NO761492L - - Google Patents

Description

The present invention relates to a method for the production of new cephalosporin and penicillin derivatives which are usable as antibiotics.

Compounds of general formula I are useful as antiobiotic agents:

Formula I

wherein aryl is selected from phenyl or 2-thienyl, Y is selected from hydrogen, chlorine, bromo', a straight or branched lower alkyl group of from 1 to 4 carbon atoms or an alkoxy group of from 1 to 4 carbon atoms provided that when aryl is 2- thienyl Y is hydrogen, each of R 1 , R 2 and R 3 is selected from hydrogen or a straight chain or branched lower alkyl group having from 1 to 4 carbon atoms, Z is selected from a bond, oxygen, sulfur or

imino provided that when aryl is 2-thienyl, Z is a bond,. W is selected from hydrogen, methyl, amino, hydroxy, SO3H, or COOR^ where is selected from hydrogen or 5-indanyl, n is zero, 1 or 2 provided that when W is different from hydrogen or

methyl and Z is different from a bond, n is not zero, R 5 is selected from hydrogen or methoxy, R fi is selected from the group

wherein M is selected from hydrogen, a pharmaceutically acceptable non-toxic anion or cation charge, alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight chain or branched, alkanoylaminomethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight chain or

branched and where the amino nitrogen may be substituted with an alkyl group with from 1 to 4 carbon atoms, alkoxycarbonylaminomethyl where the alkoxy part contains from 1 to 4 carbon atoms and ' may be straight chain or branched and where the amino nitrogen may be substituted with an alkyl group with from 1 to 4 carbon atoms, p -(alkanoyloxy)-benzyl where the alkanoyl part contains from 1 to 5 carbon atoms and can be straight or branched or aminoalkanoyloxymethyl where the alkanoyl part contains from 2 to 15

carbon atoms, and the amino nitrogen may be mono- or disubstituted with a lower alkyl group of from 1 to 4 carbon atoms.

X is selected from hydrogen, acetoxy, 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio, 1-methyl-tstrazol-5- ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio and pharmaceutically acceptable salts thereof.

In the general formula I, the substituent groups as represented by Mi in addition to being hydrogen<:> or a pharmaceutically acceptable non-toxic anion or cation charge may also be alkanoyloxymethyl as represented by the structure

where is selected from a straight-chain or branched lower alkyl group with from 1 to 4 carbon atoms, alkanoylaminomethyl or . Alkoxycarbonylaminomethyl as represented by the structure where R 8 denotes a straight-chain or branched lower alkyl group with from 1 to 4 carbon atoms or a straight-chain or branched alkoxy group with from 1 to 4 carbon atoms and R<9> denotes hydrogen or a lower alkyl group with from 1 to 4 carbon atoms , p-(alkanoyloxy)-benzyl as represented by the structure where R"*"^ is straight chain or branched lower alkyl of from 1 to 4 carbon atoms, or amirioalkanoyloxymethyl as represented by the group

o

wherein n1' is 0 to 5, each of R 11 and R 12 is selected from

hydrogen or lower alkyl having from 1 to 4 carbon atoms, and . , each of R±i J o and R 14 is selected from hydrogen or a straight chain or branched lower alkyl group having from 1 to 4 carbon atoms.

Illustrative examples of straight-chain or branched lower alkyl groups having from 1 to 4 carbon atoms that Y, R 1 , R 2 R^, R~^, R^, R"^, R"^ and R"^ may represent are methyl, ethyl , n-propyl, isopropyl, n-butyl and tert-butyl.

Examples of lower alkyl groups with from 1 to 4 carbon atoms that R^,-R"<*>"\ and R^ can represent are methyl, ethyl, n-propyl and n-butyl.

Examples of lower alkoxy groups that Y can represent are methoxy, ethoxy, n-propoxy and n-butoxy.

Illustrative examples of straight-chain or branched lower alkoxy groups that R<8> can represent are methoxy, ethoxy, n-propoxy, isopropoxy, sec.-butyoxy and n-butoxy.

In general formula I, the substituent group X may represent, in addition to hydrogen or acetoxy, a heterocyclic group selected from 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol- 5-ylthio, 1-methyl-tetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio as represented by the following structures: When the aryl group in the compounds of general formula I represents phenyl, each of the isothioureamethyl substituent and the Y-substituent can be individually connected to any of the positions 2-6 of the phenyl ring. Compounds of this type can be represented by the following general formula II

The preferred positions for attachment of the isothiourea-methyl substituent in the above formula II are ortho and para positions of the phenyl ring. ' In the formula given above

12 3

II, the substituents represented by Y, R , R , R , Z, n, W, R b _ and R c have the same meanings as defined for general formula I.

When the aryl group in the compounds of general formula I represents 2-thienyl, Y is hydrogen and Z is a bond. Connections of this type can be represented by the following formula

III;

In the compounds of the above formula III, the isothiourea substituent group can be attached at the 4- or 5-position of the thienyl group. In the above-mentioned formula III, the substituents represented by "R2, R"*, n, W, R^ and R** have the same meanings as defined for general formula I.

It is obvious from the preceding description of general formula I that the compounds according to the invention are either penicillin derivatives when R denotes the part

or cephalosporin derivatives when R denotes the moiety

where M and X have the previously stated meanings.

The cephalosporin derivatives which represent a preferred embodiment of the invention are represented by the following formula IV.

wherein aryl is selected from phenyl or 2-thienyl, Y is selected from hydrogen, chlorine, bromine, a straight or branched lower alkyl group of 1 to 4 carbon atoms, or an alkoxy group of from 1 to 4 carbon atoms provided that when aryl is 2- thienyl, Y is hydrogen,'

each of , R 2 and R 2 is selected from hydrogen, or a straight or branched lower alkyl group having from 1 to 4 carbon atoms,

Z is selected from a bond, oxygen, sulfur or imino .provided that when aryl is 2-thienyl, Z is a bond,

W is selected from hydrogen, methyl, amino, hydroxy, SO^H or COOR4 A where R A is selected from hydrogen or 5-indanyl, n is 0, 1 or 2 provided that when W is different from hydrogen or methyl and Z is different from a bond, n is not zero,

5 R is selected from hydrogen or methoxy, M is selected from hydrogen, a pharmaceutically acceptable non-toxic anion or cationic charge, alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight chain or branched, alkanoylaminomethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and can be straight chain or branched and where the amino nitrogen can be substituted with an alkyl group with from 1 to 4 carbon atoms, alkoxycarbonylaminomethyl where the alkoxy part contains from 1 to 4 carbon atoms and can be ..straight chain or branched and the amino nitrogen can be substituted with an alkyl group with from 1 to 4 carbon atoms, p-(alkanoyloxy)-benzyl where the alkanoyl part contains from 1 to 5 carbon atoms and can be straight chain or branched, or aminoalkanoyloxymethyl where the alkanoyl part contains from 2 to 15 carbon atoms and the amino nitrogen can be mono- or di-substituted with a lower alkyl group having from 1 to 4 carbon atoms, X is selected from hydrogen n, acetoxy, 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio, l-methyltetrazol-5-

ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio and pharmaceutically acceptable salts thereof.

The penicillin derivatives which represent a preferred embodiment of the invention can be represented by the following formula V:

where aryl is phenyl or 2-thienyl, Y is selected from hydrogen, chlorine, bromine, a straight or branched lower alkyl group having from 1 to 4 carbon atoms or an alkoxy group having from 1 to 4 carbon atoms provided that when aryl is 2-thienyl, is Y hydrogen,

■i n O

each of R, R and R is selected from hydrogen or a lower alkyl group having from 1 to 4 carbon atoms, Z is selected from a bond, oxygen, sulfur or imino provided that when aryl is 2-thienyl Z is a bond,

W is selected from hydrogen, methyl, amino, hydroxy, SO3H or

4 4

COOR where R is selected from hydrogen or 5-indanyl, n is zero, 1 or 2 provided that when W is different from hydrogen or methyl and Z is different from a bond n is not zero,

r<5>is selected from hydrogen or methoxy, M is selected from hydrogen, a pharmaceutically acceptable non-toxic anion or cation charge, alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight chain or branched, alkanoylaminomethyl wherein the alkanoyl moiety contains from .1 to 5 carbon atoms and can be straight chain or branched and where the amino nitrogen can be substituted with an alkyl group with from 1 to 4 carbon atoms, alkoxycarbonylaminomethyl where the alkoxy part contains from 1 to 4 carbon atoms and can be straight chain or branched and where the amino nitrogen can be substituted with a alkyl group with from 1 to 4 carbon atoms, p-(alkanoyloxy)-benzyl where the alkanoyl part contains from 1 to 5 carbon atoms and can be straight-chain or branched, or aminoalkanoyloxy where

the alkanoyl moiety contains from 2 to 15 carbon atoms, and the amino nitrogen may be mono- or di-substituted with a lower alkyl group of from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.

In the compounds of formula IV and V it is obvious

that the R^-substituent can be either cis or trans in relation to the hydrogen atom at the 6-position in the cephalosporin derivatives of formula IV and at the 5-position of the penicillin derivatives of formula V.. The compounds of formulas IV and V where the R^-substituent is cis i ratio to the hydrogen atoms indicated above is preferred.

Other preferred embodiments of this invention are: (A) compounds where W denotes hydrogen, hydroxy, amino, . SO^H and COOR^, where R^ denotes hydrogen in that such substituents lead to compounds that have a wider spectrum of activity and/or improved oral activity, for example compounds in which (1) W denotes hydroxyl are more resistant to 3-lactamase organisms , (2) W denotes SO3H or COOR^ where R^ denotes hydrogen has a wider gram-negative spectrum,

(3) W denotes NH 2 has improved oral activity,

(B) compounds in which R 1 denotes methoxy are of particular interest in that such compounds exhibit antibacterial activity against cephalosporinase-producing gram-negative organisms. (C) compounds in which X denotes acetoxy, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1-methyltetrazol-5-ylthio. Of the preferred embodiments set forth in (A), (B) and (C), compounds where Z represents a bond are more preferred.

