US3391141A - Synthetic cephalosporins - Google Patents

Description

United States Patent Oflice 3,391,141 Patented July 2, 1968 3,391,141 SYNTHETIC CEPHALOSPORINS William Joseph Gottsteiu, Fayetteville, and Ann Hallstrand Eachus, Syracuse, N.Y., assignors to Bristol- Myers Company, New York, N.Y., a corporation of Delaware No Drawing. Filed July 7, 1966, Ser. No. 563,355 16 Claims. (Cl. 260-243) This invention relates to new synthetic compounds of value as antibacterial agents, as nutritional supplements in animal feeds, as agents for the treatment of mastitis in cattle, and as therapeutic agents in poultry and animals, including man, in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria and, more particularly, relates to certain 7-[N,N-disubstituted-carbarnoyl (and thiocarbamoyl-)mercapto-acetamido]cephalosporanic acid and related salts and derivatives.

Antibacterial agents in the past have proven highly effective in the therapy of infections due to either Grampositive or Gram-negative bacteria but few are effective against both. It was the objective of the present invention to provide novel compounds effective against both Grampositive and Gram-negative bacteria including the resistant strains. It was a further object of the present invention to provide cephalosporins active against Grampositive and Gram-negative bacteria which are also efficiently absorbed upon parenteral or oral administration to man and animals.

The objects of the present invention have been achieved by the provision, according to the present invention, of the compounds of the formula wherein X is oxygen or sulfur, B is a secondary amino group; A is hydrogen, hydroxyl, (lower)alkanoyloxy con taining 2-8 carbon atoms, e.g., acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, etc. benzoyloxy, a quaternary ammonium radical, e.g. pyridinium, quinolinium, picolinium, lutidinium, or, when taken together with M, a. m-onovalent carbon-oxygen bond; and M is hydrogen, a pharmaceutically acceptable nontoxic cation, an anionic charge when A is the quaternary ammonium radical, or, when taken together with A, a monovalent carbon-oxygen bond.

The term (lower)alkyl as used herein means both straight and branched chain aliphatic hydrocarbon radicals having from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. Similarly, where the term (lower) is used as part of the description of another group e.g. (lower) alkoxy, it refers to the alkyl portion of such group which is therefore as described above in connection with (lower)alkyl and thus includes such radicals as met'hoxy, ethoxy, isopropoxy, etc.

In addition to the secondary amino groups in which two bonds of the nitrogen atom form part of a nonaromati-c carbocyclic or herterocyclic ring, the term secondary amino group includes, but is not limited to, groups of the formula in which each of A and 13 represents a radical selected from the following list:

(1) Aliphatic radicals, for example:

Alkyl radicals, e.g.:

Methyl Ethyl Propyl (nand iso-) B'utyl (n-, sec-, iso', and tert-) A'myl (n-, sec-, iso-, and tert-) Hexyl radicals, e.g.: n-Hexyl Sec-hexyl 2,2-dimethyl-3 butyl 2,2-dimethyl-4-butyl 2,3-dimet-hyl-2-butyl Z-methyl-l-pentyl 2-methyl-2-pentyl 3-methyl-lpentyl 3-methyl-2-pentyl, etc. Heptyl radicals, e.g.:

n-Heptyl Sec-hepty-l 2,3-dirnethyl-3-pentyl 2,4-dimethyl-2-pentyl 2,4-dimethyl-3-pentyl 2,2,3-trimethyl-3-butyl 3-ethyl-2-pentyl' .2-methyl-2-hexyl, etc. Octyl radicals, e.g.:

n-Octyl' 2-ethyl-hexyl Diisobutyl Capryl Nonyl radicals, e.g.:

Di-isobutyl-carbinyl n-Nonyl Decyl radicals, e.g. n-decyl Dodecyl radicals, e.g. lauryl Tetradecyl radicals, e.g. myristyl Hexadecyl radicals, e.g. cetyl Octadecyl radicals, e.g. stearyl Alkenyl radicals, e.g.:

Vinyl Propenyl radicals, e.g.:

Allyl Isopropenyl Butenyl radicals, e.g.: n-Butenyl l n-Butenyl-Z n-Butenyl-3 Isobutenyl Pentenyl radicals, e.g.: n-Penteny-l-l' n-Pentenyl-2 n-Pentenyl-3 Hexenyl radicals, e.g.: n-Hexenyl-1 nl-Iexenyl-2, etc. 4,4-dimethyl-butenyl-2 3,4-dimethyl-butenyl-l, etc. Heptenyl radicals, e.g. n-heptenyl Octenyl radicals, e.g.:

n-Octenyl Diisobutenyl Nonenyl radicals, e.g. n-nonenyl Decenyl radicals, e.g, n-decenyl Dodecenyl radicals, e.g.:

n-Dodecenyl triisobutenyl Alkenyl radicals having the formula C H where n is an integer from 18 to 38 inclusive,

elg. those derived from paraffin wax, mineral oils, and pctr'olatum. (2) Cycloaliphatic radicals, for example:

Cycloalkyl radicals,-e.g.: I

Cyclopentyl, alkylated-cyclopcntyl, cyclohexyl,

and alkylated-cyclohexyl radicals, c.g.:

Monoand poly-methyl-cyclopentyl radicals Monoand poly-methyl-cyclohexyl radicals Monoand poly-ethyl-cyclohexyl radicals Monoand poly-isopropyl-cyclohcxyl radicals Monoand ply-tert-amyl-cyclohexyl radicals n-Octyl-cyclohexyl;radicals Diisobutyl-cyclohexyl (i.e. tert-octy1-cyclohexyl) radicals 'Nonyl-cyclohexyl radicals Diiso-amyl-cyclohexyl radicals Lauryl-cyclohexyl radicals Cetyl-cyclohexyl radicals Naphthenyl radicals Hydroabietyl radicals Cycloalkenyl radicals, e.g.:

Cyclopentenyl, alkylated-cyclopentenyl, cyclohexenyl, and alkylated-cyclohexenyl radicals,

Monoand poly-methyl-cyclopentenyl radicals Monoand poly-methyl-cyclohexenyl radicals Monoand poly-ethyl-cyclohexcnyl radi cals Monoand poly-isopropyl-cyclohexenyl radicals Monoand poly tert arnyl-cyclohexenyl radicals n-Octyl-cyclohexenyl radicals Diisobutyl-cyclohcxenyl radicals Nonyl-cyclohexenyl radicals Diiso-amyl-cyclohexenyl radicals Lauryl-cyclohexenyl radicals Cetyl-cycl ohexcnyl radicals Dehydronaphthenyl radicals Abietyl radicals (3) Aryland cycloalkyl-substituted aliphatic radicals,

for example:

(a) Phenyland alkyl-phenyl-substituted alkyl radicals, e.g.:

Benzyl Methyl-benzyl Capryl-benzyl Diisobutyl-benzyl Phenyl-ethyl Phenyl-propyl Phenyl-octadecyl (b) Xenyland alkyl-xenyl-substituted alkyl radicals, e.g.:

Xenyl-methyl Capryl-xenyl-methyl Xenyl-ethyl Diisobutyl-xenyl-methyl (c) 'Napthyland alkyl-naphthyl-substituted alkyl radicals, e.g.:

