyl 3 - formyl - 7. (2 - thienyl - acetamido) - 3 - cephem - 4 - carboxy41574 late (155 mg) in tetrahydrofuran (15 ml) is added a solution of (sulfolane - 3 - yl)hydrazihe (70 mg) and 1.5 equivalents of hydrochloric acid in water (3 ml), and the mixture is kept at room temperature for hours. The crystals obtained by concentration of the reaction'mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl - (sulfolan - 3 - ylhydrazono)methyl - 7 - (2thienyl acetamido) - 3 - cephem - 4 - carboxylate (142 mg), m.p. 117—125°C. Yield. 76%. IR: vNu3o1 3275, . max 1785, 1715, 1675, 1530cm.

Example I—5.

To a solution of 3 - formyl - 7 - (2 - thienylacetamido) - ·7 - methoxy - 3 - cephem - 4 - carboxylic acid hemiacetal lactone (115 mg) in tetrahydofuran (9 ml) is added a solution of p - carboxyphenylhydrazine hydrochloride (84.8 mg) in water (3 ml), and the mixture is kept at room temperature for 3 hours. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give 3 - (2 - p - carboxyphenylhydrazono)methyl - 7 - (2 - thienylacetamido- 7methoxy - 3 - cephem - 4 - carboxylic acid monohydratc (87 mg), m.p. 156—162°C (decomposition). Yield: 56%. IR:VNu;|01 3260, 1770, 1681, 1605, 1533cm1. max PtOH UV: λ 236nm (e=15100): 288nm (e=6900). NMR: max z Sdg-DMSO 3>39s2H< 3.42s3H, 3.85s2H, 5.25slH, 6.9—7.5n 3H, 8.30S1H, 9.78slH, 12.80slH [a]^3 -78.6° (c=0.280, DMSO).

Example I—6.

To a solution of 3 - formyl -7-(2- thienyl- 23 acetamido)-7-methoxy-3-cephem-4-carboxylic acid hemiacetal lactone (115 mg) in tetrahydrofuran (9 ml) is added a solution of acetylhydrazine (44.4 mg) in water (3 ml) containing hydrogen chloride (2 equivalents), and the mixture is kept at roqm temperature overnight. The reaction mixture is concentrated to give oily materials, which are extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The thusobtained residue is triturated in ether to give 3-(2acetylhydrazono)methyl-7-(2-thienylacetamido)-7-methoxy3-cephem-4-earboxylic acid (68 mg), m.p. 173-176°C (decomposition). Yield: 52%i IR: V Nu^01 3260, 1788, max 1714, 1675, 1597 (Shoulder), 1535, 1525cm-1. UV: λ Et0H max 234nm(s = 13400),- 319nm(ε = 21300). KMR: δ d6-DMS0 (60MHz)1.92s+2.12s3H, 3.40s3H, 3.74d(5Hz)2H, 3.83s2H, 5.25slH, 6.90-7.45m3H, 8.12s+8.28slH, 9.48slH., [a]D23*5 +125° (c = 0.305 DMSO).

Example 1-7.

By a procedure similar to that described in Example 1-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-2cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are allowed to react in a mixture of tetrahydrofuran (8 ml) and water (1.5 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2thienylacetamido)-2-cephem-4-earbaxylate (95 mg), m.p. 168-178°C. (decomposition).

Yield: 83%. IR: V N“£o1 3280, 1760, 1743, 1695, 1667, max 1697, 1677, 1538cm-1. UV: λ E*°H 301nm(e = 31700).

NMR: 6CDCl3 (60MHz) 1.81s3R, 3.38s2H, 5.07d(4Hz)lH, .40slH, 5.50brlH, 6.63brlH, 6.83slH, 6.88-7.58m- Example 1-8. + 416° (c = 0.501, CHC13) By a procedure similar to that described in Example 1-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3cephem-4-carboxylate 1-oxide (107 mg) and acetylhydrazine (30 mg) are allowed to react in a mixture of tetrahydrofuran (8 ml) and water (1.5 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)-methyl-7-(2thienylacetamido)-3-cephem-4-carboxylate 1-oxide (104 mg), m.p. 205-214°C (decomposition).

Yield: 88%. IR: v Nujo1 3270, 1787, 1722, 1675, 1690 1530cm-1. UV: λ Et0H 329nm(ε = 22530). NMR:δ d6-DMS0 max (60MHz) 1.92s+2.13s3H, 3.88s2H, 5.05d(4Hz)lH, 5.98dd(4;9HZ)1H, 6.82-7.72ml4H, 8.37s+8.52s2H, 11.45d(9Hz)lH. [a)D23 _234° (o = 0.487, CHClg).

Example 1-9 By a procedure similar to that described in Example 1-3, diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3cephem-4-carboxylate (104 mg) and acetylhydrazine (30 mg) are allowed to react in a mixture of tetrahydrofuran (8 ml) and water (1.5 ml) in the presence of hydrochloric acid (2 equivalents) at room temperature overnight to give diphenylmethyl 3-(2-acetylhydrazono)methyl-7-(2thienylacetamido)-3-cephem-4-carboxylate (101 mg), m.p. 130-138°C.

Yield: 88%. 3250, 1782, 1715, 1670, 1597 — RfOH nnm 1535 cm 1. UVi λ 327nm(e = 24000). NMRi [α]β23 -258° (c = 0.493,CHC13).

Example II-l.

A solution (2 ml) of 2-thienylacetyl chloride prepared from 2-thienylacetic acid (78 mg) and thionyl chloride (0.05 ml) in chloroform is added dropwise to a solution of 7-amino-3-(2-ethoxalylhydrazono)methyl-3 cephem-4-carboxylic acid (171 mg) and triethylamine (0.14 ml) in chloroform (2 ml), and the mixture is stirred for 1 hour. The residue obtained by concentration of the reaction mixture is dissolved in a mixture of water and ether. The aqueous layer is acidified with 10% hydrochloric acid to pH 1.5, and extracted with ethyl acetate. The extract is washed with water and dried and then concentrated. The thus obtained residue is crystallized from a mixture of ether and ethyl acetate to give 7-(2-thienylacetamido)-3-(2-ethoxalylhydrazono)methyl-3-cephem-4-carboxylic acid monohydrate (196 mg). m.p. 134-137°C (decomposition). Yield; 84%.

Example II-2.

A mixed anhydride prepared from 2-thienylacetic acid (78 mg), isobutyl chloroformate (0.07 ml), and triethylamine (0.08 ml) is added to a solution of 7amino-3-(2-acetylhydrazono)-methyl-3-cephem-4-carboxylic acid (124 mg) and triethylamine (0.07 ml) in tetrahydrofuran (6 ml) with ice cooling. After standing for 6 hours at room temperature, the reaction mixture is concentrated and the residue is dissolved in a mixture of ethyl acetate and water. The aqueous layer is washed with a small amount of ethyl acetate, acidified to pH 2 with hydrochloric acid, and extracted with ethyl acetate. 574 The extract solution is dried and evaporated. The obtained residue is- triturated in ether to give 7-(2thienylacetamido)-3-(2-acetylhydrazono)methyl-3-cephem4-carboxylic acid monohydrate (121 mg). 184-190°C (decomposition). Yield: 65%.

Example II-3.

A solution of 2,4—dinitrophenyl 2-thienylacetate [prepared from 2-thienylacetic acid (31 mg), 2,4-dinitrophenol (40 mg) and Ν,N'-dicyclohexylcarbodiimide (36 mg), in tetrahydrofuran (0.5 ml)] in chloroform (0.2 ml) is added to a solution of 7-amino-3-(2-formylhydrazono)methyl-3-eephem-4-carboxylic acid (40 mg) and triethylamine (0.09 ml) in chloroform (0.5 ml). After 15 hours' stirring, the reaction mixture is concentrated to give a residue which is dissolved in water, washed with ethyl acetate, acidified to pH 2 with hydrochloric acid, and extracted with ethyl acetate. The dried extract is concentrated. The thus obtained residue is triturated in ether to give 7-(2-thienylacetamido)-3-(2-formylhydrazonq)methyl-3-cephem-4-carboxylic acid monohydrate (52 mg). m.p. 150-160°C (decomposition). Yield: 72%.

Example II-l.

To a solution of 7-amino-3-(2-pyridyl)hydrazonomethyl-3-cephem-4-carboxylic acid (106 mg) and triethylamine (51 mg) in dimethylsulfoxide (0.5 ml) is added N-carbethoxyphthalimide (80 mg), and the mixture is stirred for 24 hours. The reaction mixture acidified to pH 2 with hydrochloric acid is shaken with water and ethyl acetate. The aqueous layer is saturated with sodium sulfate and extracted with ethyl acetate. The dried extract solution is concentrated to give a residue which is triturated in ether to give 7-phthalimido-3(2-pyridyl)hydrazono)tnethyl-3-cephem-4-carboxylic acid (106 mg). Yield: 71%.