The most preferred compounds according to the invention are

those represented by formula VI:

wherein W is selected from hydrogen, hydroxy, amino, COOH or SO^H, X' is selected from hydrogen, acetoxy, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1-methyltetrazol-5-ylthio, and pharmaceutically acceptable salts thereof.

In the compounds of formula VI in which the hydrogen atoms at the 6- and 7-positions are in cis. relative to each other, are preferred compounds.

The individual optical isomers of the compounds according to the invention in which W is different from hydrogen are also included within the scope of the invention.

The non-toxic acid addition salts of the compounds according to the invention such as mineral acid addition salts, e.g. hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfate, sulfamate and phosphate and organic acid addition salts, e.g. maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate, moondate and ascorbate, are also included within the scope of the invention.

Also included within the scope of the invention are non-toxic pharmaceutically acceptable salts of the compounds according to the invention in which W denotes COOH or SO 3 H and compounds in which M denotes hydrogen. Illustrative pharmaceutically acceptable salts of these acid derivatives are primary, secondary or tertiary amines, e.g. cyclohexylamine, ethylamine and pyridine.

The pharmaceutically acceptable cations which may be present as the group M in the compounds of general formula I to VI include, alkali metal ions, e.g. sodium ion, potassium ion, calcium ion as well as ammonium, and organic amine cations, e.g. lower, alkylammonium groups.such as triethylammonium and N-ethylpiperidine. The salt forms of compounds of formula I to VI in which M is a pharmaceutically acceptable cation are prepared according to the methods known in the art and can be formed in situ or by combination of the corresponding acid with a base, e.g. sodium bicarbonate or triethylamine.

The compounds of the present invention can be administered in a similar manner to many well-known cephalosporin compounds, e.g. cephalexin, cephalothin or cephaloglycin. They can be administered alone or in the form of pharmaceutical preparations either orally, parenterally and topically to warm-blooded animals, i.e. birds and mammals, e.g. cats, dogs, cattle and horses and humans. For oral administration, the compounds may be administered in the form of tablets, capsules or pills or in the form of elixirs or suspensions. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other dissolved substances, e.g. enough physiological saline-water or glucose to make the solution 'isotonic'. For topical administration, the compounds may be incorporated into creams or ointments.

Illustrative examples of bacteria against which the compounds according to the invention are active are Staphylococcus aureus/Salmonella schottmuelleri, Klebsiella pneumoniae, Diplococcus pneumonia and Streptococcus pyogenes.

An illustrative example of a cephalosporin derivative according to the invention is 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl)-phenyl)-acetyl)-aminoj-8-oxo-5-thia-l-azabicyclo -(4.2,o)oct-2-en-2-carboxylic acid An illustrative example of a penicillin derivative according to the invention is 6-((2-('4-(ispthiourea-methyl)phenyl)acetyl)amino)-3,3 -dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid.

Further examples of compounds according to the invention are indicated below in the specific compounds which are representative of the invention.

The compounds of formula I in which R 1 is hydrogen can be prepared by treating a derivative of the formula

with a derivative of the formula wherein aryl is selected from phenyl or 2-thienyl, halogen is selected from chlorine or bromine, Y is selected from hydrogen, chlorine, bromine, a straight-chain or branched lower alkyl group of from 1 to 4 carbon atoms or an alkoxy group of from 1 to 4 carbon atoms provided that when aryl is 2-thienyl, Y is hydrogen, Z is selected from a bond, oxygen,' sulfur or imino provided that when aryl is 2-thienyl, Z is a bond, W 2 is selected from hydrogen, methyl, amino, hydroxy, SO3H or COOH, n is zero, 1 or 2, provided that when W is different from hydrogen or methyl and Z is different from a bond, n is not zero, R c is selected from -hydrogen or methoxy , R tr is selected from the part

wherein M is selected from hydrogen, one pharmaceutically acceptable non-toxic anion or cation charge, alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight chain or branched, alkanoylaminomethyl wherein alkanoyl-

part contains from 1 to 5 carbon atoms and can be straight-chain or branched and in which the amino nitrogen can be substituted with a lower alkyl group with from 1 to 4 carbon atoms, alkoxycarbonylaminomethyl where the alkoxy part contains from 1 to 4 carbon atoms and can be straight-chain or branched and in which the amino nitrogen can be substituted with an alkyl group with from 1 to 4 carbon atoms, p-(alkanoyloxy)-benzyl where the alkanoyl part contains from 1 to 5 carbon atoms and can be straight-chain or branched or aminoalkanoyloxymethyl where the alkanoyl part contains from 2 to 15 carbon atoms, and aminonitrogens. be mono- or disubstituted with a lower alkyl group having from 1 to 4 carbon atoms, X is selected from hydrogen, acetoxy, 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5- ylthio, tetra-zol-5-ylthio, l-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxa-diazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5- ylthio, every 12 5

of R , R , and R . are selected from hydrogen or a straight-chain or branched lower alkyl group having from 1 to 4 carbon atoms.

The above-mentioned reaction is carried out in an alcoholic solvent at temperatures of from 0°C to 100°C, preferably from 25 to 50°C during 1 hour to 6 hours, forming the corresponding isothiouronium hydrochloride derivative in solution. The organic solvent is evaporated and the residual oil is triturated with suitable organic solvents such as ether, hexane, ethyl acetate or acetonitrile to form the isothio-ureamethyl-substituted compound.

When the substituent group W 2 in the above formula VII represents an amino group, suitable blocking groups, e.g. an acid salt such as a hydrochloride salt, an acyl group or tertiary butoxycarbonyl is used to protect the amino function. Such blocking groups are removed after the coupling reaction by methods known in the art, e.g., spm described by Lémieux et al. in US patent specification 3,657,232.

Illustrative examples of compounds of formula VIII are isothiourea, 1-ethyl-3-n-propylisothiourea, 1-ethyl-3-n-butylisothiourea, 1,1-di-n-propyl-3-ethylisothiourea, 1-ethyl-3- isopropylisothiourea, 1,1,3-triethylisothiourea, 1,1-di-n-propyl-3-methyliso.thiourea, 1,3-di-sec .-butylisothiourea, 1,3-di-n-propylisothiourea,. l-n-butyl-3-methylisothiourea, 1-ethyl- 3-methylisothiourea, 1,l-diethyl-3-methylisothiourea, 1,3-di-ethylisothiourea, 1-ethylisothiourea, 3-n-propylisothiourea, 1,3-dimethylisothiourea, 1,3-diisopropylisothiourea, 1,3-di-n-butylisothiourea, 1-methyl-3-ethylisothiourea and 1,1-dimethyl-3-ethylisothiourea.

Compounds of general formula VII. can be prepared by coupling a derivative of the formula

with an acid of the formula

or a functional derivative thereof where aryl, halo, Y,Z,n, W P , R<5>and R<6> have the same meanings as for general formula

VII.

When the substituent group W 2 in the above formula X denotes an amino group, suitable blocking groups are used, e.g. an acid salt such as hydrochloride salt, tertiary-butoxycarbonyl or carbobenzyloxy to protect the amino function in a similar manner as previously described.

Functional equivalents of the acids represented by formula X include the acid halides, e.g. the acid chloride, acid anhydrides including mixed anhydrides with e.g. alkyl phosphoric acids, lower aliphatic mpnoesters of carboxylic acid, or alkyl or aryl sulfonic acids. Furthermore, the acid azide or an active ester or thioester, e.g. with p-nitrophenol, 2,4-dinitrophenol, or thioacetic acid is used, or the free acid as represented by formula X can be coupled with the 7-aminocephalosporanic acid derivative or a 6-aminopenicillanic acid derivative as represented by formula VIII after first reacting the acid with N ,N 1 - dimethylchloroforminium chloride or by using a carbodiimide reagent, e.g. N,N'-diisopropylcarbodiimide, N,N<1->dicyclohexylcarbodiimide or N-cyclohexyl-N'-(2-morpholinoethyl)-carboimide.

The coupling reaction is generally carried out in the presence of a solvent. Suitable solvents include ethyl acetate, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran and dimethylformamide. Mixtures of these solvents with water are used as hydrophilic solvents, which are also suitable for the above-mentioned reaction. The coupling reaction can be carried out in the presence of a base, e.g. an alkali bicarbonate. The temperature of the reaction can vary from -10° to 100° C and the reaction time can vary from 1 hour to 10 hours.. The cephalosporin products are isolated according to known methods.. .The compounds of general formula VII can also be prepared by combining a modified polystyrene containing nitrophenol or hydroxysuccinimide groups with an acid of general formula X and mixing the activated acid thus formed with a compound of general formula IX by the method described in Canadian Patent Document No. 892,580 by using a compound of general formula IX instead of penicillanic acid derivative -the ones described therein. The compounds of formula IX can be more fully de- is written by the following formulas XI and XII

wherein R^, M and X have. the same meanings as defined for formula I.. Compounds of formula XI and XII wherein is hydrogen, M is hydrogen or a pharmaceutically acceptable non-toxic

anion or cation and X is hydrogen or acetoxy are commercially available or can be prepared by methods known in the art. The corresponding compounds in which R5 is methoxy can be prepared according to the methods described in US Patent 3,778,432.0

Compounds of formula XI and XII in which M is alkanoyloxymethyl can be prepared by reacting the corresponding acid in the form of a salt such as an alkali metal salt or triethylammonium salt with a compound of the formula

wherein halo is chlorine or bromine and R 7 is a straight

chain or branched lower alkyl group with from 1 to 4 carbon atoms according to the method described in US Patent 3,655,658.

Compounds of formula XI and XII wherein M is alkanoylaminomethyl or alkoxycarbonylaminomethyl are prepared by treating the sodium salt of the acid derivatives of formula XI and XII in an organic solvent such as dimethylformamide or hexamethylphosphoramide at room temperature with an equivalent amount of an alkanoylaminomethyl halide or alkoxycarbonylaminomethyl halide for \ hour to 3 hours, after which the mixture is poured into ice water. The resulting precipitated product is isolated by known methods.