Naphthyl-methyl Tert-arnyl-naphthyl-methyl Naphthyl-ethyl Cetyl-naphthyl-ethyl (d) Cyclohexyland alkyl-cycloheXyl-substituted alkyl radicals, e.g.:

Cyclohexyl-ethyl Methyl-cyclohexyl-ethyl 'Ethyl-cycloheXyl-ethyl Cyclohcxyl-propyl 4 Tert-amyl-cyclohexyl-butyl (4) Oxygen containing aliphatic and cycloaliphatic radicals, for example:

(a) Oxygen-containing aliphatic radicals, e.g.:

Alkoxy-substitutcd alkyl radicals, e.g.: Propoxy-ethyl radicals, e.g.:

n-Propoxy-ethyl Iso-propoxy-cthyl Butoxy-ethyl radicals, e.g.

n-Butoxy-ethyl Iso-butoxy-ethyl Tert-butoxy-ethyl Octoxy-ethyl radicals, e.g.:

n-Octoxy-ethyl Diisobutoxy-ethyl Di-butoxy-propyl radicals, e.g.:

2,3-di-n-butoxy-propyl 3,3-di-iso-butoxy-propyl Di-octoxy-propyl radicals, e.g.:

3,3-di-n-octoxy-propyl 2,3-bis-(diis0butoxy)propyl Cycloalkoxy-substituted alkyl radicals, c.g.:

Cyclohexoxy-methyl Cyclohexoxy-ethyl radicals, e.g.: Beta-cyclohexoxy-ethyl Alpha-cyclohexoxy-ethyl Cyclohexoxy-butyl radicals, e.g.: 2-(cyc1ohex0xy)-butyl 2,3-di-cyclohexoxy-butyl Methyl-cyclohexoxy-propyl radicals, e.g.:

2- (o-methyl-cyclohexoxy) -propyl 2- p-methyl-cyclohexoxy) -pr0pyl Butyl-cyclohexoxy-ethyl radicals, e.g.:

Betap-tert-butyl-cyclohexoxy) -ethyl Alpha-(o-scc-butyl-cyclohexoxy)- ethyl Cyclopentoxy-ethyl radicals, e.g.:

Alpha-cyclopentoxy-ethyl Bct-a-cyclopentoxy-ethyl Propyl-cyclopentoxy-rnethyl radicals, e.g.:

-Iso-propyl-cyclopentoxy-methyl radicals n-Propyl-cyclopentoxy-methyl radicals Alkenoxy-substituted alkyl radicals, e.g.: Propenoxy-ethyl radicals, e.g.:

Allyloxy-ethyl Iso-propenoxy-ethyl Octenoxy-ethyl radicals, e.g. diisobutenoxyethyl Di-octenoxy-propyl radicals, e.g. 2,3-bis- (diisobutenoxy)-propyl Aroxy substituted alkyl radicals, for example, phenoxy and alkyl-phenoxy-substituted alkyl radicals, e.g.:

Phenoxy-methyl Phenoxy-ethyl Cetyl-phenoxy-ethyl Phenoxy-phenethyl Capryl-phenoxy-phenethyl b) Oxygen-containing cycloaliphatic radicals, e.g.:

Alk0xy-, alkenoxy-, and aroxy-substituted cycloalkyl radicals, e.g.:

Alkoxy substituted cyclopentyl radicals,

Monoand poly-ethoxy-cyclopentyl Octoxy-cyclopentyl radicals, e.g. dissobutoxy-cyclopentyl Alkoxy-substituted cyclohexyl radicals, e.g.:

Monoand poly-methoxy-cyclohexyl Octoxy-cyclohcxyl radicals, e.g. diisobutoxy-cyclohexyl Alkenoxy-substituted cyclopentyl radicals,

Propenoxy-cyclopentyl radicals, e.g.:

Allyloxy-cyclopentyl Methyl-polychloro-phenyl radicals, e.g.:

Methyl-dichloro-phenyl radicals Methyl-trichloro-phenyl radicals Ethyl-monochloro-anthracyl radicals, e.g,:

Ethyl monochloro alpha anthracyl radicals Triethyl monochloro beta-anthracyl radicals Ethyl-polychloro-anthracy1 radicals, e.g.:

Ethyl-dichloro-alpha-anthracyl radicals Diethyl-trichloro-beta anthracyl radicals Alkyl-nitro-aryl radicals, e.g.:

Methyl-nitro-phenyl radicals Dimethyl-nitro-phenyl radicals Ethyl-dinitro-phenyl radicals Butyl-nitro-naphthyl radicals, e.g.:

Tert-butyl-nitro-naphthyl radicals Sec butyl dinitro-naphthyl radicals Propyl-nitro-phenanthryl radicals, e.g.: Isopropyl dinitro phenanthryl radicals Di-n-propyl-dinitro phenanthryl radicals Of those set out above, the preferred secondary amino groups are those having a molecular weight of less than 300.

For clarity, we have illustrated below the formulae of the compounds when, in Formula I, X is oxygen, B is diethylamino, A is a quaternary ammonium radical (pyridinium) and M is an anionic charge, and when A and M together are a monovalent carbon-oxygen bond.

A preferred group of compounds within the present invention is the group having the formula wherein X is oxygen or sulfur; B is a secondary amino group, said secondary amino group containing in addition to its single nitrogen atom solely the elements carbon and hydrogen; A is hydrogen, hydroxyl, (1ower)alkanoyloxy, benzoyloxy, a quaternary ammonium radical or, when taken together with M, a monovalent carbon-oxygen bond; and M is hydrogen, a pharmaceutically acceptable nontoxic cation, an anionic charge when A is a quarternary ammonium radical or, when taken together with A, a monovalent carbon-oxygen bond.

Another preferred group of compounds within the present invention is the group having the formula wherein X is oxygen or sulphur; B represents di(lower)- alkylamino wherein the alkyl group may be alike or different, piperidino, methyl-piperidino, dimethylpiperidino, pyrrolidino, rnethylpyrrolidino, dimethylpyrrolidino, morpholino, methylrnorpholino, dimethylmorpholino, N'- (lower)alkylpiperazino, N (lower) alkylmethylpiperazino, N'-(lower)alkyl-dimethylpiperazino, trimethyleneimino, hexamethyleneimino or a radical of the formula Ar-(OH,),,-N- 1'1 wherein n is zero, one, two or three, R is (lower)alkyl and Ar is a radical of the formula I I N wherein R and R are each hydrogen, fluoro, chloro, bromo, (lower)alkyl or (lower)alkoxy; A is hydrogen, hydroxyl, (lower) alkanoyloxy, benzoyloxy, a quaternary ammonium radical or, when taken together with M, a monovalent carbon-oxygen bond; and M is hydrogen, a pharmaceutically acceptable nontoxic cation, an anionic charge when A is a quaternary ammonium radical or, when taken together with A, a monovalent carbon-oxygen bond.

