IE45985B1 - Cephalosporins - Google Patents

Description

The invention relates to novel 3,7-disubstituted cephalosporins, to processes for and intermediates in their preparation, and to therapeutic compositions containing them.

The novel cephalosporins of the invention are 7-acylamino-3-pyrazinylthiomethyl-3-cephem-4-carboxylic acids having the general formula I: R-CONH· S-RJ :oor2 wherein R represents an alkyl group having from 1 to 5 carbon atoms, a group R3—CH^— 1-( 1H)-tetrazolylmethyl or a group having the general formula II,'III, IV or V: II r3-y-(ch,) - ; r3-ch- ? hooc-ch-(ch2)3n I I NH- NHIII IV -245985 in which X is a chlorine or fluorine atom· r R3 is a thienyl, phenyl, 1,4-cyclohexadienyl, phenoxy or pyrazinyl group or a thienyl, phenyl, phenoxy or pyrazinyl group that is substituted by one or more chlorine or bromine atoms or hydroxy, lower alkyl or lower alkoxy groups; Y is an oxygen or sulphur atom; and n is an integer from 1 to 4; R1 represents a pyrazinyl group of the general formula VI, VII or VIII X.X· I VII XX VIII R6 different, is each a fluorine, chlorine, bromine or hydrogen atom or a lower alkyl, phenyl, cyano, thiocyano, carboxyl, carboxy-lower alkyl, carboxamido, thiocarboxamido, hydroxy,' lower alkoxy, mercapto, lower aIky1-thio, amino, lower alkyl-amino, or phenyl group; and R represents an alkali metal or hydrogen atom, an equivalent of an alkaline earth metal atom or a lower alkyl, benzyl, trichloroethyl, methoxybenzyl, -3459 8 5 benzhydryl, pivaloyloxymethyl, acylamidomethyl, acyloxymethyl, 5-oxo-tetrahydro-2-furyl or phthalidyl group.

In this Specification the terms lower alkyl 5 and lower alkoxy mean alkyl and alkoxy groups respectively containing up to 4 carbon atoms.

The new cephalosporin derivatives of the general formula I exhibit a broad spectrum antibacterial activity and are useful as therapeutic agents in the 10 treatment of infectious diseases caused by gram-negative and gram-positive bacteria. For such purpose, they may be administered either parentally or orally.

The invention accordingly provides a therapeutic composition comprising one or more compounds of the general formula I in admixture with a pharmacologically acceptable diluent or carrier.

Compounds of the formula I in which R is hydrogen may be prepared according to the invention by reacting various cephalosporins of the general formula IX COOH in which R is as defined above, with appropriate mercaptopyrazines R-'sH. The cephalosporins IX which may be used include cephalosporin C.

The cephalosporins IX can be obtained by the action of an appropriate acylating agent on 7-amino-cephalosporanic acid (7-ACA), o Alternatively, compounds of the formula I in which R is hydrogen can be prepared by treating a 3-thiolated 7-ACA of the formula X.

COOH in which R2 is as defined above with a suitable acylating agent, for example an acid chloride, acid anhydride, acid azide or activated ester.

The compounds X are novel compounds according to this invention and may be prepared by replacing the acetoxy group of a cephalosporin derivative with the appropriate pyrazinylthio group -SR1, for example by reacting 7-ACA or cephalosporin C with a suitable mercaptopyrazine, either in its free form or in the -5458 8 0 form of a metal salt. The reaction may be carried out in the presence of an inert solvent such as acetone, dioxan, methanol, ethanol or tetrahydrofuran, in a mixture of the above solvents, in an aqueous solution of the above mentioned solvents, in water or in a buffer solution, for example of borate or phosphate buffers, by following the general procedure (see: MURPHY C.F. and J.A. WEBBER : CEPHALOSPORINS and PENICILLINS, Chemistry and Biology E.H. FLYNN, Academic Press, New York, 1972 Chapter 4) illustrated in the Examples herein.

When cephalosporin C is used as starting material, the resulting 3-thiolated cephalosporin C may be hydrolyzed according to well known procedures (see: F.M. HUBER, R.R. CHAUVETTE and B.G. JACKSON, reference quoted above, Chapter 2) to give the desired 3-thiolated 7-ACA of the formula X . This hydrolysis, or amide cleavage, is preferably effected by the use of phosphorus pentachloride on a protected system such as silylated 3-thiolated cephalosporin C ester, followed by transformation of the initial imino chloride into the corresponding imino ether by reacting with an alcohol, to give after hydrolysis the expected 3-thiolated 7-ACA.

