7-Thioacetamido cephalosporanic acid derivatives

Abstract

The compounds of the following formula are antibacterial agents: ##SPC1##In whichR is --H, --CN, carbo(lower)alkoxy, phenyl, halophenyl, nitrophenyl, carboxy,--C.tbd.CH, or --CH=CH.sub.2 ;R.sup.2 is --H, lower alkanoyloxy or, when M is --H, N-pyridinium;M is --H, an alkali metal, an alkaline earth metal or the ammonium ion;AndA is =NCN, =NSO.sub.2 CH.sub.3, =CHNO.sub.2 or ##EQU1## wherein X is --CN, --CONH.sub.2, phenyl or --SO.sub.2 CH.sub.3.

Description

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of antibacterial compounds of the formula: ##SPC2##

In which

R is --H, CN, carbo(lower)alkoxy, phenyl, halophenyl, nitrophenyl, carboxy, --C CH, --CH=CH.sub.2 ;

R.sup.2 is --H, lower alkanoyloxy or, when M is --H, N-pyridinium;

M is --H, an alkali metal, an alkaline earth metal or the amonium ion;

And

A is =NCN, =NSO.sub.2 CH.sub.3, = CHNO.sub.2 or ##EQU2## wherein X is --CN, --CONH.sub.2, phenyl or --SO.sub.2 CH.sub.3.

The carbo(lower)alkoxy group represented by R may contain from 1 to 6 carbon atoms in the alkoxy moiety. The lower alkanoxyloxy groups represented by R.sup.2 may be acetoxy, propionyloxy, butanoyloxy or amyloxy, the acetoxy group being preferred.

The compounds of this invention are useful for the treatment of bacterial infections amenable to treatment by cephalosporins. They effectively inhibit the growth of gram-positive, gram-negative and penicillin resistant bacterial strains as are more specifically detailed in the examples. The activity of the compounds of this invention was established in accordance with the well known, scientifically recognized agar serial dilution test procedure whereby the minimum inhibitory concentration of a specific antibacterial agent required to completely inhibit the growth of a given bacterium is established. In accordance with the results obtained with the antibacterial compounds of this invention, their usefulness is established in the fields of comparative pharmacology and microbiology for the purpose of inhibiting the growth of undesirable bacterial colonies.

The compounds of this invention are prepared by reacting a compound of the formula: ##EQU3## in which A and R are defined above and M is an alkali metal, especially sodium or potassium, with 7-bromoacetamido cephalosporanic acid. The product is readily converted to an alkali metal, alkaline earth metal or ammonium salt by treatment with the corresponding base under mild conditions. Sodium or potassium 2-ethylhexanoate provide a convenient reagent for neutralization to the alkali metal salts of the cephalosporanic acids of this invention.

The reactants: ##EQU4## as defined above, are generally known in the chemical literature. The specific reactants employed in the production of the compounds of this invention are produced by the methods used for the production of the known compounds. Exemplary of the literature references, exclusive of those specifically cited in the following examples, are:

Jensen et al., Acta. Chem. Scand.,22,1107(1968)

Davis et al., J. Chem. Soc. (C)124(1967)

Yokoyama, Bull. Chem. Soc. Japan, 43,2938(1970)

Freund, Ber. 52,542(1919)

Matthews et al. J. Org. Chem. 25,266(1960)

and

Brownstein, J. Org. Chem. 23,113(1958).

The nmr spectra described in the following examples pertains to the spectra obtained upon exchanging acidic hydrogens with deuterium and are described in ppm (.delta.). The small amount of water and/or solvent carried into the products is readily removed by gently heating the material under vacuum. The biological activity data presented after each example illustrates the activity of the product against specific bacterium of the designated strain in terms of the minimum inhibitory concentration in micrograms per milliliter needed to completely inhibit growth of the test organism. The abbreviations used are:

Ba su -- bacillus subtilis St AU -- Staphylococcus aureus Ne ca -- neisseria catarrhalis Es co -- escherichia coli Sa pa -- salmonella paratyphi Kl pn -- klebsiella pneumoniae Bo br -- bordetella brochiseptica Pr vu -- proteus vulgaris He sp -- herellea species En se -- enterobacter aerogenes Ps ae -- pseudomones aeruginosa Es in -- escherichia intermedia

EXAMPLE 1

7-(2[2,2-Dicyano-1-(ethoxycarbonylmethylthio)ethenylthio]acetamido)cephalosporanic acid

Suspend malononitrile (6.6 g, 0.1 moles) and powdered potassium hydroxide (13.2 g, 0.2 moles, 85% pure) in 100 ml of dry dioxane. The mixture is cooled to 10.degree.C and a solution of carbon disulfide (7.6 g, 6 ml, 0.1 moles) in 10 ml of dioxane is added. The mixture is stirred for 1 hour. A yellow precipitate collects on the walls which is dislodged upon addition of 75 ml of water. The solution thus obtained is cooled to 5.degree.C and ethyl bromoacetate (16.7 g, 11.02 ml, 0.1 moles) is added. After stirring for one hour the solution is acidified with 6 ml of concentrated hydrochloric acid, and is flash concentrated to 10 ml at 20.degree.C. The residue is extracted with ethyl acetate and saturated sodium chloride. The organic phase is dried, flash concentrated and added to 800 ml of diethyl ether-dichloromethane (1:1 ratio). The yellow product obtained is [(2,2-dicyano- 1-mercaptovinyl)thio] acetic acid ethyl ester, sodium salt, 4.4 g (17.5% yield), mp. 230.degree.-232.degree.C. nmr (DMSO-D.sub.6) 1.20 (t, 3), 4.10 (q, 2), 4.13 (s, 2)

