IE42435B1 - Penicillin antibiotics - Google Patents

Description

This invention relates to novel penicillin derivatives useful as antibiotics, and to processes for their preparation.

Accordingly, the present invention provides compounds, of the following general Formula I, which are useful as antibiotic agents: RN \ /' (Aryl>Z-(CH-) -CH-C-NHZ H ι O CHX CHR -N-C-S-CHS.

COOM Formula I wherein either Aryl is a benzene ring, Y is hydrogen, chlorine, bromine, or alkyl or n-alkoxy of from 1 to 4 carbon atoms, and Z is a bond, oxygen, sulfur or imino, or Aryl is a thiophene ring attached to Z at its 212 3 position, Y is hydrogen and Z is a bond? R , R and R are each hydrogen or alkyl of from 1 to 4 carbon atoms; W is hydrogen, methyl, amino, hydroxy, SOgH, or COOR4 wherein R4 is hydrogen or 5-indanyl; n is zero, 1 or 2 with the proviso that it is not zero when W is not c hydrogen or methyl and Z is not a bond; R is hydrogen or methoxy? M is hydrogen; a pharmaceutically acceptable - 3 non-toxic cation; alkanoyloxymethyl as represented by the structure 1, -ch2-o-cr' wherein R is alkyl of from 1 to 4 carbon atoms; alkanoyl5 aminomethyl or alkoxycarbonylaminomethyl as represented by the structure 8 -ch2~nr -cor° o wherein R is alkyl or alkoxy of from 1 to 4 carbon g atoms and R is hydrogen or n-alkyl of from 1 to 4 carbon 10 atoms; £-(alkanoyloxy)benzyl as represented by the structure wherein R10 is alkyl of from 1 to 4 carbon atoms; or aminoalkanoyloxymethyl as represented by the group II 111? 1 3 14 -CH2OC(CH2)m-CR R -NR R wherein m is zero or an integer of from 1 to 5, R^ and 12 R are each hydrogen or n-alkyl of from 1 to 4 carbon atoms, and R13 and R14 are each hydrogen or alkyl of from one to 4 carbon atoms; and pharmaceutically acceptable salts thereof.

Illustrative examples of straight or branched alkyl 12 3 groups of from 1 to 4 carbon atoms which Y, R , R , R , R7, R8, R10, R13 and R14 may represent are methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl. 48435 Examples of alkyl groups of from 1 to 4 carbon atoms which R9, rH and R^2 may represent are methyl, ethyl, n-propyl and n-butyl.

Examples of alkoxy groups which Y may represent are 5 methoxy, ethoxy, n-propoxy and n-butoxy.

Illustrative examples of straight or branched lower e alkoxy groups which R may represent are methoxy, ethoxy, n,propoxy, isopropoxy, sec-butoxy, and n-butoxy.

When the Aryl group in the compounds of general 10 Formula I represents phenyl, the isothioureamethyl substituent and the Y substituent may be individually attached to any of the positions 2 to 6 of the phenyl ring. Compounds of this type may be represented by the following general Formula II.

The preferred positions of attachment of the isothioureamethyl· substituent in the above Formula,II are the orthoand para- positions of the phenyl ring. In the above o 3 Formula II the substituents as represented by Y, R , R , R , 5 Z, n, W, R , and M have the meanings 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. Compounds of this type may be represented by the following Formula III RXN R -Ν — C-S-CH L rO 2^CS > (CH2)n-CH-C-: •NH· SX<GH3 CH3 •COOM Formula III In the compounds of the above Formula III the isothiourea substituent group may be attached at the 4 or 5 position 5 of the thienyl group. In the above Formula III the 3 5 substituents as represented by R , R , R , n, W, R , and M have the meanings defined for general Formula I.

In the compounds of Formula I it is apparent that c the R substituent may be either cis or trans to the 10 hydrogen atom at the 5-position of the penicillin deri5 vatives, The compounds of Formula I wherein the R substituent is cis to the aforementioned hydrogen atom are preferred.

Other preferred embodiments of this invention are: (A) compounds wherein W represents hydrogen, hydroxy, 4 amino, SO^H or COOR wherein R represents hydrogen in that such substitution results in compounds having broader spectrum of activity and/or improved oral activity for example compounds wherein 20 (1) W represents hydroxy are more resistant to filactamase organisms? 4 (2) W represents SO^H or COOR wherein R represents hydrogen have broader gram negative spectrum; (3) W represents NH2 have improved oral activity; (B) compounds wherein R^ represents methoxy are of particular interest in that such compounds demonstrate antibacterial activity against cephalosporinase-producing gram negative organisms.

Of the preferred embodiments set forth in (A) and 30 (B) compounds wherein Z represents a bond, are parti2435 - 6 cularly preferred.

The most preferred compounds of this invention are those represented by the following Formula VI wherein W' is hydrogen, hydroxy, amino, COOH or SOgH, and pharmaceutically acceptable salts thereof.

In the above Formula VI, compounds wherein the hydrogen atom at the 5- and 6- positions are cis to one another are preferred.

The individual optical isomers of the compounds of this invention wherein W is other than hydrogen are also included within the scope of this invention.

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

Also within the scope of this invention are the non-toxic pharmaceutically acceptable salts of the compounds of this invention wherein W represents COOH or SOgH and compounds wherein M represents hydrogen. Illustrative pharmaceutically acceptable salts of these acid derivatives are salts with primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine and pyridine. 48439 - 7 The pharmaceutically acceptable cations which may be present as the group M in the compounds of general Formulas I to VI include alkali metal ions, for example sodium ion, potassium ion, calcium ion as well as ammonium, and organic amine cations, for example, lower alkyl ammonium groups, such as triethylammonium, and Nethylpiperidine.

The salt forms of compounds of Formulas I to VI wherein M is a pharmaceutically acceptable cation are prepared in the manner recognized in the art and may be formed in situ or by reacting the corresponding acid with base for example sodium bicarbonate or triethylamine.

The compounds of this invention may be administered in a manner similar to that of many well known cephalosporin compounds, for example, cephalexin, cephalothin, or cephaloglycine. They may be administered alone or in the form of pharmaceutical preparations either orally, parenterally and topically to warm blooded animals, that is, birds and mammals, for example, 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 solutes, for example, enough saline 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 of this invention are active are Staphylococcus aureus, Salmonella schottmuellerl, Klebsiella pneumoniae, Plplococcus pneumonia, and Streptococcus pyogenes.

An illustrative example of a penicillin derivative of this invention is 6-//2-/4-(isothioureamethyl)pheny17acetyl7 aminq7-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo/3.2.0/42435 - 8 ίο heptane-2-carboxylic acid. Additional examples of compounds of this invention are set forth hereinbelow in the specific compounds which are representative of the invention.

The compounds of Formula I wherein R4 is hydrogen may be prepared by treating a derivative of the formula Y λ 11 fAryi;— z-(cH2)n-cH-cNHhaloCHW‘ r~ COOM Formula VII with a derivative of the formula R1NH RXN R -N C—S R-N— C— SH Formula VIII wherein halo is chlorine or bromine; W is hydrogen, methyl, amino hydroxy, SOgH or COOH; and Aryl, η, Y, Z, R3-, R2, R3, R5 and M are as defined for Formula I.

The above reaction is carried out in an alcoholic solvent at temperatures of from 0°c to 100°C, preferably from 25 to 50°C, for from % hour to 6 hours yielding the corresponding isothiouronium hydrochloride derivative in solution. The organic solvent is evaporated, and the residual oil is triturated with appropriate organic solvents such as ether, hexane, ethyl acetate or acetonitrile, to give the isothioureamethyl substituted compound.

When the substituent group W in the above Formula VII represents an amino group, suitable blocking groups, e.g., an acid salt such as hydrochloride salt, an acyl group, or tert-butoxycarbonyl should be employed to protect the amino function. Such blocking groups are removed after the coupling reaction by methods generally known in the art, e.g. as described by Lemieux et. al., in U.S. Patent 3,657,232.

Illustrative examples of compounds of Formula VIII are isothiourea, l-ethyl-3-n-propylisothiourea, l-ethyl-3-n-butylisothiourea, l,l-di-n-propyl-3-ethylisothiourea, l-ethyl-3-isopropylisothiourea, 1,1,3triethylisothiourea, 1,l-di-n-propyl-3-methylisothiourea, 1,3-di-sec-butylisothiourea, 1,3-dl-n-propylisothiourea, l-n-butyl-3-methylisothiourea, l-ethyl-315 methylisothiourea, l,l-dlethyl-3-methylisothiourea, 1,3-diethylisothiourea, 1-ethylisothiourea, 3-n-propylisothiourea, 1,3-dimethylisothiourea, 1,3-diisopropylisothiourea, 1,3-di-n-butylisothiourea, l-methyl-3ethylisothiourea, and l,l-dimethyl-3-ethylisothiourea.

Compounds of general Formula VII may be prepared by coupling a derivative of the formula CH3 CH COOM Formula IX with an acid of the formula 2435 -ΙΟ(Ary l·)- Ζ- (CH2) n-CH-COOH haloCii] 2 2 Formula X or a functional derivative thereof wherein Aryl, halo, Y, Z, n, W , R and M have the meanings defined in 5 general Formula VII.

When the substituent group W in the above Formula X represents an amino group suitable blocking groups, e.g., an acid salt such as hydrochloride salt, tertbutoxycarbonyl, or carbobenzyloxy are employed to protect the amino function in a manner similar to that described hereinabove.

Functional equivalents of the acids as represented by Formula X include the acid halides, for example, the acid chloride, acid anhydrides, including mixed Is anhydrides with, for example, alkylphosphoric acids, lower aliphatic monoesters of carbonic acid, or alkyl or aryl sulfonic acids. Additionally, the acid azide or an active ester or thioester, for example, with £-nitrophenol, 2,4-dinitrophenol, or thioacetic acid, may be used, or the free acid as represented by Formula X may be coupled with the 6-amincpenicillanic acid derivative as represented by Formula VIII after first reacting the acid with Ν,Ν'-dimethylchloroforminium chloride or by use of a carbodiimide reagent, for example, Ν,Ν'-diiso25 propylcarbodiimide, Ν,Ν'-dicyclohexylcarbodiimide, or N-cyclohexyl^N'-(2-morpholinoethylJ carbodiimide.

