NOVEL CEPHALOSPORIN COMPOUNDS AND PROCESSES FOR PREPARATION THEREOF

Abstract: The present invention provides a cephalosporin compound represented by formulas (I-S) and (I-R), wherein R<1> is a C1-4 alkyl, C3-4 alkenyl, C3-4 cycloalkyl, amino optionally substituted with a C1-4 alkyl radical, phenyl, or 2-, 4- or 6- substituted phenyl group with two or fewer substituents chosen from C1-4 alkyl, C1-3 alkoxy, halogen and hydroxy radicals; R<2> is hydrogen or a C1-4 alkyl group; R<a> and R<b>, which should be different from each other, are hydrogen or a C1-4 alkyl group; and Q is N or CH, and the pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, which possess potent and broad antibacterial activities. The invention also provides processes for preparing these compounds and to pharmaceutical compositions containing them as active ingredients.

Description: NOVEL CEPHALOSPORIN COMPOUNDS AND PROCESSES FOR PREPARATION THEREOF Field of the Invention The present invention relates to novel cephaiosporin compounds, pharmaceutically acceptable non-tox1c salts thereof, and physiologically hydrolyzable esters, hydrates and solvates thereof, which possess potent and broad antibacterial activities. The invention also relates to processes for preparing these compounds and to pharmaceutical compositions containing them as active ingredients. Description of the Prior Art Antibiotics of cephaiosporin series are widely used in therapy for treatment of diseases which are caused by general pathogenic bacteria 1n human beings and animals. It has been known that such antibiotics are useful for the treatment of diseases caused by bacteria exhibiting resistance to other antibiotics, e.g., penicillin-resistant bacteria, and for treatment of penicillin-sensitive patients. In most circumstances, it 1s desirable to employ antibiotics possessed with broad antibacterial activities, e.g., against both Gram-positive and Gram-negative bacteria. In this regard, there were many studies made in developing a variety of cephaiosporin antibiotics with such broad-spectrum antibiotic activities. For example, GB Patent No. 1 ,399,086 disclosed 7/3 - acylamido-ceph-3-em-4-carboxyl 1c acids having the formula of: wherein: R is hydrogen or an organic group; R d 1s an etherifylng monovalent organic group linked to the oxygen atom through a carbon atom; B is S or S → 0; and P is an organic group. Stimulated by the discovery of these compounds, there followed many attempts to develop antibiotic compounds having Improved properties with respect to certain microorganisms, especi¬ ally to Gram-negative bacteria. Such efforts resulted in the deve¬ lopment of, e.g., those compounds disclosed in GB Patent No. 1,522, 140, which have the following formula(B) and exist as syn isomers or as a mixture of svn and anti isomers wherein the syn isomers are present in at least 90%: O wherein: R'is a furyl or thienyl group; R"is a Cι-4 alkyl, C3-7 cycloalkyl, furylmethyl or thienyl ethyl group; and R'"1s hydrogen or a carbamoyl, carboxy, carboxymethyl , sulfonyl or methyl group. Recently, further efforts were made to prepare new and Improved antibiotics, typically by way of introducing an acylamido group Into the 7-posit1on and certain other groups into the 3-posit- ion of the cephem nucleus as shown in the foregoing formula(B)[see, e.g., BE Patent No. 852,427 assigned to Fujisawa; GB Patent Nos. 1, 603,212 and 1,604,971, both assigned to Hoechst A.G.; EP Application No. 47,977 assigned to Ciba-Ge1gy; EP Application No. 74,563 assigned to Bayer; and U.S. Patent No.4,390,534 and EP Application No. 62,321, both assigned to Fujisawa]. Among these prior art references, of particular interest are U.S. Patent Nos. 4,258,041 and 4,329,453, both assigned to Glaxo. In particular, the cephaiosporin compound singularly claimed in the latter patent, i.e., U.S. Patent No. 4,329,453, commonly known as "Ceftazidime", is one of the commercially successful and potent cephem derivatives having a broad spectrum of antibiotic activities against various organisms normally difficult to combat with ?-lactam antibiotics. Said Ceftazidime can be represented by the following formula: As disclosed in European Patent Application No. 397,511, the inventors of the present invention have also discovered that those novel antibiotic cephaiosporin compounds having the following structural formula(D), their pharmaceutically acceptable non-tox1c salts, physiologically hydrolyzable esters and solvates have surprisingly superior antibiotic activity against a wide range of organisms: wherein: R x is a Cι- 4 alkyl, C3- 4 alkenyl, C3- 4 alkynyl group, or -C(R a ) (R b )C02H, wherein R a and R b , which may be same or different, are hydrogen or a C1-4 alkyl group or R a and R b form a C3-7 cycloalkyl group with the carbon atom to which they are linked; R 1 is a C1-4 alkyl, C3-4 alkenyl, C3-7 cycloalkyl, amino optionally substituted with a C1-4 alkyl radical, phenyl, or 2-, 4- or 6-substituted phenyl group with two or fewer substituents chosen from C1-4 alkyl, C1-3 alkoxy, halogen and hydroxy radicals; R 2 is hydrogen or a Cι- 4 alkyl group; and Q is N or CH. The cephaiosporin compounds of formula(D) are either syn Isomers or mixtures of svn and anti isomers which contain at least 90% of the svn Isomer. Further, when the R x group in the formula (D) compounds is -C(R»)(R b )Cθ2H, wherein R a and R are different, the carbon atom to which R* and R b are linked becomes a chiral center and these compounds become diastereoisomers. Summary of the Invention Unexpectedly, the present Inventors have further dis¬ covered that the β and S diastereoisomers of formula(D), wherein