Compounds of formula XI and XII in which M is p-(alkanoyloxy)benzyl are prepared by adding 2 equivalents of p-(alkanoyloxy)benzyl alcohol to a suspension of the sodium salt of the acid derivatives of formula XI and XII in dimethylformamide or hexamethylphosphoramide -. whereupon the mixture is cooled to 0° C. 1.2 equivalents of dicyclohexylcarbodiimide in dimethylformamide are added dropwise to the mixture while stirring. The mixture is stirred at 0° C. for 1 hour to 3 hours and then a further 2 to 5 hours at room temperature. The dicyclohexylurea formed is removed by filtration and the filtrate is diluted with chloroform, methylene chloride or ethyl acetate, washed with water and dried to form the product.

Compounds of formula XI and XII in which M is aminoalka-noylox-methyl are prepared by mixing a suspension of the sodium salt of phenic acid of formula XI and XII and an excess of a suitable amine-protected aminoalkanoyloxymethyl halide in a solvent such as dimethylformamide, hexamethylphosphoramide or dimethylsulfoxide in 2 to 96 hours. The mixture is then diluted with a solvent such as ethyl acetate or methylene chloride, washed with water, aqueous base and then water. The organic base is separated and the precipitate is isolated by known methods.

methods followed by deprotection of the amine group during formation of the product.

Compounds of formula XII where X is a heterocyclic group as described in formula IV are prepared by dissolving 1 equivalent of the acid in the form of a salt such as the sodium salt wherein X is acetoxy in 500 to 2000 ml of water at from 50 to 80°C under a nitrogen atmosphere and followed by the addition of 1 equivalent of a base such as ■ triethylammonium or sodium bicarbonate and 1-3 equivalents of the heterocyclic thiol. The reaction mixture is stirred at 50 - 90° C for 26 hours, after which the water is evaporated and the residue is taken up in an organic solvent such as methanol, ethanol or dimethylformamide and precipitated with an organic solvent such as adetonitrile, acetone, ethyl acetate or chloroform.

In a similar way, the cephalosporin derivatives according to the invention in which X denotes a heterocyclic thio group selected from 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio, l -methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio and M denotes hydrogen, are produced by reaction of 3-( (acetyloxy)methyl) derivative with the appropriate heterocyclic thiol group as represented by the following:

In the above-mentioned formulas XV and XVI, aryl is selected from phenyl or 2-thienyl, Y is selected from hydrogen, chlorine, bromine, or a straight-chain or branched lower alkyl group with from 1 to 4 carbon atoms. or an alkoxy group with from 1 to 4 carbon atoms provided that when aryl is 2-thienyl, Y is hydrogen, each

1 2 3

of R , R and R are selected from hydrogen or a straight chain or branched lower alkyl group having from 1 to 4 carbon atoms, Z is selected from a bond, oxygen, sulfur or imino provided that when aryl is 2-thienyl Z is a bond, W is selected from hydrogen, methyl, amino, hydroxy, SO-^H or COOR<4>, where R<4> is selected from hydrogen or 5-indanyl, n is zero, .or 2 provided that when W is different from hydrogen or methyl and Z is different from a bond, n is not zero, R^ is selected from hydrogen or methoxy, and the -S-hetero moiety is selected from 1,3,4-thiadiazol-5-ylthio, 3-methyl-l ,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 2-methyl-1,3, 4-thiadiazol-5-ylthio.

In the above reaction, one equivalent of the sodium salt derivative is dissolved in water at a temperature of from 25 to 90° C. under a nitrogen atmosphere followed by the addition of one equivalent of a base such as triethylammonium or sodium bicarbonate and from one to three equivalents of the heterothiol derivative, after which the reaction mixture stirred for 2 to 6 hours at a temperature of 25 to 90°C.

The compounds of formula X are prepared by direct halo-methylation as described below, of an acid of the formula

wherein aryl, Y, Z, n and W 2 have the same meanings as given for formula VII, which is commercially available or can be obtained

. according to known methods in the field.

When the substituent group W 2 in compounds of formula XIII denotes amino, the amino group is protected by a suitable blocking group, e.g., an acyl group such as acetyl or trifluoroacetyl, before the haloethylation reaction. After completion of the halomethylation reaction, the blocking groups can be removed by acid hydrolysis according to methods known in the art.

The halomethylated derivatives of the compounds of formula XIII are obtained by several methods. For example, a compound of formula XIII is reacted with a formaldehyde source such as paraformaldehyde, ClCt^OCH^ or formalin solution in the presence of a Lewis acid such as ZnCl2, A1C13, SnCl4 or C1SO3H in a solvent such as petroleum ether, chloroform, carbon tetrachloride or benzene at a temperature varying from -10 to 100° C during which time hydrogen chloride gas or hydrogen bromide gas is bubbled through the reaction mixture, whereby compounds of general formula X are obtained.

The reaction of an acid of formula XIII with 34 - 38% formalin in concentrated hydrochloric acid at temperatures varying from ~10 to 100° C during which hydrogen chloride gas or hydrogen bromide gas is bubbled through the reaction mixture also gives compounds of general formula X.

Furthermore, compounds of general formula X are obtained by reacting an acid of formula XIII with dioxane in acetic acid or phosphoric acid by temperatures from -10 to 100° C during which hydrogen bromide or hydrogen chloride gas is bubbled through the reaction mixture. Reaction of an acid of formula XIII in the presence of a Lewis acid such as those described above, with chloromethyl ether at temperatures from -10 to 100° C, or reaction of the acid in acetic acid or concentrated sulfuric acid with dichloroethyl-<eth>er in the presence of zinc chloride will also give compounds of general formula X.

The compounds of formula X in which W 2 denotes COOH, and aryl is phenyl are preferably obtained by treating the corresponding diethyl ester of formula XIII with 40% formalin in the presence of anhydrous zinc chloride in benzene at approx. 50° C, below which hydrogen chloride or hydrogen bromide gas is bubbled into the reaction mixture followed by acid hydrolysis.

Compounds of formula X in which W 2 denotes SO^H can be obtained by the halomethylation reactions described above

2 using acid of formula XIII in which W denotes SO^H or the carboxymethyl ester thereof, where in the latter case the resulting halomethylated compound is converted to the free acid by acid hydrolysis.

In the halomethylation of compounds of formula XIII in which W 2 denotes OH, it may be advantageous to protect the oH group before the halomethylation as described by V.Reichert et al. Pharmazie 5, 10 (1050).

The compounds according to the present invention in which R<4> is hydrogen can also be prepared by coupling a derivative of formula with an acid of formula

or a functional derivative thereof wherein R is selected from hydrogen

or methoxy, R is selected from the moiety

wherein M is selected from hydrogen, a pharmaceutically acceptable non-toxic anion or cation charge, alkanoyloxymethyl wherein the alkanoyl portion contains from 1 to 5 carbon atoms and may be straight chain or branched, alkanoylaminomethyl wherein the alkanoyl portion contains from 1 to 5 carbon atoms and may be straight chain or branched and where the amino nitrogen may be substituted with an alkyl group with from 1 to 4 carbon atoms, alkoxycarbonylaminomethyl where the alkoxy part contains from 1 to 4 carbon atoms bg may be straight-chain or branched and where the amino nitrogen may be substituted with an alkyl group with from 1 to 4 carbon atoms, p-(alkanoyloxy )benzyl where the alkanoyl part contains from 1 to 5 carbon atoms and can be straight-chain or branched or amino-alkanoyloxymethyl in which the alkanoyl part contains from 2 to 15 carbon atoms, and the amino nitrogen can be mono- or disubstituted with a lower alkyl group with from 1 to 4 carbon atoms , X is selected from hydrogen, acetoxy, 1,3,4-thiadiazol-5-yl thio, 3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio, 1-methyl-. tetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-thiadiazol-5-ylthio, aryl is selected from phenyl or 2-thienyl, Y is selected from hydrogen, chlorine, bromine, a straight or branched lower alkyl group of from 1 to 4 carbon atoms or an alkoxy group of from 1 to 4 carbon atoms provided that

12 3

when aryl is 2-thienyl, Y is hydrogen, each of R , R , and R is selected from hydrogen or a straight-chain or branched lower alkyl group having from 1 to 4 carbon atoms, Z. is selected from a bond, oxygen, sulfur, or imino' provided that when aryl is 2-thienyl, Z is a bond, W 2 is selected from hydrogen, methyl, amino, hydroxy, SO3H or COOH, .ri is zero, 1 or 2 provided that when W<2>is other than hydrogen or methyl and Z is different from a bond, n is not zero.

When the substituent group W 2 in the above formula XIV denotes an amino group, suitable blocking groups are used, e.g. a mineral salt such as hydrochloride salt, tertiary butoxycarbonyl or carbobenzyloxy to protect the amino function in a similar manner as previously described.

Functional equivalents of the acids represented by formula XIV include the acid halides, e.g. the acid chloride, acid anhydrides including mixed anhydrides with e.g. alkyl phosphoric acids, lower aliphatic monoesters of carboxylic acid or alkyl or aryl sulfonic acids. In addition, the acid azide or an active ester or thioester can e.g. with p-nitrophenol, 2,4-dinitrophenol or thiacetic acid is used, or the free acid as represented by formula XIV can be coupled with. • the 7-amino-cephalosporanic acid derivative or a 6-aminopenicillanoic acid derivative as represented by formula IX after reacting the acid with N,N<1->dimethylchloroforminium chloride or by using a carbodiimide reagent, e.g. N,N<1->diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, or N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide.

The coupling reaction is generally carried out in the presence of a solvent. Suitable solvents include ethyl acetate, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran and dimethylformamide. Mixtures of these solvents with water are also used as hydrophilic solvents

are suitable for the reaction indicated above. The coupling reaction is generally carried out in the presence of a base, e.g. an alkali bicarbonate. The temperature of the reaction can vary from -10 to 100° C and the reaction time can vary from \ hour to 10 hours. The cephalosporin products are isolated by known methods.

The preparation of compounds of formula IX has been described previously.

Compounds of formula I in which R<4> is 5-indanyl are prepared by reacting the corresponding acid, i.e. compounds of formula I in which R<4> is hydrogen, with 5-indanol in an inert solvent in the presence of W, N1-dicyclohexylcarbodiimide at a pH of .ca. 2.5 and a temperature from 20 to 30° C. Equimolar amounts of the reactants are used or a slight excess of 5-indanol can be used. The molar amount of N,N<1->dicyclohexylcarbodiimide used is equivalent to the molar amount of 5-indanol. Suitable solvents for the reaction are dioxane, tetrahydrofuran, ethyl acetate, dimethylformamide and methylene chloride.