The alternative synthesis routes to the 3,7,-disubstituted cephalosporins I are summarized in the following synthesis diagram. -645985 -745985 The compounds I in which R is other than hydrogen 2 may be obtained from the above products in which R =H, by methods known per se.

The antibacterial activity of the 3,7-disubstituted 5 cephalosporin derivatives of the formula I was demonstrated by a series of comparative tests ’ carried out in vitro with the method of serial dilutions in Penassay Seed Broth Difco inoculated with 104 bacteria/ml (overnight cultures). Table 1 below gives the results of the above assays as MIC (minimal inhibitory concentration, mcg/ml).

In vivo tests for therapeutic activity were carried out on mice experimentally infected with Staphylococcus aureus and Salmonella abortivoequina (dose: 2LD^0/mouse i.p.).; groups of 6 male Swiss Cobs albino mice were used.

The infected animals were treated by the subcutaneous route 4 hours after infection. The mortality rate was recorded every day for 7 days. The activity was assessed as Εϋ^θ (Dose, in mg/kg, effective in curing 50% of the infected mice as reported by Reed and Muench, Am. J. Hyg. 27, 493, 1938). The results are reported in Table 2 below. 1 In Tables 1 and 2 the compounds tested are identified with reference to the Examples in the Specification in which their preparation is first described. Comparative results are shown for the known compounds cefazolin and cephalotin. -845935 a > 4J oil in in in • cm ο O m cm · in o m 04 o · rd\0AinArdO4COrd I Φ 0 > •H +J nJ Λ C nJ -d cole in in in m o O 04 CM o • o rd in CM m o o m in • • in 04 in • O • • CM H in A CM 10 10 Λ rd Λ CO 04 rd rd Ή Λ nJ Μ •rd £ Ο ΙΛ Λ Ο Ο · CM rd OminmOcMO · · m CM Λ Λ in Η rd 10 fO Table 1 - MIC pg/ml rd in in in in 4-1 • o • • 04 • CM o in CM 04 • U1J rd in A rd rd V0 O οϊ rd in in 0-0·· in CO ·—ί rd rd Mi m •rd r—J o wl in i in in o-HinmcMiooiin rd Ο Ο Η Ή rd Ο rd m CM rd in rd CM CO 10 co Ο Ο O in in in in 04 ID in ID in in 04 CM 04 04 J ID rd O m in CM O 04 in rd ID rd rd rd 9, in in in 04 in in 0) in in CM in rd 04 CM CM in rd CM 04 tnl rd rd ID rd CO rd rd rd CM o rd rd w . 3 Φ 04 Ol CM CO ID m m O' E· rd rd <0 ID CM rd o n 04 o co ffl o o o o rd o o o o o O o rd rd 03| o o o o o o o o o o O o O o 0 ιϋ Λ J3 nJ Λ 0 0 c CM CM 04 rd in M· 10 10 CO σ •rd 3 JJ •rd C Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ 0 rd 3 rd rd rd rd rd rd rd rd rd rd rd 0 0 CU Ii a Οι a (1, 0« Ql Qi 04 0. 04 frt N CU ε fc ε ε ε ε 6 ε ε P Λ nJ ε ΐΰ φ ra nJ <ΰ nJ nJ nJ ro a 4d 0 X X Μ X X X x X X X X Φ Φ 2J Μ Η W JiL JiL JL JiL JiL JiL JiL JiL u 0 -94598 5 TABLE 2 Therapeutic activity on mice (S, aureus) ED5Q (mg/Kg) Compound?D50 mg/Kg Example 2c 50 Example 2a 17.5 Example 2b 35 Example 1 17.5 Example 5 40 Example 4b 20 Example 4a 20 Example 6b 40 Example 6c 40 Example 9 15 cefazolin 30 cephalotin 30 From the Tables it will be seen that all the compounds I show a broad spectrum antibacterial activity. The compounds of Examples 2c,2a,2b,4b,4a,6b,6c,4c,9 appear to be of particular interest because of the 20 excellent antistaphylococcal activity, clearly superior to that of cefazolin and cephalotin.