R x is -C(R a )(R b )-C02H and R» and R b are different so that the carbon to which they are linked becomes a chiral center, when they are isolated, particularly the S isomers, exhibit superior antibacterial activities. Accordingly, the primary objective of the present invent¬ ion is to provide novel cephalosporins of formulas (I-S) and (I-R) and pharmaceutically acceptable non-tox1c salts thereof, and physiologically hydrolyzable esters, hydrates and solvates thereof. Specifically, the S isomers of the present invention may be represented as: and the R isomers may be represented as: wherein: R 1 is a C1-4 alkyl, C3-4 alkenyl, C3-4 cycloalkyl, amino optionally substituted with a C1-4 alkyl radical, phenyl, or 2-, 4- or 6-substituted phenyl group with two or fewer substituents chosen from C1-4 alkyl, C1-3 alkoxy, halogen and hydroxy radicals; R 2 1s hydrogen or a C1-4 alkyl group; R a and R b , which should be different from each other, are hydrogen or a C1-4 alkyl group; and Q is N or CH. More preferred cephaiosporin compounds of the present invention are the S_ isomers of for ula(I-S), wherein R 1 is a C1-4 alkyl, C3- 4 alkenyl or amino group; R 2 is hydrogen or a C1-2 alkyl group; R a and R b , which should be different from each other, are hydrogen or a C1-2 alkyl group; and Q is CH. Most preferred cephaiosporin compounds of the present invention are the S isomers of formula(I-S), wherein R 1 is methyl, ethyl or amino; R 2 is hydrogen or methyl; R and R b , which should be different from each other, are hydrogen or methyl; and Q is CH. Another aspect of the present invention involves pro¬ cesses for preparing the respective Isomer compounds of formulas (I-S) and (I-R), which formulas may be collectively referred to as formula(I) hereinafter. A further feature of the present invention relates to the pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates of the dlastereomers of formula(I) and processes for preparing these compounds. A still further novel contribution of the present inven¬ tion resides in the formulation of pharmaceutical compositions comprising one or more of the cephaiosporin compounds represented by formula(I) and their pharmaceutically acceptable derivatives. Detailed Description of the Invention The novel cephaiosporin compounds of formula(I) are either svn Isomers or mixtures of syn and anti isomers, with res¬ pect to the radical, -0-C(R a )(R )-Cθ2H, which contain at least 90% of the syn Isomer or not more than 10% of the anti Isomer. In addition, the compounds of formula(I) according to the present invention may exist in tautomeric forms and such tautomers are also included within the scope of the invention. Namely, when Q of formula(I) is CH, the aminothiazolyl group undergoes tautomerism to form an iminothiazolinyl group, its tauto er, as follows: When Q of formula(I) is a nitrogen atom, the aminothiadiazolyl group forms i inothiadiazolinyl group, its tautomers, as follows: The compounds of formula(I) also include the resonance isomers. Therefore, for instance, if the compounds represented by formulad-S), the compounds in accordance with the present Invention include the following structures of formulas(I-S)' and (I-S)" : Similarly, the compounds of formula(I-R) should be taken to include their resonance isomers. Furthermore, the present invention encompasses, within its scope, those pharmaceutically acceptable non-toxic salts, physiologi¬ cally hydrolyzable esters, solvates and hydrates of the diastereomers collectively represented by formula(I). Suitable pharmaceutically acceptable salts of the cephaiosporin compounds(I) are conventional non-toxic salts and may include inorganic salts, for example, metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), and alkaline earth metal salts(e.g., calcium salt, magnesium salt, etc.), ammonium salt, etc.; organic salts, for example, an organic amlne salt (e.g., trimethylamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexyl- amine salt, N,N'-dibenzylethylened1am1ne salt, tris(hydroxymβthyl- amino)methane salt, phenylethylbenzylamine salt, dibenzylethyl- enediaminβ salt, etc.); organic carboxylic or sulfonic acid salts (e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); inorganic add salts (e.g., hydrochlorlde, hydrobro ide, sulfate, phosphate, etc.); salts with basic or acidic amino ac1ds(β.g., arglnlne, aspartic add, glutamic acid, lysine, etc.); more preferably, alkali metal salts, alkaline earth metal salts, inorganic acid salts, organic carboxylic acid salts and salts with basic or acidic amino acids; and most preferably, sodium salt, potassium salt, hydrochlorlde and sulfate. Above pharmaceutically acceptable non-toxic salts may be prepared by reacting the compounds of the formula(I) with one to four equivalents of corresponding acids or bases to the salts ment¬ ioned above 1n the presence of a solvent which may be water, or a mixture of water and water-mlscible solvent (e.g..methanol, ethanol, acetonitrile, acetone, etc). The physiologically hydrolyzable esters of the compounds (I) may include, for example, methoxycarbonyloxymethyl, 1-methoxy- carbonyloxy-1-ethyl, indanyl, phthalidyl methoxymethyl, pivaloyl¬ oxymethyl, glycyloxymethyl, phenylglycyloxymethyl or 5-methyl-2-oxo- 1, 3-dioxolan-4-yl esters, and other physiologically hydrolyzable esters which have been widely used 1n the technical fields of penicillin and cephaiosporin antibiotics; more preferably, methoxy¬ carbonyloxymethyl, 1-methoxycarbonyloxy-1-ethyl, methoxymethyl or pivaloyloxymethyl; and most preferably, methoxycarbonyloxymethyl or methoxymethyl. These esters can be prepared in accordance with