Example I1-5.

Tp a solution of diphenylmethyl 7-amino-3-(2-ethox alylhydrazono)methyl-3-cephem-4-carboxylate (127 mg) and 2-thienyl acetic acid (36 mg) in tetrahydrofuran (3 ml) is added N,N1-dicyclohexylcarbodiimide (54 mg) and the mixture is stirred for 4 hours. The precipitate which separates is removed by filtration, and concentrated to give a residue which is extracted with methylene chloride. The extract is concentrated and triturated in a mixture of ether and ethyl acetate to give diphenylmethyl 7-(2thienylacetamido) -3-(2- ethoxalylhydrazono)methyl-3cephem-4-carboxylate (112 mg). Yield: 71%.

Example II-6.

The compounds prepared by the procedures of Examples 1-1 to 9 are prepared by methods similar to those of Examples II-l to 5.

Example III-1.

To a solution of sodium 3-(2-acetylhydrazono)methyl7-(o-nitrophenylsulfenyl) amino-3-cephem-4-carboxylate (100 mg) in 75% dioxane (5 ml) is added hydrochloric acid and potassium iodide (adjust to pH 3), and the separated iodine is titrated with sodium thiosulfate. The reaction mixture is acidified to pH 1.5 with hydrochloric acid, washed with ether, neutralised and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to give 7-amino-3-(2-acetylhydrazono)methyl-3cephem-4-carboxylic acid. - 28 Example IV-1.

To a solution of 3-(2-acetylhydrazono)methyl-7-(2thienylacetamido)-3-cephem-4-carboxylic acid (75 mg) in a mixture of methylene chloride and methanol is added a solution of diphenyldiazomethane in petroleum ether, and the mixture is kept at room temperature for 13 hours.

The reaction mixture is concentrated to give a residue which is dissolved in ethyl acetate and diluted with ether. The separated crystals are collected by filtrat10 ion, washed with ether, and dried to give diphenylmethyl3- (2-acetylhydrazono)methyl-7-(2-thienylacetamido)-3cephem-4-carboxylate (87 mg). m.p. 13O-138°C.

Yield: 78%.

In a manner similar to that described above, 3-(215 acetylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem4- carboxylic acid 1-oxide is esterified to give the corresponding diphenylmethyl ester.

Example V-l.

To a solution of diphenylmethyl 3-(2-carbethoxy20 methylhydrazono.) methyl-7-(2-thienylacetamido)-3-cephem4-carboxylate (108 mg) in methylene chloride (2 ml) are added anisole (0.1 ml) and trifluoroacetic acid (0.2 ml), and the mixture is kept at 0°C for 2 hours. The reactior mixture is concentrated to remove methylene chloride and trifluoroacetic acid and the thus-obtained residue is diluted with ether. The separated crystals are collected by filtration to give 7-(2-thienylacetamido)3-(2-carbethoxymethylhydrazono)methyl-3-cephem-4carboxylic acid (61 mg). m.p. 126-135°C (decomposition).

Yield 77%. IR: υ Nu3o1327O, 1795, 1745, 1665, 1605, max 1540 cm-1. UV: λ Et0H 345nm(e = 12000). max Example V-2.

To a soLution of diphenylmethyl 3-(sulfolane-3-ylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4carboxylate (122 mg) in methylene chloride (2 ml) are added anisole (0.1 ml) and trifluoroacetic acid (0.2 ml), and the mixture is kept at 0°C for 2 hours. The reaction mixture is concentrated to remove methylene chloride and trifluoroacetic acid and the thus-obtained residue is diluted with ether. The separated crystals are collected by filtration, washed with ethyl acetate and water, and dried to give 3-(sulfolan-3-ylhydrazono)methyl-7-(2-th ienylacetamido)-3-cephem-4-carboxylic acid (110 mg). m.p. 140-150°C. (decomposition). Yield: 91%.

IR: \> Nu3o1 35,00, 3230, 1790, 1660, 1605, 1530 cm-1, max UV: λ Et0H 228nm(e = 15250); 317nm( e = 7600); 400nmmax (ε=37ΟΟΟ). NMR: fid6DMS0~ 3.0-4.4m8H, 3.83s2H, 5.20d(5Hz)lH, 5.97dd(8;5Hz)2H, 6.77-7.60, 8.00slH, 9.13d(8Hz)lH. [«]D25 + 107° (c = 0.303, DMSO).

Example VI-1.

To a solution of diphenylmethyl 7-(2-thienylacetamido)-3-(2-acetylhydrazono)methyl-2-cephem-4-carboxylate (188 mg) in methylene chloride (4 ml) is added dropwise a solution of m-chloroperbenzoic acid (60 mg) in a mixture of methylene chloride (0.6 ml) and isopropanol (0.6 ml). After 1 hour, the reaction mixture is diluted with methylene chloride and petroleum ether.

The precipitate which separates is collected by filtration, washed with methylene chloride, and dried to give diphenylmethyl 7-(2-thienylacetamido)-3-(2-acetyl30 hydrazono)methyl-3-cephem-4-carboxylate 1-oxide (184 mg), m.p. 2O5-214°C (decomposition). Yield: 95%. - 30 In a method similar to that described above, diphenylmethyl 7-.{2-thienylacetamido)-3-(2-acetylhydrazono)methyl-3-cephem-4-carboxylate is oxidized with mchloroperbenzoic acid to give a compound identical with the compound prepared by the above method.

Example VI-2.

An aqueous solution of O.25M periodic acid (2.5 ml) diluted with a phosphate buffer (pHj 3.8 ml) is added to a solution of diphenylmethyl 7-(2-thienylacetamido)3-(2-formylhydrazono)methyl-3-cephem-4-carboxylate (183 mg) in dioxane (8 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated to remove dioxane and is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The thus-obtained residue is crystallized from a mixture of ethylacetate and ether giving diphenylmethyl 7-(2-thienylacetamido)-3-(2-formylhydrazono) methyl-3-eephem-4-carboxylate 1-oxide (113 mg).

Yield: 60%.

Example VIX-1.

To a solution of stannous chloride dihydrate (112 mg) and diphenylmethyl 7-(2-thienylacetamido)-3-(2-acetylhydrazono)-methyl-3-cephem-4-carboxylate 1-oxide (145 mg) in Ν,Ν-dimethylformamide (4 ml) is added acetyl chloride (0.18 ml) with ice cooling. After stirring for 2 hours the reaction mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with a dilute aqueous solution of sodium bicarbonate and water and dried, and then concentrated to give a residue which is triturated in a mixture of ethyl acetate and ether. The precipitate which separates is collected by filtration and dried to give diphenylmethyl 7-(2thienylacetamido)-3-(2-acetylhydrazono)methyl-3-cephem4-carboxylate (118 mg). m.p. 13O-138°C. Yield: 84%.

Example VIII-1.

A solution of 3-hydrazonomethyl-7-(2-thienylacetamido) -3-oephem-4-carboxylic acid (93 mg) in a mixture of acetic anhydride (0.5 ml) and pyridine (0.2 ml) is kept at room temperature for 45 hours. The mixture is diluted with ether. The thus-obtained precipitate is collected by filtration and dried to give 3-(2-acetylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4carboxylic acid monohydrate (101 mg). m.p. 184-190°C (decomposition). Yield: 96%.

Example IX-1.

To a solution of 3-(2-tertiary butoxycarbonylhydrazono)-methyl-7-(2-thienylacetamido)-3-cephem-4carboxylic acid (247 mg) in methylene chloride (1 ml) are added anisole (0.6 ml) and trifluoroacetic acid (0.6 ml), and the mixture is kept at room temperature for 1 hour. After removing trifluoroacetic acid and methylene chloride, the reaction mixture is diluted with ether. The separated crystals are collected by filtration and dried to give 3-hydrazonomethyl-7-(2thienylacetamido)-3-cephem-4-carboxylic acid in nearly quantitative yield. m.p. 164-169°C (decomposition).

IR: vNujo1 3260, 1787, 1657, 1542cm-1. UV: λ CH3°H max max 23O.5nm( ε = 12900); 304nm( ε = 6900); 402nm( e= 12400).

NMR: 5dg-DMSO (eoMHz) 3.79s2H, 3.84(12Hz)2H, 5.20d(5Hz)lH, 5.84dd(8;5Hz)lH, 6.8-7.5nm3H, 7.55s+7.78slH, 9.12(8Hz)lH, [ajp23*5 +66.2° (c-0. 5022,DMSO).

Example IX-2.