The coupling reaction is generally carried out in the presence of a solvent. Suitable solvents include ethyl acetate, acetone, dioxane, acetonitrile, chloro30 form, methylene chloride, tetrahydrofuran and dimethyl 4243S - 11 formamide. As hydrophilic solvents are employed mixtures of these solvents with water are also suitable for the above reaction. The coupling reaction may be carried out in the presence of a base, for example, an alkaline bicarbonate. The temperature of the reaction may vary from -10° to 100°C, and the reaction time may vary from about % hour to 10 hours. The cephalosporin products are isolated by conventional methods.

The compounds of general Formula VII may 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 oompound of general Formula IX by the general procedure described in Canadian Patent No. 892,580, issued February 8, 1972, by substituting a compound of general Formula IX for the penicillanic acid derivatives described therein. Compounds of Formula IX 5 wherein R is hydrogen, M is hydrogen or a pharmaceutically acceptable non-toxic anion or cation, are commercially available or may be prepared by methods well known in the art. The corresponding compounds wherein R is methoxy may be prepared by the general procedures described in U.S. Patent 3,778,432.

Compounds of Formula IX wherein M is alkanoyloxymethyl may be prepared by reacting the corresponding acid in the form of a salt, such as an alkali metal salt or the triethylammonium salt with a compound of the formula halo*-CH,-O-C-R^ wherein halo is chlorine or 7 * bromine and R is a straight or branched lower alkyl group of from 1 to 4 carbon atoms by the general procedure described in U.S. patent 3,655,658.

Compounds of Formula IX wherein M Is alkanoylaminomethyl or alkoxycarbonylaminomethyl are prepared by treating the sodium salt of acid derivatives of Formula IX in an organic solvent such as dimethyl formamide or - 12 ~ hexamethylphosphoramide, at room temperature with an equivalent amount of an alkanoylaminomethyl halide or an alkoxyoarbonylaminomethyl halide for % to 3 hours after whioh the mixture is poured into ice-water. The resulting precipitated product is isolated by standard procedures.

Compounds of Formula IX wherein M is £-(alkanoyloxy) benzyl are prepared by adding 2-equivalents of the £-(alkanoyloxy)benzyl alcohol to a suspension of the sodium salt of acid derivatives of Formula IX in dimethyl formamide or hexamethylphosphoramide after which the mixture is cooled to 0°C. 1.2 equivalents of dicyclohexylcarbodiimide in dimethyl formamide is added dropwise to the mixture with stirring. The mixture is stirred at 0°C for % to 3 hours and then an additional 2 to 5 hours at room temperature. The formed dicyclohexylurea is removed by filtration and the filtrate is diluted With chloroform, methylene chloride, or ethyl acetate, washed with water and dried to give the product.

Compounds of Formula IX wherein M is aminoalkanoyloxymethyl are prepared by mixing a suspension of the sodium salt of an acid of Formula IX and an excess of an appropriate amine protected aminoalkanoyloxymethyl halide in a solvent such as dimethyl formamide, hexa25 methylphosphoramide or dimethyl sulfoxide for 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 phase is separated and the precipitate isolated by conventional means followed by deprotection of the amine group to give the product.

The compounds of Formula X are prepared by direct halomethylation as described hereinbelow of ah acid of the formula 4243S Z-(CHJ -CH-COOH z n / Formula XIII wherein Aryl, Y, Z, n and W have the meanings defined in Formula VII which are commercially available or are obtained by methods well known in the art.

When the substituent group W in compounds of Formula XIII represents amino, the amino group is protected by a suitable blocking group, for example an acyl group, such as, acetyl or trifluoroacetyl, prior to the halomethylation reaction. Upon completion of the halomethylation reaction the blocking groups may be removed by acid hydrolysis by procedures known in the art.

The halomethylated derivatives of the compounds of Formula XIII are obtained by several methods. For example,by reacting a compound of Formula XIII with a source of formaldehyde such as paraformaldehyde, ClCi^OCHg, or formalin solution, in the presence of a Lewis acid, such as ZnCl2, AlCl^, SnCl^, or ClSO-jH in a solvent, such as petroleum ether, chloroform, carbon tetrachloride, or benzene at a temperature ranging from -10° to 100°C during which time hydrogen chloride gas or hydrogen bromide gas is bubbled into the reaction mixture 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 ranging from -10° to 100°C during which time hydrogen chloride gas or hydrogen bromide gas is bubbled through the reaction mixture also yields compounds of general Formula X.

Additionally upon reaction of an acid of Formula 42438 - 14 XIII with trioxane in acetic acid or phosphoric acid at temperatures of from -10° to 100°C during which time hydrogen bromide or hydrogen chloride gas is bubbled through the reaction mixture, compounds of general Formula X are obtained. Or, the reaction of an acid of Formula XIII in the presence of a Lewis acid, such as those described hereinabove, with chloromethyl ether at temperatures from -10° and 100°C, or the reaction of the acid in acetic acid or concentrated sulfuric acid with dichloromethyl ether in the presence of zinc chloride will give compounds of general Formula X.

The compounds of Formula X wherein W represents 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 about 50°C during which time hydrogen chloride or hydrogen bromide gas is bubbled into the reaction mixture followed by acid hydrolysis.

Compounds of Formula X wherein W represents SOgH may be obtained by the halomethylation reactions described above using an acid of Formula XIII wherein W represents SOgH or the carboxy methyl ester thereof in which latter case the resulting halomethylated compound is converted to the free COOH by acid hydrolysis.

In the halomethylation of compounds of Formula XIII wherein W represents OH it may be advantageous to protect the OH group prior to halomethylation as described by V. Reichert, et. al., Pharmazie 5, 10 (1950).

The compounds of this invention wherein R is hydrogen may also be prepared by coupling a derivative of the formula 4243S s. 5H3 h2nCH, COOM Formula IX -N with an acid of the formula Y RN (Arylj-- Z-(CH2)n-CH-COOH R-N—C-S-CH, Formula XIV or a functional derivative thereof, wherein Aryl, n, W , Y, Z, R1, R2, R3, R3 and M are as defined above. The acids of Formula XIV are described and claimed in British Patent Specification No. 1,490,452 together with processes for their preparation.

When W in the above Formula XIV represents an amino group, suitable blocking groups, e.g. a mineral salt such as hydrochloride salt, tert-butoxycarbonyl, or carbobenzyloxy are employed to protect the amino function in a manner similar to that described hereinabove .

Functional equivalents of the acids as represented by Formula XIV include the acid halides, for example, the acid chloride, acid anhydrides, including mixed anhydrides with, for example, alkylphosphoric acids, lower aliphatic mono-esters of carbonic acid, or alkyl or aryl sulfonic acids. Additionally, the acid azide or an active ester or thio-ester, for example, with £nitrophenol, 2,4-dinitrophenol, or thioacetic acid, may be used, or the free acid as represented by Formula - 16 4S43S XIV may be coupled with a 6-aminopenieillanic acid derivative as represented by Formula IX after first reacting the acid with Ν,Ν'-dimethylchloroforminium chloride or by use of a carbodiimide reagent, for example, Ν,Ν'-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, chloro10 form, methylene chloride, tetrahydrofuran and dimethylformamide. As hydrophilic solvents are employed mixtures of these solvents with water are also suitable for the above reaction. The coupling reaction is generally carried out in the presence of a base, for example, an alkaline bicarbonate. The temperature of the reaction may vary from -10° to 100°C, and the reaction time may vary from % hour to 10 hours. The penicillin products are isolated by conventional methods.

The preparation of compounds of Formula IX is described hereinabove.

Compounds of Formula I wherein R4 is 5-indanyl are prepared by reacting the corresponding acid, that is, compounds of Formula I wherein R4 is hydrogen with 5indanol In an inert solvent in the presence of N,N'25 dicyclohexyl carbodiimide at a pH of about 2.5 and a temperature of from 20° to 30°C. Equimolar amounts of the reactants are employed or a slight excess of the -indanol may be used. The molar amount of Ν,Ν'-dicyclohexylcarbodiimide employed is equivalent to the molar amount of 5-indanol. Suitable solvents for the reaction are dioxane, tetrahydrofuran,ethyl acetate, dimethyl formamide and methylene chloride.

Compounds of Formula I wherein M represents alkanoylaminomethyl or alkoxycarbonylaminomethyl and W is other than COOH may also be prepared by reacting the - 17 corresponding acid in the form of a salt such as an alkali metal salt, for example, the sodium salt with 1.5 to 2.5 equivalents of an appropriate alkanoylaminomethyl halide or alkoxycarbonylaminomethyl halide each of which may be represented by the structure I « Halo-CH0-N-C - Ic wherein halo is a reactive halogen atom such as 18 chlorine or bromine, R is selected from a straight or branched lower alkyl group of from 1 to 4 carbon atoms or a straight or branched lower alkoxy group of from 1 to 4 carbon atoms, and R is hydrogen or a lower alkyl group of from 1 to 4 carbon atoms. The reactants are stirred for about 1 to 5 hours in dimethyl formamide, hexamethylphosphoramide or a similar solvent at a temperature ranging 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 then with water and dried over magnesium sulfate. The organic solution is evaporated to dryness in vacuo to give the desired ester.

Prior to the above esterification reaction compounds wherein W represents amino are protected with blocking groups, for example, tert-butoxycarbonyl or carbobenzyloxy, such groups being removed upon completion of the esterification procedure by methods generally known in the art, for example, by the method set forth in the aforementioned U.S. patent 3,657,232.

Compounds of Formula I wherein M represents £(alkanoyloxy)benzyl and W is other than COOH may also be prepared by reacting molar equivalents of the - 18 corresponding acid and a £-(alkanoyloxy)benzyl alcohol wherein the alkanoyl moiety contains from 1 to 4 carbon atoms and may be straight or branched. The reactants are dissolved in an organic solvent such as dimethyl formamide or hexamethylphosphoramide and cooled to a temperature of from -15°C to 25°C after which an equivalent quantity of dicyclohexylcarbodiimide in dimethyl formamide or hexamethylphosphoramide is added dropwise to the reaction mixture with stirring. Stirring is continued for ¼ to 2 hours at temperatures of from -15°C to 25°C and then 4 to 6 hours at from 25° to 45°C. The formed dicyclohexylurea 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 give the product.

Compounds of Formula I wherein M is alkanoyloxymethyl and W is other than COOH may also be prepared by reacting the corresponding acid in the form of a salt, such as an alkali metal salt or the triethylammonium salt with a compound of the formula 0 II 7 halo-CHg-O-C-R wherein halo is chlorine or bromine, and R? is a straight or branched lower alkyl group of from 1 to 4 carbon atoms by the general procedure described in O.S. patent 3,655,658.