The in vitro biological properties of the new compounds were verified by successful therapy of experimental mouse infections. In fact the compounds -1045885 of Examples 2a, 1, 4b, 4a, 9 proved to be more effective than cefazolin and cephalotin on the experimental staphylococcal infection.

The new compounds are generally less active on gram-negative bacteria. However the compounds of Examples 4a, 4c, 9 demonstrated a therapeutic activity similar to that of cephalotin on Salmonella abortivoequina experimental infection of mice. In particular, the therapeutic activity of the compound of Example 9 on mice experimentally infected with !3. abortivoequina (ED50 mg/kg) was found to be 50. In comparison, the activity of cephalotin was found to be 50 and that of cephazolin was found to be 25. This suggests a different pharmacokinetics or a greater bioavailability of the new compound.

The following Examples illustrate the invention. Because of the insolubility of the free acids, NMR spectra were in the Examples obtained from the methyl esters.

Example 1 7-phenylacetamido-3-(6-carboxamidopyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid (Compound I: R=benzyl; R1 has the formula VI in which R4<=R5=H and R6=aminocarbonyl; R2=H) A solution of 3 g of 7-phenylacetamidocephalosporanic acid, 1.3 g of 2-mercapto-6-carboxamidopyrazine and 1.36 g -1110 of sodium bicarbonate in a mixture of 45 ml of water;acetone (2:1) was stirred for 3 hours at 65-7O°C. The acetone was removed under reduced pressure and the aqueous solution was adjusted to pH 2.0 with 2N HC1 under cooling at 0-5°C. The resulting crude precipitate was collected by filtration, washed with water and crystallized from aqueous acetone to give yellowish crystals (2.6 g, 70% yield) m.p. 142°C.

IR (KBr) 1775, 1705, 1690, 1655 cm-1 NMR of methyl ester (CDCl^/DMSO-dg 5/2): 3.80 δ {s, C00CH3), 3.33 δ (s, C(2)H2), 3.61 δ (s, CgH5-CH2-CO), 4.41 δ (dd, CH2-S), 4.93 δ (d, C(6)H), .66 δ (d, C (7)H) , 7.02 δ (s, CgHg), 8.56 and 8.88 δ (two s, pyrazine protons).

Example 2 In the same manner as in Example 1, by using 7-phenylacetamidocephalosporanic acid as starting material and the appropriate mercaptopyrazines for the nucleophilic displacement of the acetoxy grouping, the following products were obtained: -1245985 a) 7-phenylacetamido-3-pyrazin-2-yIthiomethyl-3-cephem-4-carboxylic acid (Compound I: R=benzyl; R1 has the formula VI in which R4=R5=R6=H; R2=H) 68% yield, m.p. 2O8°C.

IR (KBr): 1775, 1710, 1660 cm1 NMR of methyl ester (CDCl^/DMSO-dg 3.51 δ (s, C(2)H2), 3.60 δ (s, C6H5-CH2-), 3.86 δ (s, C00CH3), 4.28 δ (dd, CH2-S), 4.73 δ (d, C(6)H), .71 δ (d, C(7)H) , 7.25 δ (s, CgH5), 8.0-8.6 δ (m, pyrazine protons). /1) : b) 7-phenylacetamldo-3-(6-chloropyrazin-2-yIthiomethyl)-3-cephem-4-carboxylic acid (Compound I: R=benzyl; R1 has the formula VI in which R4=R^=H and R®=C1; R2=H) 58% yield, m.p. 210°C (ethyl acetate) IR (KBr): 1775, 1710, 1665 cm1 NMR of methyl ester. (CDCl^): 3.43 δ (s, C(2)H2), 3.83 δ (s, C00CH3 and CgHg-CI^-), 4.23 δ (dd, CH2-S), 4.88 δ (d, C(6)H), .73 δ (dd, C(7)H), 7.23 δ (s, CgH5), 8.15 and 8.24 δ (two s, pyrazine protons). -1385 c) 7-phenylacetamido-3-(pyrazin-2-ylthiomethyl-4-oxide)-3-cephem-4-carboxylic acid (Compound I: R=benzyl; R1 has the formula VIII in which R4=R5=R6=H; R2=H) 52% yield, m.p. 215°C.