Compounds of formula I in which M denotes alkanoylaminomethyl or alkoxycarbonylaminomethyl and W is different from COOH can also be prepared by reacting the corresponding acid in the form of a salt such as an alkali metal salt, e.g. the sodium salt by 1.5. to 2.5 equivalents of a suitable alkanoylaminomethyl halide or alkoxycarbonylaminomethyl halide, each of which can be represented by the structure

wherein halo is selected from a reactive halogen atom such as chlorine or bromine, R is selected from a straight or branched lower alkyl group having from 1 to 4 carbon atoms or a straight or branched lower alkoxy group having from 1 to 4 carbon atoms and R 8 is hydrogen or a lower alkyl group having from 1 to 4 carbon atoms. The reactants are stirred for 1 - 5 hours in dimethylformamide, hexamethylphosphoramide or a similar solvent at a temperature varying from 10 to 45° C, after which the reaction mixture is poured into ice water and decanted. The oily residue is taken up in an organic solvent such as ethyl acetate, methylene chloride or benzene, washed with base and then with water and dried over magnesium sulphate. The organic. solution is evaporated to dryness in vacuo to form the desired ester.

Before the above-mentioned esterification reaction, compounds in which W denotes amino are protected with blocking" groups, e.g. tertiary butoxycarbonyl or carbobenzyloxy, after which such groups are removed after the end of esterification according to known methods in the field, e.g. the method described in US patent documents 3,657,232.

Compounds of formula I in which M denotes p-(alkanoyloxy)benzyl and W is different from COOH can also be prepared by reacting molar equivalents of the corresponding acid and a p-(alkanoyloxy)benzyl alcohol in which the alkanoyl group contains from 1 to 4 carbon atoms and can be straight chain or branched. The reactants are dissolved in an organic solvent such as dimethylformamide or hexamethylphosphoramide and cooled to a temperature of -15 to 25° C, after which an equivalent amount of dicyclohexylcarbodiimide in dimethylformamide or hexamethylphosphoramide is added dropwise to the reaction mixture while stirring. Stirring is continued for \ hour to 2 hours at temperatures from -15 to 25° C and then 4-6 hours at 25 - 45° C. The dicyclohexylurea formed is removed by filtration and the filtrate is diluted with chloroform, ethyl acetate or methylene chloride and washed with water . The organic layer is dried and evaporated to form the product.

Compounds of formula I in which M is alkanoyloxymethyl<p>g W is different from COOH can also be prepared by reacting the corresponding acid in the form of a salt such as an alkali metal salt or triethylammonium salt with a compound of the for-0 or halo-CH2~ 0-C-R 7 ', wherein halo is chlorine or bromine and R 7 is

a straight-chain or branched lower alkyl group with from 1 to 4 carbon atoms by the method described in US patent 3,655,658.

Compounds of formula I wherein M is aminoalkanoyloxymethyl and W is different from COOH can also be prepared by mixing a suspension of the sodium salt of the corresponding acid and an excess of a suitable amine protected aminoalkanoyloxymethyl halide in a solvent such as dimethylformamide, hexamethylphosphoramide or dimethylsulfoxide in 2 - 96 hours. The mixture is then diluted with a solvent such as ethyl acetate or methylene chloride, washed with water, aqueous base and then water. The organic phase is separated and the precipitate x is isolated according to known methods followed by deprotection of the amino group during formation of the product.

Compounds of formula XIV can be prepared by reacting derivatives of formula VIII and X by the methods described on page 12 Items 18 - 25 and these compounds, especially those in which W 2 is different from H or CH 3 are applicable in the preparation of compounds of formula IN.

Example 1

p-chloromethylphenylacetyl chloride

(A) At a temperature from -10 to 0° C, hydrogen chloride gas is bubbled through a stirred mixture of 102 g of phenylacetic acid,

67.5 g paraformaldehyde and 67.5 g zinc chloride in 1000 ml petroleum ether for 1 hour. Stirring is continued for approx. 1 hour at room temperature, after which the mixture is boiled under reflux for 2 hours during which hydrogen chloride gas is bubbled into the mixture. 1000 ml each of methylene chloride and water are added to the reaction mixture. The organic phase is separated and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are extracted several times with a saturated sodium bicarbonate solution. The organic neutral phase is dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to form a neutral by-product further identified in Example 5. The basic aqueous phase is separated and acidified with cold concentrated hydrochloric acid at pH 2-3, and then extracted three times with methylene chloride. The methylene chloride fraction is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated. The resulting oily acid product is chromatographed on silica gel using benzene and benzene-acetone as eluent to give p-chloromethylphenylacetic acid which is recrystallized from hot chloroform. Sm..p. 147 - 149°C.

(B) A mixture of 1 g of p-chloromethylphenylacetic acid and 6 ml of thionyl chloride is stirred at room temperature for 25 hours after which

the excess of thionyl chloride is removed under vacuum to form p-chloromethylphenylacetyl chloride.

When in example 1 (A) an acid from table 1 is chosen instead of phenylacetic acid, the respective chloromethyl derivative listed in table 1 is obtained which can be converted to the acid chloride by the method according to example 1 (B).

Example 2

p-Chloromethylphenylglycine hydrochloride

A mixture of 2.03 g of trifluoroacetylated phenylglyceride, 0.8 g of zinc chloride in chloromethyl ether is heated to 65° C. for 12 hours. Excess reagent is removed under vacuum and the residue is dissolved in CH2C12/washed with saturated NaHCO3 solution and then saturated sodium chloride solution. The neutral organic phase is dried over Na^SO^ and concentrated to an oil which is purified by column chromatography. In a similar way, the chloromethyl derivatives listed in Table 2 can be prepared from the listed acid.

Example 3

p- Chloromethylphenylmalonic acid

When, in the method according to example 1 (A), an equivalent amount of phenylmalonic acid diethyl ester is used instead of phenylacetic acid, p-chloromethylphenyl malonic acid diethyl ester is obtained which gives the corresponding acid by acid hydrolysis. In a similar way, the chloromethyl derivatives listed in Table 3 can be prepared when the diethyl ester of the ti. 1corresponding acid listed in table 3 is used instead of phenylmalonic acid diethyl ester.

i' '' ■

Example 4

5- Chloromethyl- 2- thienyl acetyl chloride

2-thiophenecarboxylic acid is treated in a solution of chloroform with chloromethyl ether in the presence of 0.9 to 2.2 equivalents of aluminum chloride to form 5-chloromethyl-2-thienylcarboxylic acid. Treatment of the acid obtained with an excess of thionyl chloride at room temperature for 16 hours gives the acid chloride which is reacted with diazomethane to form the corresponding diazoketone. A methanol solution of the diazoketone is irradiated under nitrogen for approx. 1 hour with a high pressure mercury lamp using a quartz filter. The methyl-5-chloromethyl-2-thienylacetate is obtained by working up and column chromatography on silica gel. The acetate is hydrolyzed by treatment with a 1:1 mixture of acetic acid and concentrated hydrochloric acid at room temperature overnight to form 5-chloromethyl-2-thienylacetic acid. .

When in the method according to example 1 (B) 5-chloromethyl-2-thienylacetic acid is used instead of p-chloromethylphenylacetic acid, 5-chloromethyl-2-thienylacetyl chloride is obtained.

Example 5 6-hydroxymethylphenylacetic acid! acton

The neutral by-product obtained in example 1 is purified by sublimation under vacuum (0.05 mm Hg at 80° C) to form o-hydroxymethylphenylacetic acid lactone. M.p.. 82° C.

Example 6

o-bromomethylphenylacetyl chloride

To a solution of 5 ml of glacial acetic acid saturated with hydrogen bromide gas, a solution of o-hydroxymethyl-.phen<yl>acetic acid lactone (0.55 g) in 2 ml of glacial acetic acid is added at 0° C. The mixture is stirred at room temperature for 2 hours and then boiled under reflux for 1 hour, during which hydrogen bromide gas is bubbled into the mixture. Excess lactone and solvent are removed under high vacuum at room temperature. The resulting oily residue is triturated three times with hexane to form o-bromomethylphenylacetic acid. Sm.p. 110°C.

A solution of 0.18 g of o-bromomethylphenylacetic acid in an excess of thionyl chloride is stirred at room temperature for 18 hours, after which unreacted thionyl chloride is removed under high vacuum to form o-bromomethylphenylacetyl chloride as an oily residue.

Example 7

o- chloromethyl- p- methoxymandelic acid chloride

A solution of 1.1 g of 2-chloromethyl-4-methoxymandelic acid, obtained by the method described by B.Reichert et al., Pharmazie 5, 10 (1950), in 25 ml of thionyl chloride is stirred at room temperature for 16 hours after which excess thionyl chloride is removed under high vacuum to give o-chloromethyl-p-methoxymandelic acid chloride as an oil.

Example 8

3-((Acetyloxy)methyl}-7-amino-8^oxo-5-thia-l-azabicyclo(4.2.0)-oct- 2- en- 2- carboxylic acid- propionyloxymethyl ester

7.5 g of the sodium salt of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo (42.0)-oct-2-en-2-carboxylic acid are added to 35 ml of dimethylformamide , and the solution is stirred at room temperature for 30 minutes, after which 8 ml of chloromethylpropionate is added. Stirring is continued at room temperature for 3 hours. The mixture is diluted with ethyl acetate and washed with water. The organic layer is separated and evaporated to dryness. The residue is recrystallized from ethyl acetate to form 3-((acetyloxy)-methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.o)oet-2-en-2-carboxylic acid propionyloxymethyl ester.