Elemental Analysis for C.sub.8 H.sub.7 N.sub.2 NaO.sub.2 S.sub.2 : Calc'd: C, 38.39; H, 2.82; N, 11.20. Found : C, 38.14; H, 2.89; N, 11.08.

To a solution of [(2,2-dicyano-1-mercaptovinyl)thio] acetic acid ethyl ester sodium salt (1.0 g, 0.04 moles) and 7-bromoacetamidocephalosporanic acid (1.57 g, 0.04 moles) in 150 ml of acetone is added 200 mg of potassium iodide and the mixture is stirred at room temperature for 18 hours, filtered and the filtrate flash evaporated. The residue is dissolved in a mixture of water and ethyl acetate. The organic phase is dried, flash concentrated to 10 ml and added to pentane. The precipitated solid (1.75 g, 77% yield) is filtered and dried to yield the title compound, nmr (DMSO-D.sub.6) 1.25 (t, 3), 2.02 (s, 3), 3.58 (broad s, 2), 3.97-4.42 (superimposed q, 2 at 4.15, s, 2, at 4.19 and s, 2 at 4.29), 4.90 (q, 2), 5.16 (d, 1), 5.70 (d, 1).

Elemental Analysis for C.sub.20 H.sub.20 N.sub.4 O.sub.8 S.sub.3.1.5 H.sub.2 O: Calc'd: C, 42,32; H, 4.08; N, 9.87. Found: C, 41.96; H, 3.64; N, 9.65.

______________________________________Bacterium Strain Minimum Inhibitory Concentration micrograms per millititer______________________________________BA SU 6633 .244ST AU 6538P .976" Smith .976" CHP 7.81" 53-180 3.90NE CA 8193 125ES CO 9637 250SA PA 11737 125KL PN 10031 250BO BR 4617 250PR VU 6896 125______________________________________

EXAMPLE 2

7-(2-[2,2-Dicyano-1-(cyanomethylthio)ethenylthio]acetamido)cephalosporanic acid

Following the procedure presented in the first paragraph of Example 1, 2-(cyanomethylthio)-2-mercapto-1,1-vinyldicarbonitrile potassium salt is prepared in 71.4% yield from di(potassium mercapto)methylene malononitrile, m.p. 300.degree.C. (decomp.), nmr (DMSO-D.sub.6) 3.33(s).

Elemental Analysis for C.sub.6 H.sub.2 KN.sub.3 S.sub.2.H.sub.2 O: Calc'd: C, 30.36; H, 1.70; N, 17.70. Found : C, 30.77; H, 1.66; N, 17.79.

The following the procedure disclosed in the second paragraph of Example 1, the title compound is prepared in 32 percent yield from 2-(cyanomethylthio)-2-mercapto-1,1-vinyldicarbonitrile potassium salt prepared in the preceding paragraph, nmr (DMSO-D.sub.6) 2.10 (s, 3), 3.68 (broad s, 2), 4.33 (s, 2), 4.54 (s, 2), 4.96 (q 2), 5.32 (d, 1), 5.80 (d, 1).

Elemental Analysis for C.sub.18 H.sub.15 N.sub.5 S.sub.3 O.sub.6.2H.sub.2 0.1/2CH.sub.3 CO.sub.2 CH.sub.2 CH.sub.3 : Calc'd: C, 41.31; H, 3.84; N, 12.70. Found : C, 41.34; H, 3.15; N, 12.39.

The potassium salt of the title compound is prepared by reaction of the free acid with an equimolar amount of potassium 2-ethyl hexanoate in ethyl acetate. The potassium salt of 7-(2[2,2-dicyano-1-(cyanomethylthio)vinylthio]acetamido)cephalosporanic acid is recovered by diluting the ethyl acetate solution with diethyl ether, filtering and washing the product with diethyl ether.

Elemental Analysis for C.sub.18 H.sub.14 KN.sub.5 O.sub.6 S.sub.3.2H.sub.2 O: Calc'd: C, 38.08; H, 3.20; N, 12.34. Found : C, 38.33; H, 2.82; N, 11.53.