The most preferred embodiments of the present invention are the free acids and salts thereof of which the free acids have the formulae The products of the present invention wherein X of Formula I is sulfur are prepared by the reaction of a compound of the formula wherein A and M are described above (preferably in the form of a neutral salt such as the sodium salt or the triethylamine salt, i.e. when A is hydrogen, hydroxy, (lower)alkanoyloxy or benzoyloxy) with an acid having the formula (in which B has the meaning set forth above) or with its functional equivalent as an acylating agent for a pri mary amino group. The preferred reagent is the mixed anhydride prepared by reacting such an acid with isovaleryl chloride (or pivaloyl chloride) in the presence of a tertiary amine such as triethylamine as an acceptor of hydrogen chloride. Such equivalents include the corresponding carboxylic chlorides, bromides, acid anhydrides, including mixed anhydrides and particularly the mixed anhydrides prepared from stronger acids such as the lower aliphatic monoesters of carbonic acid, of alkyl and aryl sulfonic acids and of more hindered acids such as diphenylacetic acid and isovaleric acid. In addition, an acid azide or an active ester or thioester (e.g. with p-nitrophenol, 2,4-dinitrophenol, thiophenol, thioacetic acid) may be used or the free acid itself may be coupled with 7-aminocephalosporanic acid after first reacting said free acid with N,N'-dimethylchloroformiminium chloride [cf. Great Britain 1,008,170 and Novak and Weichet, Experientia XXI/ 6, 360 (1965)] or by the use of enzymes or of an N,N' carbonyldiimidazole or an N,N -carbonylditriazole [cf. South African Patent Specification 63/2684] of a carbodiimide reagent [especially N,N'- dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide or N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide; cf. Sheehan and Hess, J. Amer. Chem. Soc. 77, 1067, (1955)], or of alkynylamine reagent [cf. R. Buijle and H. G. Viehe, Angew. Chem. International Edition 3, 582 (1964)], or of a ketenimine reagent [cf. C. L. Stevens and M. E. Monk, J. Amer. Chem. Soc. 80, 4065 (1958)] or of an isoxazolium salt reagent [cf. R. B. Woodword, R. A. Olofson and H. Mayer, J. Amer. Chem. Soc. 83, 1010 (1961)]. Another equivalent of the acid chloride is a corresopnding azolide, i.e. an amide of the corresponding acid whose amide nitrogen is a member of a quasiaromatic five-membered ring containing at least two nitrogen atoms, i.e. imidazole, pyrazole, the triazoles, benzimidazole, benzotriazole and their substituted derivatives. As. an example of the general method for the preparation of an azolide, N,N'-carbonyldiirnidazole is reacted with a carboxylic acid in equimolar proportions at room temperture in tetrahydrofuran, chloroform, dimethylforamide or a similar inert solvent to form the carboxylic acid imidazolide in practically quantitative yield with liberation of carbon dioxide and one mole of imidazole. Dicarboxylic acids yield diimidazolides. The by-product, imidazole, precipitates and may be separated and the imidazolide isolated, but this is not essential. The methods for carrying out these reactions to produce a cephalosporin and the methods used to isolate the cephalosporin soproduced are well-known in the art (cf. US. Patents Nos. 3,079,314, 3,117,126 and 3,129,224 and British Patents Nos. 932,644, 957,570 and 959,054).

The compounds of Formula VI used in the present invention include 7-aminocephalosporanic acid and derivatives of 7-aminocephalosporanic acid. 7-amin0cephalosporanic acid is prepared by hydrolysis of cephalosporin C and has theformula l coon 1 I C-CHzOL CH3 Acid hydrolysis of cephalosporin C to produce 7- aminocephalosporanic acid results in the coproduction of the lactone, 3-hydroxymethyl-7-aminodecephalosporanic acid lactone, formed by the further hydrolysis of the acetoxy group and subsequent internal esterification. The lactone has the formula Enzymatic hydrolysis of the acetoxy group of 7- aminocephalosporanic acid results in the formation of 3- hydroxymethyl 7 aminodecephalosporanic acid having the formula and has been given the name 3-pyridiniummethyl-7-aminodecephalosporanic acid inner salt.

The foregoing nuclei and the preparation thereof are known in the art and are described for example in US. Patent No. 3,117,126 and British Patents Nos. 932,644, 957,570 and 959,054.

3-methyl-7-aminodecephalosporanic acid having the formula is produced by catalytic reduction of cephalosporin C followed by hydrolytic removal of the S-aminoadipoyl side chain as described in US Patent No. 3,129,224.

There is thus provided by the present invention a method for preparing antibiotic compounds having the general formula wherein X is oxygen or sulfur; B is a secondary amino wherein R taken alone, is OH, C -C acyloxy or tertiary-amino, R is OH when R is OH;

R is OH when R isC -C acyloxy; R is when R is tertiary-amino;

' I R and R when taken together are O;

which comprises acylating a compound having the bicyclic ring structure of cephalosporin C and having a general formula represented by one of where R is OH or a C -C acyloxy group and s H N-CH-(JH o0,

0=c--N C-CHz-Am 0 1-0 II 0 wherein Am is a tertiary-amino group; with an acylating agent having at least one constituent radical of the general formula it I? BC-SCHa-C- in which B and X have the meaning set forth above.

There is further provided by the present invention a method according to claim 15 for preparing antibiotic compounds having the general formula wherein X is oxygen or sulfur; B is a secondary amino group;

wherein R taken alone, is -OH, C -C acyloxy or tertiary-amino, R is -OH when R is OH;

R is OH when R is C -C acyloxy; R is 0 when R is tertiary-amino;

R and R when taken together are O which comprises acylating a compound having the bicyclic ring structure of cephalosporin C and having a general formula represented by one of wherein R is OH or a C -C acyloxy group and wherein Am is a tertiary-amino group; with an acylating agent having at least one constituent radical of the general formula X 0 B-( 'i-SCHz( J wherein B and X have the meaning set forth above; and

(a) Heating the product with acidified water to form the corresponding acylated derivative of the nuclei of cephalosporin C compounds, or

(b) Refiuxing the product in solution with an excess of a tertiary amine corresponding to Am to form the corresponding acylated derivative of the nuclei of cephalosporin C compounds, or (c) Treating the product with citrus acetylesterase in a buifered aqueous medium to form the corresponding N-acylated derivative of the nuclei of desacetyldecephalosporin C compounds.

There is also provided by the present invention a method for preparing nontoxic derivatives of the compounds produced by the methods set out above which comprises combining said products with pharmaceutically acceptable cations, anions, alcohols, ammonia or amines.

The products of the present invention wherein X of Formula I is oxygen are prepared in similar fashion by the use of an acid of the formula 0 B-fi-S-CHrCOOH (in which E has the meaning set forth above) or its functional equivalent as an acylating agent for a primary amino group. This is not the preferred method, however, as the acids of the formula are not quite as easily prepared when X is oxygen as they are when X is sulfur.