When, in a similar manner, a suitable amount of chloromethyl pivalate, chloromethyl acetate or chloromethyl butyrate is used instead of chloromethylpropionate, the following products are obtained: 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-az. abicyclo(4.2.O)-oct-2-ene-2-carboxylic acid pivalyloxymethyl ester, 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.O)-oct -2-ene-2-carboxylic acid adetyloxymethyl ester,

3-((acetyl.oxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo (4.2.o)-oct-2-en-2-carboxylic acid butyrylosymethyl ester

Example 9

3- f( acetyloxy) methyl)- 7- amino- 8- oxo- 5- thia- l- azabicyclo{ 4. 2 . O) - oct- 2- ene- 2- carboxylic acid- 2- amino- 3- methylbutyryl- oxymethyl ester

A suspension of 5 g of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid sodium salt and 8.5 g N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the method described in DTOS 2 236 620, is mixed in 100 ml of dimethylformamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and with aqueous bicarbonate and again with water. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-((acetyloxy)-methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)-oct-2- en-2-carboxylic acid N-tert-butoxycarbnyl-2-amino-3-methylbutyryloxymethyl ester from which the amine protecting group is removed by known methods to form the title product.

Example 10

3- f ( acetyloxy ) methyl)-- 7- amino- 8- oxo- 5- thia- l- azabicyclof 4 . 2. 0)-oct- 2- ene- 2- carboxylic acid- N- ethoxycarbonyl- N- methylaminomethyl ester

7.25 mg (2.5 mmol) of the sodium salt of 3-((acetyloxy)-methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4,2,0}oct-2-ene -2-

carboxylic acid in 50 ml of dimethylformamide is treated at room temperature with 375 mg (2.5 mmol) of N-chloromethyl-N-methylurethane for 1 hour. The mixture is carefully poured into ice water and the precipitated solid material is removed by filtration and washed with water. The solid material is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to form 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.o)oct-2- ene-2-carboxylic acid N-ethoxycarbonyl-N-methylaminomethyl ester.

When in the above-mentioned method is used

a suitable amount of N-methyl-N-propionylaminomethyl chloride, N-butyrylaminomethyl chloride, N-acetylaminomethyl chloride or N-methyl-N-ethoxycarbonylaminomethyl chloride instead of N-chloromethyl-N-methylurethane gives the following compounds: 3-((acetyloxy)methyl) -7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid N-methyl-N-propionylaminomethyl ester,

3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid N-butyrylaminomethyl ester,

3-.( (acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo (4.2.o)-oct-2-en-2-carboxylic acid-N-acetylaminomethyl ester and 3-( (acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid N-methyl-N-ethoxycarbonylaminomethyl ester.

Example 11 3-f(acetyloxy)methyl)-7-amino-8-oxo-5'-thia-l-azabicyclo(4.2.0.)-oct-2-ene-2-carboxylic acid-p-pivalyloxybenzyl ester

To a suspension of 6.6 mmol of 3-((acetyloxy)-methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.o)-oct-2-ene-2-carboxylic acid sodium salt 2 equivalents of p-pivalyloxybenzyl alcohol are added to 35 ml of dimethylformamide (DMF) followed by cooling to 0° C after which; 7.2 mmol of dicyclohexylcarbodiimide in 7.5 ml of DMF are added dropwise while stirring. The mixture is stirred at 0° C

for 1 hour and for a further 4 hours at room temperature. The dicyclohexylurea formed is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo to form 3-((acetyloxy)-

methyl 1-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.o)-oct-2-ene-2-carboxylic acid p-pivalyloxybenzyl ester.

When in the above-mentioned method a suitable amount of p-(propionyloxy)-benzyl alcohol, p-(acetyloxy)-benzyl alcohol or p-(valeryloxy)-benzyl alcohol is used instead of p-pivalyloxybenzyl alcohol, the following compounds are obtained: 3-( acetyloxy)-methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4■.2.o)-oct-2-ene-ene-2-carboxylic acid p-(propionyloxy)-benzyl ester,

3-((acetyloxy)-methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid p-(acetyloxy)benzyl ester and 3- ((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid p-(valeryloxy)benzyl ester.

Example 12

3-(( 2- methyl- l, 3, 4- thiadiazol- 5- ylthio) methyl) - 7- amino- 8-oxo-5-thia- l- azabicyclo( 4. 2. 0)- oct- 2- en- 2- carboxylic acid

For about. 1 liter of water dissolves 0.1 mol of the sodium salt of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0) -. oct-2-ene-2-carboxylic acid at 70° C under a nitrogen atmosphere. 1 equivalent of sodium bicarbonate and 2 equivalents of 2-methyl-1,3,4-thiadiazol-5-ylthiol are added to the solution. The mixture is stirred at 70° C. for 3 hours, after which the pH is adjusted to 3.5 and the resulting precipitate is collected to form 3-((2-methyl-.1,3,4-thiadiazol-5-ylthio)methyl) -7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid.

When an equivalent amount of 1,3,4-thiadiazol-5-ylthiol, 3-methyl-1,2,4-thiadiazol-5-ylthiol, tetrazol-5-ylthiol, 1-methyltetrazol- 5-ylthiol or 2-methyl-1,3,4-oxadiazol-5-ylthiol instead of 2-methyl-1,3,4-thiadiazol-5-ylthiol, the following products are obtained:

3- ((1,3,4-thiadiazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.o)oct-2-en-2-carboxylic acid,

3-((3-methyl-1,2,4-thiadiazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene -2-carboxylic acid,

3-((tetrazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo-(4.2.o)oct-2-en-2-carboxylic acid,

3-( (l-nethYltetrazol-5-ylthlo)iTieth.Yl)--7-amino-8-oxo-5-thi.ia-l-azabicyclo(4.2,0}oct-2-en-2-carboxylic acid and 3-((2-methyl-1,3,4-oxadiazol-5-ylthio)methyl}-7-amino-8-oxo-t-thia-l-azabicyclo(4.2.0}oct-2-en-2 -carboxylic acid.

Example 13

When, in the method according to example 12, suitable amounts of the sodium salt of the cephalosporin derivative and the heterocyclic thiol derivative indicated in Table IV are used instead of the sodium salt of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia- 1-azabicyclo(4.2.0)oct-2-en-2-carboxylic acid and 2-methyl-1,3,4-thiadiazol-5-ylthiol, the products listed in Table IV are obtained.

Example 14

3- f( acetyloxy) methyl}— 7-([ 2-( 4-( chloromethyl) phenyl}- acetyl] amino)- 8-oxo- 5-thia-l-a z ab icyclo( 4. 2. 0} oc t - 2- one- 2- c arboxy1syr e

A mixture of 1 g of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid and 1 g of p-chloromethylphenylacetyl chloride in 45 ml of ethyl acetate is refluxed for 2 hours after which the solvent is removed under vacuum to form a yellowish-brown amorphous product which is chromatographed on silica gel using benzene-acetone as eluent to give 3-((acetyloxy)methyl}-7-(( 2-(4-(Chloromethyl)phenyl)acetyl)amino)-8-oxo-5-thia-1-azabicyclo('4.2.o)oct-2-ene-2-carboxylic acid. M.p. 164 - 165° C (cleavage).

When a suitable amount of each of the acetyloxymethyl ester, the propionyloxygenyl ester, the 2-amino-3-methylbutyryloxymethyl ester, the pivalyloxymethyl ester and the N-ethoxycarbonyl-N-methylaminomethyl ester of 3-((acetyloxy)-methyl)-7-amino-8- oxo-3-((1-methy1tetrazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0) oct-2-ene-2-carboxylic acid pivalyloxybenzyl ester, 3 -((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl) -7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-en-2- carboxylic acid propionyloxymethyl ester or the corresponding pivalyloxymethyl ester or 3-( (2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo( 4 .2.0) oct -2-ene-12-carboxylic acid or 3-((1-methyltetrazol-5-ylthio)-methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene -2-carboxylic acid instead of the free 7-aminocephalosporanic acid, the following compounds are obtained: 3-((acetyloxy)methyl)-7-((2-C 4-(chloromethyl)-phenyl)-acetyl) amino) - 8- oxo- 5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxyls ure-acetyloxy-methyl ester,

3-((acetyloxy)methyl)-7-(.(2-(4-(chloromethyl)phenyl)-acetyl)amino)-8-oxo-5-thia-l-azabicyclo (4.2.0)oct-2- a--2--carboxylic acid propionyl-oxybenzyl ester,

3-((acetyloxy)methyl)-7-((2-(4-(chloromethyl)phenyl)-acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene -2-carboxylic acid 2-amino-3-methylbutyryloxymethyl ester,

3-( (acetyloxy)methyl)--7-( (2-(4-(chloromethyl)phenyl)-acetyl)amino)-

8-oxo-5-thia-l-azabicyclo(4.2.0) oct-2-ene-2-carboxylic acid pivalyloxymethyl ester,

3-((acetyloxy)methyl)--7- ((.'2-(4 - (chloromethyl)-phenyl)—acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.'. 2.o)-oct-2-ene-2-carboxylic acid-N-ethoxycarbonyl-N-methylaminomethyl ester,

3-((1-methyltetrazol-5-ylthio)methyl)-7-((2-(4-1chloromethyl)-phenyl)-acetyl)-amino)-8-oxo-5-thia-1-azabicyclo (4 2. o) oct-2-ene-2-carboxylic acid pivalyloxybenzyl ester,

3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl )phenyl)acetyl)amino)-8-oxo-5-thia- l-azabicyclo(4.2.O)oct-2-ene-2-carboxylic acid propionyloxymethyl ester,

3- ((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl )phenyl)acetyl)amino)-8-oxo-5-thia- l-azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid pivalyloxymethyl ester,

3- ((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl)phenyl)acetyl)amino)-8-oxo-5-thia- l-azabicyclo(4.2.O)oct-2-ene-2-carboxylic acid and

3- ((l-methyltetrazol-5-ylthio)methyl)-7-((2-(4-chloromethyl)-phenyl)acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2.o) oct-2-ene-2-carboxylic acid•

Example 15

7-( f2-( 4-( chloromethyl) phenyl) acetyl) amino)- 3- methyl- 8- oxo- 5- thia-1- azabicyclo( 4. 2. o) oct- 2- ene- 2- carboxylic acid

By following the procedure according to example 14 but using only 1 g of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo-(4.2.0)oct-2-en-2-carboxylic acid instead of 3 -acetyloxymethyl-7-amino-8-oxo-5-thia-1-a.zabicyclo (4.2.0) oct-2-en-2-carboxylic acid, 7-((2-(4-(chloromethyl)phenyl)acetyl) is obtained amino)-3-methyl-8-oxo-5-thia-1-azabicyclo(4.210)oct-2-ene-2-carboxylic acid. Sm.p. 145 - 146° C.