Compounds of Formula I wherein M is aminoalkanoyloxymethyl and W is other than COOH may also be prepared by mixing a suspension of the sodium salt of the corresponding acid and an excess of an appropriate amine protected aminoalkanoyloxymethyl halide in a solvent such as dimethyl formamide, hexamethylphosphoramide or dimethyl sulfoxide for 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 phase is separated and the precipitate isolated by conventional means followed by deprotection - 19 of the amine group to give the product.

Compounds of Formula XIV may be prepared by reacting derivatives of Formulas VIII and X under the conditions given for the reaction of the compounds of Formulas VII and VIII, and these compounds, particularly those 2 wherein W is other than H or CH^ are useful in the preparation of compounds of Formula I.

The following preparations and Examples illustrate the invention Preparation I p-Chloromethylphenylacetyl chloride (A) At a temperature of from -10° to 0°C hydrogen chloride gas is bubbled through a stirred mixture of 102 g of phenylacetic acid, 67.5 g of paraformaldehyde and 67.5 g of zinc chloride in 1000 ml of petroleum ether for one hour. Stirring is continued for about one hour at room temperature after which the mixture is refluxed for about 2 hours during which time hydrogen chloride gas is bubbled into the mixture. To the reaction mixture is added 100 ml each of methylene chloride and water. The organic phase is separated and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are extracted four times with a saturated sodium bicarbonate solution. The organic neutral phase is dried over anhydrous sodium sulfate, filtered and the solvent is removed under vacuum to give a neutral by-product which is further identified in Example 5 below. The basic aqueous phase is separated and acidified with cold concentrated hydrochloric acid to pH 2-3, then extracted three times with methylene chloride. The methylene chloride fraction is dried over anhydrous sodium sulfate, filtered and the solvent evaporated. The resulting oily acidic product is chromatographed on silica gel using benzene and benzene35 acetone as the eluant to give g-chloromethylphenyl42435 - 20 acetic acid which is recrystallized from hot chloroform. M.P. 147-149°C.

(B) A mixture of 1 g of £-chloromethylphenylacetic acid and 6 ml of thionyl chloride is stirred at room temperature for 25 hours after which the excess thionyl chloride is removed under vacuum to yield £-chloromethylphenylacetyl chloride.

When in Preparation I (A) an acid selected from Table 1 is substituted for phenylacetic acid the respect10 ive chloromethyl derivative listed in Table 1 is obtained which can be converted to the acid chloride by the procedure of Preparation I (B).

TABLE 1 Acid Chloromethyl derivative 15 Hydrotropic acid £-chloromethylhydrotropic acid mandelic acid p-chloromethylmandelie acid dihydrocinnamic acid p-chloromethyldihydrocinnamic acid 20 2 -methy 1 dihydrooinnamic acid £-chloromethyl-2-methyIdihydr0cinnamic acid 3-phenyllactic acid 3-(p-chloromethylphenyl)lactic acid 25 4-phenyIbutyric acid 4-(£-chloromethylphenyl) butyric acid 2-methyl-4-phenylbutyric acid 2-methyl-4-(£-chloromethylphenyl butyric acid 2-hydroxy-4-pheny1- butyric acid 2-hydroxy-4-(E-chloromethylphenyl) butyric acid - 21 Acid phenoxyacetic acid 2-phenoxypropionic 5 acid 4-phenoxybutyric acid 2- methyl-4-phenoxybutyric acid 3-phenoxypropionic acid 3- phenoxylactic acid anilinoacetic acid 15 2-hydroxy-2-(2-thienyl)acetic acid 2- anilinopropionic acid 4-anilinobutyric acid 3- anilinobutyric acid phenylthioacetic 25 acid 2-phenylthiopropionic acid 4- phenylthiobutyric acid Chloromethyl derivative £-chloromethylphenoxyacetic acid 2-(£-chloromethylphenoxy)propionic acid 4-(p-chloromethylphenoxy)butyric acid 2- methyl-4-(p-chloromethylphenoxy)butyric acid 3- (£-chloromethylphenoxy)propionic acid 3- (p-chloromethylphenoxy)lactic acid £-chloromethylanilino acetic acid 2-hydroxy-2-££-(5-chloromethyl) thieny£7acetic acid 2- (£-chloromethyl)anilinopropionic acid 4- (£-chloromethylanilino)butyric acid 3- (£-chloromethylanilino)butyric acid £-chloromethylphenylthioacetic acid 2-(£-chioromethylphenyl)thiopropionic acid 4- (£-chloromethylphenyl)thiobutyric acid - 22 4243S Acid Chloromethyl derivative o-chlorophenylacetic o-chloro-£-chloromethylacid phenylacetic acid Preparation 2 p-Chloromethylphenylglycine hydrochloride A mixture of 2.03 g of trifluoroacetylated phenylglycine, 0.8 g of zinc chloride in chloromethyl ether is heated at 65°C for 12 hours. The excess reagent is removed under vacuum, and the residue is dissolved in CH2Cl2, washed with saturated NaHCOg solution ahd then saturated sodium chloride solution. The neutral organic phase is dried over Na2S0^ and concentrated to an oil which was purified by column chromatography. Similarly the chloromethyl derivatives listed in Table 11 may be prepared from the listed acid.

TABLE 11 Acid Chloromethyl derivative phenylalanine £-(chloromethylphenyl) alanine HCl 2-amino-4-phenylbutyric acid 2-amino-4-(£-chloromethylphenyl)butyric acid HCl 2-amino-4-phenoxybutyric acid’ 2-amino-4-(£-chloromethylphenoxy)butyric acid HCl 3-phenoxyalanine 3-(£-chloromethylphenoxy)alanine HCl 2-amino-4-anilino- butyric acid 2-amino-4-(£-chloromethylanilino)butyric acid HCl 2-amino-4-phenylthiobutyric acid 2-amino-4-(£-chloromethylphenyl)thiobutyric acid HCl - 23 Acid 3-phenylthioalanine 2-(2-thienyl)glycine 2-amino-3-(2-thienyl)propionic acid 2-amino-4-(2-thienyl)butyric acid Chloromethyl derivative 3-(£-chloromethylphenyl)thioalanine HCl 2-/2-(5-chloromethyl) thienyl7glycine HCl 2-amino-3-/2-(5-chloromethyl) -thienyl/propionic acid HCl 2-amino-4-/2-(5-chloromethyl) thienyl7butyric acid HCl Preparation 3 p-Chloromethylphenylmalonic acid When in the procedure of Preparation 1 (A) an equivalent amount of phenylmalonic acid diethyl ester is substituted for phenylacetio acid, £-chloromethylphenylmalonic acid diethyl ester is obtained which yields the corresponding acid upon acid hydrolysis. In a similar manner the chloromethyl derivatives listed in Table 111 may be prepared when the diethyl ester of the corresponding acid listed in Table 111 is substituted for phenylmalonic acid diethyl ester.