______________________________________BA SA 6633 .061ST AU 6538P .488" Smith .488" CHP 1.95" 53-180 1.95NE CA 8193 15.6SA PA 11737 15.6ES CO 9637 31.3KL PN 10031 15.6BO BR 4617 62.5PR VU 6896 31.3HE SP 9955 250ES CO 920 250______________________________________

EXAMPLE 3

7-(2-[2-Carbamoyl-1-(methoxycarbonylmethylthio)-2-cyanoethenylthio]acetamido) cephalosporanic acid

A solution of [(2-carbamoyl-2-cyano-1-mercaptovinyl)thio]acetic acid methyl ester (produced by the method of Gompper et al., Ber. 95,2861(1962) (246 mg, 1 mmole), diisopropylethylamine (129 mg, 1 mmole) and 7-bromoacetamido cephalosporanic acid (393 mg, 1 mmole) in 10 ml of acetone is stirred at room temperature for 17 hours. The solution is flash evaporated, the residue is dissolved in 15 ml of water covered with 50 ml of ethyl acetate, and acidified with 6N hydrochloric acid to pH 1.5. The organic phase is separated, dried, flash concentrated to 5 ml and added to pentane. The precipitated solid (150 mg, 27% yield) is filitered and dried, nmr (DMSO-D.sub.6) 1.07 (s, 3), 3.64 (broad s, 2), 3.70 (s, 3), 4.01 (s, 2), 4.14 (s, 2), 4.93 (q, 2 ) 5.20 (d, 1), 5.86 (d, 1).

Elemental Analysis for C.sub.19 H.sub.20 N.sub.4 O.sub.9 S.sub.3.H.sub.2 O: Calc'd: C, 40.56; H, 3.94; N, 9.96. Found : C, 40.35; H, 3.86; N, 9.78.

______________________________________BA SU 6633 .122ST AU 6538P .488" Smith .488" CHP 3.90" 53-180 1.95NE CA 8193 7.81ES CO 9637 62.5SA PA 11737 31.3KL PN 10031 125PR VU 6896 62.5______________________________________

EXAMPLE 4

7-(2-[2-Carbamoyl-2-cyano-1-(ethoxycarbonylmethylthio)ethenylthio)]acetamido)cephalosporanic acid

The title compound is prepared under the conditions described in Example 3 using [(2-carbamoyl-2 2-cyano-1-mercaptovinyl)thio]acetic acid ethyl ester; [prepared by the method of Yokoyama, Bull. Chem. Soc. Japan, 44,1610 (1971)] and replacing the acetone for acetonitrile as solvent. The product is obtained in 56% yield, nmr (DMSO-D.sub.6) 1.28 (t, 3), 2.05 (s, 3), 3.60 (broad s, 2), 3.97 (s, 2), 4.26 (q, 2), 4.92 (q, 2), 5.19 (d, 1), 5.77 (d, 1).

Elemental Analysis for C.sub.20 H.sub.22 N.sub.4 O.sub.9 S.sub.3.1/2H.sub.2 O: Calc'd: C, 42.32; H, 4.09; N, 9.87. Found : C, 42.59; H, 4.03; N, 9.25.

______________________________________BA SU 6633 .061ST AU 6538P .488" Smith .488" CHP 3.90" 53-180 1.95NE CA 8193 3.90ES CO 9637 250SA PA 11737 62.5KL PN 10031 125PR VU 6896 125______________________________________

EXAMPLE 5

7-[2-[cyanoimino)(methylthio)methylthio]acetamido]cephalosporanic acid

The title compound is prepared in 45% yield by the same procedure and in the same molar amounts as described in Example 1 from potassium methyl cyanodithioimidocarbonate prepared by the method of Timmons et al. J. Org. Chem. 32,1566(1967), nmr (DMSO-D.sub.6) 2.04 (s, 3), 2.72 (s, 3), 3.58 (broad s, 2) 4.17 (s, 2), 4.86 (q, 2) 5.15 (d, 1), 5.73 (d, 1).

Elemental Analysis for C.sub.15 H.sub.16 N.sub.4 O.sub.6 S.sub.3 : Calc'd: C, 40.53; H, 3.63; N, 12.60. Found : C, 40.40; H, 3.79; N, 12.09.

______________________________________BA SU 6633 .976ST AU 6538P 1.95" Smith .976" CHP 7.81" 9637 125" 53-180 3.90NE CA 8193 250SA PA 11737 31.3KL PN 10031 125BO BR 4617 125PR VU 6896 62.5ES CO 920 250______________________________________

EXAMPLE 6

7-[2-(1-Cyanomethylthio-2-nitroethenylthio)acetamido]cephalosporanic acid

To a solution of nitro-dithioacetic acid dipotassium salt [prepared by the method of Freund, Ber., 52,542(1919)] (4.26 g, 0.02 moles) in 50 ml of acetone and 30 ml of water is added a solution of chloroacetonitrile (1.64 g. 0.02 moles) in 5 ml of acetone. The solution is stirred at room temperature for one hour and is then flash evaporated to dryness. The obtained residue is stirred with 100 ml of acetone and filtered. The filtrate is concentrated to 25 ml and the product (2.65 g, 62% yield) is crystallized upon addition of diethyl ether to yield (1-mercapto-2-nitrovinylthio)acetonitrile potassium salt, mp. 151.degree.-153.degree.C., nmr (DMSO-D.sub.6), 4.20 (s, 2), 7.57 (s, 1). Elemental Analysis for C.sub.4 H.sub.3 KN.sub.2 O.sub.2 S.sub.2 : Calc'd: C, 22.42; H, 1.41; N, 13.07. Found : C, 23.25; H, 1.66; N, 12.99.