Example 16

6- f f2- f4-(chloromethyl) phenyl) acetyl) amino)- 3/ 3- dimethyl- 7- oxo- 4-. thia-1-azabicyclo f3. 2. 0) heptane- 2- carboxylic acid

By following the procedure according to example 14 more? apply one. suitable amount of the triethylamine salt of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid in place of 3-((acetyloxy)methyl) --7-amino-8-oxo-5-thia-1-aza-blcyclo(4.2.o)-oct-2-en-2-carboxylic acid, 6-((2-(4-(chloromethyl) _phenyl)-acetyl^amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo{3.2.0)heptane-2-carboxylic acid.

Example 17

3- f( acetyloxy) methyl)- 7-({ 2 - f4-( chloromethyl) phenyl] - 2-aminoacetyl) amino)- 8- oxo- 5- thia- l- azabicyclo( 4. 2. o) oct- 2- en- 2-carboxylic acid

p-Chloromethylphenylglycine where the amino group is protected with tertiary butoxycarbonyl is treated with isobutyl chloroformate in the presence of triethylamine. The mixed anhydride thus obtained is reacted with the triethylamine salt of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.o)oct-2-en-2-carboxylic acid at 0° C for approx. 4 hours. The resulting product is isolated and the amine-protecting group is removed by acid hydrolysis to form 3-((acetyloxy)-methyl)-7-((2-(4-(chloromethyl)-phenyl)-2-aminoacetyl)amino)-8 -oxo-5-thia-1-azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid.

When a suitable amount of the triethylamine salt of 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia- l-azabicyclo-(4/2,o)oct-2-en-2-carboxylic acid or 3-((l-methyltetrazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-l- azabicyclo(4,2,o)oct-2-ene-2-carboxylic acid, 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4,2,o)oct -2-ene-2-carboxylic acid pivalyloxymethyl ester instead of the triethylamine salt of 3-.( (acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4,2,o)oct-2 -ene-2-carboxylic acid, the following products are obtained: 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl)phenyl)-2- aminoacetyl) amino) -8-oxo-5-thia-1-azabi.cyclo-(4.2,0)oct-2-ene-2-carboxylic acid,

3-((1-methyltetrazol-5-ylthio)methyl)-7-((2-(4-chloromethyl)-phenyl)-2-aminoacetyl)amino)-8-oxo-5-thia-1-azabicyclo(4.2 .0)oct-2-ene-2-carboxylic acid,

3- ((acetyloxy )methyl)-7- ((,2- (4- (chloromethyl)phenyl)-2-aminoacetyl)- amino)-8-oxo-5-thia-l-azabicyclo(4,2, O)oct-2-ene-2-carboxylic acid pivalyloxy methyl ester.

Example 18

6- f.( 2- f 4- ( chloromethyl) phenyl) - 2- aminoacetyl) amino) - 3 , 3 - dimethylf 7- oxo- 4- thia- l- azabicyclo( 3, 2, 0) heptane- 2- carboxylic acid

When, in the method according to example 17, a suitable amount of the triethylamine salt of 6-amino-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo 3,2,0 heptane-2-carboxylic acid is used instead of the triethylamine salt of 3-((acetyloxy)-methyl)-7-amino-8-oxo-. 5-thia-1-azabicyclo'(4,2,0)oct-2-ene-2-carboxylic acid, 6-((2-(4-(chloromethyl)phenyl)-2-aminoacetyl) amino)-3 is obtained, 3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid.

Example 19

3- f( acetyloxy) methyl)- 7-(( 2-( 2-( chloromethyl)- 4- methoxyphenyl) - 2-hydroxyacetyl)- amino) - 8- oxo- 5- thia- l- azabicyclo ( 4, 2 .0) oct-2-ene-2-carboxylic acid

A mixture of 1 g of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid and 1.2 g of 2- chloromethyl-4-methoxymandelic acid chloride in 200 ml of ethyl acetate is boiled under reflux for 50 minutes, after which the solvent is removed, under high vacuum. The resulting product is chromatographed on silica gel using benzene-acetone as eluent. The product obtained is triturated with ether to form 3-((acetyloxy)methyl)-7-((2-(2-(chloromethyl)-4-methoxyphenyl)-2-hydroxyacetyl)amino)-8-oxo-5-thia -1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid. Sm.p. 140 - 142° C (decomposition).

When a suitable amount of 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)-methyl)-7-amino-8-oxo-5-thia-1- azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid or 3-((l-methyltetrazol-5-ylthio)methyl)-7-amino-8- oxo-5-thia-l-azabicyclo(4.2.0 )oct-2-ene-2-carboxylic acid instead of the corresponding 3-((acetoxy)methyl)derivative and 2-(p-chloro-methylrenyl)mandelic acid chloride is used instead of 2-chloromethyl-4-methoxymandelic acid, obtaining 3- ((2-methyl-1,3,4-thiadiazol-5-ylthio)-methyl)-7-((2-(4-(chloromethyl)phenyl)-2-hydroxyacetyl)-amino)-8-oxo-5 -thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid and 3-((l-methyltetrazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl)-phenyl )-2-hydroxyacetyl)amino)-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-ene-2-carboxylic acid.

Example 20

6-(( 2-( 2-( chloromethyl)- 4- methoxyphenyl)- 2- hydroxyacetyl)- amino)-3, 3- dimethyl- 7- oxo- 4- thia- l- azabicyclo( 3. 2. o) heptane-2-carboxylic acid

By proceeding as described in Example 19 but using a suitable amount of the triethylamine salt of 6-amino-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo 3.2.0 heptane-2-carboxylic acid instead of 3 ~((acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)-oct-2-en-2-carboxylic acid is obtained 6-((2-(2-(chloromethyl )-4-methoxyphenyl)-2-hydroxyacetyl)amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.0)heptane-2-carboxylic acid..

Example 21

3-(( acetyloxy) methyl)- 7- f f2-( 5-( chloromethyl)- 2- thienyl) acetyl)-amino)- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. o) oct - 2- en- carboxylic acid

A mixture of 1.2 equivalents of 5-chloromethyl-2-thienylacetyl chloride bg 1 equivalent of 3-((acetyloxy)-methy1-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.o)oct- 2-ene-2-carboxylic acid is refluxed for 50 minutes in ethyl acetate, after which the solvent is removed, and the remaining product is purified by column chromatography on silica gel to form 3-((acetyloxy)methyl)-7-((2-(5-( chloromethyl)-2-thienyl)acetyl)amino)-8-oxo-5-thia-1-azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid.

Example 22

3-(( acetyloxy) methyl) C2 — f 4—( chloromethyl) phenyl)- 2- carboxy-acetyl) amino) - 8- oxo- 5- thia- l- azabicyclo f 4 . 2. o)' oct- 2- en- 2-/carboxylic acid

α-Carboxy-p-chloromethylphenylacetyl-nitrophenyl polymer, prepared according to the method described in Canadian patent document no. 892 580 with 4 mmol of p-chloromethylphenylmalonic acid is suspended in approx. 8 hours in 20 ml of dry methylene chloride solution containing 1 mmol of 3-((acetyloxyJmethyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.O)oct-2-en-2-carboxylic acid triethylammonium salt, which is prepared from 544 mg of 7-aminocephalosporanic acid (1 mmol) and 0.56 ml of triethylamine (1 mmol) at room temperature. After only traces of 7-aminocephalosporanic acid are left in the solution as determined by thin-layer chromatography on cellulose in 70% aqueous

propanol, the polymer is filtered off and washed with three portions of 50 ml each of methylene chloride. The combined filtrates are evaporated and the residue is dissolved in 20 ml of distilled water. This solution is acidified to pH 2 by adding 0.2N hydrochloric acid and extracted twice with ethyl acetate. The organic solution is dried over sodium sulfate and evaporated at room temperature. The remaining solid is dried overnight over phosphorus pentoxide under vacuum to give 3-((acetyloxy)methyl)-7-((2-(4-(chloromethyl)phenyl)--2-carboxyacetyl)-amino)-8- oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid.

When a suitable amount of 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)-methyl)-7-amino-8-oxo-5-thia-1- azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid, 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene -2-carboxylic acid pivalyloxymethyl ester or 3-((l-methyltetrazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0) oct-2-en-2- carboxylic acid pivalyloxybenzyl ester instead of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabi.yclo( 4 .2.0) oct-2-en-2-carboxylic acid is obtained generating products: 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl)phenyl)-2-carboxyacetyl)amino)-8- oxo-5-thia-l-azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid,

3-((acetyloxy)methyl)-7-((2-(4-(chloromethyl)phenyl)-2-carboxy-acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2.0) oct -2-ene-2-carboxylic acid pivalyloxymethyl ester, and

3-((1-methyltetrazol-5-ylthio)methyl)-7-((2-(4-(chloromethyl)-phenyl)-2-carboxyacetyl)amino)-8-oxo-5-thia-1-azabicyclo( 4.2.0)-oct-2-ene-2-carboxylic acid pivalyloxybenzyl ester.

Example 2 3

When, in the method according to example 14, a suitable amount of an acid chloride as listed in table 5 is used instead of p-chloromethylphenylacetyl chloride, the respective cephalosporin derivatives as listed in table 5 are obtained.

In a similar manner as described in example 14, a suitable amount of the triethylamine salt of 6-amino-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo (3 * 2 . o) heptane-2-carboxylic acid is reacted with a suitable amount of the acid chlorides listed in Table 5, the following penicillin derivatives are obtained: 6- ((2-(4-(chloromethyl)phenyl)-2-methylacetyl)amino)-3,3-dimethyl-'7-oxo- 4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,.