Table 111 Acid 2- sulfophenylacetic acid 3- phenyl-2-sulfopropionic acid 4- phenyl-2-sulfobutyric acid Chloromethyl derivative 2- sulfo-£-chloromethylphenylacetic acid 3- (£-chloromethylphenyl)-2-sulfopropionic acid 4- (£-chloromethyIpheny1) 2-sulfobutyric acid Acid benzylmalonic acid Chloromethyl derivative £-chloromethylbenzylmalonic acid phenethylmalonic acid £-chloromethylphenethylmalonic acid 2-phenoxyethylmalonic acid 2-(p-chloromethylphenoxy)ethylmalonic acid 2-phenylthioethyl- malonic acid 2-(g-chloromethylphenyl)thioethylmalonic acid anilinomethylmalonic acid £-chloromethylani1inomethyl- malonic acid 2-thienylmalonic acid 2-/2-(5-chloromethyl)thienylmalonic acid 2-thenylmalonic acid 2-/2-(5-chloromethy1)thenyl7malonic acid Preparation 4 -Chloromethyl-2-thienylacetyl 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 give 5chloromethyl-2-thienylcarboxylic acid. Treatment of the obtained acid with excess thionyl chloride at room temperature for about 16 hours yields the acid chloride which is reacted with diazomethane to give the corresponding diazoketone. A methanol solution of the diazoketone is irradiated under nitrogen for about one hour with a high pressure mercury lamp, using a Quarz filter. The methyl 5-chloromethyl-2-thienylacetate is obtained upon work up and column chromatography on silica gel. The acetate is hydrolyzed by treatment of a 1:1 mixture of acetic acid and concentrated hydrochloric acid at room temperature overnight to give 5-chloromethyl-2-thienyl- 35 42435 Φ αι β •Ρ +) μ ϋ rt Ό Ο μ ft 1 ι σ I > • Η -rp 1 1 1 I CM ίΗ ι\ μ s ι—1 • Ό μ 1 0 Ό >1 σ >< £0 •μ μ X ο μ μ rt μ Si 0 Φ r-r 0 ϋ μ μ μ 0 rt >1 1 CJ rt φ Η φ Η μ C* • | Η β ϋ ο Φ Φ I ro ϋ ΓΟ rt Η >i Η μ ϋ Η 's Η I rt Ό ϋ μ rt rt >1 μ μ 1 μ 0 γΗ μ 0 Ϊ>1 >1 Η ΓΟ μ X •Η >1 μ γΗ X μ >1 «· rt ο μ μ Φ υ 0 μ μ ro Ν μ μ μ β >1 Λ Φ μ 1 rt μ 0 φ Η 0 μ β φ S I rt η β *d Η rt I β σ μ ο Η 1 μ ϋ Η rt rt I ι CM ro rt 1 Φ μ rt CM 1 1 «. Ν CM 1 μ § •Η I ro I rt 1 φ Ί rt 0 »s μ μ Φ rt 1 X *Ν μ rt 1 Η 1 rt 0 α rt rt μ $ μ μ >1 μ Μ* 1 μ ft Si φ μ μ ft ‘χι 0 φ 0 Φ I μ ε μ Φ | φ 0 X μ kO ft Β μ μ νο Η rt 0 I Φ μ rt ο •Η >ι μ μ μ Ο ω Η I β |Μ —I Sp Η XI ·Η I β U5 Φ r η* ι 1 'S Λ » ΧΟΗ Ο · ϋ I CM Φ r* · I ro o Hi Ή >1 <4 H μ ‘ μ Ο >1 W X φ ο Ο S > 43 •Η Ο Μ Ό -I Φ I Λ Μ φ I ' Ν d η φ ι ι ι ν Ν, Η β θ’ I Φ β Φ +> Ή ·Η Οι β Λ ω Φ +1 43 μ μ μ >1 ι 0 μ Tp I ιο Η Φ ϋ 1 0 »0 μ rt X o •μ >1 μ 0 CJ υ rt rt •μ r- • 0 μ μ ι co | μ Η Η . ?· μ >1 «μ > μ 0 £· μ β μ «μ χ V <υ Φ υ 0 43 β μ co Οι Η 0 μ *». Π3 •μ rt «μ r—1 1 μ υ >1 CO rt I ι μ *, CM CM rtf μ co rt 1 ν* φ 1 I φ .CM Ν H 1 β rt φ rt rt μ Sj μ •μ H ft rt g μ Φ kO 0 ro μ μ 0 ο rt rt Φ Φ Φ μ > μ rt μ rt Η ο μ 0 Η μ rt «μ Η μ > μ > μ Η μ ο μ 0 W η Φ to Η Q Η Β I μ >Η ! μ μ μ >1 φ I rt rt μ _ rt rt ro φ φ Η μ rt μ rt ι μ rtl rt >1 0 0 1 0 μ •μ •μ •μ ·μ μ μ μ ό μ Φ μ μ 1 μ β 0 0 ro 0 1 to to * to μ μ •μ μ μ CM 1 Ss H >1 μ δ* CM ι μ Ό 1 0 μ 0 X μ • β β >1 0 0 Φ CO μ Γ> CM •μ ΓΟ ο μ β β «sj μ • μ κ μ μ φ •μ •μ μ ΓΟ μ ΓΟ μ >» μ Ό Ο Ό β >1 tJ β rt X α< μ μ rt μ μ rt S, Ν 0 co ϋ ϋ μ 0 ϋ σ rt μ μ *. >1 rt μ φ μ rt μ β μ >1 co 0 >i β 0 >1 μ μ rt μ Η 0 μ •μ >1 0 μ β L ο Ό μ κ, μ μ μ ϋ μ μ rt rt Φ Φ σ ro μ Φ •μ μ Φ S μ ΓΜ μ β β Ν >1 β co Λ >1 β μ μ ι rt 0 Η rt X 0 * rt X 0 μ φ Η φ μ β | 0 μ ΓΟ Ν 0 μ rt | β >1 > 0 ro μ μ 0 | rt μ 0 0 d· rt μ ·μ «μ S μ μ ν. μ μ •μ 1 μ μ μ μ «-? rt rt μ Ο1 μ rt μ ft 0 ft Φ rt υ >1 μ 0 0 β | ο 0 0 X Φ β > -S μ μ I μ rt | μ 0 μ OH I Φ μ CM I g μ CM I ft 1 μ μ 0 | 1 rtf rt μ | ι<Ρ μ Γ- rt Φ S, rt μ* φ Sj s μ φ VI >1 1 ο ΒΟ ί μ ι rt I μ1 I β 1 μ —1 • .cm >1 0 rt £Μ >1 •Μ* rt Ρ μ > CM s. μ X μ ? μ | μ Si φ J3 • S3 μ 0 ft φ 0 ft Sj β 4J co I Φ 1 Φ 0 X Φ I ι ffl ι kO β Γ* μ kO rt 0 μ kO CM β Si I r-1 & ο ft <ϋ η η >, 43 m +) ι S β o' ο β ρ ·ρ 0 § (β χ, ο η > I +> ζ 8 I Φ ι μ «χ> μ ϊ •Η Λ rt Ν ί rt cm I I ι S S· χ Ο 0 ιη Ο 42438 - 26 mandelic aqid, obtained by the procedure described by B. Reichert et al., Pharmazie 5, 10 (1950), in 25 ml of thionyl chloride is stirred at room temperature for about 16 hours after which the excess thionyl chloride is removed under high vacuum to give o-chloromethyl-£methoxymandelic acid chloride as an oil.

Preparation 8 3-/7Acetyloxy)methy17-7-/-/2-/4-(chloromethyl)pheny17~ acetyl7amin<27-8-oxo-5-thia-l-azabicyclo/7 4.2.0_7oct-210 ene-2-carboxylic acid A mixture of 1 g of 3-/7acetyloxy)methy17-7-amino8-oxo-5-thia-l-azabicyclo/“4.2.0_7oct-2-ene-2-carboxylic acid and 1 g of £-chloromethylphenylacetyl chloride in 45 ml of ethyl acetate is refluxed for about 2 hours after whioh the solvent is removed under vacuum yielding a yellow-brown amorphous product which is chromatographed on silica gel using benzene-acetone as the eluant to give the title compound M.P. 164-165°C. (dec.).

Preparation 9 3-/7Acetyloxy)methy1/-7-//2-/3-(chloromethyl)pheny17-2aminoacetyl7aminq7-8-oxo-5-thia-l-azabicyclo/~ 4.2.O_7oct2-ene-2-carboxylic acid £-Chloromethylphenylglycine wherein the amino group is protected with tert-butoxycarbonyl, is treated with isobutyl chloroformate In the presence of triethylamine.

The thus obtained mixed anhydride is reacted w)th the triethylamine salt of 3-/Tacetyloxy)methyl7-7-amino-8-oxo5-thia-l-azabicyclo/7 4.2.0_7oct-2-ene-2-carboxylic acid at 0°C for about 4 hours. The resulting product is iso30 lated, and the amine protecting group is removed by acid hydrolysis to give the title compound. - 27 Preparation 10 3-/TTAcetyloxy) methy £7-7-//2-/2- (chloromethyl) -4methoxypheny1/-2-hydroxyacety17amine/-8-oxo-5-thia-1azabicyclo/4.2.0_7oct-2-ene-2-carboxylic acid A mixture of 1 g of 3-/Tacetyloxy)methyl7-7-amino8-oxo-5-thia-l-azabicyclo/7 4.2.0 _7oct-2-ene-2-carboxylic acid and 1.2 g of 2-chloromethyl-4-methoxymandelic acid chloride in 200 ml of ethyl acetate is refluxed for 50 minutes after which the solvent is removed under high vacuum. The resulting product is chromatographed on silica gel using benzene-acetone as the eluant. The product obtained is triturated with ether to give the title compound, M.P. 140-142°C (dec.).

Preparation 11 3-/(Acetyloxy) methy 17-7-//2-/4- (chloromethyl)phenyl7-2carboxyacetyl7aminQ7-8-oxo-5-thia-l-azabicyclo/·4.2.0 Joct-2-ene-2-carboxylic acid a-Carboxy-£-chloromethylphenylacetyl nitrophenyl polymer, prepared according to the procedure described in Canadian Patent Specification No. 892,580, carrying 4 m. mole of £-chloromethylphenyImalonic acid is suspended for about 8 hours in 20 ml of dry methylene chloride solution containing 1 m. mole of 3-/( acetyloxy)methy177-amino-8-oxo-5-thia-l-azabicyclo/4,2.0_7oct-2-ene-2carboxylic acid triethylammonium salt, which is prepared from 544 mg of 7-aminocepahlosporanie acid (1 m. mole) and 0.56 ml of triethylamine (1 m. mole) at room temperature. After only traces of 7-aminocephalosporanic acid remain in solution, which is determined by thin layer chromatography on cellulose in 70% aqueous propanol, the polymer is filtered off and washed with 3 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 - 28 to pH 2 by adding O.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 the title compound .

In a similar manner as described in Preparation 8 when an appropriate amount of the triethylamine salt of 6-amino-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo/* 3.2.0 J10 heptane-2-carboxylic acid is reacted with an appropriate amount of the acid chlorides listed in Table IV the following respective penicillin derivatives are obtained. 6-//2-/4-(chloromethyl)phenyV-2-methylacetyl7aminq7~ 3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/* 3.2.0_/heptane15 2-carboxylic acid, 6-//3-/5-(chloromethyl)phenyI7proplonyl7amino7~3,3dimethyl-7-oxo-4-thia-l-azabicyclo/ 3.2.0 J'heptane-2catboxylic acid, 6-//3-/4-(chloromethyl)pheny17-2-methylpropiony1/amino/“ 3,3-dimethyl-7-oxo-4-thia-l-azabicyclo/3.2.0_7heptane2-carboxylic acid, 6- //T-/3-(chloromethyl)phenyl7-2-methylbutyryl7amin<273.3- dimethyl-7-oxo-4-thia-l-azabicyclo/ 3.2.0 J7heptane2-carboxylic acid, 6-//2-/4-(chloromethyl)phenoxy7acetyl7amino7“3,3-dimethyl 7- oxo-4-thia-l-azabicyclo/' 3.2.0_7heptane-2-carboxylic acid, 6-//2-/4-(chloromethyl)phenoxy/-2-methylacetyI/amino73.3- dimethyl-7-oxo-4-thia-l-azabicyclo/3.2.0/7heptane30 2-carboxylic acid, 6-//5-/4-(chloromethyl)phenoxy/*-2-methylbutyry17amino?3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/_ 3.2.O_7heptane-2carboxylic acid, - 29 (chloromethyl)anilinq7acetyl7aminq7-3,3-dimethyl7-oxo-4-thia-l-azabicyclo/“3.2.0_7heptane-2-carboxylic acid, 6-//3-/4-(chloromethyl)anilino7-2-methylpropionyl7amino/3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/ 3.2.0 _7heptane2-carboxylic aoid, 6-//2-/4-(chloromethyl)phenylthio7acetyl7amino7-3,3dimethyl-7-oxo-4-thia-l-azabicyclo/7 3.2.0 _7heptane-2carboxylic acid, 6-//2-/2-(chloro)-4-(chloromethyliphenyl/acetyl/amino/3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/73.2.0J7heptane2-carboxylic acid, 6-//4-/4-(chloromethyl) pheny lthi0/butyryl/aitiino7-3,3dimethyl-7-oxo-4-thia-l-azabicyclo/~ 3.2.0[7heptane-2carboxylic acid.