A very effective and most unexpected method for producing the compounds of Formula I wherein X is oxygen is the process provided by the present invention of reaction of a compound of Formula IV directly with an acid of the formula S I B-(i-S-CHzCO OH speed the reaction within reasonable limits, e.g. about O50 C. The iodide/sodium iodide solution is, preferably but not necessarily, added gradually to the aqueous 1 B-OS-CH3GOOH wherein B is a secondary amino group and X is oxygen or sulfur are prepared by the methods reported in the literature and exemplified below, i.e. from the appropriate secondary amine (B-H) as follows:

KOH 1. ClCHzCOONa B--H+ C8; B-C-SK ---9 KOH ll 1. ClOHzCOONa. B-H+ COS B-CSK 1 B--S-CHzCOOH Procedure No. 1

To a solution of diethylamine (36.57 g.; 0.5 mole) in 300 ml. absolute ethanol there was added 32.75 g. (0.5 mole) of 85.4% aqueous potassium hydroxide. When the solution had cooled to room temperature there was added to it 38.07 g. (0.5 mole) carbon disulfide. After stirring for 2.5 hours the solvent was removed by distillation in vacuo to leave the product, potassium N,N-diethyldithiocarbamate as a yellow oil which crystallized on cooling and was used directly in the next reaction by dissolving it in about 150 ml. water and adding thereto with stirring 58.3 g. soduim chloroacetate. The dark green mixture thus produced was heated in a steam bath for one hour. The pH was adjusted to 2 with hydrochloric acid. The product, carboxymethyl N,N-diethyldithiocarbamate, separated as an oil which crystallized upon the addition of more water and cooling as tan crystals where were collected, recrystallized from hot water and found to weigh 51.5 g. and to melt at 94-96" C. K. A. Jensen, J. Prakt. Chem., 159, 189-192 (1941) reported M.P. 89 C.

Analysis.-Calcd for C7H13NS202: C, 40.5; H, 6.32. Found: C, 40.98; 40.82; H, 6.38; 6.40.

Potassium hydroxide (6.55 g., 0.1 mole) was dissolved in 125 ml. absolute ethanol and cooled to 20 C. Carbon disulfide (7.6 g., 0.1 mole) and piperidine (8.5 g., 0.1

mole) were added and the solution was cooled and stirred for thirty minutes. The solvent was removed by distillation in vacuo to leave the product potassium N,N-penta- 14 methylenedithiocarbamate, as a faintly yellow, crystalline solid, 20.4 g., M.P. 228 C.

Potassium N,N-pentamthylenedithiocarbamate (9.95 g.,' 0.05 mole) and sodium chloroacetate (5.8 g., 0.05 mole) were combined in 50 ml. water and heated at 30- 35 C. for 1.3 hours. The solution was filtered and cooled. Acidification to pH 2 with hydrochloric acid precipitated crystalline S-carboxyrnethyl N,N-pentamethylenedithiocarbamate(which is also named l-piperidinecarbodithioic acid, carboxymethyl ester), which was collected by filtration and found to weigh 8.68 g., M.P. 148149 C.

G. Nachmais, Ann. Chi'm. (Paris), 7, 584-631 (1952); Chem. Abstr., 45, 7963 and 48, 597 reported M.P. 143 C.

To a solution of morpholine (26.1 g., 0.3 mole) in ml. water there was slowly added 22.8 g. (0.3 mole) carbon disulfide and 11.7 g. (0.3 mole) potassium hydroxide. Soon the solution was homogeneous and then 34.2 g. (0.03 mole) sodium chloroacetate was added and the mixture was heated on the steam-bath for thirty minutes. It was necessary to add a few milliliters of 10% sodium hydroxide to keep the pH above 8. The mixture was filtered and acidified to pH 2 with dilute phosphoric acid to precipitate the product, herein called S-carboxymethyl morpholino-dithiocarb-amate having the structure given above and also named 4-morpholinecarbodithioic acid, carboxymethyl ester, which was collected, recrystallized from hot isopropyl alcohol and found to weigh 26 g., M.P. 169170 C.

G. Nachmais, ibid, reported M.P. 162 C.

Procedure N 0 4 0113 ll: ClCHaCOONa 2. HCI

s H @om-n-o-s-omo 0 0H Procedure N 0. 5

1. 01015120 0 0Na 2. H01

5 I @n-d-s-omoo on Potassium hydroxide (6.55 g.) was dissolved in 100 ml. water and cooled in ice. The icebath was removed and carbon disulfide (6.03 ml.) and N-methylaniline (10.85 ml.) were added. The mixture was stirred for four hours; most of the oil disappeared. Sodium chloroacetate (10.0 g.) was added and the pH was lowered to about 7. The solution was stirred for 40 minutes and then acidified to pH 2 with HCl to precipitate the product, carboxymethyl N-phenyl-N-methyldithiocarbamate, as a crystalline solid which was collected by filtration, 9.4 g., M.P. ZOO-202 C.d.

Analysis.Calcd for C H NO S C, 49.76; H, 4.60; S, 26.58. Found: C, 50.16; H, 4.77; S, 27.05.

Holmberg, J. Prakt. Chem. 2, 82, 446; Beilstein, 12, I, 252 reported M.P. 197198 C.

1. C1-CHzCOONa Pyrrolidine (10.64 g., 0.15 mole) was dissolved in a solution of 8.25 g. KOH in 100 ml. water and cooled to C. Carbon disulfide (11.4 g., 0.15 mole) was added in 2 ml. portions while stirring in ice; when the additions were complete the pH was slightly alkaline, Sodium chloroacetate (17.5 g., 0.15 mole) was added and the solution was warmed on a hot plate. Stirring was continued for 40 minutes. The solution was acidified with hydrochloric acid and the precipitated product, S-carboxymethyl N,N-tetramethylenedithiocarbamate (also named 1-pyrrolidinecarbodithioic acid, carboxymethyl ester), was collected by filtration and recrystallized from methanol to yield 21.5 g., M.P. l62l63 C.

Analysis.Calcd for C H Ns O z C, 41.0; H, 5.30; N, 6.84. Found: C, 41.29; H, 5.55; N, 6.80.

Afanaseva, Chem. Abstr. 54, 20997i 141-143 C.

reported PROCEDURE NO. 7

Diethylamine (14.6 g., 0.2 mole) was dissolved in 150 ml. diethyl ether and carbonyl sulfide was bubbled into the cooled solution until 6.0 g. (0.1 mole) had been added. The solution was stoppered and stored overnight. The solvent was removed at 33 C. to leave as the residue 13.67 g. of diethylammonium N,N-diethylthiocarbamate as an oil which crystallized on cooling and was then dissolved in 75 ml. water. Sodium chloroacetate (7.74 g., 0.066 mole) was added and the solution was stirred at room temperature for 3 hours, heated at 50-55" C. for 50 minutes and then stored overnight at room temperature. The solution was acidified with HCl and extracted with ether. The ethereal extract was washed twice with water and dried over MgSO Removal of the solvent by distillation left as the residue 6.5 g. S-carboxymethyl N,N- diethylthiocar bamate as an oil which crystallized on standing in ice and was heated slowly to 50 C. in vacuo (water pump) and then allowed to stand. Melting point 36-38 C.

Analysis.Calcd for C7H13NO3SZ C, 43.96; H, 6.85; N, 7.32. Found: C, 44.00; H, 7.01; N, 7.36.