6-((3-(4-(chloromethyl)phenyl)propionyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6-((3-(4-(chloromethyl)phenyl)-2-methylpropionyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6- ((4-(4-(chloromethyl)phenyl)-2-methylbutyryl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6-((2-(4-(chloromethyl)phenoxy)acetyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6- ((2-(4-(chloromethyl)phenoxy)-2-methylacetyl)amino)-3,3-dimethyl-7-OXO-4-thia-1-azabicycio(3.2.o)heptane-2-carboxylic acid,

6- ((4-(4-(chloromethyl)phenoxy)-2-methylbutyryl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6-((2-(4-(chloromethyl)anilino)acetyl)amino\-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6-((3-(4-(chloromethyl)anilino)-2-methylpropionyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6-((2-(4-(chloromethyl)phenylthio)acetyl)amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.o)heptane-2-carboxylic acid, 6- ( (2-(2-(chloro)-4-(chloromethyl)phenyl)acetyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6-((4-(4-(chloromethyl)phenylthio)butyryl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid.

Example 24

When in the method according to example 17 a suitable amount of an acid is used as listed in the following table 6

instead of p-chloromethylphenylglycine, cephalosporin derivatives listed in Table 6 are obtained:

When, in a similar manner as described in example 17, a suitable amount of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo-(3.2.0}heptane-2-carboxylic acid is reacted with a suitable amount of the acids listed in Table 6, the following penicillin derivatives are obtained: 6-((3-(4-(chlorometh<y>l)phen<y>l}-2-aminopropionyl)amino)-3,3-dimethyl-7 -oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6-((4-(4-(chloromethyl)phenoxy)-2-aminobutyryl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6- ((4-(4-(chloromethyl)anilino)-2-aminobutyryl)amino-3,3-dimethyl-7-oxo-4-thia_1-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6-((3-(4-(chloromethyl)phenylthio)-2-aminopropionyl)amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6-((2-(5-(chloromethyl)-2-thienyl)-2-aminoacetyl)amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.O)heptane-2 -carboxylic acid,

6-((4-(5-(chloromethyl)-2-thienyl)-2-aminobutyryl)amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.6)heptane-2 -carboxylic acid.

Example 25

When, in the method according to example 19, a suitable amount of an acid chloride as listed in the following table 7 is used instead of 2-chloromethyl-4-methoxymandelic acid chloride, the corresponding cephalosporin derivatives listed in table 7 are obtained:

When, in a similar manner as described in Example 19, a suitable amount of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo-.

(3,2,0}heptane-2-carboxylic acid is reacted with a suitable amount of the acid chlorides listed in Table 7, the following penicillin derivatives are obtained: 6- {(3-(4-(chloromethyl)phenyl}-2-hydroxypropionyl) amino)-3,3-dimethyl-7-oxo-4.-thia-l-azabicyclo(3.2.0)heptane-2-carboxylic acid,

ormethyl)phenyl)-2-hydroxyburyryl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.o)heptane-2-carboxylic acid,

6-((2-(5-(chloromethyl)-2-thienyl)-2-hydroxyacetyl)-amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3,2.o) heptari-2-carboxylic acid.

Example 26

When in the method according to example 22 a suitable amount of an acid as listed in table 8 is used instead of . p-chloromethylphenylmalonic acid, the cephalosporin derivatives listed in Table 8 are obtained:

t

t

When, in a similar manner as described in example 22, a suitable amount of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3,2,0)-hepta^2-Carboxylic acid is reacted with the acids listed in Table 8, the following penicillin derivatives are obtained: 6- ({-2-(4-(chloromethyl)phenyl)-2-sulfoacetyl)amino)-3,3-dimethyl-7-oxo-4-thia -1-azabicyclo(3.2.0)heptane-2-carboxylic acid.,

6-( ( 4-( 4-(chloromethyl) phenyl) -2-sulf obutyryl) amino) -3, 3-dimethyl-, 7- oxo-4-thia-l-azabicyclo(3.2.0) heptane-2- carboxylic acid,

6-((3-(4-(chloromethyl)phenyl)-2-carboxypropionyl)amino)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo(3,2,0)heptane-2- carboxylic acid,

6- ((4-(4-(chloromethyl)phenyl)-2-carboxybutyryl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclp(3.2.0)heptane-2-carboxylic acid,

6-( (4(-.-4-(chloromethyl)phenylthio)-2-carboxybutyryl)amino)-3n3-dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.0)heptane-2-carboxylic acid,

6-((3-(4-(chloromethyl)anilino)-2-carboxypropionyl)amino)-3,3-dimethyl-7~oxo-4-thia-l-azabicyclo(3.2.0)heptane-2-carboxylic acid and

6-((3-(5-(chloromethyl)-2-thienyl)-2-carboxypropionyl)amino)-3,3-..dimethyl-7-oxo-4-thia-l-azabicyclo(3.2.0)heptane -2-carboxylic acid.

Example 27

3- f( Acetyloxy) methyl)~ 7~(( 2 — f4 —( isothioureamethyl) phenyl) - acetyl) amino)- 8- oxo- 5- thia- l- azabicyclo( 4. 2. 0) oct- 2- ene-2-carboxylic acid hydrochloride

A hot solution of 0.12 g of 3-((acetyloxy)methyl)-7-((2-(4-(chloromethyl)phenyl)acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2. 0)oct-2-ene-2-carboxylic acid and 0.12 g of isothiourea in 30 ml of ethanol are boiled under reflux for 4 hours, after which the solvent is removed under high vacuum, at room temperature, forming an oil which is triturated with 80 ml of benzene-acetone (2:1) to form 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl)phenyl)acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2. 0)oct-2-ene-2-carboxylic acid hydrochloride.

When the halogen methylated derivatives and the isothiourea derivatives listed in subsequent table 9 are reacted in a similar manner, the respective products listed in table 9 are obtained.

Example 28 3-(( Acetyloxy) methyl)- 7-(( 2-( 4-( isothioureamethyl) phenyl)- 2-aminoadetyl) amino)- 8- oxo- 5- thia- T-azabicyclo( 4. 2. o ) oct-2-ene-2-carboxylic acid (A) A mixture of 7.5 g of 3-((acetyloxyjmethyl)-7-((2-(4-(chlororaethyl)phenyl)-2-aminoacetyl)amino)-8 -oxo-5-thia-l-azabicyclo(4é2.0)oct-2-en-2-carboxylic acid in which the 2-amino group is bound with a hydrochloride salt and 1.03 g of isothiourea in 50 ml of ethanol are heated for several hours to reflux temperature, after which dissolved the oxidizing agent is removed in vacuo at room temperature to form an oil. The oil is triturated with 2:1 benzene-acetone to form the corresponding isothioureamethyl derivative. (B) At 0° C, 10 ml of trifluoroacetic acid is added to 5 g of 3-(.(acetyloxy ) methyl)-7-( (2-(4-(isothioureamethyl)phenyl).-2-amino acetyl) amino) -8-oxo-.5-thia-l-aazabkcyclo (4 . 2 . o) oct-2-en-2-carboxylic acid where the 2-amino group is protected with tertiary butoxycarbonyl obtained in the above-mentioned step (A ). The mixture is stirred for several hours under a nitrogen atmosphere leading to a clear solution which is stirred for a further 15 minutes at room temperature perature. Excess trifluoroacetic acid is removed in vacuo and the remaining residue is triturated with diethyl ether and then dissolved in 175 ml of water. The solution is filtered and the pH of the filtrate is adjusted to 5.5 by adding Amberlite IR4B resin which has been washed several times with water. The resin is filtered off and the water is concentrated in a vacuum. A precipitate forms from the concentrate which is removed and washed with ethanol to give 3-((acetyloxy)'methyl)-7-((2-(4-(isothioureamethyl)-phenyl)-2-aminoacetyl)amino)-8 -oxo-5-thia-1-azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid.

When, in a similar manner, the halomethylated derivative and the isothiourea derivative listed in the following table 10 are reacted as described in example 28 (A) and the resulting product is then treated as described in example 28(B), the products are obtained which are listed in Table 10.

Example 29

3- ( ( Acetyloxy) methyl}- 7- ((2- (4- ( isothioureamethyl) phenyl) acetyl)~ amlno)-- 8- oxo- 5- thia- T- azabicyclo (' 4 . 2 . o) oct - 2- en- 2- carboxylic acid- N- ethoxy' ycarbonyl- N- methylamiiromethylester

A mixture of 1.2 g of the sodium salt of 3-((acetyloxy)-methyl}-7-((2-(4-(isothioureamethyl)phenyl)acetyl)amino)-8-oxo-5-thia-l-azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid and 0.5 g of N-chloromethyl-N-methylurethane in 40 ml of dimethylformamide are stirred at room temperature for 2 hours. The mixture is poured into ice water and decanted. The oily residue is collected in 75 ml of ethyl acetate and washed with 5 ml of dilute aqueous sodium bicarbonate and 15 ml of water and then dried over magnesium sulfate, filtered and evaporated to give 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl )phenyl )-acetyl)amino)-8-oxo-5-thia-1-azabicyclo-(4.2.o)oct-2-ene-2-carboxylic acid-N-ethoxycarbonyl-N-methylaminomethyl ester.

Example 30 j 3-( ( Acetyloxy) methyl) - 7-( ( 2-( 4-( isothioureamethyl) phenyl) *-acetyl) amino)- 8- oxo- 5- thia- l- azabicyclo( 4. 2. o) oct-2-ene-2-carboxylic acid p-pivalyloxybenzyl ester

To a solution of 1.8 g of 3-((acetyloxy)methyl)-7-((2- .

(4-(isothioureamethyl)phenyl)acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid hydrochloride in 25 ml of dimethylformamide is added 0.78 g p -pivalyloxybenzyl alcohol followed by cooling to 0° C, after which 3.7 mol of dicyclohexylcarbodiimide in 7.5 ml of dimethylformamide are added dropwise while stirring. The reaction mixture is stirred for 1 hour at 0° C. and further i

4 hours at room temperature. The dicyclohexylurea formed is removed

by filtering. The filtrate is diluted with chloroform and washed with water. The organic layer is then dried over magnesium sulfate, filtered and evaporated in vacuo to give an oil which is triturated with ether to give 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl)phenyl)acetyl)amino) -8-oxo-5-thia-1-azabicyclo(4.2.o)oct-2-ene-2-carboxylic acid p-pivalyloxybenzyl ester.