TABLE IV ACID CHLORIDE £-chloromethylhydrotropic acid chloride £-chloromethyldihydrocinnamic acid chloride £-chloromethyl-2-methyldihydrocinnamic acid chloride 2-methyl-4-(£-chloromethylphenyl)butyric acid chloride £-chloromethylphenoxyacetic acid chloride 2-(£-chloromethylphenoxy)propionic acid chloride 2- methyl-4-(£-chloromethylphenoxy)butyric acid chloride £-chloromethylanilinoacetic acid chloride 3- (£-chloromethylanilino)butyric acid chloride £-chloromethylphenylthioacetic acid chloride o-chloro-£“chloromethylphenylacetic acid chloride 4- (£-chloromethylphenyl)thiobutyric acid chloride ?.42435 - 30 In a similar manner as described in Preparation 9 when an appropriate amount of 6-amino-3,3-dimethyl-7oxo-4-thia-l-azabicyclo/— 3.2.0_7heptane-2-carboxylic acid is reacted with an appropriate amount of the acids listed in Table V the following respective penicillin derivatives are obtained. 6-//3-/4- (chloromethyl) phenyl7-2-amint>propionyl7aminp73.3- dimethyl-7-oxo-4-thia-l-azabicyclo/73.2.O_/heptane2-carboxylic acid, 6-//3-/3-(chloromethyl)phenoxy7~2-aminobutyryl/amino/3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/7 3.2,0/7heptane2-carboxylic acid, 6-//4-/4-(chloromethyl)anilino72-aminobutyryl7amino3.3- dimethyl-7-oxo-4-thia-1-azabicyclo/’3.2.0 J/heptane15 2-carboxylic acid, 6-//3-/3-(ehloromethyl)phenylthio7-2-aminopropiony £7 aminq73,3-dimethyl-7-oxo-4-thia-l-azabicyclo/_ 3.2.0/7heptane-2-carboxylic acid, 6-//2-/5-(chloromethyl)-2-thienyl72-aminoacetyl7amino7 20 3,3-dimethyl-7-oxo-4~thia-l-azat>i cyclo/-3.2.0_7heptane2-carboxylic acid, 6-//3-/5-(chloromethyl)-2-thienyl7-2-aminobutyryl7aming7~3,3-dimethyl-7-oxo-4-thia-l-azabicyclo/~3.2.0/7,heptane-2-carboxylic acid.

TABLE V Acid £-(chlororae thylphenyl) alanine 2-amino-4-(£tchloromethylphenoxy)butyric acid 2-amino-4-(£-chloromethylanilino)butyric acid 3-(jr-chloromethylphenyl)thioalanine 2-/T- (5-chloromethyl)thienyl/glycine - 31 TABLE V (continued) Acid 2-amino-4-/S-(5-chloromethyl)thienyl/butyric acid Xn a similar manner as described in Preparation 10 when an appropriate amount of 6-amino-3,3-dimethyl-7oxo-4-thia-1-azabicyclo/-3.2.Oj7heptane-2-carboxylic acid is reacted with an appropriate amount of the acid chlorides listed in Table VI the following respective penicillin derivatives are obtained. 6-//3-/4-(chloromethyl)phenyl/-2-hydroxypropiony17amino?3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/7 3.2.0 J7heptane2-carboxylic acid, 6-//3-/4-(chloromethyl)pheny17-2-hydroxybutyryl7aminQ7 3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/”3.2.0/7heptane2-carboxylic acid, 6-//2-/5-(chloromethyl)-2-thienyl/r2-hydroxyacetyl7amino3.3- dimethyl-7-oxo-4-thia-l-azabicyclo/7 3.2.0J/heptane2-carboxylic acid, TABLE VI Acid Chloride 3-{£-chloromethylphenyl)lactic acid chloride 2-hydroxy-4-(£-chloromethylphenyl)butyric acid chloride 2-hydroxy-2-/2-(5-chloromethyl)thienyl/acetic acid chloride £-chloromethylmandelic acid chloride In a similar manner as described in Preparation 11 when an appropriate amount of 6-amino-3,3-dimethyl -7-OXO-4-thia-l-azabicyclo/”3.2.0/7heptane-2-carboxylic acid is reacted with the acids listed in Table VII the following respective penicillin derivatives are - 32 obtained; 6-//2-/4-(ohloromethyl)pheny37~2-sulfoacetyl/amin673.3- dimethyl-7-oxo-4-thia-l-azabicyclo/ 3.2.O/7heptane2-carboxylic acid, 5 6-//4-/4- (chloromethyl)phenyl/-2-sulfobutyryi7amin073.3- dimethyl-7-oxo-4-thia-l-azabicyclo/73.2.O/heptane2-carboxylic acid 6-//3-/4-(chloromethyl)phenyl7-2-carboxypropiony £7amino/3.3- dimethyl“7-oxo-4-thia-l-azabicyclo/~3.2.0_7heptane10 2-carboxylic acid, 6-//4-/4-(chloromethyl)phenyl/-2-carboxybutyry£7amino73.3- dimethyl-7-oxo-4-thia-l-azabicyclo/3.2.0/7heptane2-carboxylic acid, 6-/74-/4-(chloromethyl)phenylthiq7-2-carboxybutyryl7amina7 3,3-dimethyl-7-oxo-4-thia-l-azabicyclo/73.2.0_/heptane2-qarboxylic acid, 6-//3-/4-(chloromethyl)anilino7-2-carboxypropionyl7amino73.3- dimethyl-7-oxo-4-thia-1-azabicyclo/* 3.2.0/7heptane2-carboxylic aoid, and 6-//3-/5-(chloromethyl)-2-thienyl7-2-carboxypropionyl7amino/-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo/ 3.2.0 Jheptane-2-carboxylic acid.

TABLE VII 2-sulfo-£-ehloromethylphenylacetic acid 4-(p-chloromethylphenyl)-2-sulfobutyric acid £-chloromethylbenzylmalonic acid 2- (£-chloromethylphenoxy)ethylmalonie acid 2-(£-chloromethylphenyl)thioethylmalonic acid £-chloromethylanilinomethyImalonic acid 2-/2- (5-chloromethyl) thenyl J7malonic acid - 33 Example 1 3-/7(Acetyloxy)methyl_7-7-//2-/3-(isothioureamethyl)phenyl/acetyl7aminq7-8-oxo-5-thia-l-azabicyclo/* 4.2.0 _7oct-2ene-2-carboxylic acid hydrochloride A warm solution of 0.12 g of 3-/( acetyloxy) methy 17 7-//2-/3-(chloromethyl)pheny17acety l_7aminq/-8~oxo-5thia-l-azabicyclo/4.2,0_7oct-2-ene-2-carboxylic acid and 0.12 g of isothiourea in 30 ml of ethanol is refluxed for 4 hours after which the solvent is removed under high vacuum at room temperature yielding an oil which is triturated with 80 ml of benzene-acetone (2:1) to give the title compound.

In a similar manner when the halomethylated derivatives and the isothiourea derivatives listed in the following Table VIII are reacted the respective products listed in Table VIII are obtained. β ο fi Ό Ο Μ fa I β β I Φ ίχ g σ ι α «3* ri ri* Ν. ίΜ ri1 β >1 β β Φ Φ ε υ β ίΜ X ο Μ Ό >ι I •Η β β Ν β I ri I β ri <* I ο ϋ ri ri ίΜ Χ Ο β Μ β ϋ I CM I Φ fi X β Ο β ri ϋ β β β Ο I ω cm ri 1 Τί> Q £ ι ω <μ β Si ft Xj >1 I X ko Ο ft φ β rι ri ix ΪΜ Ο1 β Φ ·§ Τ3 I CM Q Ο ri CO ϋ - >1 ΓΟ Ο ύ ri ο β φ fi I 0 fi r χ 1 0 ri ri ft 0 1 β 0 Γ- Ο β fi 1 » *0 0 ft ri CM •Η 01 ri ΪΜ α ri' >1 β cn β ri β β Sj ίΜ β Φ ο β Φ ε 0 ri β ε ri ri ri Φ I rfi ϋ >1 ri CM 1 >1 X ’Ό 1 cn o 0 1 m cn ri β β fi *. >1 1 β β ri G tx Ν ϋ χ-** Φ O’ β 1 1 Λ fi I CM a ri ε r—1 1 Φ 1 ι—1 β β fi 5 !> ri β β β β ίΜ β ft 1 φ fi 1 Φ k£> ε 0 ri β Ό ϋ I ri ri 0 0 ri 1 ri β ίΜ ri ϋ X >ί ίΜ 0 1 I 0 β I 1 ϋ ri ,—, ri I β β CM ri ri ri ri π ri fi Φ .1 rfi β s {Μ I β β 1 tx 1 β X β cn β o cn ri1 cn Ν 0 β ·* Ν ι I >1 » β β Φ cn β CM ri fi cn 1 fi I I 1 ίΜ Φ β β Φ. ri Ό I ri I β ri β β I ri I o X 0 I ΓI ri >1 CM β · β cn Φ L ε χί β ϋ I CM φ fi β β ft φ β ο φ Μ fi Ο ri β β Ο οι ri rtf β fM 4J XI o I oi kO ri Ο1 I fi β ri ri ε β β 1 ri I ο X ο X ϊ} >1 β φ ϋ β β ft φ β 'Ί ο <Ν Ο Si fi Χ| Φ I β kO ft ΪΜ O β ri β ϋ Φ >1 ε □ Η β φ φ β φ Η fi > Μ Η dri fi > 0 β 0 ω ri β β > ri β β β ri β ι 0 fi 0) Φ Η Ω iso 01 1 ri ri ri β β ri >1 β >1 β 0 Φ β β 01 fi β β Φ ri fi φ Φ ε ri Ο •Η fi •Η ΪΜ ri Ό I fi Ό β β β 0 1 β Φ β cn ri ri Φ fi Ο β «. 1 fi 01 ri β ri m Ο ri 'ϋ Φ β β ri φ >1 > β·Η β β φ β ε > Ο ri ri fi β Φ fa Ω I >ι * J Ο IX β θ’ β fi φ ri ε g < β 5μ β fi ri β t CM ri 1 ϊ .