IR (KBr): 1770, 1715, 1665, 1260 cm1 NMR of methyl ester (CDCl^/DMSO-dg 1/1): 3.44 δ (s, C'(:2)H2), 3.73 δ (s, cooch3), 3.83 δ (S, CgH5-CH2) 4.51 δ (dd, CH2-S), 4.91 δ (d, C(6)H), 5.88 δ (dd, C(7)H), 7.16 δ (s, CfiH_), 7.8-8.3 δ (m, pyrazine protons).

Example 3 Starting from 7-phenoxyacetamidocephalosporanic acid and the appropriate mercaptopyrazines, by using the procedure described in Example 1, the following products were obtained: a) 7-phenoxyacetamido-3-pyrazin-2-ylthiomethyl-3-cephem-4-carboxylic acid (Compound I: R=benzyloxy; R1 has the formula VI in which R4=R3=R®=H; R2=H). (52% yield), m.p. 19O°C.

IR (KBr): 1785, 1710, 1675 cm1. 144 S 9 8 5 b) 7-phenoxyacetamido-3-(6-carboxamidopyrazin-2-ylthiomethyl)-3-cephem-4-carboxyllc acid (Compound I: R=phenoxymethyl R1 has the formula VI in which R4=R^=h and R®=aminocarbonyl; R2=H). (60% yield), m.p. 140°C.

IR (KBr): 1780, 1710-1650 (acid and amides) cm-1. c) 7-phenoxyacetamido-3-(pyrazin-2-ylthiomethyl-4-oxide)-3-cephem-4-carboxylic acid (Compound I: U=phcnoxyinetby1 R1 has the formula VIII in which R4=R5=R6=H; R2=H) . (49% yield), m.p. 132°C.

Example 4 Operating as described in Example 1 and using 7-(2-thienyl)-acetamido-cephalosporanic acid as staring material for the nucleophilic replacement of the acetoxy group with a suitable mercaptopyrazine, the following compounds were prepared: a) 7-(2-thienyl)-acetamido-S-pyrazin-S-ylthiomethyl·^-cephem-4-carboxylic acid (Compound I: R=2-thienylmethyl; R1 has the formula VI in which R4=R5=R6=H; R2=H). 78% yield, m.p. 204°C(aqueous methanol). analysis: calculated for ClgH16N4O4S3: C=48.19; H=3.59; S=21.44 found: C=48.38; H=3.65; 3=21.06 IR(KBr): 1770, 1705, 1655 cm1 NMR of methyl ester (CDCl^): 3.57 δ (dd, C(2)H2), -154 5 9 8 S 3.73 δ (s, 2-thienyl-CH^.-), 3.82 δ (s, C00CH3), 4.27 δ (dd, CH2-S), 4.97 δ (d, C(6)H), .26 δ (dd, C(7)H), 6.8-7.0 and 7.1-7.3 δ (mf thiophen protons), 8.0-8.4 δ (m, pyrazine protons). b) 7-(2-thienyl)-acetamido-3-(6-carboxamidopyrazln-2-ylthiomethyl)-3-cephem-4-carboxylic acid (Compound I: ~ 4 5 R=2-thienylmethyl; R has the formula VI in which R =R =H 2 and R =aminocarbonyl; R =H). 76% yield, m.p. 150°C (methylene dichloride-methanol) analysis: calculated for : C=46.42; H=3.48; S=19.56 found: C=45.89; H=3.75j S=19.46 IR (KBr): 1770, 1705, 1695, 1655 cm1. c) 7-(2-thienyl)-acetamido-3-(3-methoxy-pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid (Compound I: 4 R=2-thienylmethyl; R has the formula VI in which R =-OCH2 and R5=R5=H; R2=H) 69% yield, m.p. 2O5°C (ethanol) analysis: calculated for ει9Η18Ν4θ5θ3·· C=47.7O; H=3.79; N=11.71 found: C=47.28; H=3.91; N=ll.lO IR (KBr): 1770, 1715, 1660 cm-1 -1645985 NMR of methyl ester (CDC13): 3.50 δ (dd, C(2)H2), 3.80 δ (s, thienyl-CH^-), 3.87 δ and 3.97 δ (two s, COOCHj and 0CH3,, 4.73 δ (dd, CH2-S), 4.85 δ (d, C(6)H), 5.73 δ (dd, C(7)H), 6.8-7.3 6 (m, thiophen protons), 7.6-7.9 δ (two s, pyrazine protons).