Example 31

(A) When. in the method according to example 14, a suitable amount of 3-((acetyloxy)methyl)-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo (4..2.0}oct-2-ene is used -2-carboxylic acid produced • by acid hydrolysis of the corresponding benzhydryl ester described in US patent 3,778,432 or the corresponding 3-((2-meth<y>l-1,3,4-thiadiazol-5-<y>lthio)meth <y>l)-derivate instead of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo-(4.2.o)oct-2-en- 2-carboxylic acid/obtained 3-((acetyloxy)methyl)-7-((2-(4-(chloromethyl)phenyl)acetyl)amino)-7-methoxy-8-oxo-5-thia-1-azabicyclo(4i2 .o)oct-2-ene-2-carboxylic acid and the corresponding 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-derivatives.

(B.) When, in the method according to example 27, suitable amounts of each of the 7-methoxy derivatives obtained above are used instead of 3-((acetyloxy)methyl)-7-((2-(4-(chloromethyl) )-phenyl)acetyl)amino)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-2-carboxylic acid, 3-((acetyloxyJmethyl)-7-((2-( 4-(isothioureamethyl)phenyl)acetyl)amino)-7-methoxy-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid and 3-(2-methyl-l ,3, 4-thiadiazol-5-vlthio)methyl)-7-((2-(4-(isothioureamethyl)phenyl)acetyl)-amino)--7-methoxy-8-oxo-5-thia-l-azabicyclo (4 .2.0) oct-2-ene-2-carboxylic acid..

Example 32

3-(( Acetyloxy) methyl)- 7- f f2- f4-( isothioureamethyl) phenyl)-2-( 5-indanyloxycarbonyl) acetyl) amino)- 8- oxo- 5- thia- l- azabicyclof4. 2. o) oct-2-ene-2-carboxylic acid

6N hydrochloric acid is added to 25.3 mmol of the cephalosporin in 35 ml of dioxane to a pH of 2.5. Then 24.1 mmol of N,N<1->dicyclohexylcarbodiimide are added in 35 ml of dioxane and the mixture is stirred at room temperature for 15 - 20 minutes followed by the addition of 24.1 mmol of 5-indanol. The mixture is stirred for 4 hours. The N,N'-dicyclohexylurea formed is removed by filtration and the filtrate is extracted three times with methylisobutyl ketone. The organic extract is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo to give 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl)phenyl)}-2-(5- ■indanyloxycarbonyl) )acetyl)amino}-8-oxo-5-thia-1-azabicyclo-(4.2.o)pct-2-ene-2-carboxylic acid.

Example 33

p- isothioureamethylphenylacetic acid hydrochloride

A solution of 0.25 g (1.33 mmol) p-chlorophenylacetic acid and 0.25 g (3.33 mmol) isothiourea is refluxed in 65 ml of ethanol for 3.5 hours, after which the solvent is removed in vacuo at room temperature. The resulting oil is triturated with 110 ml of acetone/benzene (1:2) to give p-isothioureamethylphenylacetic acid hydrochloride as a white solid. material with a melting point of 173 - 175° C.

When suitable amounts of the acid derivatives and isothiourea derivatives listed in Table 11 are used in a similar manner instead of p-chlorophenylacetic acid and isothiourea, the products listed in Table 11 are obtained.

Example 34

3- f ( Acetyloxy ) :methyl)— 7-( (2-(4-(i sothloréamethyl) phenyl) acetyl)-amino)-8-oxo-5-thia-l-azabicyclo f 4 . 2*. o) oct-2-ene-2-carboxylic acid

A mixture of 1.2 g of 3-((acetyloxy)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-en-2-carboxylic acid and 1.2 g p-isothioureamethylphenylacetic acid HCl in 55 ral ethyl acetate is refluxed for 1 hour after which the solvent is removed to form 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl)phenyl)acetyl)amino)-8 -oxo-5-thia-1-azabicyclo(4.2.o)oct-2-en-2-carboxylic acid which can be further purified by column chromatography.

When, in a similar manner, a suitable amount of 6-amino-3,3-dimethyl-7-o.xo-4-thia-l-azabicyclo (3 . 2 . o ) heptane-2-carboxylic acid is used in place of 3-( (acetyloxy)methyl)-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.o)oct-2-en-2-carboxylic acid in the above procedure, 6-((2-(4 -(isothioureamethyl)-phenyl)acetyl)amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo-(3.2.0}heptane-2-carboxylic acid.

When, in the above-mentioned method, suitable amounts of the cephalosporin derivative and the isothiourea derivative are used as the acid chloride hydrochloride listed in the following Table 12 instead of 3-((acetyooxy)methyl)-7-amirio-8 -oxo-5-thia-l-azabicyclo(4.2„o)oct-2-en-2-carboxylic acid and p-isothibureamethylphenylacetic acid, the products listed in table 12 are obtained.

Example 35

3,- r(. 2- m, ethylT- 1# 3, 14-, thladia, 2o, 1- 5- ylthio). methyl}- 7- f (. 2.- f 4- ( isothioureamethyl) f gnyl)" a' cetyl' Vamino')~-' 8'- bxo- 5- tKia- l'- a' z' abl' cyclo -f 4 .2.0)oct-2-ene-2-carboxylic acid

A solution of 3 mmol of 3-((acetyloxy)methyl)-7-((2-(4-(isothioureamethyl)phenyl)acetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2.0)oct -2-en-2-carboxylic acid in 100 ml of water is treated with 3 mmol of sodium bicarbonate and 6 mmol of 2-methyl-1,3,4-thiadiazol-5-ylthio at 70° C. under nitrogen for 3 h. The water is removed under vacuum and the residue is taken up in methanol. A large excess of acetonitrile is added to precipitate the product which is isolated by filtration and dried in a vacuum desiccator to give 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-((2 -(4-(isothioureamethyl)phenyl)acetyl)amino)-8-oxo-5-thia-1-azabicyclo-(4.2.o)oct-2-ene-2-carboxylic acid.

When suitable amounts of the cephalosporin derivatives and thiol derivatives listed in table 13 are used instead of the cephalosporin derivative and thiol derivative used in the above-mentioned method, the products listed in table 13 are obtained:

Example 36

When, in the method according to example 14, suitable amounts of 3-((2-methyl-1,3,4-thiadiazol-5-ylthio)-methyl}-7-amino-8-oxo-5-thia-1 are used -azabicyclo (4.2.0}-oct-2-ene-2-carboxylic acid or 3-((l-methyltetrazol-5-ylthio)methyl)-7-amino-8-oxo-5-thia-l-azabicyclo (4\ 2'. o)oct-2-ene-2-carboxylic acid,

instead of 3-acetyloxymethyl-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid and 2-sulfo-p-chloromethylphenylacetyl chloride, prepared from the corresponding acid instead of p-chloromethylphenylacetyl chloride, the following products are obtained.

3-((2-methyl-1,3,4-thiadiazol-5-ylthio)methyl)-7-(^-^-(chloromethyl)phenyl)-2-sulfoacetyl)amino)-8-oxo-5-thia -1-azabicyclo-(4.2.0)oct-2-ene-2-carboxylic acid and 3-((1-methyltetrazol-5-ylthio)-methyl)-7-((2-(4-(chloromethyl)phenyl) -2-sulfoacetyl)amino)-8-oxo-5-thia-1-azabicyclo (4 . 2 . o ) oct-.2-ene-2-carboxylic acid .

When, in the method according to example 27, a suitable amount of each of the chloromethyl-substituted cephalosporin derivatives obtained above is used instead of 3-((acetyloxy)methyl)-7-( (.2-(4-(chloromethyl)phenyl ) acetyl) amino) -8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-en-2-carboxylic acid, the following products are obtained: 3-((2-methyl-1,3,4-thiadiazole -5-ylthio)methyl)-7-((2-(4-(isothioureamethyl)phenyl)-2-sulfoacetyl)amino)-8-oxo-5-thia-l-azabicyclo(4.2.o)oct-2- ene-2-carboxylic acid and 3-((1-methyltetraaol-5-ylthio)methyl)-7-((2-(4-(isothioureamethyl)phenyl)-2-sulfo-acetyl}amino)-8-oxo-5 -thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid.

Claims (2)

1. Starting material for use in the production of therapeutically active cephalosporin and penicillin derivatives characterized in that they have the general formula: ' wherein aryl is selected from phenyl or 2-thienyl, Y is selected from hydrogen, chlorine, bromine, a straight-chain or branched lower alkyl group with from 1 to h carbon atoms or an alkoxy group with from 1 to k carbon atoms provided that when aryl is 2-thienyl,' is Y 1 2 3 hydrogen, each of R , R , and R is selected from hydrogen or a straight or branched chain. lower alkyl group with from 1 to k-carbon atoms, Z is selected from a bond, oxygen, sulfur or imino provided that when aryl is 2-thienyl, - Z is a bond, W 2 is selected from hydrogen, methyl, amino, hydroxy, SCUH or COOH, n is zero, 1 or 2 provided that when W2 . is different from hydrogen or methyl and Z is different from a bond, n is not equal to zero. 2. Procedure for the preparation of compounds according to claim 1, of general formula: where aryl is selected from phenyl or 2-thienyl, -Y is selected from hydrogen,, chlorine, bromine or a straight or branched lower alkyl-. group having from 1 to k carbon atoms or an alkoxy group having from 1 to h carbon atoms provided that when aryl is 2-thienyl, Y is hydrogen, each of R , R , and R 3 is selected from hydrogen or a straight or branched lower alkyl group of from 1 to h carbon atoms', Z is selected from a bond, oxygen-, sulfur or imino provided that when aryl is 2-thienyl, Z is a bond, W 2 is selected from hydrogen, methyl, amino, hydroxy, SO^H or COOH, n is zero,.! or 2 provided that when W is different from.hydrogen or methyl and Z is different from a bond, n is not equal to zero, character- i s e r t in that a derivative of the formula: is converted with a derivative of the formula: wherein halo is selected from chlorine or bromine, and aryl, Y, Z, n, ¥ 2, 12^ R , R and RJ have the previously stated meanings, in an alcoholic solvent at temperatures of from 0 to 100°C for 0.5 hour to 6 hours.