PROCEDURE NO. 8

1. ClCHgG O ONa 2. 1101 SCH;COOH

A solution of 13.1 g. (0.2 mole) potassium hydroxide in 100 ml. water was cooled to 15 and l-methylpiperazine (20. 0g., 0.2 mole) was added. Carbon disulfide (12.0 ml., 0.2 mole) was then added in 2 ml. portions while maintaining the temperature at about 10 C., taking minutes for the additions. The pH was then lowered to 9 with HCl. Sodium chloroacetate (23.2 g., 0.2 mole) was added and the mixture was stirred overnight and then filtered to remove a small amount of a precipitate. The filtrate was evaporated at 38 C. to leave the product, S- carboxymethyl 1-methylpiperazino-dithiocarbamate (also called 1-methyl-4-piperazinecarbodithioic acid, carboxymethyl ester), as a solid residue which was recrystallized from methanolether. On standing in water at pH 6 the produce crystallized and was found to have an NMR spectrum consistent with the assigned structure.

In the process for the preparation of the compounds of Formulae (I) and (VII) above, the compounds are sometimes in aqueous solution in the form of their sodium or potassium salt. These compounds in the aqueous phase can then be converted to the free acid, preferably in the cold under a layer of ether by the addition of dilute mineral acid, e.g. 5 N H 50 to pH 2. The free acid can then be extracted into a water-immiscible, neutral organic solvent such as ether, the extract washed with water quickly in the cold, if desired, and dried, as with anhydrous Na 'SO and the free acid recovered from the ethereal solution. The product in the ethereal extract in its free acid form can then be converted to any desired metal or amine salt, particularly the pharmaceutically acceptable nontoxic amine salts described above, by treatment with the appropriate base, e.g. a free amine such as procaine base or a solution of potassium Z-ethylhexanoate in dry n-butanol. These salts are usually insoluble in solvents such as ether and can be recovered in pure form by simple filtration.

The following examples will serve to illustrate this invention without limiting it thereto. All temperatures are given in degrees centigrade.

In the structural formulae given below -ACA represents the moiety having the formula To a solution of 1. 8 g. (0.001 mole) of S-carboxymethyl N,N-dimethyldithio-carbamate (Eastman Kodak Co.) and 1.0 g. (0.001 mole) triethylamine in 50 ml. tetrahydrofuran (THF) there was added at 0 C. 1.2 g. (0.001 mole) of isovaleryl chloride. A white precipitate formed which dissolved upon the addition of 2.8 g. (0.001 mole) 7-aminocepholosporanic acid (7-AOA) as its triethylammonium salt dissolved in water. The tetrahydrofuran was removed by evaporation under reduced pressure at 35 C. The remaining aqueous mixture was diluted with water and acidified to pH 2 with dilute phospheric acid and extracted into ethy-lacetate which was cedure No. 3) dissolvediin 100 ml. tetrahydrofuran there was added 1.6 g. (0.0158 mole) triethylamine and then, at C., 1.9 g. (0.0158 mole) isovaleryl chloride (D.P.I.). The mixture was stirred for15 minutes and there was then added a solution of 4.3 g. (0.015 8 mole) 7-aminocephalosporanic. acid dissolved in waterby the addition of su fiicient triethylamine to dissolve it completely. The resulting clear solution was stirred for 30 minutes and the triethylamine was evaporated off at 30 C. under reduced pressure. The aqueous phase was lowered to pH 2 with dilute phosphoric acid and the product in its acid form wasthen extracted into ethyl acetate. The ethyl acetate extract was washed with water, dried over MgSO .and filtered. To the filtrate there was then added sodium 2- ethylhexanoate which precipitated the product of the formula given above;'it was collected, dissolved in a minimum amount of Water, reprecipitated by the addition of acetone, collected, recrystallized three times from wet n-butanol and found to weight 4 g. Analysis.Calcd for C H NaN O S C, 41.00; H, 1.03;"N, 8.45.'Found: C, 41.03; H, 4.03; N, 8.22.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.25 mcg./ml. versus S. aureus Smith, of about 1.6 mcg./ml. versus the benzylpenicillinresistant Staph. aureus BX-1633-2 of about 1.6 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.25 meg/m1. versus D. pneumoniae and of about 0.25 mcg./ ml. versus Str. pyrogenes Digonnet 7.

Example 5 To 2.4 g. (0.01 mole) of S-carboxymethyl N-phenyl- N-methyldithiocarbamate (prepared according to Procedure No. 5) in 100 ml. tetrahydrofuran there was added 1.0 g. (0.01 mole) triethylamine. The solution was cooled to 0 C. in an ice-bath and 1.2 g. (0.01 mole) pivaloyl chloride (trimethylacetyl chloride) was added. The mixture was stirred for ten minutes and there was then added a solution in 100 ml. water of 2.7 g. (0.01 mole) 7-aminocephalosporanic acid and 10 ml. triethylamine. The solution was stirred for 30 minutes and then the organic solvent was evaporated under reduced pressure to leave an aqueous solution of the triethylamine salt of the product which was converted to its acid form by diluting with 20% phosphoric acid and extraction into ethyl acetate. The ethyl acetate extract was dried over anhydrous ,MgSO Addition thereto of sodium 2-ethylhexanoate in dry n-butanol precipitated 3 g. of the product of the formula given above which was dissolved in wet n-butanol and azeotroped at 40 C. to give a crystalline solid with some oil present. The solid was collected, dissolved in 100 ml. wet butanol and evaporated under reduced pressure to the point where an oil precipitated. Diatomaceous earth (Celite) was added and the mixture was filtered. Azeotroping of the filtrate was continued to precipitate the product as crystalline rosettes, 200 mgm.

Analysis.--Calcd for C H NaN O S C, 46.42; H,

3.90; N, 8.12. Found: C, 46.60; H, 4.12; N, 7.85.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.125 mcg./ml. versus S.

aureus Smith, of about 0.4 mcg./ml. versus the benzylpenicillin-resistant Staph. aureus BX-1633-2, of about 0.4 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.06-0.125 meg/ml. versus D. pneumoniae and of about 0.062 meg/ml. versus Str. pyogenes Digonnet 7.

Example 6 S O H H N-o-s oH c AoANa 'S- -"carboxymethyl N,N -'tetramethylene-dithiocarbamate (p'repared'according to Procedure No. 6 and also named l-pyrrolidine-carbodithioic acid, carboxymethyl ester) =Twas used in the process of the above examples to produce 'the productof theformula given above in 42% yield; Its decomposition point after recrystallization from water-acetone was 160 C.

Analysis.Calc.d for. C N NaN O S -3H O: C, 39.45; H, 4.68; N, 8.12. Found: C, 39.59; H, 4.45; N, 7.50." i v N methyl N benzyldithiocarbamylacetic acid (2.5 g'., 0.01 mole, prepared according to Procedure No. 4 and also'namedS carboxymethyl N methyl N- benzyldithiocarbarnate) was dissolved in 100 ml. tetrahy drofurantat 5 -C..and 1. g. .triethylamine was added. The solution was stirred for ten minutes in an ice-bath and 1.2 g. (0.01 mole) isovaleryl chloride (Eastman Kodak Co.) was added. A white precipitate formed immediately. An aqueous solution of 2.7 g. (0.01 mole) 7-aminocephalosporanic acid solubilized by the addition of triethylamine was added all at once to produce a clear solution which was stirred 15 minutes. The tetrahydrofuran was removed by evaporation, 50 ml. water Was added and the pH was lowered to 2 with dilute phosphoric acid to convert the product to the acid form which was then extracted into ethyl acetate. The sepa rated ethyl acetate was washed with water, dried over anhydrous MgSO and treated with sodium 2-ethylhexanoate to precipitate 560 mgm. of the product having the formula given above.