The title compound is prepared in 60% yield by the same procedure and in the same molar amounts as described in Example 1 from (1-mercapto-2-nitrovinylthio)acetonitrile potassium salt, nmr (DMSO-D.sub.6) 1.07 (s, 3), 1.61 (broad s, 2), 4.23 (s, 2), 4.43 (s, 2), 4.92 (q, 2), 5.17 (d, 1), 5.80 (d, 1).

Elemental Analysis for C.sub.16 H.sub.16 N.sub.4 O.sub.8 S.sub.3.H.sub.2 O.

Calc'd: C, 37.94; H, 3.58; N, 11.07. Found : C, 37.97; H, 3.36; N, 10.73.

To a solution of the product of the preceding paragraph (867 mg, 1.71 mmoles) in 25 ml of ethylacetate, a solution of potassium 2-ethylhexanoate (2M, 0.857 ml, 1.71 mmoles) is added under vigorous stirring. The mixture is diluted with diethyl ether, filtered, washed repeatedly with diethyl ether and dried, the product is obtained in 87% yield.

Elemental Analysis for C.sub.16 H.sub.15 KN.sub.4 O.sub.8 S.sub.3.H.sub.2 O: Calc'd: C, 35.28; H, 3.15; N, 10.29. Found : C, 35.42; H, 2.96; N, 9.55.

______________________________________BA SU 6633 .122ST AU 653P .976" Smith .976" CH 3.90" 53-180 3.90NE CA 8193 62.5PS AE 10145 250EX CO 9637 62.5ES IN 65-1 250SA PA 11737 7.81KL PN 10031 62.5BO BR 4617 125PR VU 6896 31.3HE SP 9955 125ES CO 920 125______________________________________

EXAMPLE 7

7-[2-[(cyanoimino) (cyanomethylthio)methylthio]acetamido]cephalosporanic acid

The title compound is prepared in 64% yield by the same procedure and in the same molar amounts as described in Example 1 from potassium cyanomethyl cyanoimidodithiocarbonate (produced by the method of Timmons, U.S. Pat. No. 3,658,901) nmr (DMSO-D.sub.6) 2.05 (s, 3), 3.60 (broad s, 2), 4.38 (s, 2), 4.52 (s, 2),4.91 (q, 2), 5.19 (d, 1) 4.78 (d, 1).

Elemental Analysis for C.sub.16 H.sub.15 N.sub.5 O.sub.6 S.sub.3.H.sub.2 O: Calc'd : C, 39.41; H, 3.52; N, 14.37. Found : C, 39.43; H, 3.30; N, 12.55.

The potassium salt of the title compound is prepared in 69% yield by the same procedure as described in Example 6 from the product of Example 7.

Elemental Analysis for C.sub.16 H.sub.14 KN.sub.5 O.sub.6 S.sub.3.2H.sub.2 O: Calc'd : C, 35.35; H, 3.34; N, 12.88. Found : C, 35.01; H, 2.84; N, 11.68.

______________________________________BA SU 6633 .061ST AU 6538P .488" Smith .488" CHP 195" 53-180 .976NE CA 8193 31.3ES CO 9637 31.3ES IN 65-1 62.5EN AE 13048 7.81BO BR 4617 15.6PR VU 6896 31.3HE SP 9955 31.3______________________________________

EXAMPLE 8

7-(2-[2-Cyano-1-(cyanomethylthio)-2-phenylethenylthio]acetamido)cephalosporanic acid

To a solution of cyanophenyldithioacetic acid disodium salt (prepared by the method of Davis et. al., J. Chem. Soc. (C) 124(1967) in aqueous acetone is added an equimolar amount of chloroacetonitrile in acetone. The solution is stirred at room temperature for one hour and taken to dryness. The residue is stirred with 100 ml. of acetone and filtered. The filtrate is concentrated to 25 ml. and the product is crystallized upon addition of diethyl ether. Recrystallization from dichloromethane gives (2-cyano-1-mercapto-2-phenylvinylthio)acetonitrile sodium salt m.p. 205.degree.-207.degree.C., the nmr spectrum indicates the product is a mixture of cis and trans isomers, nmr (DMSO-D.sub.6) 4.40 (s), 4.48 (s), 7.1-7.6 (m), 8.0-8.4 (m).

Elemental Analysis for C.sub.11 H.sub.7 N.sub.2 NaS.sub.2 : Calc'd: C, 51.95; H, 2.77; N, 11.02. Found : C, 51.65; H, 2.85; N, 10.84.

The title compound is prepared in 77% yield, by the same procedure and in the same molar amounts as described in Example 1, from the compound produced in the preceding paragraph. The nmr spectrum indicated that the product consists of an approximately equal mixture of cis and trans isomers, 2.03 (s, 3), 3.59 (broad s, 2), 3.80 and 3.97 (two s, total area 2), 4.10 and 4.25 (two s, total area 2), 4.90 (q, 2) 5.15 (d, 1), 5.73 (d, 1) 7.53 and 7.58 (two s, total area 5).

Elemental Analysis for C.sub.23 H.sub.20 N.sub.4 O.sub.6 S.sub.3.1/2H.sub.2 O: Calc'd : C, 48.98; H, 3.82; N, 10.12. Found : C, 49.79; H, 3.68; N, 10.00.