A solution of 3-[2-(N-tertiary butoxycarbonylglycyl)-hydrazono]methyl-7-(2-thienylacetamido)-3-cephem 4-carboxylic acid (120 mg) in a mixture of anisole (0.6 ml) and trifluoroacetic acid (1.2 ml) is kept at 0°C for 1 hour. The reaction mixture is concentrated to remove trifluoroacetic acid and the thus-obtained residue is diluted with ether. The separated crystals are washed with ether and water and dried to give 3-(2-glycylhydraz ono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (60 mg) . m.p. 204-209°C. (decomposition). Yield: 62%. IR:V Nu7o1 3260, max 1767, 1660, 1600, 1585 cm-1. UV: λ Et°H 235nm; . max 316nm (Saturated solution). NMR: fi d6 DMS0 3.58s2H, 3.9dd2H, ,17d(4Hz)lH, 5.75dd(8?4Hz)lH, 6.80-7.47m3H, 8.20slH, 9.13d(8Hz)lH. · 4157 4 Ν CN +1 nt φ £ φ +ι ε ο ο Μ Ο J23 & Cn Reaction Time (hours) Acid (equivalent) Solvent tn ε ID cn rH 00 r>· 10 Φ o CN CN rH r-t rH rH G CN - CN 0 η m h m 1 O · u * £ H £ r-t O o *0 O <0 CN CN · CN · W ’M* W £ + + + + + 4* a ™ ή CN 3 H 3 H 3 r-t Eh eh EH CN Η O in <*) U cn io r* ·—* Ό rH -— ο ίΛ Η ΪΗ ο Ίη Reaction tilne (hours) Acid (equivalent) Solvent i~4 ε tn ε ω r* cn CD . r· r- CO O CM CD tn in «—I rH rH m • cn CM in H m H in □ · I u · EG ί-1 W rH O o o CMD CM or* ffi ffi · + + in + CM έ + & + 3 CM 3 CM 3 Eh H Eh r-l Eh rH in • CM CO pH pH pH σ» rH rH tn ε rH rH <*) rH rH rH Ό rd ~ Q) Reaction time (hours) Acid (equivalent) Solvent r* ω in o o co in ’d’ m 00 x* co 00 H m • 00 n CM O O o nr* Cl mn W · £p · + co + in + CN ή + & ± 3 N S OJ S rd EH rH Eh H H cn co CN o o rd H (55 W H CN a O O' ΰ3 Reaction time (hours) Acid (equivalent) Solvent h ε O' ε OH CM Η Η H ra ra m co h h H h £ H 0 CM H in H H in O · a U · ffi H ffi ra W H o o O OJ LQ OJ m oj H ffi » • W • + + r· + m & + & + + 3 CM 3 tp aj Ej H &j H H r-1 ra m ra ra (141) (90) Q) •rl >-* >4 Οι Ο o bi Reaction time (hours) Acid (equivalent) Solvent g ro rH rH in rH in ro r- h- co rH ID co CO CO in CO r—1 rH CO in 10 • CH H m H w 1 o · o · a rH a rH O o o CH CH CH CO ta a a · + co + + co a + a + a ± a a a o £ H rH H VD ’Φ 01 10 10 51· Ϊ ID > CO rd rd H Ό Ο Τη Reaction time (hours) Acid (equivalent) Solvent E tr> g o m co co O σι Γ* co rd ι-1 rd CO c H rd 0 rd rd tn u · ffi rd 1 -I in & H O O o CM Φ CM tn cm m w · 8 • W · + + co + H CM + Pm + ja + 8 CM 8 <4* W o Ε-» rd fr* rd Ε-ι ω si· co tn co CM CO H Ό ι-Η φ g £ CL'' o tn μ β ο — Reaction time (hours) Acid (equivalent) Solvent B Cn E cn O rH rH CM CM CO ω cn 10 cn m in 10 rH co H in r* • rH <3* CM CJ W ω co 0 Id· 0 • (M · N O w 0 W + + + + 5f in 6 σι b + • E · K £N 1—1 IH rH EJ H <4.