known methods, e.g., by reacting the compounds of formula(I) with corres¬ ponding alkyl halides(e.g, , methoxymethyl chloride or methoxy¬ carbonyloxymethyl cholride) in the presence of a base (e.g. ,triethyl- amine, pyridine or sodium bicarbonate). Exemplary solvates of the cephaiosporin compounds of formula(I) may include solvates with water-miscible solvents, e.g., methanol, ethanol, acetone or acetonitrile; and more preferably, ethanol. The present invention also Includes within its scope pharmaceutical compositions comprising one or more of the compounds (I) as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives. The antibiotic compounds(I) of the invention may be formulated for administration in unit dose or multi-dose containers. The compositions may take various forms such as solution, suspension or emulsion in an oily or aqueous vehicle, which can contain convent- ional additives such as a dispersant, suspending agent, stabilizer and the like. Alternatively, the active ingredient may be formed Into a dried powder that can be normally dissolved in an aqueous solution of sterile pyrogen-free water before use. The compounds(I) may be also formulated into suppositories containing conventional suppository bases such as cocoa butter or other glycerides. The pharmaceutical compositions 1n a unit dose form may preferably comprise about from 50 to 1,500mg of the active Ingredient, depending on the age and body weight of the patient, the nature and severity of the Illness, and so on. In general, it has been shown advantageous to administer the active compounds 1n an amount of about 500 to 5,000mg per day in order to achieve the desired results, depending on the routes and frequency of admini¬ stration. In case of intramuscular or intravenous administration for adult human treatment, the dosage of about 150 tσ 3,000mg per day is thought to be sufficient, although it may vary in case of treatment for specific Infections caused by certain strains. If desired, the compounds(I) can be administered 1n combination with other antibiotics such as penicillins or other cephalosporins. The compounds of the present invention, as described above, exhibit potent and broad antibacterial activities against Gram-positive bacteria and a variety of Gram-negative bacteria as well., particularly against Pseudomonas. Also, these compounds have high stability to /3-lactamases produced by a number of Gram- negative bacteria. The diastereomers of formula(I) may be produced by a number of different methods. One of them is to simply isolate the S and R isomers by chromatography, with an βluent, from a mixture of the Isomers. Exemplary eluents which may be employed in the separation process Include: a mixture of buffer and water-m1sdble solvent (e.g., methanol, acetonitrile, isopropyl alcohol); and more prefer- ably, a mixture of buffer and acetonitrile. Said isolation process may be conducted under the following conditions: Eluent: Buffer/CH3CN=85/15 ~ 95/5(v/v) (Buffer: phosphate, pH 7.0, 0.01M) Column: ODS Column Detector: UV 254 nm The preferred method of preparing a compound of formula(I) comprises reacting a compound of formula (II-S) or (II-R), which may be collectively referred to as formula (II) hereinafter, in the presence of a solvent, with a compound of formula(III) as follows: r f wherein: R a , R b , R 1 , R 2 and Q have the same meanings as defined above; n 1s 0 or 1; R 3 1s hydrogen or an amino protecting group; R 4 1s hydrogen or a carboxyl protecting group; R 5 is hydrogen or a carboxyl protecting group; and L is a leaving group. The amino protecting group in R 3 above may Include acyl substituted or unsubstituted aryl(lower)alkyl(e.g. , benzyl, diphenylmethyl, triphenylmethyl and 4-methoxybenzyl), halo(lower) alkyl(e.g., trichloromethyl and trichloroethyl), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene or substituted cycloalkylidene. The acyl group as an amino protecting group may include, for example, Cι-β(lower) alkanoyKe.g. , formyl and acetyl), C2-β alkoxycarbonyKe.g. , methoxycarbonyl and ethoxycarbonyl), (lower)alkanesulfonyl(e.g. , ethanesulfonyl and ethanesulfonyl), or aryl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl), where the acyl group can be substituted with 1-3 substituent(s) such as halogen, hydroxy, cyano or nitro. In addition, the amino protecting group may include reaction pro¬ ducts obtained from amino groups and silane, boron or phosphorus compounds. The carboxyl protecting group of R 4 or R 5 may include, for example, (lower)alkylesters(e.g. , methylester and t-butylester), (lower)alkenylesters(e.g. , vinylester and allylester), (lower) alkoxy(lower)alkylesters(e.g. , methoxymethylester), (lower)alkyl- thio(lower)alkylesters(e.g. , methylthio ethylester), halo(lower) alkylesters(e.g. , 2,2,2-trichloroethylester), substituted or unsubstituted aralkylesters(e.g. , benzylester and p-nitrobenzyl- ester) or silylesters, which can be selected after consideration of the chemical property of the desired compounds(I). The leaving group L in formula(III) may include, for example, halogen such as chlorine or bromine, a (lower)alkanoyloxy group such as acetoxy, a (lower)alkanesulfonyloxy group such as methanesulfonyloxy, an arenesulfonyloxy group such as p-toluenesul- fonyloxy, an alkoxycarbonyloxy group and the like. The term "lower" as used hereinabove and elsewhere in this specification, for example in reference to "lower alkyl," encompasses groups having 1 to 6 carbon atoms, more preferably, 1 to 4 carbon atoms. In the preparation of the objective compounds(I), the compounds of the formula(II) are used preferably in an amount of from 1 