Example 5 7-pyrazin-3-yithioacetamido-cephalosporanic acid (Compound IX R=pyrazin-2-ylthiomethyl, To a solution of 7 g of sodium 7-chloroacetamido-cephalosporanate in 20 ml of water, a solution of 2.7 g of 2-mercaptopyrazine in aqueous sodium bicarbonate was added at 0.5°C by adjusting the pH to 7 with saturated sodium bicarbonate. After stirring for 3 hours at room temperature, the cooled solution was acidified to pH 2 and the resulting precipitate (8.3 g) was filtered and crystallized from ethanol to give 7.8 g (74% yield) of 7-pyrazin-2-yltbioacetamido-cephalosporanic acid, m.p. 145°C.

IR (KBr): 1780, 1740, 1715, 1670, 1650 cm1 NMR of methyl ester (CDClj): 2.10 δ (s, CH3-CO-), 3.34 δ (dd, C(2)H), 3.78 0 (s, COOCH3 and -S-CHj-CO-), -174S9 8 5 4.80 δ (d, C(6)H), 4.89 δ (dd, CH2-OCOC(H3)), .80 δ (dd, C(7)H), 8.1-8.6 δ (m, pyrazine protons).

The same product was also obtained starting from both 7-bromoacetamido-cephalosporanic acid and 7-iodoacetamido-cephalosporanic acid.

Example 6 By using 7-pyI’azin_2-ylthioacetamido-cephalosporaiiic acid and the appropriate mercaptopyrazines the following products were prepared by following the procedure described in Example 1: a) 7-pyrazin-2-ylthioacetamido-3-pyrazin-2-ylthioniethyl-3-ceFbstn -4-carboxyllc acid (Compound I: R=pyrazin-2-ylthiomethyl; R·*· has the formula VI in which R4=R^=R^=H; R2=H) . (65% yield) m.p. 175°C. b) 7-pyrazln-2-ylfchioacetamido-3-(6-chloropyrazin-2-ylthiomethyl) -3-cephem-4-carboxyllc acid (Compound I: R=pyrazin-2-ylthiomethyl; R^ has the formula VI In-which R4=R5=H and R6=C1; R2=H) 72% yield, m.p. 165°C (aqueous acetone).

IR (KBr): 1810, 1715, 1690 cm-1 NMR of methyl ester (CDClj-DMSO-dg : 1/1): 3.59 δ (dd, C(2)H2), 3.84 δ (s, COOCH3), 3.93 δ (s, S-CH2-CO), 4.27 δ (dd, CH2-S), 4.99 6 (d, C(6)H), -1845985 .68 δ (dd, C(7)H), 8.1-8.5 δ (m, 5 pyrazine protons). c) 7-pyrazin-2-ylthioacetamido-3-(pyrazin-2-ylthlomethyl-4-oxide)-3-cephem-4-carboxylic acid (Compound I: R=pyrazin5 -2-yIthiomethyl; R1 has the formula VIII in which R4=R5=R6=H; R2=H). 70% yield, m.p. 175°C. analysis: calculated for ci8H16N6°5S3: c=43·89’ «=3.27; S=19.52 found: C=43.89; H=3.73; S=18.3 IR (KBr): 1775, 1705, 1670-1660 (amides), 1265 cm-1.

Example 7 7-amlno-3-pyrazin-2-ylthiomethyl-3-cephem-4-carboxylic acid.

(Compound X; R1 =pyrazin-2-yl).

To a suspension of 8.16 g of 7-aminocephalosporanic acid and 4.03 g of 2-mercaptopyrazine in a 120 ml mixture of water-acetone (2:1), 5.54 g of sodium bicarbonate was added and the resultant solution was heated to 65-70°C for 2 hours.

The pH was maintained between 7-7.5 by occasional additions of NaHCO^ or HC1. The solvent was removed in vacuo and the solution was acidified to pH 3.5 with 4N HC1 under cooling. The resulting precipitate was collected by filtration and washed, several times, with methanol. The crude material G.6 g) was suspended in water, dissolved with 6N HCl and decolourized with -1945 charcoal, under cooling.