CM *3* rH -03 HO CN CO CN CN CN Ό in O m in r- m io tn S-S Ci σι Reaction Time (hours) Acid (equivalent) Solvent g tn S rd a a m rd CN CN a a + tn + ft + a + a cn a oi EH rd &< rd 00 CO » CO H rd CD THF+H„0 HCl 1.5 118 (141) -NNHC0C0NHNH- (71) 12+4 1.5 « Ο in Ζ d kO CM h· CM O ”&l S-s Reaction Time (hours) Acid (equivalent) Solvent g in CO O n· co co 00 in CM cn r* co H H G a H in 0 ί 8 Γ I 1—1 h in kJ cn H H □ · O W H υ S OJ o o kO O CM kO CM ffi · • a sf + + kO + · & + fa + a 3 CM 8 CM a + Eh H Eh r-1 Eh CO -OO HO co 01 O CH CH CO ο 5> Reaction Time (hours) Acid (equivalent) Solvent Γ- rH CO Ι'- Γ— CO CH > O H CH rH in in • « in CH CH H r-I m rH in ϋ υ · y • a ch W tn rH o o o CM CH Γ— CH co tn 5f a • a • + • + CH + O Pq CH fa + fa + tn + a 51* a 5l* h CD Β» rH B4 rH in in io r*· io I t- II II II H cm ω σι tn σι Ό γΜ φ ο Cn ΰ3 Reaction Time (hours) Acid (equivalent) Solvent g! to fp Ο oo Ο cn M· Γ* m in in r—l i-l rd in in CM CM .π m u · a h a O CM to o CM to o CM to • a • a • o + M· + + & + a + a (M a CM El r-l Em rd CH.C0- CH. rt in id mm m Ό rH ω ο 5 S3 Reaction Time (hours) Acid (equivalent) Solvent g o ω ω σι CM rH rH O CM rH 00 CM rH in u • 1 rH o o CM m io w a · + CM + -φ a + a + 3 M· S M rH Eh rM rH oi «H THF+H-O HCl 4 138 141) =NNHCOOCH, (54) 14+3 1.5 oi o o af u ο ϊ? Reaction Time (hours) Acid (equivalent) Solvent g tn £ CO σ» co cn co in in Φ co ID Γ- (M ID O m CM 0) rd rd rd C co rd 0 rd in rd in u · y · 1 8 H 8 rd o O o CM ID cm cn CM 8 · 8 · 8 d· CO + ω d· φ Py d- Py + £l ± 3 ’M* 3 ’M* 3 r- Ed H Ed rd Ed rd CM 0) r« r01 (200) (227) ο α ο •Ρ Q 1S74 to in io · - 46 - ο Ο 0 0 Q υ 00 10 οι Γ- 00ο U 0 • 00 a • ΓΟ a • ιη 0 ιη 10 ο υ Η co ο ο co ο ιη • sf ω no ιη rd ηο οι m « m ΟΙ • a μ* rd • ω cn . sf οι I Ο U oj1 Ο Ο οι ι ο CM Γ- a o a a Η H o Tf in rf-X a H *0 ω «κ * x 03 a 00 a 00 a ii H x 03 *0 a Ol a a in « H in H a a O sf in cn H «. H cn • «·. x rf—x in N H P- ω • »—» w 03 • X in 00 a a a 03 a l- σ n H Γ- OI a X—* 00 s si* in Γ- OJ m 1 B a a rf—. OI H oi * •0 6 00 x-rf a OI H 00 rd < in ia • 03 a Ό in ·—* si* a. χ • ω • r* « a 00 x H OI 05 a Tf 05 00 a ID + a 05 sf in a 00 50 Γ- o H co a rd U1 rd • • χ H • • 1 H a X·’ X H x co cn σ τ* a cn a m 00 a in a N a Γ- N O' ·» 00 N Γ- a 05 Ό P- N a rd a * rd co g a x Η x 10 a x O g a in *—x co a • Xkrfrf 10 00 a «- a a a Γ» O co s-· N x_rf OI in Ό • x-rf cn Ol H x rd OI a a x—rf Ό a ». T3 03 a Ό Γ- *0 03 cn rf—. a 03 03 in CO Ό O in in OJ O oj r- I 05 si* N H rd o | O CN «w in rd ¢0 50 co o co wa O co x co H • 00 • N • a a a a in N a a a a a in *—* r- 05 cn a in (0 05 cn < a 00 cn H 10 05 o a X a x · 0 X rf—. rf—X rf—X >—X 05 rf—. o Q o s δ OI O o O o o o H O St· 05 05 50 O Xrf 05 OI in 10 OJ 05 in <0 H H Ol a H CN a a Xrfrf’ ·>—<* x-rf o -X·* Xrfrf· o o si* Ol Γ- 50 cn 50 O m cn O o cn 50 a cn in a OI cn si* OI cn a oi cn o X X r- OI OJ m CN P- CO co si* Γ- 05 O P- 05 Γ- in r* 50 50 Γ» 50 Η H H H H Η Hw x a o P- O in m sf tn > 50 10 in . 00 H in cn 50 O 05 OI 10 OI 10 m οι Γ- in cn H cn H H H Γη H H U • U a u a io 0 10 σ ι 0 0 Sf 05 0) OI 50 QJ m cn 50 10 •σ in m •ύ p- co •ϋ H H X«* H H —· Η H — Ο Ο in Φ οο Μ cn Φ ιη cn η η ι-1· >1 U *ιί ι Ο υ ΟΙ a υ \ - 47 ο °μ Ο ίί u +J υ ω _ ftffi ?s Β Ε Η ρ L £ Ε -μ Ο ϋ Φ Η 01 Ο W *Γ» 1 5 <Κ 25 η ; ft β Ν II rH >1 Ο Ο CN ω rH £ 00 ιη ί>· ο ϋ Ο CN η Ο cn I Ο ω » rH • £ sh σι Ο 1 Ο U οι Ο U ω0 S ιη Ο μ rH 4 1 CN 10 0 10 U O IS 10 o o Q CN O in rH in wo Ο M* W • CN • £ cn · £ ’tf* 1 o O CN 1 o Q CN *P rH £ • 00¼ £ o rH 1 £ a 1 rH CN S' a £ a in rH rH 1 00 <« rH 00 (A • ffl rH Λ rH co <0 • X IP CO £ m co O z-x • cn CN a • cn N 10 cn • a. cn CN N 10 m rH 10 xa* £ • X 00 cn • £ A • «a $ in £ £ rH CN rH £ CN Ό • 00 rH rH in ii a rH CN rH £ Ό H Ul *0 Ό rH CO rf £ rH σι H Ui * O tn X x in z-x 00 * o Xa* σι CN N cn £ 00 r* £ £ rH N CN £ o *0 N • • £ CN rH • • Γ* H • £ «·> rH • rH £ 00 in m «*x cn in E <—x in in 00 Z-X <# CN in co N o • 00 ffl x σι ffl x 00 X ffl X in 00 £ £ co £ a ω £ •x-z £ 00 £ ‘x-' CN CN Ό £ cn rH *—* CN t> *w* CN * Ό CO Ό r- co Ό CO Ό E CO £ <0 o N cn g CN o N cn cn o cn in r·» CN CN co £ t** O rH Η B ω rH co 10 10 O 00 r-x ts • 00 • • m • • • • • • • £ • cn rH m co σι cn ·—* 10 σι cn in r- Ol £ in X Η Η ω σ» cn • οο £ r* Ε ιη cn οο X • x • X • X • Z-X <-> X zx X ZX z-x Z“X Q o ί o a-X O o — O o o O «η o σι ’l O σι o cn O in 88 O in o cn o 10 cn 10 M· in 10 in in ω s in t^ CN CN £ rH 1*X cn rH σι CN rH rH ffl X»z XaZ O Xa* XaZ X_Z XaZ Xa* \Z o aa* o CN in cn in cn co 10 cn f* 10 cn cn CN ts £ cn co Γ-* cn Is* Φ £ cn £ £ CN cn O CN CN cn CN CN cn ϋ CN £ υ X • X • X X • x « o o in o O in O in O 2 £ rH r- σι rH 10 r- φ o in «φ n in in CN <0 in CN 10 m rH 10 £ rH rH rH cn rH rH cn rH rH cn iM rH X X X X XK X X X X X x o CN o o o Q O cn rH o CN O 10 10 CO Γ* O 00 10 O co CO H CN 10 tn ’Φ Γ- 10 10 rH t*x ι© cn rH rH cn Η rH cn rH rH cn rH H ZX □ • □ • o ♦ U · 1 o u I 0 O ο 1 0 u > 0 Φ CN O Φ Ο Φ 00 CN Φ r- QQ T3 10 Γ- T3 10 T3 in 10 T3 rH rH H rH CN rH H Ό Γ* γΗ σι υ ο Ρ ο 0 Ο § Q Γ* in « Γ- « η O o ο o rH • *4* 1 O CM ι σ CO • w o o u o cn w o CM • a in 1 o Q CM υ ο <υ μ &§ a 'ιο g Ό «Ο K * τί <—. 3 a 1 > N rH * rH CO rH 3 a • • tn N rH £ to cn • • 3 Ul 3 a ’Φ tn m * % rH • cn * 3 3 Ul τί <· • τί rH rH cn m co • o 01 O CM co 3 CM N O • • -—· rH • 3 m rH m Ό 3 m m • rH Ό m N co CD g 3 00 X 3 r* CM co 3 «—- ·. 3 CM • • CM τί 3 rH ω in r* »0 U τί tn o 1 in CO Γ* S £3 co κ co r4 tn in tn 3 • 3 • « « • 00 cn rH tO Φ cn in »► , . z—* Ρ ι Μ Ε ψί ξ Ο ΰ) η Λ ο to ·ο I 3 a. a ft β o o o o o o O o o , o o o o O σ* o cn r* co co rH Γ* cn tn to in O rH tn CM CM 3 H rH CM *— *—* o *—<<· >—· —* cn tn in cn O CM to tn CO CM in 3 to cn CM cn CM tn O CM CM cn S tn m in CM cn O r- o tn si· si* cn O 00 to in tO in * r* CO fx 10 in rH rH rH rH rH rH rH • ,K • • O in in o O o tn O r* o m co r* O CM Γ* to Sf tO rH tn CM to ID in CM to in cm r* to sf tn rH rH rH cn rH rH tn rH H rH Q • o • □ • | 0 □ 1 0 0 Λ o u O CO 0 co cn 0) O in 0) p* O τι r*· CO τί cm cn τί rH CM rH rH CM CM *-* 210- 3240, 1770, 215°C 1685, 1660, (dec.) 1595, 1535 C1 rH +> Q Ο ΙΟ [0 ΙΟ Ό <ο M ~ •P g □ B Φ Aa ω o i +> gw <<· Φ rH & 0 W ’HI 2 ? w S Q 0 cn o· O a O cn 0 rH · m + O OJ a a OJ OJ 6 * ω r- a co 01 rH co • W co · ω • m Ο ω ο S § ιη co. a rH θ' ~ 1 Ό ο- cn Ν rH • · cd σι ο σι u • ο a ο ίο Η Ο ιη Η fc η · a ι ο □ «η in in Ό • 00 00 (*) Ι-Η • * tn *0 a co cn * o* w a · co oj in cm S. S3 + 00 H 01 H *» in - m os in S3 • co m H * • • ·» · O • * , o O Q o o o 00 O 0 O 0 Q O 0 cn O cn O O 0 cn cn rH cn in CO O' OJ σι rH o* cn rH rH OJ in CD 1H, 6.8-7.5m3H, 8.18s+ 8.32slH, 9.13d(8.5Hz)1H. 00 r— o in Ol cn cn in OJ rH 0 5f cn rH cn η OJ cn 5f cn CH cn ch cne • • d o o in in o O in in O O co CD cn 01 CD M· CO in m o· Ί* Ol co tn O' CO m O' co Ol co in cn rH rH 1 rH rH rH rH fn rH rH * * • o o in o in in O o in O co CO o σι O r ΓΗ O CD 00 cn 00 O' m o* CD Ol o* CD CH CD m si· Γ- CO cn rH cn rH rH cn rH rH όη H rH □ • □ o · O · 1 o U 1 0 1 0 O ι 0 O o 0 Φ co m Ο Ο Φ si· ο φ M* a Ό oi cn in co τί co σι Ό H rH rH rH rH rH —* rH rH - 50 Ο Ο CM ο ο ο Ρ Q ι Έ1 ο υ 0 Ε • «—1 0 Γ** Ο CM Ο ιη • σ ϋ Ο cn ω · σ» CM Ο r-H · S to • ιη 1 Ο Ω CM ι Ο CM μ Ο Γ- (Μ Η · • σ» m - Μ *Ρ Ε Ο C Φ η ο ι ρ ga Μ Σ Ρ < □ Φ Η Οι 0 οι ·η ι fi Ε Ε Η ο. £ ω * ίΒ Ε Ό cn a CM Ό £ rH Ό ιη m Ό Γ*» • Ν <η • Γ Ε • ιη I 00 cn 00 S 1 TJ Η Ε φ cn Ε Η Η CM S • 01 Ν Ε σ» ω Ε Η ιη Nt ·»-«. • Ν Ε cn Ό Ε rH fQ —- 01 00 Ν ο Ε rH Ε CM rH • m • -ν Η £ ιη ιη 00 Ν Ε cn 1 Ε <η • * 00 « 00 τί £ <η Ε *-* Ε Γ*- CM ι CM Ό co Ό CM • ο a ω »ο £ CM • to • co m Ο Η ιη 1 00 ι—Ι 00 Γ*·» tO « 00 01 • a ι σι 1 • I co in Γ* • Ε in Ε μ 1 > a Μ1 cn A * * Ι*» Ε Η £ % £ CM Ε Ε co Η Μ Η Ε ιη • σι η a 01 Α • r—l • CM 01 to Ο CM t*· 1—1 Ο ,Ν • 1 Ν I ”t Ε • r* Ε 00 • ιη Ε ω «Η • Nt • E Η *** Η + Η cn *-* to κ · « ♦ Ό -X. Φ P o o o o §§ O O o o (0 0 o σι ω co σι cn M •rl ^t cn rH > in rH 3 P r-l CM rH rH rH CM * • P fi ί—* *—» *—* *—* in to fi H Nt Φ m cm cn σι cn rd to 0 m rH cn cm M rH CM CO *“* 9 cm cn cm cn cm cn * k «» a a * * · Γ*· o in O in rH cn r* cn cn to o r* cn co o to > cn cn r*» to m r- to Nt r> to in rH rH rH rH rH rH rH rH rH rH * * • * * » * «» » o o in o in O O cn O CM Φ to to co to O oo cn to σι σι CM to m CM to CM tO in H to in cn i—l rH cn rH cn H 1—1 Μ Hr! __ς □ a u · ϋ a a · » 0 ϋ ΙΟ ϋ 1 0 ϋ 1 Ο ϋ 34 σ\ Φ O in Φ to to Φ o m φ O O rH Η Ό σι o Ό σ σι Ό CM CM CM CM rH CM ι—l ι-Η *-* -U Q 'o’ in • oo vo σι Ο O [-· oj too Η · B VD I O fl n 0 0 <0 kO o σι rd a O co u • kD a 0 1 cn a 0 « Tp „0 in in o in co tp o in kO d O in in cn m d cn cn • tP ta · rd a ^p d • a Tp Ol • S * 1 O Q Ol 1 O u d 1 o fi CN k I B in r-l tl·' in k a -PH SH w — o i g * 3 in in co — al • a oo a® oj Ό η τί g τί ο* in o oi ο* o* in rd οι τί ω «<σ > ffi Ο O' Ol kO • r-k · cn n ko S3 » o* * W — S3 O' -rl ra CO CO OJ Ol OJ OJ • · * rd in S3 1 £ a 1 OJ a' a in in H Ok k rd ι—1 co Ό ««-% • N «—» • • Ol « n kO a n N k0 r> rd a a in a a 1 • rd in • co in in σι Oi a σι a co in *0 I—l ·>—· τί τί rd • σι d k τί 00 d ——· kO a d H rd d £3 rd cn • a O • • a l—l in in • σι in in a ω ·«. co • 4» a i-t ZlS W S co m n *'* * a co a co Ό ra ra ra E r- r- in a — a co οι Ό ra — ffl 6 g Ό O co in ΓΟΟ r· Μ1 h * . · · ra O oi cn io Φ cn oj ko in cn κ h . u * io υ cn ko φ r* ο* τί rd rd *—* rd OJ Ol rd rd Ol kO ch cn d oj cn Ο O m io σι cn d lo in cn η H □ · I O O M* O' Φ cn m τί rd rd *-* cn in O· CO rd cn in O' s , k. τί 88 rd φ •P Ή in kO TP rt O H rd cn rd Ol 3 •P ·« •P p OJ rd kO nJ rd cn rd cn ω 0 OJ cn OJ Oi * * * O Tp O O r* o· kO kO d kO d kO cn rd cn rd * * • * • o cn kO O cn GO m r* σι 00 co σι M· O' m M· O' in cn rd rd cn rd rd U · io o om o ra ra Ό Η H u ‘ io o in ra φ Ο O fl IN CJ — - 52 41574 ο Ρ Ρ 0 0 CN ο ο sf Ο ο a ιη a 0 • ρ- 0 0 Γ*- Γ* Η ο ιη ιη cn Ο ιη σ> rd Ο CO Γ • CN si* Μ · (0 si* rd • a st* rd S V rd • 1 Ο α CN 1 Ο Ω CM 1 Ο tn 8 CO <—s. Ό ^-x 00 X rd rd Ό c/i O si* 8 tfl tX O 3 O CN 3 rd X Φ Φ CN m a in 00 x a rd si* a a in 4x X rd a *μ» m 00 co x 00 x a 3 8 tn o 5* *-» a X X- 8 8 m rd St* rd 8 x X rd 8 T3 co rd •X— ✓X si* «. < 8 03 8 «~x w nJ g 03 a 8 CO CN m ro N 00 r> θ £3 CN a 00 rd 00 ω r- g 8 r* Γ* in 3 CN in «—'» a CN a si* GO a a • in a «X X n m rd in a «·«-* co in m in 8 8 • 1*- Ό a 1 nJ • σ» m si· x I CO 8 x x in CO x co g a a 8 Φ rd rd 8 8 00 rd 8 rd 00 CN x rd » a Ifl CN rd • a CN Π3 » Mm» ω 8 <*» Φ tfl x-x 10 Φ tfl •O 00 O CN N si* CN N CO Φ I in co •»«x 8 x x in 8 ·, x > 00 rd a in 8 8 co • in 8 8 • » • co 3 *-’· H rd rd CO rd rd co in 10 0) Ε Η Ρ 'ε +1 Ο Sh 8·* μ ι ο ra «a ε Η ? rd ο X a X X X • o o o O «-Χ o O o o o O o o O si* rd co CO o CN co CN Φ rd in Φ > rd CN rd rd CN rd CN »M* sl* 10 si* Φ si* sl* o co rd CO rd O CO co CN CO CN CO sl* CN co X X a Xt X χ o CN CN o P* rd in co 10 Φ CO o 10 <0 co O CN 10 in CO 10 m 10 CN rd rd co rd rd rd rd X X X X X χ X X a o co CN O O in in sj· rd CO O o 00 O 10 10 si* CN P* 10 si* P* 10 CN 10 in co rd rd co rd rd CO rd rd a υ . u · 1 0 U 10 0 1 0 0 co o Φ CN 00 Φ Ο O IB si* m Ό co co Ό r~ CO Ό rd rd rd rd *** 1 T-I - κ ο CM a ο m CM SS οκ —ο ο=ο ι Ο ο CM Κ ο ο υ CM a ο ι ο υ CM a ο ιο CM ί-.