to 2 molar equivalents based on the compounds of the formula(III). Amino or acid protecting groups can be readily removed by any of the conventional deprotectlon methods which are well known in the field of cephaiosporin antibiotics. For example, add- or base-hydrolysis or reduction is generally applicable. For further example, when the protecting group is an amido group, it is feasi¬ ble to subject such compounds to 1m1πo-halogenation and imlno- etherlflcation, and then followed by hydrolysis. Acid hydrolysis 1s preferred to remove such groups as tri(di)phenylmethyl or alkoxycarbonyl; and 1s carried out in the presence of an organic acid, such as formic add, trlfluoroacetic acid, or p-tolueneacetic acid, or an inorganic acid such as hydrochloric acid and the like. Reduction of S-oxide can be conventionally carried out, for example, by adding potassium Iodide and acetyl chloride to the reac- tants, followed by quenching the reaction mixture with sodium m-bisulf1te. The reaction for introducing the compounds(III) Into the 3-position of the compounds(II) to prepare the compounds(I) is carried out 1n the presence of a solvent such as water, or a mixture of water and a water-mis ' cible solvent, wherein the pH of the reaction solution may range from 5 to 8, more preferably, from 6 to 7.5; and the temperature may range from 20 to 100°C, more preferably from 60 to 80°C. The starting materials of the compounds(II) are known intermediates conventionally employed for the preparation of cepha- losporin compounds. The dotted Hne of formula(II) represents a single bond or a double bond; and, therefore, the compounds of formula(II) may be the compounds of formula(II-a), or the compounds of formula(II-b), or mixtures thereof: wherein: n, R a , R b , R 3 , R 4 , R 5 , Q and L have the same meanings as defined before. To stabilize the reaction products and their intermedi¬ ates, one or more salts selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, potassium bromide and potassium thiocyanate can be used as a stabilizer. The separation and purification of the compounds(I) can be carried out using a conventional method such as recrystallization, O9 - 19 - column chromatography over silica gel or ion-exchange chromatography. The following examples illustrate how some of the compounds of formula(I) can be prepared. 5. Example 1: Synthesis of Compound(I-S-1) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino] 0 acetamido]-3-[(1,4,6-triam1nopyrim1din1um-2-yl)thiomethyl]-3- cephem-4-carboxylate, having the following formula, was synthesized: To a solution containing 500mg of 3-acetoxymethy1-7-[(Z)- 2-(2-aminoth1azol-4-yl)-2-[(S)-1-carboxyeth-1-oxyiminoJacetamido]- 3-cephem-4-carboxyl1c hydrochlorlde suspended in 5ml of distilled 0 water were added 200mg of 1,4,6-tr1amino-2(1H)-pyrimidinethione and 800mg of potassium iodide. The reaction solution was heated to 70°C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 5 2N-aqueous hydrochloric acid solution to produce precipitates which were washed with 5ml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(ODS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile (95:5) as an eluent, to give 190mg of the title compound as a white solid(m.p.>195°C , dec). NMR: δ (D2O, NaHCOs, 270MHz) 1.46(d, 3H), 3.58(ABq, 2H), 4.22(ABq, 2H), 4,65(q, 1H), 5.17(d, 1H), 5.56(s, 1H), 5.79(d, 1H), 7.00(s, 1H). MS: 61KFAB, M + 1 ) IR(KBr, cm- 1 ): 1771(£-lactam), 1650, 1535 UVλmax H0 (nm,£ ): (220, 33957), (232, 34794), (275, 23323), (274, 23915) [ ]o 25 : -105.5° (c 1.0, 0.05N aqueous sodium bicarbonate solution) HPLC analysis condition column: μ. -Bondapak C-18 detector: UV 254nm folw rate: 2mfi/min retention time: 7.2 min Example 2: Synthesis of Compound(I-S-2) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxy1mino]ace- tamido]-3-[(4,6-d1am1no-1-methylpyrimidin1um-2-yl)thiomethyl3-3- cephem-4-carboxylate, having the fol lowing formula(I-S-2) , was synthesized: To a solution containing 500mg of 3-acetoxymethyl-7- [(Z)-2-(2-am1nothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxy1mino]ace- tamido]-3-cephem-4-carboxylic hydrochloride suspended in δmfi of distilled water were added 200mg of 4,6-diamino-1-methyl-2-(1H)- pyrl idinethione and 800mg of potassium iodide. The reaction solution was heated to 70°C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room tem¬ perature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce precipitates which were washed with 5mfi of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile(92:8) as an eluent, to give 195mg of the title com¬ pound as a white solid(m.p.> 180°C, dec). NMR: δ (D 2 0, NaHCOs , 270(MHz) 1.49(d, 3H), 3.59(s, 3H), 3.59(ABq, 2H), 4.36 (ABq , 2H) , 4.67 (q, 1H) , 5. 17(d , 1H) , 5.61 (s , 1H) , 5.79(d , 1H) , 7.01 (s , 1H) . MS: 610(FAB , M + 1 ) IR(KBr, cm" 1 ): 1775(0 -lactam) , 1635, 1535 UVλmax" ° (nm,fi ): (217, 34252), (232, 32672), (275, 23323) [α ]D 25 : -124.1° (c 1.0, 0.05N aqueous sodium bicarbonate solution) Example 3: Synthesis of compound(I-S-3) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2[(S)-1-carboxyeth-1-oxy1mino] acetamido]-3-[(4,6-diamino-1-ethylpyrimidinium-2-yl)thiomethyl]- 3-cephem-4-carboxylate, having the following formula(I-S-3), was synthesized: To a solution containing 500mg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-t(S)-1-carboxyeth-1-oxyim1no] acetamldo]- 3-cephem-4-carboxylic hydrochloride suspended in δml of distilled water were added 200mg of 4,6-diamino-1-ethyl-2(1H)-pyrimidinethione and 800mg of potassium iodide. The reaction solution was heated to 70 β C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to 5 pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce precipitates which were washed with 5ml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile(92:8) 0 as an eluent, to give 180mg of the title compound as a white solid (m.p.