The potassium salt of the title compound is prepared in 79% yield by the same procedure as described in Example 1.

Elemental Analysis for C.sub.23 H.sub.19 KN.sub.4 O.sub.6 S.sub.3.H.sub.2 O. Calc'd : C, 45.98; H, 3.52; N, 9.32. Found : C, 45.95; H, 3.17; N, 9.16.

______________________________________BA SU 6633 .031ST AU 6538P .244" Smith .244" CHP .976" 53-180 .976NR CA 8193 3.90SA PA 11737 62.5KL PN 10031 62.5BO BR 4617 250PR VU 6896 250ES CO 920 250ES CO 9637 25______________________________________

EXAMPLE 9

7-[2-(1-Benzylthio-2-nitroethenylthio)acetamido]cephalosporanic acid

Following the procedure presented in the first paragraph of Example 6, 1-(benzylthio)-2-nitroethenethiol potassium salt is prepared in 47% yield from nitro-dithioacetic acid dipotassium salt and benzyl bromide, m.p. 196.degree.-198.degree.C., (decomp.), nmr (DMSO-D.sub.6) 4.40 (s, 2), 7.30 (s, 5), 7.54 (s, 1)

Elemental Analysis for C.sub.9 H.sub.8 NS.sub.2 O.sub.2 K.1/2H.sub.2 O: Calc'd : C, 39.39; H, 3.31; N, 5.38; S, 23.37. Found : C, 39.65; H, 2.98; N, 5.11; S, 22.96.

The title compound as a mixture of cis and trans isomers is prepared in 50% yield by the same procedure and in the same molar amounts as described in Example 1 from 1-(benzylthio)-2-nitroethenethiol potassium salt, nmr (DMSO-D.sub.6) 2.04 (s, 3), 3.58 (broad s, 2) 4.03 and 4.11 (two s, 2), 4.42 and 4.50 (two s, 2) 4.89 (q, 2), 5.1 (two d, 1), 5.7 (m, 1), 7.42 (s, 5), 7.50 (s, 1).

Elemental Analysis for C.sub.21 H.sub.21 N.sub. 3 O.sub.8 S.sub.2.1/2H.sub.2 O: Calc'd : C, 45.97; H, 4.04; N, 7.55. Found : C, 46.26; H, 4.25; N, 7.66.

______________________________________BA SU 6633 .031ST AU 6538P .122" Smith .122" CHP .488" 53-180 .488NE CA 8193 7.81SA PA 11737 62.5KL PN 10031 125BO BR 4617 250PR VU 6896 125ES CO 9637 250______________________________________

EXAMPLE 10

7-[2-[ (cyanoimino) (phenylmethylthio)methylthio]acetamido]cephalosporanic acid

The title compound is prepared in 53% yield by the same procedure and in the same molar amounts as described in Example 1 from potassium benzyl cyanoimidodithiocarbonate (produced by the method of Timmons, U.S. Pat. No. 3,658,901), nmr (DMSO-D.sub.6) 2.05 (s, 3), 3.6 (broad s, 2), 4.20 (s, 2), 4.62 (s, 2), 4.9 (q, 2), 5.13 (d, 1), 5.64 (d, 1) 7.40 (s, 5).

Elemental Analysis for C.sub.21 H.sub.20 N.sub.4 S.sub.3 O.sub.6.2 1/2H.sub.2 O: Calc'd: C, 44.59; H, 4.46; N, 9.90. Found : C, 44.08; H, 3.80; N, 9.70.

The potassium salt of the title compound is prepared in quantitative yield by the same procedure as described in Example 6 from the product of Example 10.

Elemental Analysis for C.sub.21 H.sub.19 KN.sub.4 O.sub.6 S.sub.3.2H.sub.2 O: Calc'd C, 42.40; H, 3.90; N, 9.42. Found : C, 42.22; H, 3.94; N, 8.85.

______________________________________ES CO 9637 15.6NE CA 8193 62.5SA PA 11737 3.90KL PN 10031 15.6BO BR 4617 15.6PR VU 6896 15.6ES CO 920 62.5BA SU 6633 .122ST AU 6538P .976ST AU Smith .976ST AU CHP 3.90ST AU 53-180 1.95______________________________________

EXAMPLE 11

7-[2-(2-Cyano-1-cyanomethylthio-2-methylsulfonylethenylthio)acetamido]cephalosporanic acid

Following the procedure presented in the first paragraph of Example 1, 3,3-dimercapto-2-methylsulfonyl-2-propenenitrile dipotassium salt is prepared, m.p. 270.degree.-271.degree.C., (decomp.) nmr (DMSO-D.sub.6) 3.30 (s, 3).