CM •μ α Ί? ΰο υ co § Α Q » 1 I CO a £ <ο Μ Ε 4J C U φ a ΑΟ η +J ι a h 'ο υ Φ Η Α Ο 10 ·ΓΊ 1 2 3% 0 Γ Γ· CO CO Ο Ο Ο Tt Ο ΙΛ X· ω -φ co co rH * a Η · 1 Ο Q Ο 1 Ο ο υ ωο a m Ο Ν «* a ι x 1 1 r- O z-x c N a Η 00 * rH U a rH ro co O t— Γ- σι ss in • « 00 • x a rH • to • ΟΟ co oi m r- —«* Ν Φ a tM OI Ol N CO O CO • «X 1 a 6 • a 00 X χ • X in ω o o m * fi σί O 5f X a • a X a a a 00 Ol χ—* a O rH a rH co rH a rH rH oi * *ύ • • Ό rH • CO rH w *“» rH 10 Z“x to a S CO σι ω ζ~\ co 1 * ro z—» o x tj z-x ro N o Ol CO ΟΙ a Ol n in • a a w co s co 00 — r% X x • a. co • .rH • a • a OI in a • • N · a a in a 00 in co rH 1 —-» in co —·* (0 a m rH rH r— N to Γ- Ό £ V 00 CO to co X a x CO X 1 γο co X co χ H x CO CO a * a co a *—· a h • OI «*—» a rH a ·- a CO in ΟΙ »O a rH sz Ol Ί3 co rQ M* » tJ a co OI rH • « ω Π3 ro W Π3 to 5 6 o 1 in S g σι (0 CO ·*— CO co 00 01 E CO o o ro t— Γ- 0 I— 00 -< N C— • r- < in • CO rH co • co • O • • rH οο * a 00 • a x a «· • gs % a X a ω in r- 00 01 co m co rH ro OI tn Γ— rH oi rH co • X • X · χ · z-x z-x z—x Ζ—X ζ—χ z^ O o ο Q 0 ο o 0 co Η 0 o ο Q Ol tn in co σι χί· 0 co co Ο in 5l< ιη Ol co H co H Ol Η Ol Xz 0 co tn O C0 o co 5j< co CO co co co co OI co Ol to Ol ro X X X 1 X X X a X X , X X X a σι Ol Ol in Q in o m CO Ο Ο in o o Γ- m σι O σι O H M· Oi CO co cO co co CO Γ- co m in Ι- Γ- CO m Γ- co m ΟΙ Γ- co m Η H H H Η Η H H Η H Η co Η H H X X X X X X X X χ X X X CO in σι H ο in in O in CO Ol in in co in CO 01 ro co I— r- co 0 Γ- o ο οι O Ol σι OI co co in ΟΙ r- co co ΟΙ Γ- co co Γ- in co H H H co H H H co Η Η co H Η H r> • Ό • □ • O • 1 O O 1 ο 0 io 0 IO 0 co 00 Φ ο 00 Φ O m φ o O Φ 01 01 Ό CO CO Ό CO σι Ό in CO Ό Η H Η H *«-* H Η Η H •x-Λ 41^ u ο -Ρ Q r—1 • 03 si* οι Ο Ο <4* <η ωο Η · S si* ι Ο Q ν si* • Ο Φ Ο Ο ϋ ρ* η W0 Η · S si* I Ο Q (Μ P* • in a ω in O O m rH · ί O O ωθ 3 cn U CM Ό cn 3 I P· σι τί <·» H cn rH • cn 3 · p* • • cn CM in co cn a ω cn • ·- < Ό ιη ιη <η οι * - 3 3η rH rH W χ*. ω ρ* ν m CM a rm in in · cn * in co — 33 cm * τί tn h ra 3 £ g ~ O CM Ο Ο N ω —- co in 3 • N · · 00 P* — •0 rH 3 σι , st* . 3 , w cn rH * in 3· ω «α sf rH rim Q • · * o sf in 3 jn co . 3 ' CM CM ' ω « oo 3 ι • p* tn η ι 00 • CO I *0 • P- 3 3 % rH * in Γ* 3 «. 6 □ * 3 rH 3 ·* 3 co rH rH 3 a cn + 3 rH Ul tn P* rH 1 • to cn rH • tn m Ol ω tn tO σι o to P· rH g N rH oo *3 Ol O £3 l o in 3 * 00 b<3 • si* 3 co « CO si* • 3 in a 3 si* in • o p- — rH CM rH rH rH CM — to — g (Η Μ 'g Ρ □ 0 Φ Η ft Ο Μ ·ΓΊ I $ 3 Η -, Q-* o o O o o o o cn O o o O o o o P* O o CM o CM co co co P- cm ri in si* to co to cn O — co rH CM rH CM rH rH rH in h »—» «— -- —<· ·»—» *—* • » o in tn rH CM to p- rH si* cn tn cn O si* CM rH CM tn CM tn CM cn tn cm cn * , O in O in H in CM O CM O si* to rH to O rH Φ cn OO to cn co cn Ol to in CM p. in Ρ» to in p· in cn rH rH cn rH rH rH rH rH rH rH rH W. H « ,, o o to to o tn oi o o ω rH ω O CM to CO rH cn co in O si* tn O to Si* in m Ol p* to in CM P· to in CM tO cn rH rH rH tn rH rH rH cn rH rH rH U • o · u • . ° 0 u l 0 0 ι 0 □ I 0 co tn 0) in CO (D r* O Φ in oo si* in Ό cn tn τί tn o Ό si* si* rH H rH rH rH Ol s_- H r-H O cn \ cn / o CI \· »—I cn cn si* cn tn cn h +) ϋ (U rd Α Ο O 0 in CM cn u in O a a CM cn 0 to 0 a rH o ϋ 0 cn rH O rH cn O in tn O cn < 0 in σι □ O to co ω • σι a a Nt rH a E Nt CM a g rH rH o CM 1 o O CM 1 o Ω CM ω TJ CM co o z—s O z—% ω co TJ N CM co TJ N ω CM co a CO E a » r> E rH a E Nt m rH in 00 co rH in CM in in a a «* • «« a ·» 00 in co in co ω K co a E •mX E E E a E ·*-* * E CM * TJ co rH CM TJ K rH CM TJ E rH ω E TJ £ ω E TJ E ζ—κ 0) TJ cn co CM in <5 n co CM CM cn N co in £ £3 r* p* in E Γ P* £ E P- tn E a Έ a a 00 a £ a in CO • • • 00 cn E in P* CO E in a cn m p* 00 1 TJ a 00 ps TJ • l TJ * rH 00 co E K rH K 1 in E • 00 co E Ik E rH rH E 4K E ω rH rH E E p- rH co CM rH a a W σι CM rH a • W cn rH a a ω cn to σ rH ω CO z—» to σ> co tO σι co *«z M to m ««— N σ» O £3 to a 8 E in E E rH Nt a tfE m in E E ό m E in E E co eC 'Z rH rH rH tH 4! rH rH rH CM rH rH a s a «. • z-s z—* z—K z—» * z—> 88 88 O o σι 8 σι σι P* 00 Nt CM co Nt to cn CM CM O co rH CM rH CM rH > co KZ x»z *—' *—* *»Z CO co cn in CO rH I> co H co rH CO σι in CM cn CM cn CM CM co * K * * , w K * • O 00 w tn o in 00 o O o O in 00 to Nt p* O o in σι σι o CM P*· to in CM P» in CM r> in in co rH rH rH CO rH rH co rH rH rH K * K a K K * * K K * o CM in O tn rH CO σι CO O o σι 38 O Nt 8 co to Nt tn CM P* m in co to Nt CM to in cn cn rH rH rH cn rH rH cn CO rH rH □ a o a u 10 u1 Q. ϋ 1 0 o oo Φ m O Φ co σι σι σι TJ in co TJ to P* rH rH Η H k-z H rH u · u So -OO HO Insofar as the present invention includes a method for inhibiting the growth of bacteria in an environment, which method comprises administering to the environment an effective amount of a compound in accordance with the invention pr salt thereof, provided that the double bond is at position 3 of the six-membered ring, of a pharmaceutical formulation in accordance with the invention, or of a pharmaceutical composition in accordance with the invention, it should be clearly understood that we make no claim herein to such a method when used in the treatment or prevention of disease in a human being.