> 193°C. dec). NMR: δ (D2O, NaHC03, 270MHz) 1.34(t, 3H), 1.48(d, 3H), 3.59(ABq, 2H), 6 4.04(q, 2H), 4.34(ABq, 2H), 4.67(d, 1H), δ.1δ(d, 1H), δ.δ8(s, 1H), δ.79(d, 1H), 7.01(s, 1H). MS: 624(FAB, M + 1 ) IR(KBr, cm" 1 ) : 1775( 0 -lactam) , 1640, 1530. 0 UVλ max" ° (nm, 6 ) : (220 , 34648) , (234, 32700) , (276, 22620) [ α 3 D 2 5 : -110.3° (c 1 .0, 0.05N aqueous sodium bicarbonate solution) δ Example 4: Synthesis of Compound(I-S-4) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino]ace- tam1do]-3-[(4,6-diamino-1-propylpyrimidinium-2-yl)thiomethyl]-3- cephem-4-carboxylate, having the following formula(I-S-4), was synthesized: To a solution containing 500mg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino]acetamido]- 3-cephem-4-carboxyl1c hydrochloride suspended in 5ml of distilled water were added 200mg of 4,6-diamino-1-propyl-2(1H)-pyr1m1dinethione and 800mg of potassium iodide. The reaction solution was heated to 70°C, while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce precipitates which were washed with δ l of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitr1le(90:10) - 2δ - as an eluent, to give 1δ0mg of the title compound as a white solid (m.p.> 197 β C, dec). NMR: δ (D2O, NaHCOs, 270MHz) 0.98(t, 3H), 1.48(d, 3H), 1.77(m, 2H), 3.61(ABq, 2H), 3.97(t, 2H), 4.38(ABq, 2H), 4.68(q, 1H), 5.19(d, 1H), δ.60(d, 1H), δ.81(d, 1H), 7.01(s, 1H). MS: 638(FAB, M + 1) IR(KBr, cm" 1 ): 1778(0 -lactam), 1646, 1δ2δ UVλmax" °(nm,£ ): (222, 37377), (232, 35410), (276, 23831). t ]D 25 : -105.4° (c 1.0, 0.05N aqueous sodium bicarbonate solution) Example 5: Synthesis of Compound(I-S-δ) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-t(S)-1-carboxyeth-1-oxyim1no] acetamido]-3-[(4,6-d1amino-1-phenylpyrimidinium-2-yl)thιomethyl]- 3-cephem-4-carboxylate, having the following formula(I-S-δ), was synthesized: To a solution containing δOOmg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino]acetamido]- 3-cephem-4-carboxylic hydrochlorlde suspended in δ l of distilled water were added 200mg of 4,6-diamino-1-|Jshenyl-2(1H)-pyr1midinethione and 800mg of potassium iodide. The reaction solution was heated to 70°C, while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce pre- 0 dpltates which were washed with 5ml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile(87:13) as an eluent, to give 120mg of the title compound as a white solid δ (m.p.>190°C, dec). NMR: δ (D2O, NaHCOs, 270MHz) 1.48(d, 3H), 3.48(ABq, 2H), 4.25(ABq, 2H), 4.67(q, 1H), 5.14(d, 1H), δ.69(s, 1H), 0 5.79(d, 1H), 7.00(s, 1H), 7.43-7.81(m, δH). MS: 672(FAB, M + 1) IR(KBr, cm" 1 ) : 1777(0 -lactam) , 16δ0 , 1515 UVλ max" ° (nm, ε ) : (221 , 31548) , (235 , 29524) , (273 , 18827) . 5 [ α ]o 25 : -8. 1 ° (c 1 .0 , 0.05N aqueous sodium bicarbonate solution) Example 6: Synthesis of Compound(I-S-6) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino] acetamido]-3-[(4,6-diamino-1,5-dimethylpyrimidinium-2-yl)thiomethyl]- 3-cephem-4-carboxylate, having the following formula(I-S-6), was synthesized: To a solution containing δOO g of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino]acetamido]- 3-cephem-4-carboxylic hydrochloride suspended in 5ml of distilled water were added 200mg of 4,6-diamino-1 ,5-dimethyl-2(1H)-pyrimidine- thione and 800mg of potassium iodide. The reaction solution was heated to 70"C , while the pH was adjusted to 7.1 to 7.2 with addit¬ ion of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to pro¬ duce precipitates which were washed with 5ml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and aceton1trile(91:9) as an eluent, to give 210mg of the title compound as a white solid (m.p.>183°C , dec). NMR: <y (D2O, NaHCOβ, 270MHz) 1.48(d, 3H), 1.92(s, 3H), 3.57(s, 3H), 3.60(ABq, 2H), 4.38(ABq, 2H), 4.69(q, 1H), δ.17(d, 1H), 5.81(s, 1H), 7.03(s, 1H). MS: 672(FAB, M + 1) 0 IR(KBr, cm- 1 ): 1765(0-lactam), 1645, 1560 UVλmax H °(nm,e ): (203, 34313), (232, 32588), (281, 24089). [a ]D 25 : -121.4° (c 1.0, 0.05N aqueous sodium bicarbonate solution) δ Example 7: Synthesis of Compound(I-S-7) This example shows how one of the preferred compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino] 0 acetamido]-3-[(5-methyl-1,4,6-triam1nopyrim1dinium-2-yl)th1omethyl]- 3-cephem-4-carboxylate, having the following formula(I-S-7), was synthesized: To a solution containing δOO g of 3-acetoxymethyl-7-[(Z)- 2-(2-am1nothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxy1mino]acetamido]- 3-cephem-4-carboxyl1c hydrochlorlde suspended in δml of distilled water were added 200mg of δ-methyl-1,4,6-triamino-2(1H)-pyrim1dinethione and 800mg of potassium iodide. The reaction solution was heated to 70"C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.δ with 2N-aqueous hydrochloric acid solution to produce pre- cipltates which were washed with 5ml of distilled water after fil¬ tration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm)using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile(93:7) as an eluent, to give 220mg of the title compound as a white solid (m.p.>181°C, dec). NMR: δ (D2O, NaHCOβ, 270MHz) 1.48(d, 3H), 1.85(s, 3H) , 3.58(ABq, 2H), 4.32(ABq, 2H), 4.67(q, 1H), 5.18(d, 1H), 5.77(d, 1H), 6.94(s, 1H). MS: 625(FAB, M + 1) IR(KBr, cm" 1 ): 1770(0 -lacta ). 