Elemental Analysis for C.sub.4 H.sub.3 K.sub.2 NO.sub.2 S.sub.3 : Calc'd: C, 17.69; H, 1.11; N, 5.16; Found : C, 18.08; H, 1.28; N, 5.26;

Following the procedure presented in the latter part of the first paragraph of Example 1, 3-cyanomethylthio-3-mercapto-2-methylsulfonyl-2-propanenitrile potassium salt is prepared. Following the procedure disclosed in the second paragraph of Example 1 the title compound is prepared in 20% yield from 3-cyanomethylthio-3-mercapto-2-methylsulfonyl-2-propenenitrile potassium salt nmr (DMSO-D.sub.6) 2.05 (s, 3), 3.30 (s, 3), 3.65 (broad s, 2) 4.1-4.2 (m, 4), 4.95 (q, 2) 5.33 (d 1), 5.8 (m, 1).

Elemental Analysis for C.sub.16 H.sub.17 KN.sub.4 O.sub.8 S.sub.4.H.sub.2 O: Calc'd : C, 33.20; H, 3.08; N, 9.68. Found: C, 33.47; H, 3.31; N, 9.19.

______________________________________BA SU 6633 15.6ST AU 6538P 250ST AU Smith 250______________________________________

EXAMPLE 12

7-[2-[(cyanoimino)(2-ethoxy-2-oxoethylthio)methylthio]acetamido]cephalosporanic acid

The title compound is prepared in 54% yield by the same procedure and in the same molar amounts as described in Example 1 from potassium ethoxycarbonylmethyl cyanoimidodithiocarbonate (produced by the method of Timmons, U.S. Pat. No. 3,658,901), nmr (DMSO-D.sub.6) 1.28 (t, 3), 2.08 (s, 3) 3.65 (broad s, 2), 4.15 (q, 2) 4.27 (broad s, 4), 4.95 (q, 2), 5.15 (d, 1), 5.7 (m, 1).

Elemental Analysis for C.sub.18 H.sub.20 N.sub.4 S.sub.3 O.sub.8 : Calc'd: C, 41.85; H, 3.90; N, 10.85. Found : C, 41.08; H, 4.19; N, 10.87.

The potassium salt of the title compound is prepared in 61% yield by the same procedure as described in Example 6 from the product of Example 12

Elemental Analysis for C.sub.18 H.sub.19 N.sub.4 S.sub.3 O.sub.8 K.1/2H.sub.2 O: Calc'd: C, 38.35; 3.58; 9.94. Found : C, 38.38; 3.26; 9.62.

______________________________________BA SU 6633 .122ST AU 6538P .976ST AU Smith .488ST AU CHP 3.90ST AU 53-180 1.95NE CA 8193 62.5ES CO 9637 250SA PA 11737 31.3KL PN 10031 31.3BO BR 4617 250PR VU 6896 62.5ES CO 920 250______________________________________

EXAMPLE 13

7-[2-[(cyanoimino)(4-nitrophenylmethylthio)methylthio]acetamido]cephalosporanic acid

The title compound is prepared is 35% yield by the same procedure and in the same molar amounts as described in Example 1 from potassium p-nitrobenzyl cyanoimidodithiocarbonate (produced by the method of Timmons, U.S. Pat. No. 3,658,901), nmr (DMSO-D.sub.6) 2.07 (s, 3), 3.5 (broad m, 2), 4.21 (s, 2), 4.72 (s, 2) 15.01 (q, 2), 5.13 (d, 1), 5.7 (m, 1), 7.95 (q, 4)

Elemental Analysis for C.sub.21 H.sub.19 N.sub.5 S.sub.3 O.sub.8 : Calc'd: C, 44.95; H, 3.39; N, 12.38. Found : C, 44.92; H, 3.68; N, 11.63.

The potassium salt of the title compound is prepared in 95% yield by the same procedure as described in Example 6 from the product of Example 13.

Elemental Analysis for C.sub.21 H.sub.18 N.sub.5 S.sub.3 KO.sub.8.1/2H.sub.2 O: Calc'd: C, 41.15; H, 3.00; N, 11.43. Found : C, 41.18; H, 3.49; N, 11.10.

______________________________________BA SU 6633 .488ST AU 6538P 1.95ST AU Smith 1.95ST AU CHP 3.90SU AU 53-180 3.90NE CA 8193 62.5ES CO 9637 250SA PA 11737 62.5KL PN 10031 250BO BR 4617 125PR VU 6896 62.5______________________________________

EXAMPLE 14

7-[2-[(cyanomethylthio)(methylsulfonylimino)methylthio]acetamido)cephalosporanic acid

Following the procedure presented in the first paragraph of Example 6, methylsulfonylcarbonimidodithioic acid cyanomethyl ester potassium salt is prepared from (methylsulfonyl) carbonimidodithioic acid dipotassium salt. nmr (DMSO-D.sub.6) 3.08 (s, 3), 3.90 (s, 2).

Elemental Analysis for C.sub.4 H.sub.5 KN.sub.2 O.sub.2 S.sub.3 : Calc'd: C, 19.34; H, 2.02; N, 11.28. Found : C, 20.22; H, 2.03; N, 10.95.

The title compound is prepared in 48% yield, by the same procedure and in the same molar amounts as described in Example 1 from the product of the preceding paragraph, nmr (DMSO-D.sub.6) 2.03 (s, 3), 3.22 (s, 3), 3.59 (s, 2), 4.20 (s, 2), 4.40 (s, 2), 4.89 (q, 2), 5.13 (d, 1), 5.76 (d, 1).