$· X fi I Φ cn β * ft cn ι I: β Ν I β CM I I ri Ό β ίΜ Ο β ~ I I CM ΓΜ ίΜ Si cj Xj φ I β kO ft I γ— ι ri IX >< o’ β ft φ β CM Q rQ 0 I ri m o ri - ίΜ ϋ cn ϋ β Φ fi β β ft Φ β O ri • Ο CM β D •Η ri £ _ ο ίΜ β ϋ fi <4 Ο ri ϋ I !> >1 G I Φ cn β ft ri ~ I ri X O’ β fi ri § >1 fi >1 β G I β fi ri XJ ίΜ I β ftf β S» ω xj ε I I VD CM Φ g fi o ri β O l β Ν I β CM I I β β •Η β β ft β Φ I ri I ο X ο I Γ· Λ <Μ >1 Ο > Λ Η X +) Ο Ο Φ >1 Λ g Ο G •Η ri β τ, β o β h * Ο ri • U CM β <η ο ri X I Ο r* fi I φ ri β >j ft β β ri φ ίΜ ε β 'J β τι φ ι § ” fi cn 0 J ri |X β Ol o fi *-* ri & £ XI Φ I 0 kO β I M o M n ι τ) XJ -H O U r-1 β o ίΜ Ο ϋ ri ri ri β ίΜ β X Ν Ο β ι ri I β ri β β I ri I Ο X Ο A ϋ fi Ό Ο Μ Οι - 35 - I I O' z-* 1 r- V rH M· I 1 1 1 CM >1 1 A bs A • KJ X 1 0 KJ ίχ θ' ίχ A A X o A X fi X Si o 0 A 0 • ϋ A A A 0 rt >1 1 CM rt 0 A 0 A ii A « I A £ ϋ □ 0 0 1 rn ϋ rn fi A >1 A k 0 A A 1 rt KJ ϋ A fi rt >1 A A 1 A ίχ 0 rH X 0 >1 >1 A cn A X A >1 A rH X X ΪΧ *> rt 0 X X 0 o 0 A X cn N A A A £ >< A 0 A I rt k 0 0 A 0 M £ 0 bs 1 rt to £ KJ A rt £ σ A ϋ •rl l 1 A □ A rt fi 1 I CM cn rt I «Μ» Φ A rt CM I 1 N CM 1 k § A 1 rn rt 1 0 fi 0 X A 0 fi X N, A fi | A r-r 1 rt £ 0 fi σ fi 1 rt rt A £ X A >1 A Tf 1 A JL 0 A A Oi 0 0 0 0 X g X 0 1 to ϋ X X VD Qi fl A X VD A rt 0 1 χ*» I r-i >1 γ-? >1 fi Ο Α Οι Ο k Οι Η >ι X A Α Ο Φ ω £ A I <Μ I fi <*1 H Kl H *S| H I fi io ra I *> Ο > +3 κ ι o fl ” ω ® i HOC H « » r* fi A Γ- I cn □ A X 1 A >1 <4 •rl A il A A A ίΧ X 0 >1 1 >1 X A A X A fi A 0 0 0 KJ 0 0 £ >1 A I X £ A ϋ k cn Qi A KJ A rt X—L kJ 1 A ϋ A A I cn rt b cn N CM 1 A *» cn rt rtf A cn * cm ca * m o ι A X* o >ι X Ο k 1 A I uz fi rt 1 .CM £ rt A fi rt 0 A A Λ 0 k fi A rt A A Qi X 0 1 fi £ X 0 A X VO 0 rt A X kJ fi fi A A fi ϋ H H H > ω x rt rt 0 0 0 k > k fi A fi 0 A 0 A rt A X X A A A O k 0 to 0 to A Q •rl 5n I X A A s 0 A I rt rt fi rt cn 0 0 X 0 A k fi k fi dl k fi >1 0 0 1 0 X A A •rl A A X X KJ X 0 A A 1 A £ 0 0 cn 0 1 to (0 to A A A A A CM 1 >5 A >1 X CM O1 1 A KJ 1 0 A 0 X A • fi • fi ΪΧ 0 0 0 m •rH r· CM A cn 0 A fi £ k, A • A K A A 0 A A A cn A co X >1 X KJ o KJ fi >1 <4 KJ fi rt X Qi A A rt X A rt bs. 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X I • 1 X 1 s rri fi ti Φ ti IX 1 kF 1 Φ ft fi kF 1 Φ X 0 rri >< CM X 0 rri X c o 33 Q 1 ri 1 s 1 ft 1 fi 1 fi Λ cn 1 fi ft • >, 0 fi X . ffl O 1 £ 1 ό Oj r5 % *X -ri I ft V? ft ti ft CU Φ ft (Xl rl Xl ft I 1 -rt kO CM nJ ft CM Φ · § im 3 ft , _ ,Χί X Φ Xl 3 OH iCM 3 Xi X <4 ft ι i CM - 37 42435 I ο ι Η Α -μ ο fi ϋ Tf ο to Ω Ό Φ α •Η fi Ο ϋ H H H > ra H φ φ to > A 0 fi 1 0 fi •η ra A > fi fi o to ω Φ Η Ω Tf Φ fi ra fi φ ih > A fi fi fi φ ra e > fi fi to ra φ w Ω ω Φ fi ϋ r—| ra Sh Ο A Md fi Η Φ 0 β ω I I CO CM Η tri, id r-? A >ι fi G Φ Φ 1 £ rd |V >1 X* fl t Φ ko to fi -i fi I iri tri ra fi fl fi © fl A fl © fi 1 ft ε 1 CM fi τΡ 1 1—1 c0 ι o I co 1 0 ra ra fi •rl φ >1 fi to A ih 0 fi A 0 Φ fi •id 1 Φ A fi £ fi CM I G1 Φ ih A fi Φ £ to fi ih ' A cm fi · Φ »co £ fi Tf I co fi Φ ϋ ra rfM 0 I 0 ό ra Φ 0 ra fi 04 Φ A h o cm Ό •ri >1 Α co fi ft Φ co co to ϋ ih o id A ra N ra Φ to fi A fi io fi I CO to rd ϋ >1 ϋ •r| A ra N ra ι rd KO CM Tf •rl o ra □ fi η ? o A to ra o ι CM Φ ra fi φ A fi A fi 0 ω fi fi >1 . . 04 X O O to A Oi to ι ra 01 o CO CM ii A ih I fi I Cto M* 0 1 to O 04 X >1 O I CM J Φ ra fi Φ I o fi A fi ω ih •η κ fi o ih A 7 rs ra fil fi >1 A ‘ fi I tP I X 0 I rfi Φ I co to to ra ϋ G| CM I Φ G ra fi Φ A to o A co 04 I r-ί to >c £ fl -ri fl 6 © ,ra to | to ι S tn co g fi O tJ S>1 fi U ϋ fi ra A ra ϋ N ra ι rd ra fi A fi co IS I ih fi X ih O A G fi Φ Φ A I 04 fi *—» <5 ζ I ra fi A Sh fi ih X o •8 ra o I CM Φ to fi A fi ω fi r0 1 ra fi fi ra 1 co 1 0 ra fi ra fi >1 φ fi fi φ ih 04 to ih ih to A 0 0 A fi 0 fi to 0 fi 0 0 Φ 0i fi Φ A fi 1 A | 1 A fi Gt fi fi Gl fi 0 Tf fi fi 1 ϋ ϋ CM 1 ih ra 1 to y fi 0 7? •η ih A •rl tri 1 A G ra fi fi co ra Φ | M ih © ft N TJ A ra X fl CO ra fi 04 ft 1 0 ft I 1 u *··> co fi A «^ft is fi ra fi | 1 to fi σ | tri ra ra tri G ra 0 fl 0‘ fi 0 fl fi •id fi fl G A 1 fl £ A fi © fi fi CM © ra fi N ih ra x o A to ra o t CM £ to fi A o Φ G ra fi Φ A § M* Edl 0 >1 ' to S 0 A 0 Md I I h tos 0 *s w I I KO (M X 0 I tI fi ih o A · fi CM Φ · £ co Η ι Tf Si ε n Ο H1 to fi A ϋ & 0 •ri ft — O I M ,v ft V & to a *s to ι ra Ko o I CM I Φ G ra fi 04 O’ Φ I A Tf 0 is fi X ‘ 0 ο o ra 7) X G c0 1 fi 0 ϋ fi ra | ϋ fi Sh 0 TJ □ fi 1 fi fi co A ih ft ra X co N 0 s, ra A fi ih A fi Φ to o r- cm o I · fi fi co fi >« i >1 A M X fi 0 0 Φ fi A £ O to fi th ra Tf Ο ϋ to ih to i? 0 A I >i g I Λ to* M Si ni <3 o I I KO CM to fi ra ι υ ra ι fi CM A I fi Φ tp ra I fi 0 04 g 2 Λ to I o fi · iri CM -1) · fl cn I to © ra ο β Ό Ο μ ft § β ♦Η ra β ο ο 1 ra >t ra I CM ra £ o ra I ra • φ r St φ CM m 0 ra m 1 ra ra 4S n3 <1 tn +> cn 0 13 ft ra ·» ra ra 0 >1 o □ μ β 1 tH Φ ft 1 Φ ra *0* o ra ϋ ¢1 q« β ra ra ra Φ ra ra ra g N tn υ >1 Φ Φ X ί ra ra s> ' 1 ra 0 £ ra φ >1 | μ ε μ Φ φ ra 3 >1 ra o φ ra ra I I μ β ra CM β 0 8, I Φ I ra X | β N ra • 0 0 Φ ra 0 ra u X 0 ra ft 1 ω φ | φ IP ra 0 p* ra β ra at m 0 ra 1 ra φ ra ra ra > 13 >1 ra ra 1 ft 0 μ ra O co φ w μ H Ω ra ft I Ο φ ω φ ή μ Η β >ι Ο ra -η ra ra φ ra φ ra φ rd £ ra φ φ S !> ο γΗ >1 J3 +J Φ ε ο Μ Ο γ4 ra ο I I Ν I κο >ι I +> S § ΓΗ £ ο ra 1 8 CM g ι ra K 13 O> I ra cn ra * ra m I CM I Φ β Φ ra o< φ ξ CM Ό • ra m O Φ o o ra ra o ra tn tn o X ra o 8 Ν Φ φ υ - 39 Example 2 3-/(Acetyloxy)methy17-7-/72-/4- (isothioureamethyl) phenyl7-2-aminoacetyl7amlno7-8-oxo-5-thia-l-azabicyclo/~4.2.0 7oct-2-ene-2-carboxyllc acid (A) A mixture of 7.5 g of 3-/]acetyloxy)methy17 7//2-/4-(chloromethyl)phenyl/-2-aminoacetyl7aming7-8-oxo5-thia-l-azabicyclo/T4.2.0 _7oct-2-ene-2-carboxylic acid wherein the 2-amino group is protected with hydrochloride salt and 1.03 g of isothiourea in 50 ml of ethanol is heated for several hours at reflux after which the solvent is removed in vacuo at room temperature yielding an oil. The oil is triturated with 2il benzeneacetone to give the corresponding isothioureamethyl derivative.