1635, 156δ UVλmax H °(nm,β ): (204, 35861), (232, 35288), (281, 24807). [α 3D 25 : -118.0° (c 1.0, 0.05N aqueous sodium bicarbonate solution) Example 8: Synthesis of Compound(I-R-1) This example shows how one of the isomeric compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3 acetamido3-3-[(1,4,6-tr1am1nopyrimidinium-2-yl)thiomethyl3-3- cephem-4-carboxylate, having the following formula(I-R-l), was synthesized: To a solution containing 500mg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyim1no]acetamido3- 3-cephem-4-carboxylic hydrochlorlde suspended in 5ml of distilled water were added 200mg of 1,4,6-tr1amino-2(1H)-pyrimidinethione and 800mg of potass-ium iodide. The reaction solution was heated to 70"C, while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce pre¬ cipitates which were washed with 5ml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile(9δ:δ) as an eluent, to give 180mg of the title compound as a white solid (m.p.>190 β C , dec). δ NMR: δ (D2O, NaHCθ3, 270MHz) 1.46(d, 3H), 3.68(ABq, 2H), 4.22(ABq, 2H), 4.6δ(q, 1H), δ.17(d, 1H), δ.δ6(s, 1H), δ.71(d, 1H), 7.00(s, 1H). MS: 61KFAB, M + 1) 10 IR(KBr, cm- 1 ): 1772(0 -lacta ), 1660, 1630 UVλrnax" °(nm,e ): (218, 32713), (232, 31842), (275, 21786). [CT 3D 25 : -48.7° (c 1.0, 0.05N aqueous sodium bicarbonate solution) 5 HPLC analysis condition column: μ -Bondapak C-18 detector: UV 254nm flow rate: 2ml/min retention time: 11.5 min 0 Example 9: Synthesis of Compound(I-R-2) This example shows how one of the isomeric compounds, 7-[(Z)-2-(2-am1nothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3 5 acetamido3-3-[(4,6-diam1no-1-methylpyrimidinium-2-yl)thiomethyl]- 3-cephem-4-carboxylate, having the following formula(I-R-2), was synthesized: To a solution containing δOOmg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminoth1azol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3acetamido3- 3-cephem-4-carboxylic hydrochlorlde suspended 1n δml of distilled water were added 200mg of 4,6-d1amino-1-methyl-2(1H)-pyrimid1nethione and 800mg of potassium iodide. The reaction solution was heated to 70 β C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 5 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce pre¬ cipitates which were washed with δml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm) using mixtures of ammonium phosphate,buffer solution at pH 7 and aceton1trile(92:8) as an eluent, to give 19δmg of the title compound as a white solid (m.p.>1δ2°C, dec). NMR: δ (D2O, NaHC03, 270MHz) 1.4β(d, 3H), 3.δ3(s, 3H), 3.δ9(ABq, 2H), δ 4.36(ABq, 2H) , 4.67(q, 1H), 5.17(d, 1H), 5.61(s, 1H), δ.73(d, 1H), 7.01(s, 1H). MS: 610(FAB, M + 1 ) IR(KBr, cm" 1 ) : 177δ( 0 -lactam) , 1636, 1δ3δ. Example 10: Synthesis of Compound(I-R-3) δ This example shows how one of the isomer1c compounds, 7-[(Z)-2-(2-am1nothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxy1m1no] acetam1do]-3-[(4,6-diam1no-1-ethylpyrim1dinium-2-yl)thiomethyl - 3-cephem-4-carboxylate, having the following formula(I-R-3), was 10 synthesized: To a solution containing δOOmg of 3-acetoxymβthyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-t(R)-1-carboxyeth-1-oxyimino]acetam1do3- 3-cephem-4-carboxylic hydrochlorlde suspended in δml of distilled water were added 200mg of 4,6-d1amono-1-ethyl-2(1H)-pyrim1dinethione 0 and 800mg of potassium iodide. The reaction solution was heated to 70°C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.6 with 2N-aqueous hydrochloric acid solution to produce pre¬ 6 cipitates which were washed with δml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and aceton1trile(92:δ) as an eluent, to give 1δ0mg of the title compound as a white solid (m.p.>191 β C, dec). NMR: δ (D 2 0, NaHCOs, 270MHz) 1.34(t, 3H), 1.4β(d, 3H), 3.59(ABq, 2H), 4.04(q, 2H), 4.34(ABq, 2H), 4.67(q, 1H), δ.1δ(d, 1H), δ.δβ(s, 1H), δ.71(d, 1H), 7.02(s, 1H). MS: 624(FAB, M + 1) IR(KBr, cm- 1 ): 1776(0-lactam), 1640, 1630. Example 11: Synthesis of Compound(I-R-4) This example shows how one of the isomeric compounds, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3 acetamido3-3-[(4,6-d1am1no-1-propylpyr1midinium-2-yl)thiomethyl - 3-cephem-4-carboxylate, having the following formula(I-R-4), was synthesized: - 36 - To a solution containing 500mg of 3-acetoxymethyl-7-[(Z)- 2-(2-am1noth1azol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3acetamido3- 3-cephem-4-carboxylic hydrochlorlde suspended in 5ml of distilled water were added 200mg of 4,6-diamino-1-propyl-2(1H)-pyrimid1nethione and 800mg of potassium iodide. The reaction solution was heated to 70°C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric add solution to produce 0 precipitates which were washed with δml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(0DS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitrile(90:10) as an eluent, to give 150mg of the title compound as a white solid δ (m.p.>193°C , dec). NMR: <y (D2O, NaHC03, 270MHz) 0.9δ(t, 3H), 1.4β(q, 3H), 1.77(m, 2H), 3.61(ABq, 2H), 3.97(t, 2H), 4.3δ(ABq, 2H), 4.68(q, 1H), 5.19(d, 1H), δ..60(s, 1H), δ.73(s, 1H), 7.01(s, 1H). MS: 638(FAB, M + 1) IR(KBr, cm" 1 ): 1778(0 -lactam), 1645, 1525. Example 12: Synthesis of Compound(I-R-δ) This example shows how one of the isomeric compounds, δ 7-[(Z)-2-(2-am1nothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3 acetam1do3-3-t(4,6-diamino-1-phenylpyrimidinium-2-yl)thiomethyl3- 3-cephem-4-carboxylate, having the following formula(I-R-5), was synthesized: 1δ To a solution containing δOOrng of 3-acetoxymethyl-7-[(Z)- 2-(2-aminoth1azol-4-yl)-2-[(R)-1-carboxyeth-1-oxyim1no3acetam1do3- 3-cephem-4-carboxyl1c hydrochloride suspended 1n δml of distilled water were added 200mg of 4,6-diamino-1-phenyl-2(1H)-pyrim1dinethione and 800mg of potassium iodide. The reaction solution was heated 20 to 70°C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.6 with 2N-aqueous hydrochloric acid solution to produce precipitates which were washed with δml of distilled water after 2δ filtration. The filter cake was applied to the chromatography on prep-column(ODS steel column, 19mm x 300mm) .using mixtures of ammonium phosphate buffer solution at pH 7 and aceton1tr1le(δ7:13) as an eluent, to give 120mg of the title compound as a white solid (m.p.