Elemental Analysis for C.sub.16 H.sub.18 N.sub.4 O.sub.8 S.sub.4 : Calc'd: C, 36.77; H, 3.47; N, 10.72. Found : C, 36.77; H, 3.23; N, 10.15.

The potassium salt of the title compound is prepared in 85% yield by the same procedure as described in Example 6 from the product of Example 14

Elemental Analysis for C.sub.16 H.sub.17 KN.sub.4 O.sub.8 S.sub.4.H.sub.2 O: Calc'd: C, 33.20; H, 3.08; N, 9.68. Found : C, 33.47; H, 3.31; N, 9.19.

______________________________________BA SU 6633 .244ST AU 6538P 1.95ST AU Smith 1.95ST AU CHP 7.81ST AU 53-180 7.81NE CA 8193 125PS AE 10145 125ES CO 9637 125SA PA 11737 15.6DL PN 10031 31.3BO BR 4617 62.5PR VU 6896 31.3HE SP 9955 250ES CO 920 125______________________________________

EXAMPLE 15

7-[2-[(cyanoimino)(2-hydroxy-2-oxoethylthio)methylthio]acetamido]cephalosporanic acid

Following the procedure presented in the first paragraph of Example 6, cyanocarbonimidodithioic acid carboxymethyl ester dipotassium salt, potassium bromide is prepared in 98% yield from cyanoimidodithiocarbonate dipotassium salt.

Elemental Analysis for C.sub.4 H.sub.2 K.sub.2 N.sub.2 O.sub.2 S.sub.2. KBr : Calc'd: C, 12.93; H, 0.54; N, 7.54. Found : C, 12.67; H, 0.48; N, 7.13.

The title compound is prepared in 25% yield by the same procedure and in the same molar amounts as described in Example 1 from cyanocarbonimidodithioic acid carboxymethyl ester dipotassium salt, potassium bromide, nmr (DMSO-D.sub.6) 2.05 (s, 3), 3.52 (broad s, 2), 4.2 (m, 4), 4.9 (q, 2), 5.2 (d, 1), 5.7 (d, 1).

Elemental Analysis for C.sub.16 H.sub.16 N.sub.4 O.sub.8 S.sub.3.H.sub.2 O: Calc'd : C, 37.93; H, 3.58; N, 11.06. Found : C, 38.40; H, 3.80; N, 10.82.

______________________________________BA SU 6633 1.95ST AU 6538P 15.6ST AU Smith 7.81ST AU CHP 62.5SA PA 11737 125KL PN 10031 250PR VU 6896 125______________________________________

EXAMPLE 16

7-[2-[(3-chlorophenylmethylthio) (cyanoimino)methylthio]acetamido]cephalosporanic acid

Following the procedure presented in the first paragraph of Example 6, cyanocarbonimidodithioic acid 3-chlorobenzyl ester potassium salt is prepared in 92% yield from cyanoimidodithiocarbonate dipotassium salt, nmr (DMSO-D.sub.6) 4.20 (s,2), 7.2-7.5 (m, 4).

Elemental Analysis for C.sub.9 H.sub.6 ClK N.sub.2 S.sub.2.H.sub.2 O : Calc'd : C, 37.29; H, 2.43; N, 9.67. Found : C, 37.15; H, 2.16; N, 9.90.

The title compound is prepared in 59% yield by the same procedure and in the molar amounts as described in Example 1 from cyanoimidodithioic acid 3-chlorobenzyl ester potassium salt, nmr (DMSO-D.sub.6) 2.02 (s, 3), 3.56 (broad s, 2) 4.18 (s, 2), 4.58 (s, 2), 4.86 (q, 2), 5.08 (d,1), 5.67 (d, 1), 7.5 (m, 4).

Elemental Analysis for C.sub.21 H.sub.19 ClN.sub.4 S.sub.3 O.sub.6.2H.sub.2 O : Calc'd: C, 42.67; H, 3.92; N, 9.48. Found : C, 42.89; H, 3.45; N, 9.76.

The potassium salt of the title compound is prepared in 91% yield by the same procedure as described in Example 6 from the product of Example 16.

Elemental Analysis for C.sub.21 H.sub.18 ClKN.sub.4 O.sub.6 S.sub.3.1/2H.sub.2 O : Calc'd: C, 41.88; H, 3.18; N, 9.30. Found : C, 41.60; H, 3.23; N, 9.03.

______________________________________BA SU 6633 .122ST AU 6538P .976ST AU Smith 1.95ST AU CHP 1.95ST AU 53-180 3.90NE CA 8193 125ES CO 9637 250SA PA 11737 31.3KL PN 10031 125BO BR 4617 250PR VU 6896 125ES CO 920 250______________________________________

EXAMPLE 17

7-[2-[(cyanoimino) (2-propynylthio)methylthio]acetamido]cephalosporanic acid

Following the procedure presented in the first paragraph of Example 6, cyanocarbonimidodithioic acid 2-propynyl ester, potassium salt is prepared in 35% yield from cyanoimidodithiocarbonate dipotassium salt and propargyl chloride.