After filtering, the acidic solution was cooled and adjusted to pH 3.5 with 5N NaOH. The precipitate and was filtered£ washed several times with water and acetone.

The.product (3.35 g) was used without further purification.

IR (KBr) : 1800, (β lactam C=0), 1540 (carboxylate C=0) cm NMR (D2O+DC1): 3.82 δ (dd, C(2)H2), 4.53 δ (dd, CH2-S) 8.4-9.1 δ (m, pyrazine protons) Example 8 7-/1- (IH) -tetrazolylacetamido/—3-pyrazin-2-yl thiomethyl-315 -cephem-4-carboxylic acid (Compound I: R=l-(IH)-tetrazolylmethyl; R1 has the formula VI in which R4=R^=R^=H; R2=H).

To a solution of 0.65 g of 1-(IH)-tetrazolylacetic acid and 0.7 ml of triethylamine in 25 ml of anhydrous acetone, 0.6 ml of pivaloylchloride in acetone was added at 0°C. The reaction mixture was then stirred for 30 minutes. After filtering off the triethylamine hydrochloride) the filtrate was added dropwise, over a period of 30 minutes, to a solution of 1.08 g of 7_amino-3-pyrazin-2-ylthiomethyl-3-oephem-4-carboxylic acid, and 0.37 ml of triethylamine in 35 ml of a mixture -20of water-acetone (2:1) at 5°C. The reaction mixture was stirred for 1 hour at the same temperature and for 2 additional hours at room temperature. The solvent was removed under reduced pressure and the aqueous solution was acidified to pH 1.5 with 5% HC1 and extracted.with ethyl acetate. The organic layer (dried) was evaporated in vacuo and the residue was washed with diethyl ether and crystallized from aqueous acetone to give 7-^1-(1H)-tetrazolylacetamido/-3-pyrazin-2-ylthiomethyl-3-cephem--4-carboxylic acid (0.9g, 69% yield) as pale white crystals, m.p. 200°C. analysis: calculated for ci5Hx4N8°4S2: C=41.47; H=3.28; N=25.79 found: 0=41.16; H=3.48; N=24.5O NMR of methyl ester (CDClg/DMSO-dg : 1/1): 3.57 δ (dd, C(2)H2), 3.84 δ (s, COOCH3), 4,30 δ (dd, CH2-S), 4.97 δ (d, C(6)H) , .28 δ (s, N-CH2C0), .66 δ (dd, C(7)H), 8.05-8.60 δ (m, pyrazine protons), 9.03 δ (s, tetrazole protons).

IR (KBr): 1770, 1705, 1680 cm-1 -214S985 Example 9 7-(2-thienylacetamido)-3-(6-methoxypyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid (Compound I: R=2-thienylmethyl; 4 5 6* R has the formula VI in which R =R =H and R =methoxyj r2=h).

Operating as described in Example 8, the above compound was obtained, m.p. 195°C, Yield 81-83%.

Analysis: calculated for C19H18N4°5S3: C=47.7O; H=3.79; N=11.70 found: C=47.79; H=3.95; N=11.50 IR (KBr): 1775 -1 cm -1 Y C=0 β-lactam 1710 cm Y C=0 acid 1660 -1 cm Y c=o amide NMR(DMSO-d,); 0 3.39 δ (dd, C(2)H2) , 3.75 6 (s, CH2~C0), 3.93 δ (s, CH3O), 4.40 δ (broad s, CH2S), 4.95 δ (d, C(6)H), .46 δ (dd, C(7)H), 6.90 δ (m, 2 thiophen protons), 7.26 δ (m, 1 thiophen proton), 7.90 and 8.10 δ (two s, 2 pyrazine protons) and 8,97 δ (d, CONH).

Example 10 7-(2-thienyl)-acetamido-3- (3-amino-6-methoxypyrazin-2-ylthiomethyl)-3-cephem-4-carboxylic acid. (Compound I: 4 R=2-thienylmethyl; R has the formula VI in which R = -2245985 fi 2 amino, R =H and R =methoxy; R =H).