Analysis.-Calcd for C H NaN O S C, 47.45; H, 4.17; N, 7.90. Found: C, 47.93; H, 4.47; N, 7.82.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.125-1.0 mcg./ml. versus S. aureus Smith, of about 0.4 mcg./m1. versus the benzylpenicillin-resistant Staph. aureus BXl633-2, of about 0.4 mcg./ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, and of about 0.5 meg/ml. versus Str. pyogenes Digonnet 7.

aminocephalosporanic acid (6.82 g., 0.025 mole) were combined in 150 ml. water and adjusted to pH 7 with NaOH. The solution was cooled to 4% C. and 25 ml.

cold 1 N potassium iodide-iodine solution (i.e. prepared by'dissolving 166.01 g. potassium iodide and 253.81 g. iodine q.s. to one liter in water) was added. The pH was kept at about -7 by adding sodium hydroxide. Stirring was continued for about 20 minutes after the last addition of KII solution. The reaction mixture was then acidified with H PO and shaken with ethyl acetate; the whole mixture was filtered to remove unreacted 7- aminocephalosporanic acid so that the phases could be separated. The separated ethyl acetate phase containing the free acid form of the product was washed with water and the solvent was removed at 35 C. to precipitate 4.3 g. of crystalline product as the free acid. The material was partially dissolved in hot ethyl acetate, filtered and the diethyl ether was added. to the filtrate. Storing overnight in the cold precipitated crystals of the product (as the free "acid monohydrate) which were collected, .washedwith a little ether, dried at 56 C. in vacuo over P 0 425 mgm., M.P. 96 C. An analytical sample was recrystallized from acetone-water and dried in vacuo over P Analysis.-Ca1cd for c15H19N OqS /2H2OI C, H, 4.71; N, 9.82; S, 14.99. Found: C, 41.74; H, 4.95; N, 9.51; S, 15.57; H O, 2.42.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.5 mcg./ml. versus S. aureus Smith, of about 0.8 mcg./ml. versus the benzylpenicillin-resistant Staph. aureus BX-l633-2, of about 0.8 mcg./rnl. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.5 mcg./ml. versus D. pneumom'ae, of about 0.25 meg/ml. -versus Str. pyogenes Digonnet 7 and of about 3.1 mcg./ml. versus S. enteritidis.

Example 9a CHQCHQ O O CH CH;

7-arninocephalosporanic acid (80% pure, 1.36 g., 0.005 mole) and 3-carboxymethyl N,N-diethyl-dithiocarbamate (1.24 g., 0.006 mole, prepared by Procedure No. 1) were dissolved in 100 ml. 2 M pH 7 phosphate buffer maintained at pH 7 by the addition of sodium hydroxide. A 1 N solution of 1 in 1 N NaI (10 ml.) was added over a 20 minute period with both solutions held at 4 C. After adjusting the pH to 7 with 10% NaOH the solution was stirred for two hours at room temperature. The reaction mixture was filtered to remove a small amount of solid and the filtrate was extracted with ether. The aqueous phase was acidified with 40% H PO and the free acid form of the product was extracted into ethyl acetate. The ethyl acetate extract was washed with water and the solvent was removed to leave the product as an oil which was converted by use of sodium 2-ethylhexanoate to the monohydnate of the product of the formula given above. Recrystallization from acetone-dimethyltormamide gave 160 mgm., M.P. 152-155 C. with decomposition.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.25-0.31 meg/ml. versus S. aureus Smith, of about 0.8 mcg./ ml. versus the benzylpenicillin-resistant Staph. aareus BX-1633-2, of about 0.8 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.31-015 meg/ml. versus D. pneumonia and of about 0.16-0.25 meg/ml. versus Str. pyogenes Digonnet 7.

This product is exceptionally well absorbed upon oral administration.

Example 9b CHaCH: O H

N-ii-s-oHl-o-AOA-Na CHaCHg (from 7-aminocephalosporanic acid (8.7 g., 0.032 mole) and S-carboxymethyl N,N-diethyldithiocarbamate (7.25 g., 0.035 mole) were combined in 200 ml. pH 7 phosphate buffer (0.2 M), cooled to 8 and adjusted to pH 7 with NaOH; to this mixture there was added 98 ml. of 1 N Kl-I solution. The solution was stirred until the pH remained constant; some I was unreacted. The solution was acidified and extracted with ethyl acetate. The organic layer was washed with water and the solvent evaporated to leave the free acid form of the product as an oil. Acetone was added and then sodium 2-ethylhexanoate to precipitate 5.2 g. of the product of the formula given above.

This material was recrystallized successively from acetone-water and butanol-water twice, dried over P 0 and submitted for analysis.

CHaCHz S /N- SC H20 0 OH CHaCHg 22 Analysis.Calcd for C H NaN O OS -H O: C, 41.64; H, 4.93; N, 8.57. Found: C, 41.91; H, 5.21; N, 8.60; H O, 4.64.

Example CHaCHa CHQCHB 0 from To a cooled solution of N,N-diethylcarbamoylacetic acid (3.2 g., 0.0167 mole, prepared according to Procedure No. 7) and 1.77 g. (0.0175 mole) triethylamine in ml. tetrahydrofuran there was added 2.12 g. (0.0175 mole) isovaleryl chloride. Stirring was continued for 20 minutes. There was then added a cooled solution of 5 ml. triethylamine and 4.82 g. (0.0167 mole) 7- aminocephalosporanic acid in 50 ml. water and stirring was continued for 25 minutes. The solution was diluted with cold water, acidified with H PO and extracted with ethyl acetate. The ethyl acetate extract was washed two times with water, filtered and the solvent evaporated to leave the free acid of the product as an oil which was then dissolved in acetone to which was added a solution of sodium 2-ethylhexanoate in acetone. The product of the formula above precipitated in crystalline form and was collected and recrystallized from water-acetone to yield 2.5 g.

CHgCHz Example 10 7-aminocephalosporanic acid (6.44 g., 0.024 mole) and S-carboxyrnethyl N,N pentamethylenedithiocanbarnate (4.38 g., 0.02 mole, prepared according to Procedure No. 2 and also named 1-piperidine-carbodithioic acid, carboxymethyl ester) were almost completely dissolved in ml. pH 7 0.2 molar phosphate buffer at 0 C. There was then added over 20 minutes 62 ml. 1 N 1;; in 1 N K1 solution. The solution was stirred for an additional hour while warming toward room temperature. The solution was filtered. and extracted with ethyl acetate. The aqueous phase was separated, acidified with H PO and the product in its acid form was extracted into ethyl acetate. The ethyl acetate was separated and washed with water and the ethyl acetate was removed at 33 C. to leave the product as an oil which was diluted with acetone and filtered. The addition of sodium 2- ethylhexanoate precipitated the product as its sodium salt (having the formula given above) as fine crystals which became gummy when collected by filtration. The product was dried in vacuo overnight, found to weigh 3.7 g., recrystallized from aqueous n-butanol and again from a mixture of one part water and one part dioxane to which three parts of acetone were added.