(B) At 0°C 10 ml of trifluoroacetic acid is added to 5 g of 3-/(acetyloxy)methy£7-7-/72-/4-(isothioureamethyl ) pheny£?-2-aminoacety£7amini27‘“8-oxo-5-thia-lazabicyclo/4.2.0_7oct-2-ene-2-carboxylic acid wherein the 2-amino group is protected with tert-butoxycarbonyl obtained in (A) above. The mixture is stirred for several minutes under a nitrogen atmosphere resulting in a clear solution which is stirred an additional 15 minutes at room temperature. The excess trifluoroacetic acid is removed in vacuo, and the remaining residue is triturated with diethylether and then dissolved in 175 ml of water. The solution is filtered and the pH of the filtrate adjusted to 5.5 by adding Amberlite 1R41 resin (Amberlite is a Registered Trade Mark) that had been washed several times with water. The resin is filtered off and the water concentrated in vacuo. A precipitate forms from the concentrate which is removed and washed with ethanol to give the title compound.

Xn a similar manner when the halomethylated derivative and the isothiourea derivative listed in the following Table IX are reacted as in Example 2 (A) and - 40 the resulting product subsequently treated as in Example 2 (B) the respective products listed in Table IX are obtained.

A ϋ ο Μ CM iti >1 C οι fl ft r—( >1 A JJ Φ ix I A X A ’ Φ O β · A Ol Tti I CO m o ι\ I >1 r. ι rd § ft oj ~ E CM Tti Α A ϋ ϋ Φ ο •Η A Φ rd tti >« π, κ >s ι o ri a o •—I A >ι Tti ri A I iti co A Ki - 0 CO rd U O >i ri o •fd Ή I -8 K N r-ί (ti $1 I I 1 id 0 >1 1 fl fl m μ A id ϋ A I A 1 s> +> fl A Ol 1 3 A I 1 Λ A fl· Φ n 0 A r ri β I 0 fl id fl* κ o I O' V1 I V© 04 ϋ fl A A >1 κ o A M fl O I OJ I Φ ri fl A ft ~ I rd A >i Tti A I A co Φ * § Φ K id 0’ G ri Ο A A § A i •«d A rd φ N ϋ ft fl 0 0 M ri ft A «' ? ί OJ Is I rd» .OJ > S fi Nl Φ I A M5 ft I Tti 0 id fl >1 ϋ •td rd n κ fl o I A rd id i fl fl □ •id I κ ft ο Φ rd >1 A Cti A · Φ v*> S NJ I fl J φ s M 3 G >i •id A A ω A’ I κ1 o A M fl I A cti fl fl φ Φ Φ id > id G A G O A 0 A fl •id A !> A A A A 0 id 0 ω Φ fl H Q A Tti Φ A fl Α Φ >1 > A A A A Φ fl £ > 0 A rd M fl Φ ® Q iti >1 & rd £ A Φ g X I rd ϋ >1 □ A A fl tti fl I A I fl h! a >1 I fi fl· A o I A A Oft.. — 0 0 id I ft 0 ri A I 5S I ( vO Ol ϋ A A ίΧ κ o fl 0 I A OJ A ' Φ c fl I A 0 ft κ φ A 'ti r· A ΪΧ Cti A · Tti A CO A Φ I U ε x a j? fl A 1 Φ OJ A I ? k co fi * A rd rd i ri a* fl Ni I · H Λ* >1 Nj a Nj A 1 Φ vo ε fl 0 A fl Φ fl JX Φ id A A id G A fl A G 0 >1 Φ Φ 0 A ft M A •id A 0 G Tti A A id 0 1 A 0 ft A A 0 fl 1 A «. fl •id ril A A A I $? ri Φ A ft tx co A Φ ε o M 0 A 8 I I X A VO § ο τ) A A ϋ ϋ ix fl 0 A ϋ A A fl A N >1 fl κ I 0 A A I M fl fl A 0 I OJ I Φ ri fl A ft Φ A iti ΰ OJ X! 1 ft ω ·» A CO I fl N I fl OJ .3 . £ d A bs A 0* fi A Φ ri fl fl A A fl· I 0 I t*· A >1 0 A A A 0 T Itf O A • 0 Cti fl CO □ ΪΧ κ _ o >1 A U id Φ ε A A fl Tti A Φ I 0) β nJ +) ft OJ fl X I fl· I κ o 1 ΓI rd £ · A cd is co Iti A A A Tti A C I fl fl CO N - fl A co I N 1 A 0 ri •rd A Φ ε o id O A I fl A A fl A SU >1 I β 0 O X 8 0 ri A I Λ· Ο Ό >1 id OJ CO A A >1 κ o A id >1 fl 0 0 (continued) u 0 β ra ra 03 •H IX co O 0 ra g Ρ* 1 | fe ίχ nJ ra to o CM co o tn ra 1 1 ra 0 ra CM ίχ CM 0 ra ra ra ra • ra β nJ ra φ N. ra CO ix ra N >1 φ <4 U ra g nJ X CO ra g ra ra (0 0 1 ra ra 0 0 Φ t\ ra ra ra ra υ ra to g r-? μ ra N ra 0 rt >1 nJ nJ o ra >1 co tx o φ ra ra o β ra β *» 0 ra μ φ ra φ φ co ra ra β 0 ra CM 0 g ra ra ο nJ I μ ra ft tx CO X ra 0 N Φ ft U xfe o’ N 0 ra β 1 β i ra β (0 ra. +> ra 0 to ra ix ra 1 μ O g X ra K. ra g ra <0 03 rt 0 ft ra ra rt 1 0 ra I 1 Φ Si (0 ra t CM I CM I p* ξ φ £ f Φ s ra O μ 0 β | >1 ra * XO β ra sf (0 fi ra CM Xi Ο ra i ra κο ra ft o μ ft , r φ ra ι ra vo ra φ £ co fl *M χ ω o ra nJ >. nJ φ φ jd 0 Φ μ > jj 03 μ β ra 0) ra nJ β o ra B ra Φ ο ra nJ ra ίχ μ ra ra > U ra β ra ra ra t ra ο ra ο μ ra φ ra 0 w φ ra 03 Η Ω ra CO ra ra fl φ +) id r-l Φ !X> Λ A 8 Φ gS rH fi Id Φ K □ Λ I +) -fi r-l fl >1 I ft fl Φ jd η Οι I fl o* >i fi rfi fl +> E Φ 3 S X O fl> fi >1 0 fi fl O Λ fl Ο Qi O I fi <, o' fl ix I r-f r-i ίΧ >1 c ra φ ra ra ra ra ι CM o CM ί 0 D N 0 I co ra ra nJ r ra *~ 0 0 μ ra co tx to ra nJ tx .1 ϋ t 0 ra Κ •rj 0 nJ 1 ra o’ ra ra ra CM φ β Φ ra ra I e ra N ΪΧ ra Φ o £ nJ X 1 β μ £ 1 0 M* nJ0 ra ra’ ra ra t ra l μ 0 ft ra tx nJ (0 X φ o ra ra 0 0 ra *— φ ra I p*. t u § ra t CM 1 1 o N Φ ra • 1 β J β b n _ ra · u ra co ra φ ι o SNA kD CM O - 43 Preparation 12 p-Isothioureamethylphenylacetic acid hydrochloride A solution of 0.25 g (1.33 mM) of £-chloromethylphenylacetic aoid and 0.25 g (3.33 mM) of isothiourea is refluxed in 65 ml of ethanol for 3¾ 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 £-isothioureamethylphenylacetic acid hydrochloride as a white solid, M.P. 173-175°C.