Claims (76)

CLAIMS:

1. A compound of the formula: A B x COX R I C=Z (I) wherein A and B are each independently hydrogen or an amino protecting group or represent a single amino protecting group when considered together; X is hydroxy or a carboxy protecting group; Y is hydrogen, halogen, alkyl, alkoxy, or, alkylthio; R is hydrogen or alkyl; Z is a group of the formula =N-N \r 2 1 2 in which either R and R are the same or different and are each hydrogen, an optionally substituted hydrocarbon group (as hereinbefore defined), organic acyl or a group of the formula M' -C in which M and M' are the same or different and are each 3 1 oxygen or sulfur and R xs a hydrocarbon groupjor R and R are combined together either directly or through a heteroatom; m is 0 or 1 and the broken line indicates the presence of a double bond at position 2 or position 3. - 58 2. A compound as claimed in claim 1, wherein A and/or B is/are acyl, silyl, sulfinyl, hydrocarbyl or any other amino protecting group containing from 1 to 20 carbon atoms. 3. A compound as claimed in claim 2, wherein A and/or B is/are selected from side chains of known natural or synthetic penicillins and cephalosporins. 4. A compound as claimed in claim 2, wherein A and/or B is/are selected from carbonic acyl, sulfuric acyl, phosphoric acyl, alkanoyl, cycloalkanoyl, aralkanoyl, aroyl, alkylsulfonyl, arylsulfonyl, and alkylphosphonyl, optionally unsaturated and/or substituted, or A and B together represent a diacyl group of a polybasic add. 5. A compound as claimed in claim 2, wherein A and/or B is/are selected from easily removable aliphatic hydrocarbon groups containing from 1 to 20 carbon atoms and easily removable mono-cyclic aromatic hydrocarbon groups, optionally unsaturated and/or substituted, or A and B together represent a divalent hydrocarbon group. 6. A compound as claimed in claim 1, wherein A and B form a cyclic group when considered together with the nitrogen atom at position 7. 7. A compound as claimed in claim 1, wherein A is hydrogen and B is selected from: 1) alkanoyl groups containing from 1 to 3 carbon atoms;

2. ) haloalkanoyl groups containing 2 or 3 carbon atoms;

3. ) azidoacetyl;

4. ) cyanoacetyl;

5. ) acyl groups of the formula: Ar—CQ 2 — coin which Q ia hydrogen or methyl and Ar is thienyl, furyl, pyrrolyl, pyridyl, phenyl, or phenyl substituted by chlorine, bromine, iodine, fluorine, trifluoromethyl, hydroxy, alkyl containing 1 to 3 carbon atoms, alkoxy containing 1 to 3 carbon atoms, cyano or nitro;

6. ) acyl groups of the formula: Ar—G—CH^—CO — wherein G is oxygen or sulfur and Ar is as defined above;

7. ) acyl groups of the formula: Ar—CHT—CO — wherein Ar is as defined above and T is i) amino, ammonium, amino protected by benzyloxycarbonyl, alkoxycarbonyl containing from 1 to 4 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, triphenylmethyl, 2,2,2-trichloroethoxycarbonyl, guanidylcarbamoyl, sulfo, or amino protected in the form of phthalimido,> or an enamine derived from acetoacetate or acetylaoetone, ii) hydroxy or alkanoyloxy containing from 1 to 6 carbon atoms, iii) carboxy or alkoxycarbonyl containing from 2 to 7 carbon atoms, or iv) azido, cyano, carbamoyl or sulfo; 8. ) 2-sydnon-3-alkanoyl containing from 3 to 5 carbon atoms; 9. ) (tetrazol-1-yl)alkanoyl containing from 1 to 4 carbon atoms; and 10. ) 5-aminoadipoyl, 5-aminoadipoyl protected at the amino group by alkanoyl containing from 1 to 3 carbon atoms or chloroalkanoyl containing from 1 to 3 carbon atoms, or 5-aminoadipoyl protected at the carboxy group by benzhydryl, 2,2,2-trichloroethyl, alkyl containing from 1 to 6 carbon atoms, nitrobenzyl or methoxybenzyl; or wherein A and B together represent a diacyl group derived from a polybasic carboxylic acid containing from 4 to 12 carbon atoms.