Analysis.Ca-lcd for C H NaNgO s- C, 45.09; H, 4.63; N, 8.76. Found: C, 45.17; H, 4.94; N, 8.49.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.25 meg/ml. versus S. aareus Smith, of about 0.8 mcg./ml. versus the benzylpenicillin-resistant Staph. aureus BX-1 633-2, of about 0.8 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.25 meg/ml. versus D. pneumoniae and ofabout 0.25 meg/ml. versus Str. pyogenes Digonnet 7.

This product is exceptionally well absorbed upon oral administration.

7-aminocephalosporanic acid (6.82 g., 0.025 mole) and S-carboxymethyl N,N-tetramethylenedithiocarbamate (5.13 g., 0.025 mole prepared according to-Procedure No. 6 and also named l-pyrrolidinecarbodithioic acid, carboxymethyl ester) were dissolved in 100 ml. water by adjusting to pH 7 with NaOH; There was then added over 30 minutes 100 ml. of 1 N '1 in 1 N 'Kl solution while adjusting the pH to 7 after each addition. The solution was then stirred for one hour while adding NaOH to keep the pH at 7. It was then acidified with H 1 0, and the product in its acid'form was extracted into ethyl acetate, which was separated and washed with water. Evaporation of the solvent left the product as an oil which was dissolved in dioxane; addition thereto of sodium 2- ethylhexanoate in acetone precipitated the product as its sodium salt having the formula given above. The crystals were collected by filtration, washed with acetone, found to Weigh 4.3 g., recrystallized from butanol-water and then from Water-acetone and dried over P Analysis.-Calcd for C H NaN O S C, 43.86; H, 4.33; N, 9.03; S, 13.78; H O, none. Found: C, 43.74; H, 4.48; N, 8.93; S, 14.00; H O, none.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.25 meg/ml. versus S. aureus Smith, of about 0.8 meg/ml. versus the benzyl penicillin-resistant Staph. aureus BX-l633-2, of about 0.8 meg/ml. versus the benzylpenicillin resistant Staph. aztreus 52-75, of about 0.25 mcg./ml. D. pneumoniae and of about 0.25 meg/ml. versus Str. pyogenes Digonnet 7.

Example 12 7-aminocephalosporanic acid (5.84 g., 0.02 mole) and S carboxymethyl N methyl N phenyldithiocarbamate (4.82 g., 0.02 mole prepared according to Procedure No. 5) were combined in 225 ml. water and l N Kl-I solution was added while adjusting to pH 7 as needed with NaOH during the addition. The solution was filtered and acidified with H PO The product in its acid form was extracted into ethyl acetate which was separated, washed with water and evaporated to leave the product as an oil which was then taken up in acetone. The addition thereto of sodium 2-ethylhexanoate precipitated the product as its sodium salt having the formula given above, 2.5 g. The product was dissolved in water, filtered, decolorized with carbon, diluted with n-butanol and evaporated at 33 C. until an oil began to form. Diatomaceous earth (Celite) was added and the solution was filtered. The filtrate was evaporated until it became turbid; the addition of acetone then precipitated the product as fine crystals, 650 mgm. A portion was recrystallized from water-acetone and dried in vacuo over P 0 Analysis.-Calcd for C H NaN O S C, 47.90; H, 4.02; N, 8.38; S, 12.79. Found: C, 47.64; H, 4.25; N, 8.22; S, 12.65, 12.45.

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.25 meg/ml. versus S. aureus Smith, of about 0.4 meg/ml. versus the benzylpenicillin-resistant Staph. aureus BX-1633-2, of about 0.4 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.125 meg/ml. versus D. pneumoniae and of about 0.125 meg/ml. versus Str. pyogenes Digonnet 7.

4 '1 Example. 13

This product is prepared by using in the procedure of Examples 10, 11 or 12 the reagent s earboxyme'thyl 1-methylpiperazino-dithiocarbamate prepared according toProcedure No. 8. i

Example 7-aminocephalosporanic acid (6.82 g., 0.025 mole) and S-carboxymethyl morpholinodithiocarbamate (5.13 g., 0.023 mole prepared according to Procedure No. 3) were combined in ml. water adjusted to pH 7 with NaOH. The mixture was cooled in ice and 25 ml. of 1 N Kl-I solution was added while keeping the pH at about 7 with NaOH. After the addition'was complete the solution was stirred for 15 minutes and then acidified with H PO and extracted with ethyl acetate. The ethyl acetate was separated and washed with water; removal of the solvent by evaporation left the product in its acid form as an oil which was dissolved in acetone; the addition thereto of sodium 2-ethylhexanoate precipitated the product of the formula given above as 4.5 g. crystals which were recrystallized from water-acetone. V

This product exhibited Minimum Inhibitory Concentrations (M.I.C.s) of about 0.5 mcgJml. versus S. aureus Smith, of about 1.6 meg/ml. versus theben zylpenicillin-resistant Staph. aureus BX-1633-2, of about 1.6 meg/ml. versus the benzylpenicillin-resistant Staph. aureus 52-75, of about 0.5 meg/ml. versus D.- priedmoniae, of about 0.5 meg/ml. versus Str. pybgenes Digonnet 7 and of about 12.5 meg/ml. versus S. enteritidis.

This product is prepared by mixing 2 g. nicotinamide and 1 g. of the product of Example 9 in 10 mlfwater, saturating the solution with nitrogen and storing it at 56 C. for 19 hours.

Example 16 Replacement of the diethylamine in Procedure No. 1 with an equimolar 'weight of the amines having the formula used in the procedures of Examples 2 nd 9b, respectively, to produce the compounds of the formula respectively, wherein X is S when Example 245 followed and X is when Example 9b is followed and wherein R and R have the meanings tabulated below:

R R Ethyl Methyl n-Propyl do i-Propyl do n-Butyl do Sec.butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do 2-hexyl do 3-hexyl do Methyl Ethyl n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do Z-hexyl do 3-hexy1 do Methyl n-Propyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do Z-hexyl do S-hexyl do Methyl i-Propyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-arnyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do 2-hexyl do 3-hexyl do Methyl n-Butyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-arnyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do R R 2-hexyl do S-hexyl do Methyl iso-Butyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dirnethylbutyl do 2-hexyl do B-hexyl do Methyl sec.-Butyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Arnyl do Iso-amyl do n-HeXyl do Iso-hexyl do 3,3-dimethylbuty1 do Z-hexyl d0 3-hexy1 do Methyl n-Amyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbuty1 do 2-hexyl do 3-hexyl do Methyl Iso-amyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-butyl do Tert.-butyl do Iso-butyl do n-Amyl do Iso-amyl do n-Hexyl do Iso-hexyl do 3,3-dimethylbutyl do Z-hexyl do 3-hexy1 do Methyl n-Hexyl Ethyl do n-Propyl do i-Propyl do n-Butyl do Sec.-buty1 do Tert.-butyl do Iso-butyl do n-Amyl do 26 R R R R Iso-amyl do 3,3-dimethylbutyl do n-Hexyl do 2-heXy1 do Iso-hexyl d0 3-heXyl do 3,3-dirnethylbutyl do Methyl- 3,3-dimethylbutyl Z-hexyl do Ethyl do 3-hexyl do n-Propyl do Methyl Iso-hexyl i-Propyl do Ethyl do n-Butyl do n-Propyl do Sec.-butyl do i-Propyl d0 Tert.-butyl do n-Butyl do Iso-butyl do Sec.-butyl do n-Amyl do Tert.-butyl do Iso-amyl do Iso-butyl do n-Hexyl do n-Amyl do Iso-hexyl do Iso-arnyl do 3,3-dimethylbutyl do n-Hexyl do 2-hexy1 do Iso-hexyl do 3-hexyl do 3,3-dimethylbutyl do Methyl Tert.-buty1 2-hexyl d0 Ethyl do 3-hexyl do n-Propyl do Methyl 2-hexyl i-Propyl do Ethyl do n-Butyl do n-Propyl do Sec.-butyl do i-Propyl do Tert.-butyl do n-Butyl do Iso-butyl do Sec.-butyl do n-Arnyl do Tert.-butyl do Iso-amyl do Iso-butyl do n-Hexyl do n-Amyl d Iso-hexyl do Iso-amyl do 3,3-dimethylbutyl do n-Hexyl do Z-hexyl do Iso-hexyl do S-hexyl do 3,3-dimethylbutyl do Methyl Neo-pentyl 2-hexy1 do Ethyl do 3-hexyl do n-Propyl do Methyl 3-hexy1 i-Propyl do Ethyl do n-Butyl do n-Propyl do Sec.-butyl do i-Propyl do Tert.-butyl do n-Butyl do Iso-butyl do Sec.-butyl do n-Amyl do Tert.-butyl do Iso-arnyl do Iso-butyl do n-Hexyl do n-Arnyl do Iso-hexyl do Iso-amyl do 3,3-dimethylbutyl do n-Hexyl do 2-hexyl do Iso-hexyl do 3-hexyl do Example 17 Replacement of the l-methylpiperalzine in Procedure No. 8 with an equimolar weight of l-ethylpiperazine, l-n-propylpiperazine, l-isopropylpiperazine, 1 -n-butylpiperazine, l-sec.-butylpiperazine, l-tert.-butylpiperazine, l-isobutylpiperazine, l-n-amylpiperazine, l-isoamylpiperazine, l-n-hexylpiperazine,

1-(3',3'-dimethylbutyl) -piperazine,

1-(2'-heXyl)-piperazine,

1- (3 '-hexyl) -piperazine and l-neopentylpiperazine, respectively,

produces the corresponding S-carboxymethyl 1-(lower)- alkylpiperazinodithiocarbamates (also named as the corresponding l-(lower)alkyl-4-piperazine-carbodithioic acid carboxymethylesters) which are used to replace on an equimolar basis the S-carboxymethyl N,N-diethyldithiocarbamate used in the procedures of Examples 2 and 9b, respectivelyflo produce the compounds of the formula 7-aminocephalosporanic acid (2.7 g., 0.01 mole) and S-carboxymethyl N-methyl-N-benzyldithiocarbamate (2.5 g., 0.01 mole, M.P. 102103 C., prepared by Procedure No. 4) were combined in 80 ml. water and 25 ml. 1n 'I -Kl was added to the solution after the material had been dissolved by adjusting to pH7 with NaOH. While theI -Kl solution was being added the pH was maintained at '7 with 10% NaOH. When the addition was complete and the solution remained at constant pH, the solution was extracted with ethyl acetate and then the aqueous phase was acidified with H PO filtered and again extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over MgSO and to it was added a solution of sodium 2-ethylhexanoate in acetone to precipitate the product of the formula given above. After air drying this material weighed 175 mgm. and was recrystallized from water-n-butanol and dried in vacuo overnight at room temperature and then at 56 C. for two hours. On heating the sample darkened above 153 C. and decomposed at about 203-205 C.

While in the foregoing specification various embodiments of this invention have been set forth in specific detail and elaborated for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of the details can be varied widely without departing from the basic concept and the spirit and scope of the invention.

We claim:

- 1. A compound having the formula wherein X is oxygen or sulfur;

B represents di(lower)alkylamino wherein the alkyl group may be alike or different, piperidino, methylpiperidino, dimethylpiperidino, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, methylmorpholino, dimethylmorpholino, N'-(lower) albylpiperazino, N (lower)albyl methylpiperazino, N (lower)alkyl dimethylpiperazino, trimethyleneimino, hexamethyleneimino or a radical of the formula wherein n is zero, one, two or three, R- is (lower)alkyl and Ar is a radical of the formula R and R are each hydrogen, fiuoro, chloro, bromo,

(lower)alkyl or (lower) alkoxy;

'A is hydrogen, hydroxyl, (lower)alkanoylox'y, benzoyloxy, a quaternary ammonium radical of the formula wherein each of W and Z is hydrogen or methyl or, when taken together with M, a monovalent carbonoxygen bond; and

M is hydrogen, a pharmaceutically acceptable nontoxic cation, an anionic charge when A is a quaternary ammonium radical or, when taken together with A, a monovalent carbon-oxygen bond.

2. A compound of claim 1 having the formula wherein X is oxygen orsulfur, M is a pharmaceutically acceptable, nontoxic cation, n'is' zero, one two or three, R is (lower) alkyl and Ar is a radical of the formula l 1? B it in which R and R are each hydrogen, fluoro, chloro, bromo, (lower)a11cyl or (lower)alkoxy.

4. A compound of claim 1 having the formula X is oxygen or sulfur and M is a pharmaceutically acceptable, nontoxic cation. 5. A compound of claim 1 having the formula X is oxygen or sulfur,

n is one, two, three or four and M is a pharmaceut-ically acceptable, nontoxic cation. 6. A compound of claim 1 having the formula X is oxygen and sulfur and R and R each represent hydrogen or methyl. 7. A compound of claim 1 having the formula X is oxygen or sulfur, n is one, two, three or four and R and R represent hydrogen or methyl. 8. The acid of claim 1 having the formula and its nontoxic, pharmaceutically acceptable salts.

9. The acid of claim 1 having the formula lit and its nontoxic, pharmaceutically acceptable salts.

11. The acid of claim 1 having the formula 011, (I?

and its nontoxic, pharmaceutically acceptable salts.

12. The acid of claim 1 having the formula and its nontoxic, pharmaceutically acceptable salts.

13. The acid of claim 1 having the formula and its nontoxic, pharmaceutically acceptable salts.

14. The acid of claim 1 having the formula and its nontoxic, pharmaceutically acceptable salts.

15. The acid of claim 1 having the formula CH3 0=C--N 0H10-00H3 0 00011 and its nontoxic, pharmaceutically acceptable salts.

16. The acid of claim 1 having the formula and its nontoxic, pharmaceutically acceptable salts.

References Cited UNITED STATES PATENTS NICHOLAS S. RIZZO, Primary Examiner.

Claims (1)

1. A COMPOUND HAVING THE FORMULA