>187°C, dec). δ NMR: δ (D2O, NaHCθ3, 270MHz) 1.48(d, 3H), 3.48(ABq, 3H), 4.25(ABq, 2H), 4.67(q, 1H), δ.14(d, 1H), 5.69(s, 1H), 5.71(d, 1H), 7.00(d, 1H), 7.43-7.81(m, δH). MS: 672(FAB, M + 1) 10 IR(KBr, cm- 1 ): 1777( -lactam), 1660, 1515. Example 13: Synthesis of Compound(I-R-6) This example shows how one of the Isomeric compounds, 5 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxy1mino3 acetam1do3-3-t(4,6-d1amino-1,5-d1methylpyr1m1d1n1um-2-yl)th1ome- thyl3-3-cephem-4-carboxylate, having the following foumula(I-R-6), was synthesized: 5 To a solution containing δOOmg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino]acetamido3- 3-cephem-4-carboxylic hydrochlorlde suspended in δml of distilled water were added 200mg of 4,6-diam1no-1,5-dimethyl-2(1H)-pyrimid1- nethione and δOOmg of potassium iodide. The reaction solution was heated to 70"C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric add solution to produce precipitates which were washed with δml of distilled water after filtration. The filter cake was applied to the chroma- tography on prep-column(0DS steel column, 19mm x 300mm) using mix¬ tures of ammonium phosphate buffer solution at pH 7 and acetoni- trile(91:9) as an eluent, to give 210mg of the title compound as a white solid(m.p.>179 β C , dec). δ NMR: δ (D2O, NaHCOs , 270MHz) 1.4δ(d, 3H), 1.92(s, 3H), 3.δ7(s, 3H), 3.60(ABq, 2H), 4.38(ABq, 2H), 4.69(q, 1H), δ.17(d, 1H), 5.77(d, 1H), 7.03(s, 1H). MS: 624(FAB, M + 1) 0 IR(KBr, cm" 1 ): 1765(0-lactam), 1645, 1560. Example 14: Synthesis of Compound(I-R-7) This example shows how one of the 1somer1c compounds, 5 7-[(Z)-2-(2-aminoth1azol-4-yl)-2-[(R)-1-carboxyeth-1-oxy1mino3 acetamido3-3-[(δ-methyl-1,4,6-triam1nopyrim1d1n1um-2-yl)thiomethyl3- 3-cephem-4-carboxylate, having the following formula(I-R-7) , was synthesized: To a solution containing δOOmg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(R)-1-carboxyeth-1-oxyimino3acetamido3- 3-cephem-4-carboxyl1c hydrochlorlde suspended 1n δml of distilled water were added 200mg of 6-methyl-1,4,6-tr1am1no-2(1H)-pyr1m1dine- thione and δOOmg of potassium Iodide. The reaction solution was heated to 70 β C , while the pH was adjusted to 7.1 to 7.2 with addit- ion of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric acid solution to produce precipitates which were washed with δml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(ODS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and aceton1trile(93:7) as an eluent, to give 220mg of the title compound as a white solid (m.p.>175°C , dec). NMR: δ (D2C NaHCOs , 270MHz) 1.48(d, 3H), 1.65(s, 3H), 3.δβ(ABq, 2H), 4.32(ABq , 2H) , 4.67(q, 1H) , 5. 1β(d, 1H) , δ.71 (d, 1H) , 6.94(s, 1H) . MS: 62δ(FAB, M + 1) IR(KBr, cm" 1 ): 1770(0 -lactam), 1635, 1566. Example 16: Synthesis and Isolation of Compounds( -S-1) and (I-R-1) from a Mixture Thereof As stated above, the S and R diastereomers can be obtained from a mixture thereof. Accordingly, this example is Intended to show how their mixture was first synthesized; and then separated into the isomers having the structural formulas(I-S-l) and (I-R-1), respec¬ tively, as described 1n Examples 1 and 8 above. To a solution containing δOOmg of 3-acetoxymethyl-7-[(Z)- 2-(2-aminothiazol-4-yl)-2-[(R, S)-1-carboxyβth-1-oxy1m1no3acetamido3- 3-cephem-4-carboxylic hydrochlorlde suspended 1n δml of distilled water were added 200mg of 1,4,6-tr1am1no-2(1H)-pyr1m1d1nethione and δOOmg of potassium Iodide. The reaction solution was heated to 70"C , while the pH was adjusted to 7.1 to 7.2 with addition of aqueous sodium bicarbonate solution. The resultant solution was stirred for 4 hours, cooled to room temperature and adjusted to pH 3 to 3.5 with 2N-aqueous hydrochloric add solution to produce precipitates which were washed with δml of distilled water after filtration. The filter cake was applied to the chromatography on prep-column(ODS steel column, 19mm x 300mm) using mixtures of ammonium phosphate buffer solution at pH 7 and acetonitr1le(9δ:δ) as an eluent, to give 90mg and 80mg of the title compounds (I-S-1) and (I-R-1), respectively, as white solIds. δ The compounds synthesized in Examples 1 to 14 above are listed in Table 1 in a summary fashion. R 1 and R 2 shown in Table 1 have the same meanings as those of formula(I). 10 δ 0 5 Table 1. Summary of Compounds Synthesized in Examples 1-14 The cephaiosporin compounds(I) of the present Invention, their non-toxic salts, esters, solvates and hydrates, as mentioned above, show potent antibacterial activities against a variety of general pathogenic microbial organisms Including Gram-negative and Gram-positive bacteria; and, therefore, they are especially useful in therapy for treatment of bacterial infections in human beings and animals. In order to illustrate their surprisingly superior antibacterial effectiveness, the minimal Inhibitory concentrations (MIC) of the 14 compounds synthesized 1n Example 1 through 14 against standard strains were determined and compared with Cβfta- zidime of formula(C), which was used as the control compound. These MIC values were taken by employing a two-fold dilution method: that is, two-fold serial dilutions of each of the test compounds were made and dispersed in a