8. A compound as claimed in any one of the preceding claims, wherein X is selected from alkoxy containing from 1 to 8 carbon atoms, aralkoxy containing from 7 to 20 carbon atoms, mono- or bicylic aryloxy, organometaloxy, organic or inorganic acyloxy containing from 1 to 8 carbon atoms, metaloxy wherein the metal is in groups I, II or III in the periodic table, thiol esters, thiocarboxy groups, or amide, hydrazide or azide groups, optionally unsaturated and/or substituted.

9. A compound as claimed in claim 8, wherein X is selected from haloalkyl esters containing from 1 to 3 carbon atoms, acylalkyl esters containing from 2 to 10 carbon atoms, alkoxyalkyl esters containing from 2 to 8 carbon atoms, acyloxyalkyl esters containing from 2 to 8 carbon atoms, carbalkoxyalkyl esters containing from 3 to 8 carbon atoms, phenyl esters, aralkyl esters containing from 7 to 20 carbon atoms, esters with an oxime containing from 2 to 10 carbon atoms, N-alkoxyamide containing from 1 to 5 carbon atoms, imide with saccharin, imide with phthalimide, Ν,Ν'-diisobutylhydrazide, metal salts, or alliylamine salts containing from 1 to 6 carbon atoms.

10. A compound as claimed in claim 8, wherein X is selected from acyloxymethyl esters, phenacyl esters, the benzaldoxime ester, the Ν,Ν-dimethylaminoethyl esters, alkali metal salts, and alkaline earth metal salts.

11. A compound as claimed in any one of claims 1 to 7, wherein X is benzhydryloxy, p-nitrobenzyloxy, hydroxy or alkali metal-oxy.

12. A compound as claimed in any one of the preceding claims wherein Y is hydrogen, alkoxy containing from 1 to 3 carbon atofos, alkylthio containing from 1 to J 3 carbon atoms, alkyl containing from 1 to 3 carbon atoms 5 or halogen.

13. A compound as claimed in any one of claims 1 to 11, wherein Y is hydrogen or methoxy.

14. A compound as claimed in any one of the preceding claims, wherein R is methyl, ethyl, propyl, 10 isopropyl or cyclopropyl.

15. A compound as claimed in any one of claims 1 to 13, wherein R is hydrogen or methyl.

16. A compound as claimed in any one of the preceding claims, wherein m is zero. 15 17. A compound as claimed in any one of the preceding claims, wherein Z is a hydrazino group selected from: (1) hydrazono; (2) 2-(o- or p-carboxyphenyl)hydrazono, 2-(p20 alkylsulfonyIphenyl)hydrazono in which the alkyl moiety contains from 1 to 3 carbon atoms or 2-(p-sulfophenyljhydrazono which can form a salt with an alkali metal ion; (3) 2-phenyl-2-alkylhydrazono in which the alkyl moiety contains from 1 to 3 carbon atoms; 25 (4) 2-(2-pyridyl)hydrazono, 2-(thiazol-2-yl)hydrazono, 2-(l-amino-5-mercapto-l, 3, 4-triazol-2-yl)hydrazono, 2-(purin-6-yl)-hydrazono or 2-(4-oxoimidazolin2-yl)hydrazono; (5) 2-(sulfolan-3-yl)hydrazono or 2-(carbalkoxy30 methyl)hydrazono in which the carbalkoxy moiety contains from 2 to 5 carbon atoms; (6) (4-methyl-l,4-dihydro-pyrazin-l-yl)imino or (2-pyridon-l-yl) imino;

I (7) 2-(alkanoyl)hydrazono in which the alkanoyl moiety contains from 1 to 4 carbon atoms, 2-glycylhydrazono, 2-(n-tertiary butoxycarbonyl-glycyl)hydrazono, 2-(trimethylammoniumacetyl)hydrazono, 2-(pyridiniumacetyl) hydrazono, 2-oxalylhydrazono, 2-(alkoxalyl)hydrazono in which the alkoxalyl moiety contains from 3 to 6 carbon atoms, 2-(amidoxalyl)-hydrazono, 2-(hydrazinodicarbonyl) hydrazono, 2-(cyanoacetyl)-hydrazono, 2-(gluconoyl)hydrazono, 2-(benzoyl)hydrazono, 2-(furoyl)hydrazono, 2- (isoxazol-3-yl)carbonylhydrazono, 2-(5-methylisoxazol3- yl)carbonylhydrazono, 2-(1,2,5-thiadiazol-3-yl) carbonylhydrazono or 2-(5-methyl-l,2,3-thiadiazol-4-yl)carbonylhydrazono; and (8) 2-(carbalkoxy)hydrazono in which the carbalkoxy moiety contains from 2 to 5 carbon atoms or 2-(dithiocarbalkoxy) hydrazono in which the dithiocarbalkoxy moiety contains from 2 to 5 carbon atoms.

18. A compound as claimed in claim 1, wherein A, Y and R are each hydrogen; B is thienylacetyl; X is hydroxy; m is zero; the broken line represents a double bond at position 3; and Z is a group selected from hydrazono, 2-methyl-2-phenylhydrazono, 2-(o- or p-carboxyphenyl)hydrazono, 2-(p-methanesulfonylphenyl)hydrazono, 2-(sodiooxysulfonylphenyl)hydrazono, 2-(2-pyridyl)hydrazono, 2-(4-methyl-l,4-dihydropyrazin-l-yl) imino, 2-(thiazol-2-yl)hydrazono, 2-(5-mercapto-1-amino-1,3,4triazol-2-yl)hydrazono, 2-(purin-6-yl)hydrazono, 2(sulfolan-3-yl)hydrazono, 2-(carbethoxymethyl)hydrazono, 2-(carbomethoxymethyl)hydrazono, 2-formylhydrazono, 2acetylhydrazono, 2-glycylhydrazono, 2-(N-tertiary butoxycarbonylglycyl)hydrazono, 2-(trimethylammoniumacetyl)hydrazono, 2-(pyridiniumacetyl)hydrazono, 2-oxalyl- 63 hydrazono, 2- ethoxalylhydrazono, 2-amidoxalylhydrazono, 2-(hydrazinyldicarbonyl)hydrazono, 2-(cyanoacetyl) hydrazono, 2-gluconylhydrazono, 2-benzoylhydrazono, 2furoylhydrazono, 2-(isoxazol-3-yl)oarbonylhydrazono, 2-(5-methylisoxazol-3-yl)oarbonylhydrazono, 2+(1,2,5thiadiazol-4-yl)oarbonylhydrazono, 2-(5-methyl-1,2,3thiadiazol-4-yl)oarbonylhydrazono, (2-pyridon-1-yl) imino, 2-carbomethoxyhydrazono, 2-(tertiary butoxycarbonyl)hydrazono, 2-(methylthiothiooarbonyl)hydrazono and 2-(4hydroxyimidazol-2-yl)hydrazono.

19. An alkali metal salt of a compound as olaimed in claim 18.

20. A compound as claimed in claim 1, wherein A and R are each hydrogen; Y is methoxy; B is thienylacetyl; X is hydroxy; m is zero; the broken line represents a double bond at position 3; and'Z is an acetylhydrazono or 2-(p-carboxyphenyl)hydrazono group.

21. An alkali metal salt of a compound as claimed in claim 20.

22. A compound as claimed in claim 1, wherein A, Y and R are each hydrogen; X is hydroxy; m is zero; the broken line represents a double bond at position 3; and B and Z are selected from the following pairs: furoyl and acetylhydrazono; phenylacetyl and acetylhydrazono; 2,2,2-trichloroethoxycarbonyl and acetylhydrazono; (ΙΗ-tetrazol-l-yl)acetyl and formylhydrazono; phenylglyeyl and ethoxalylhydrazono; phenylmalonyl and cyanoacetylhydrazono; mandeloyl and butyrylhydrazono; and hydrogen and acetyl-hydrazono, respectively.

23. An alkali metal salt of a compound as claimed in claim 22,

24. A compound as claimed in claim 1, wherein Y and R are each hydrogen; X is hydroxy; m is zero; the broken line represents a double bond at position 3; A and B are phthalyl or benzal; and Z is an acetylhydrazono or 2-pyridylhydrazono group.