Operating as described in Example 8, the above compound was obtained, m.p. 19O°C. IR (KBr): 1765 cm-1 γ C=0 g-lactam 5 1665 cm-1 γ C=0 acid 1605 cm-1 γ C=0 acid salt NMR(DMSO-dg): 3.36 6 (dd, C(2)H^), 3.75 δ (broad s, CH2CO and OCH3) 4.33 δ (broad s,CH2S), 10 4.93 δ (d, C(6)H), 5.50 δ (m, C(7)H), 6.85 δ (m, 2 thiophen protons); 7.30 δ (m, 1 thiophen proton and proton) and 15 8.97 δ (d, CONH).

Claims (24)

1. A 3,7-disubstituted cephalosporin of the general formula I herein.

2. 7-Phenylacetamido-3-(6-carboxamidopyrazin-2-ylthiomethyl)3- cephem-4-carboxylic acid.

3. 7-Phenyl.acetaroido-3-pyrazinylthiomethyl-3-cephem-

4. Carboxylic acid. A. 7-Phenylacetamido-3-(6-chloropyrazin-2-ylthiomethyl)-3cephem-4-carboxylic acid.

5. 7-Phenylacetamido-3-(pyrazin-2-ylthiomethyl-4-oxide)-3cephem-4-carboxylic acid.

6. 7-Phenoxyacetamido-3“Pyi’azin-2-ylthiomethyl-3-cephem-4carboxylic acid.

7. 7-Phenoxyacetamido-3-(6-carboxamidopyrazin-2-ylthiomethyl) -3-cephem-4-carboxylic acid.

8. 7-Phenoxyacetamido_3-(pyrazin-2-ylthiomethyl-A-oxide) -3-cephem-4-carboxylic acid.

9. 7-(2-Thienyl)-acetamido-3-pyrazin-2-ylthiomethyl-3-cephem4- carboxylic acid.

10. 7-(2-Thienyl)-acetamido-3-(6-carboxamidopyrazin-2-ylthiomethyl) -3-cephem-A-carboxylic acid.

11. 7-(2-Thienyl)-acetamido-3-(3- me 'fchoxypyrazin-2-Ylt.hiomethyl)3-cephem-A-carboxylic acid.

12. 7-Pyrazin-2-yIthioacetamido-3-pyrazin-2-ylthiomethyl-3cephem-4-carboxylic acid.

13. · 7-Pyrazin-2-ylthioacetamido-3-(S-chloropyrazin-2-ylthiomethyl) -3-cephem-4-carboxylic acid. 1 A. 7-Pyrazin-2-ylthioacetamido-3-(pyrazin-2-ylthiomethyl-4oxide)-3-cephem-4-carboxylic acid. -2445985

14. 15. 7-/1-(1H)-tetrazolylacetamido/-3-(pyrazin-2-ylthiomethyl)3-cephem-4-carboxylic acid.

15. 1 6. 7-(2-Thienyl)-acetamido-3-( 6-methoxypyrazin-2-ylthiomethyl) -3-cephem-4-carboxylic acid.

16. 17 . 7-( 2-Thienyl)-aretainido-3-( 3-amino-6-methoxy-pyrazin-2ylthiomethyI)-3-cephem-4-carboxylic acid.

17. 18. A process for preparing a compound according to claim 1, which comprises reacting a cephalosporin of the general formula IX herein with a mercaptopyrazdne of the general formula R^SH.

18. 19. A pi'ocess according to claim 18, wherein the cephalosporin IX is cephalosporin C and the product is hydrolyzed with phosphorus pentachloride to a give a product of the general formula X herein which is acylated at the 7-position to give the desired compound I.

19. 20. A process for preparing a compound according to claim 1, in which 7-aminocephalosporanic acid is reacted with a mercaptopyrazine of the gerneral formula R^SH to give a compound of the general formula X herein which is then acylated at the 7-position to give the deeired compound I.

20. 21. A process for preparing a compound according to claim 1, which comprises reacting 7-aminocephalosporanic acid with an acylating agent to give a compound of the general formula IX herein which is then treated with a mercaptopyrazine of the general formula R^SH to give the desired compound I,

21. 22. A process according to any of claims 18 to 21, which comprises forming a salt or ester of the product so as to produce another desired compound of the general formula I in which R is other than a hydrogen atom.

22. 23. A process for preparing a compound according to claim 1, substantially as disclosed in any of Examples 1 to 4, 6 and 8 to 10 herein. -254598 3

23.

24. A therapeutic composition comprising one or more compounds of the general formula I herein in admixture with a pharmacologically acceptable diluent or carrier.