In a similar manner when appropriate amounts of the acid derivatives and isothiourea derivatives listed below in Table X are substituted respectively for £ehloronethylphenylacetic acid and isothiourea in the above procedure the respective products listed in Table X are obtained. 4243S 1 A Ό A ra 0 Iri A 0 0 ϋ ίχ 0 k 0 k A k A fi rt fi k ίχ Qi kJ A 0 0 KJ A 0 >, ϋ X 0 A ίχ fi k X * rt Qi A X X X Qt A rH A A A «**» k kj ix 0 0 κί >1 0 A A X 0 (0 a X fi 0 >1k A rt A o 0 A χ kJ β1 0 0 A rt fi A A A 0 B KJ X ίχ 0 A fl) k X ra A 0 X 0 X fi A g 0 Q< 0 k fi A A Qi rt o I A A k 0 0 0 fi A A β CM χ} >1 fi A X £ 0 0 KJ 0 X 0 X Qi 1 A X X KJ o A o A A o A cn Qi A A A k ίχ k 0 0 X 0 ίχ l 0 0 0 0 k ό, X KJ KJ A k X A k £ Kj £ 0 jj >, A O kJ A Ql rt A rt A g X 0 k k 0 to A ίχ X ’ 0 § X A 0 M k Q 0 M $ ra kJ β A A 0 0 X fi A fi 0 0 A 0 X ΪΧ KJ 0 KJ A 0 0 X 0 k k 0 A 0 Qi A k A KJ fi A 0 A KJ 3 rt X 0 0 0 fi k I 0 X 0 X o A k k rt o 0 A X A k A X A 0 0 kJ Qi A A ·» Qi 0 0 kJ 0 X A (0 >1 1 0 X X A KJ to E? to KJ A A X fi A A υ *—' A A A X A A o I I k 0 0 I ΪΧ k 1 . 1 , O 10 β 04 KJ 04 ΪΧ (0 k ^04 X 0 04 kJ 04 rt A β A A A KJ Si A A A 1 A I 0 1 fi I , ΪΧ 0 X I 0 l o Pj ϋ rt TP X o4 X CM £ 0 tp rt CM A rt rt rt 0 0 0 0 k > k k fi A fi fi 0 A 0 0 A rt A A X > X X A A A A 0 k 0 0 (0 0 to (0 H Q A A 0 rt A 0 rt rt to 0 >1 (0 0 0 A k X A k k a rt fi A A rt fi fi >1 0 0 0 ίχ 0 0 0 & k A A x k A A 0 fi X KJ ri P X X k 0 A 1 0) 0 A A Qi A 0 A ε h 0 0 1 X to K 1 Xi (0 to C +1 A A cn ri A A 1 0 0 A fi O o A 0 A fi 0 o 0 A A ri A k. A k Qi K & kJ A ίχ O ri 0 ίχ 0 A 0 k ro k X rt fi A Qi X) Qi A A A A ri» X—k kJ 0 fcx ίχ 0 a A A 0 X X fi ίχ ίχ ίχ . rt 0 0 A X fi fi Ci fi A A 0 0 * cu 0 A 0 X X 0 fl X s £ Qi CU fi ft Q< rt 1 A A 0 A A A CM ίχ ίχ X >1 ίχ & 1 X X Qi X X X A A A A A A A >1 nJ 0 0 K 0 0 X •rl £ £ X! £ £ § A 0 o 0 ri o 0 0 0 rt k k 9 k k k £ 0 0 ε 0 0 0 0 o A A 0 A A A k A X X ri X X X 0 0 □ 0 0 0 0 A 1 1 A Qj 1 I X fi 04 kJ 04 kJ X KJ KJ 04 KJ 01 0 fi A A o A A A *“* 1 A { ϋ | 0 04 0 I 0 1 0 I 04 0 cn rt tp rt rt CM rt TP rt CM lA o m ι—1 rri •id Φ *0 Tf ra β A fi fi φ ra Φ 1 04 1 to I to to η Tf ra fi fi 0 fi 0 0 0 ih fi φ th ih fi ih fi 0 to A to to Tf A A A A A fi Tf fi 0 0 fi fi fi ϋ fi ϋ A ih φ fi 0 □ Φ Φ Φ O Φ 0 fi A E A fi ra TJ £ to £ to 0 fi ra □ A fi ra Tf ra TJ ra TJ □ φ 0 fi o Φ to φ ih φ ih fi fi 0 to to 0 •η to 0 to A to A fi 0 »0 0 Tf w fi 0 fi 0 0 £ ra 0 0 th fi φ 0 A 0 TJ 0 TJ A to •id A fi o •η ϋ •id fi fi fi fi □ 04 A ?h ra A 0 A ϋ A 0 Φ fi fi Tf A 0 fi to fi ra fi rd fi fi 0 fi fi fi 0 TJ 0 0 Tf Φ £0 ϋ Φ A ω th w 0 ra ϋ I ϋ fi ra £ fi fi A fi ή •η fi fi ra fi 1 fi Φ 1 1 to 1 to ft fi >1 o CO ih Tf 0i TJ 01 ih 01 ih fi Sh 04 fi 1 β fi fi ftz» fi fi «W* G 0 to fi Φ to 1 0 1 0 1 0 I Φ to >1 A 0 Tf ra tp A Tp A 01 A 04 fi A 04 fi 1 | I <-» 1 04 Φ Tf 1 0 fi A 0 o 0 >1 0 0 0 Tf 0) G A Φ fi ϋ β •η β x G G Md fi •id 0 1 ih 0 •id to fi 0 fi fi fi >1 to β 0| 0 fi A to £ >1 £ β £ fi 0 A 0 fi β *—» fi Tf ra fi ra φ ra fi ra fi fi fi 1 fi | Φ ih t 0 I A | G 1 Φ A β TP fi 04 £ A CM A CM 04 CM ra CM £ O X M ra φ φ fil to > 9 Eh 0 fi 0 fi fi ra A i> fi fi o to ra Φ H Q o ra ra ra fi ra ra 1 1 Φ φ φ ih φ fi CO 0 to to to A to fi ra I ra « 0 0 0 fi 0 Sh φ fi •rl Φ 0 0 0 Φ 0 04 to ih fi to •id fi •id fi fi 0 0 A ih 0 A A A Tf A to 0 fi A 0 fi fi fi 1 fi 04 fi Φ fi fi 0 0 0 fi 0 1 A | Φ A ra ra ra ft ra G fi fi £ fi •η fi fi fi fi ϋ •id to 0 ih fi fi fi 0 Φ A ϋ I ra rd 0 0 Sh G •rd A fi A fi fi fi Φ fi rd g . G ih 0 TJ 1 φ G to fi ! I fi Φ 0 ϋ Sh A fi rfl A 04 A fi fi □ Φ ih | £ A 01 0 fi to Φ I 0 £ TP fi 0 1 A to 0 ϋ 0 G 1 fi fi 01 Tf A TJ g ft— ·η ϋ fi ra 1 o 1 □ 1 tp ra 01 ra CM m ι rd ih A fi Φ £ Tf ih A fi Φ £ TJ & fi >1 A Ό 0 fi 0 fi fi fi to □ to 0 O 0 ra 0 ra £ ra fi fi 0 A ϋ A o to o ϋ fi ϋ ♦η 0 fi | to | to fi to 01 ih 0t ih A ih A fi 0 TJ fi 1 0 I 0 1 , fi 0 Tp A Tp A 01 Q A 1 z—X 1 ι ra 0 ih 0 0 0 rd G X G G fi 0 ih fi 0 •id fi fi fi G £ G £ fi 0 fi Φ ra Φ ra fi ra φ A 1 A 1 G I u 04 CM 04 CM ra cm ra o in fi fi p-chloromethylphenylmalonic isothiourea ja-isothioureamethylphenylmalonic acid acid hydrochloride TABLE X (continued) ι ri | o >1 ri fi β >1 »d β β >1 Φ β β ε Φ 0 φ Ό α »0 ri ri ri Φ O ri fi β fi β ri 0 0 fi fi ri fi 0 b β β •rl ri ri □ 0 β fi N 0 fi β 0 β fi fa 0 ri β ra β Φ ΪΜ ri ε ε β ri Λ ra >1 >1 φ »0 ft β fi ri 0 β fi 0 fi φ 0 β ft φ ri f1 >; Τ3 β □ X ri β ri 0 fi 0 fi OJ α 0 ra 0 φ ri - ri ri β β οί β CM & ϋ ε β φ Φ fi > firi 0 4J ri Λ > β ri 0 fi ra Φ Η Ω I 0 β ra φ ri fi ri β fi >1 Φ 0 ft fi ri 0 fi β fi 0 · β ft ri 0 1 . β ra fil β ri Ό ri ϋ I ri >1 £ Φ X*. g1 fi Φ β ft ri I ri -j? β Φ § fi >1 fi Λ β +> ri >1 ε ό β τι 0 ·Η β ri G 0 φ- ο 0 © ε β rrt 0 jS 0 μ υ 0 -rt 0. ri1 . C ri fi 04 0 β 0 —’ rrt 0 ri 1 © . J N S Q4 ε m

Claims (15)

1. CLAIMS:1. A compound of the formula wherein either Aryl is a benzene ring, Y is hydrogen, 5 chlorine,bromine, or alkyl or n-alkoxy of from 1 to 4 carbon atoms, and Z is a bond, oxygen, sulfur or imino, or Aryl is a thiophen ring attached to Z at its 2-position, Y is hydrogen and Z is a bond; W is hydrogen, methyl, amino, 4 4 hydroxy, SO,H, or COOR wherein R is hydrogen or 5I 2 3 10 indanyl; R , R and R are each hydrogen or alkyl of from 1 to 4 carbon atoms; n is zero, 1 or 2 with the proviso that it is not zero when W is not hydrogen or methyl and Z is not a bond;is hydrogen or methoxy; M is hydrogen, a pharmaceutically acceptable non-toxic cation; II 7 15 -CH 2 -0-CR' wherein R is alkyl of from 1 to 4 carbon atoms; Λ Ο ft -CH 2 ~NR -COR wherein R is alkyl or alkoxy of from 1 to 4 carbon atoms and R® is hydrogen or n-alkyl of from 1 to 4 carbon atoms; CH_ OCR wherein R is alkyl of from 1 to 4 carbon atoms; or 4 2435 - 48 -CH -O-OC-(CH~)' -0^¼ 12 ^^ 3 ^ 14 wherein m is zero or 2 2 m 11 12 an integer of from 1 to 5, R and R are each hydrogen 13 14 or n-alkyl of from 1 to 4 carbon atoms and R and R are each hydrogen or n-alkyl of from 1 to 4 carbon atoms; and 5 pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1 wherein W is hydrogen.

3. A compound as claimed in claim 1, wherein W is methyl. 10

4. A compound as claimed in claim 1, wherein W is hydroxy.

S. A compound as claimed in claim 1, wherein W is amino.

6. A compound as claimed in claim 1, wherein W is COOR or SO 3 H.

7. A compound as claimed in any of claims 1 to 6, wherein Z is a bond.

8. A compound as claimed in any of claims 1 to 6 wherein Z is oxygen or sulfur. 20

9. A compound as claimed in any of claims 1 to 6, wherein Z is imino.

10. A process for the preparation of a compound as claimed in claim 1 wherein W is hydrogen, methyl, amino, hydroxy, SO^H or COOH, which comprises treating a compound of the formula - 49 Υ JjlrylhaloCH„ ° R 5 Z— (CH„) -CH-C-NH· Z II ι :,2 o r~ S CH 3 CH 3 COOM wherein Aryl, Y, Z, n, R- and M are as defined in claim 2 5 1; W is W as defined above; and halo is chlorine or bromine, with a compound of the formula C-SH 12 3 wherein R , R and R are as defined in claim 1, in an alcoholic solvent at from 0°C to 100°C for from % to 6 hours, with the proviso that when W is amino, the amino group is protected with a suitable blocking group prior 10 to treatment.

11. A process for the preparation of a compound

4. 4 as claimed in claim 1 wherein W is COOR wherein R is 5-indanyl which comprises reacting the corresponding compound wherein R 4 is hydrogen with 5-indanol in an 15 inert solvent in the presence of Ν,Ν'-dicyclohexylcarbodiimide at from 20°C to 30°C and at a pH of about 2.5.

12. A process for the preparation of a compound as claimed in claim 1 wherein W is hydrogen, methyl, amine, hydroxy, SOgH or COOH which comprises reacting a compound 20 of the formula wherein R 3 and M are as defined In claim 1, with an acid of the formula R^N Ary 1-)—- Z — (CH 2 ) £—CH—COOH R-—N-C— S— CH5 or a functional derivative thereof, wherein Aryl, Y, Z, 12 3 2 n, R , R and R are as defined in claim 1 and W is W as defined above in the presence of a solvent selected from ethyl acetate, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran and 10 dimethyl formamide, optionally in the presence of an alkali bicarbonate, at from -10° to 100°C for from 30 minutes to 10 hours, with the proviso that when W is amino, the amino group is protected with a suitable blocking group prior to the reaction. 15

13. A process for the preparation of a compound as claimed in claim 1 substantially as herein described with reference to any of the Examples,

14. A compound as claimed in claim 1 when prepared by a process according to any of claims 10 to 13. 20

15. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 9 and 14 in association with a pharmaceutically acceptable carrier.