25. An alkali metal salt of a compound as claimed in claim 24.

26. A process for preparing a compound as claimed in claim 1, which process comprises reacting a compound of the formula: , wherein A, Β, X, Y, R, m and the broken line have the meanings set out in claim 1, or a reactive derivative thereof, with a compound of the formula: H 2 Z CHI) wherein Z is as defined in claim 1, or a reactive derivative thereof.

27. A process as claimed in claim 26, wherein the reactive derivative of compound (II) is an acetal.

28. A process as claimed in claim 27, wherein the acetal is a dialkylacetal, a diacylacetal, a hemiacetal lactone with the carboxy group at position 4.

29. A process as claimed in any one of claims 26 to 28, wherein the reactive derivative of compound (ill) is a salt thereof with an acid, an N-acyl derivative, an alkylidene derivative or an aralkylidene derivative.

30. A process as claimed in any one of claims 26 to 29, wherein the reaction is effected in a solvent which is tetrahydrofuran, tetrahydropyran, ethyleneglycol, dimethyl ether, dimethylformamide, dimethyl-acetamide, dimethylsulfoxide, water, or a mixture thereof.

31. A process as claimed in any one of claims 26 to 30, wherein the reaction is effected at a neutral or weakly acid pH.

32. A process for preparing a compound as claimed in claim 1 wherein A and/or B is/are an amino protecting group(s), which process comprises subjecting a compound (I) wherein A and/or B is/are hydrogen to the reaction of an amino protecting group introducing reagent.

33. A process as claimed in claim 32, wherein the reagent is an acylating reagent.

34. A process as claimed in claim 33, wherein the acylating reagent is an acyl halide, an anhydride, a reactive ester or amide or an azide.

35. A process as claimed in claim 32, wherein the reagent is a silyl halide, a silazane, a sulfenyl halide, a halohydrocarbon, an aldehyde or a ketone.

36. A process for preparing a compound as claimed in claim 1 wherein A and/or B is/are hydrogen, which process comprises subjecting a compound (I) wherein A and/or B is/are an amino protecting group(s), to a deprotection procedure known per se.

37. A process as claimed in claim 36, wherein A and/or B in the starting compound (I) is/are an acyl group(s) and the starting compound (I) is subjected to the action of carbonium ion-forming reagents, acid, acid halides, toluene-p-sulfonic acid, hydrazine, or phosphorus pentaehloride followed by alcohols and acids.

38. A process as claimed in claim 36, wherein A and/or B is/are a benzyloxycarbonyl or haloalkoxycarbonyl group(s) and the starting compound (I) is subjected to the action of a reducing metal with acid 5 or catalytic hydrogenation.

39. A process as claimed in claim 36, wherein A and/or B is/are a silyl or sulfenyl group(s) and the starting compound (i) is subjected to the reaction of an acid or base. 10

40. A process as claimed in claim 36, wherein A and/or B is/are an aralkyl, 1-alkylene,alkylidene or atalkylidene group(s) and the starting compound (I) is subjected to the action of an acid, catalytic hydrogen or a hydtogenolytic reducing reagent. 15

41. A process for preparing a compound as claimed in claim 1 wherein X is a carboxy protecting group, which process comprises subjecting a compound (I) wherein X is hydroxy to the action of a carboxy protecting group introducing reagent. 20

42. A process as claimed in claim 41, wherein the reagent is an esterification reagent, an amidating reagent, a base or a salt suitable for cation exchange, a silyl halide, a disilazane, a tin halide or a reactive organic silyl or tin derivative. 25

43. A process as claimed in claim 41, wherein the carboxy protecting group to be introduced is an alkali metal salt group or an organic base group and said group is introduced by an ion exchange reaction.

44. A process for preparing a compound as claimed in claim 1 wherein X is hydroxy, which process comprises subjecting a compound (I) wherein X is a carboxy protecting group to a deprotection procedure known per se. - 67

45. A process as claimed in claim 44, wherein the deprotection procedure comprises the action of an acid, water, a base, a reducing reagent, an alkali metal thio+ phenoxide or a cation exchange resin (H - form) on the starting compound (I).

46. A process for preparing a compound as olaimed in claim 1 wherein m is 1, which process comprises subjecting a compound (I) wherein m is 0 to the action of an oxidizing reagent.

47. A process as claimed in claim 46 wherein the oxidizing reagent is selected from oxidizing inorganic salts, inorganic or organic peracids or their salts, salts, esters, or amides of hypohalogenous acids, iodobenzene salts, metal peroxides, hydrogen peroxide, oxygen, ozone-, and other reagents capable of oxidizing sulfide to sulfoxide.

48. A process for preparing a compound as claimed in claim 1 wherein m is zero, which process comprises subjecting a compound (I) wherein m is 1 to the action of a reducing reagent.

49. A process as claimed in claim 48 wherein the reducing reagent is selected from reducing inorganic salts,phosphorous trihalides, phosphines, hydrides, hydrogen or other reducing reagents capable of reducing sulfoxides to sulfides.

50. A process for preparing a compound as claimed in claim 1 wherein said compound has a free or protected functional group, which process comprises subjecting the corresponding compound (I) having a protected or free functional group, respectively, to a procedure known per se for the removal or introduction, respectively, of the protecting group.

51. A process as claimed in claim 50, wherein one or more of the groups A, Β, X and Z in the starting compound (i) has a free or protected functional group.

52. A process as claimed in claim 50 or claim 51, 5 wherein said procedure is any one of those listed hereinbefore in paragraphs 8 and 9. in pages 15 and 16.

53. A process as claimed in any one of claims 32 to 52, wherein the reaction is effected at a temperature of from -50° to 100°C. 10

54. A process as claimed in any one of claims 32 to 53, wherein the reaction is effected in a solvent.

55. A process as claimed in claim 26 and substantially as hereinbefore described with reference to Example 1-1 and any one of runs 1 to 39 listed in the 15 foregoing Tables, or with reference to any one of the runs of Example 1-2 or any one of Examples 1-3 to 1-9.

56. A process as claimed in claim 32 and substantially as hereinbefore described with reference to any one of Examples II-l to II-5 or any one of the runs of 20 Example XI-6.

57. A process as claimed in claim 36 and substantially as hereinbefore described with reference to Example III-l.

58. A process as claimed in claim 41 and substan25 tially as hereinbefore described with reference to either of the runs of Example IV-1.

59. A process as claimed in claim 44 and substantially as hereinbefore described with reference to either of Examples V-l and V-2.

60. A process as claimed in claim 46 and substantially as hereinbefore described with reference to either of the runs of Example VI-1 or with reference to Example VI-2. 41S74

61. Ά process as claimed in claim 48 and substantially as hereinbefore described with reference to Example VII-1.

62. A process as claimed in claim 50 and substan5 tially as hereinbefore described with reference to Example VIII-1 or either of Examples IX-1 and IX-2.

63. A compound as claimed in claim 1 which has been prepared a process as claimed in any one of claims 26 to 62. 10

64. A compound as claimed in claim 1 and specifically referred to hereinbefore.

65. A pharmaceutical formulation which comprises as an acitive ingredient a compound as claimed in any one of claims 1 to 17, 63 or 64 or a salt thereof, 15 provided that the double bond is at position 3 of the six-membered ring, said compound or salt being formulated for pharmaceutical use.

66. A pharmaceutical formulation as claimed in claim 65 and in unit dosage form. 20

67. A pharmaceutical formulation as claimed in claim 65 and suitable for parenteral administration, wherein said formulation contains from 0.1 to 10 g of said compound or salt and is in the form of powder, lyophilizate or crystals in a vial. 25

68. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 17, 63 or 64 or a salt thereof, provided that the double bond is at position 3 of the six-membered ring, and a pharmaceutically acceptable diluent, carrier or excipient. 30

69. A pharmaceutical composition as claimed in claim 68 and in unit dosage form.

70. A pharmaceutical composition as claimed in - 70 claim 68 or claim 69, which composition is in the form of a powder, a solution, a vial of material, an injectable composition, capsules, tablets or an ointment.

71. A pharmaceutical composition as claimed in 5 any one of claims 68 to 70 wherein the composition contains 0.01% or more of the active compound (I).

72. A method for inhibiting the growth of bacteria in an environment, which method comprises administering to the environment an effective amount of a compound as 10 claimed In any one of claims 1 to 17, 63 or 64 or a salt thereof, provided that the double bond is at position 3 of the six-membered ring, of a pharmaceutical formulation as claimed in any one of claims 65 to 67, or of a pharmaceutical composition as claimed in any one of claims 68 15 to 71.

73. A method as claimed in claim 72 when applied to the treatment or prevention of disease in a nonhuman animal.

74. A method as claimed in claim 72 when applied 20 to the treatment or prevention of disease in a plant.

75. A method as claimed in claim 72 when applied to the prevention of decay in a perishable substance.

76. A method as claimed in claim 72 when applied to the disinfection of an article or building structure.