Elemental Analysis for C.sub.5 H.sub.3 KN.sub.2 S.sub.2.3/4H.sub.2 O : Calc'd: C, 28.89; H, 2.18; N, 13.48. Found : C, 28.64; H, 1.63; N, 13.60.

The title compound is prepared in 50% yield by the same procedure and in the same molar amounts as described in Example 1 from cyanocarbonimidodithioic acid 2-propynyl ester, potassium salt, nmr (DMSO-D.sub.6) 2.05 (s,3), 3.3 (m, 1), 3.6 (broad s, 2), 4.2 (broad s, 4), 4.85 (q, 2) 5.11 (d, 1), 5.7 (m, 1).

Elemental Analysis for C.sub.17 H.sub.16 N.sub.4 O.sub.6 S.sub.3.2H.sub.2 O : Calc'd: C, 40.47; H, 4.00; N, 11.10. Found : C, 40.55, H; 3.45; N, 10.91.

The potassium salt of the title compound is prepared 95% yield by the same procedure as described in Example 6 from the product of Example 17.

Elemental Analysis for C.sub.17 H.sub.15 KN.sub.4 O.sub.6 S.sub.3.2H.sub.2 O : Calc'd: C, 37.62; H, 3.53; N, 10.33. Found : C, 37.56; H, 3.02; N, 10.02.

______________________________________BA SU 6633 .122ST AU 6538P .488ST AU Smith .488ST AU CHP 3.90ST AU 53-180 3.90NE CA 8193 125ES CO 9637 31.3SA PA 11737 7.81KL PN 10031 7.81PR VU 6896 62.5ES CO 920 62.5______________________________________

EXAMPLE 18

7-[2-[(4-Chlorophenylmethylthio) (cyanoimino)methylthio]acetamido]cephalosporanic acid

Following the procedure presented in the first paragraph of Example 6, cyanocarbonimidodithioic acid 4-chlorobenzyl ester, potassium salt is prepared in 95% yield from cyanoimidodithiocarbonate dipotassium salt and nmr (DMSO-D.sub.6) 4.18 (s, 2) 7.36 (m, 4).

Elemental Analysis for C.sub.9 H.sub.6 ClKN.sub.2 S.sub.2.1/2H.sub.2 O Calc'd: C, 37.29; H, 2.43; N, 9.67. Found : C, 37.54; H, 2.31; N, 9.67.

The title compound is prepared in 52% yield by the same procedure and in the same molar amounts as described in Example 1, from cyanocarbonimidodithioic acid 4-chlorobenzylester, potassium salt, nmr (DMSO-D.sub.6) 2.04 (s, 3) 3.6 (broad s, 2), 4.19 (s, 2), 4.59 (s, 2), 4.87 (q, 2), 5.13 (d, 1), 5.70 (d, 1), 7.46 (s, 4).

Elemental Analysis for C.sub.21 H.sub.19 ClN.sub.4 O.sub.6 S.sub.3.H.sub.2 O : Calc'd : C, 44.01; H, 3.69; N, 9.78. Found : C, 44.17; H, 3.48; N, 9.78.

______________________________________BA SU 6633 .488ST AU 6538P 1.95ST AU Smith 1.95ST AU CHP 7.81ST AU 53-180 3.90NE CA 8193 250ES CO 9637 250SA PA 11737 31.3KL PN 10031 125BO BR 4617 125PR VU 6896 62.5ES CO 920 250______________________________________

EXAMPLE 19

7-[2-[(cyanoimino)(2-propenylthio)methylthio]acetamido]cephalosporanic acid

The title compound is prepared in 74% yield by the same procedure and in the same molar amounts as described in Example 1 from potassium allyl cyanoimidodithiocarbonate (produced by the method of Timmons, U.S. Pat. No. 3,658,901), nmr (DMSO-D.sub.6) 2.02 (s, 3), 3.57 (broad s, 2), 3.98 (d, 2) 4.17 (s, 2), 4.9 (q, 2), 5-6 (m, 4).

Elemental Analysis for C.sub.17 H.sub.18 N.sub.4 O.sub.6 S.sub.3.1/2H.sub.2 O : Calc'd: C, 42.58; H, 3.99; N, 11.67. Found : C, 42.73; H, 3.97; N, 11.67.

The potassium salt of the title compound is prepared in quantitative yield by the same procedure as described in Example 6 from the product of Example 19.

Elemental Analysis for C.sub.17 H.sub.17 KN.sub.4 O.sub.6 S.sub.3.H.sub.2 O : Calc'd: C, 38.76; H, 3.64; N, 10.64. Found : C, 38.47; H, 3.27; N, 10.74.

______________________________________BA SU 6633 .488ST AU 6538P 1.95ST AU Smith 1.95ST AU CHP 7.81ST AU 53-180 3.90NE CA 8193 250ES CO 9637 250SA PA 11737 31.3KL PN 10031 125BO BR 4617 125PR VU 6896 31.3ES CO 920 250______________________________________

Claims

1. A compound which is 7-[2-[(cyanomethylthio)-(methylsulfonylimino)methylthio]acetamido]cephalosporanic acid or an alkali metal, alkaline earth metal or ammonium salt thereof.