Muller-Hlnton agar medium; 2μi of the standard test strain which had the 10 7 CFU(Colony Forming Unit) per ml was inoculated on the medium; and these were Incubated at 37°C for 20 hours. The results of the MIC tests are shown 1n Table 2. In addition, the acute toxldty tests for the 14 compounds were carried out at LD50 by Intravenously administering each of the test compounds in varied amounts 1n a stepwise manner Into 5 ICR mice (5 weeks old), which were observed for 14 days. The results are shown in the last row of Table 2. As can be seen from Table 2. the diastereomers of the present invention, particularly those Isomers, exhibit surpri¬ singly effective antibacterial activity against a broad spectrum of strains. Table 2. Antibacterial Activity and Toxldtv Data HIC, M /mi Strain I-S-1 1-8-2 1-6-3 I-S-4 1-8-6 I-S-6 I-B-T •Table 2. (Continued) MIC, μg/al Strain I-R-1 I-R-2 I-R-3 I-R-4 I-R-5 I-R-β I-R-7 CTZ* CTZ': Ceftazidime In addition to the in vitro tests described above, jn. vivo absorbency tests for the two selected compounds of formulas(I-S-l) and (I-R-1), along with Ceftadizime, were carried out by administer¬ ing intravenously, in a dose of 20mg/kg, each of these two compounds Into SD rats(male) weighing 220 to 340g; and drawing blood samples from the femoral vein of the rats every hour after administration, which were analyzed by employing the b1o-assay or agar well method. About 10 to 15 rats were used for each of the compounds. Tab 3. In V1vo Abso bencv Test DataCPlasma Concentration: Table 3(continued) Notes: (1) Two-Compartment Model (2) Dose: 20mg/kg (3) Tested Aminal: Rats(male; 220-340g) From the data shown 1n Tables 2 and 3. it can be readily appreciated that the novel compounds of the present invention, especially those S isomers, possess surprisingly superior antibac- terial potency of wide spectrum and excellent absorbency/pharmacoki- netic characteristics.

Claims: Claims A cephaiosporin compound represented by formula(I-S) and the pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein: R 1 is a Cι- 4 alkyl, C3- 4 alkenyl, C3-4 cycloalkyl, amino optionally substituted with a C1-4 alkyl radical, phenyl, or 2-, 4- or 6- sub¬ stituted phenyl group with two or fewer substitutents chosen from Cι- 4 alkyl, C1-3 alkoxy, halogen and hydroxy raidcals; R 2 is hydrogen or a Cι- alkyl group; R a and R b , which should be different from each other, are hydrogen or a Cι- alkyl group; and Q is N or CH. 2. The cephaiosporin compound of claim 1 and the phar¬ maceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein R 1 is a C1-4 alkyl, C3-4 alkenyl or amino group; R 2 is hydrogen or a C1-2 alkyl group; R a and R , which should be different from each other, are hydrogen or a C1-2 alkyl group; and Q is CH. 3. The cephaiosporin compound of claim 1 and the pharma- ceutically acceptable non-tox1c salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein R 1 is methyl, ethyl or amino group; R 2 is hydrogen or methyl; R* and R , which should be different from each other, are hydrogen or methyl; and Q is CH. 4. The cephaiosporin compound of claim 1 and the pharma¬ ceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein the compound is 7- t(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxyimino]ace- tamido-3-[(1,4,6-triam1nopyrim1din1um-2-yl)th1omethyl]-3-cephem-4- carboxylate. 5. The cephaiosporin compound of claim 1 and the pharma¬ ceutically acceptable non-tox1c salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein the compound is 7- [(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carboxyeth-1-oxy1mino]acet- amido-3-[(4,6-diamino-1-methylpyr1m1d1n1um-2-yl)th1omethyl]-3- cephem-4-carboxylate. 6. The cephaiosporin compound of claim 1 and the pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein the compound is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carbox- yeth-1-oxyιnπno3acetamido-3-[(4,6-diamino-1-ethylpyrimidinium- 2-yl jtr.ioTietnyl]-3-cephem-4-carboxylate. 7. The cephaiosporin compound of claim 1 and the pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein the compound is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carbox- yetn-1-oxyιmιno]acetamido-3-[(4,6-diamino-1-propylpyrimidinium- 2-yl )thτomethyl]-3-cephem-4-carboxylate. 8. The cephaiosporin compound of claim 1 and the pharmaceutically acceptable non-toxic salts, physiologically hyαrolyzable esters, hydrates and solvates thereof, wherein the compound is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carbox- >eth-i-oxyιmιno]acetamido-3-[(4,6-diamiπo-1-phenylpyrimidinium- 2- 1Jthiornethylj-3-cephem-4-carboxylate. is. The cephaiosporin compound of claim 1 and the pharmaceutically acceptable non-toxic salts, physiologically ny ro /zable esters, hydrates and solvates thereof, wherein the compound is 7-[(Z)-2-(2-aminothiazo1-4-yl)-2-[(S)-1-carbox- yeth-i-ϋxyιmιno] icetamido-3-[(4,6-diamino-1 ,5-dimethy pyrimi¬ enmurr-._:-;> " 1 )thιomethyl3 _ 3 _ cepnem-4-carboxylate. - 61 - 10. The cephaiosporin compound of claim 1 and the pharmaceutically acceptable non-toxic salts, physiologically hydrolyzable esters, hydrates and solvates thereof, wherein the compound is 7-[(Z)-2-(2-aminothiazol-4-yl)-2-[(S)-1-carbox- yeth-1-oxyimino3acetamido-3-[(δ-methyl-1,4,6-triaminopyrimi- dinium-2-yl)thiomethyl -3-cephem-4-carboxylate. 11. A process for preparing a compound of formula(I-S) wherein: R , R 2 , R a , R b and Q have the same meanings as defined in claim 1, which comprises reacting a compound of formula(II-S) wherein: R 3 is hydrogen or an amino protecting group; - 62 - R 4 and R 5 are hydrogen or a carboxyl protecting group; L is a leaving group; and n is 0 or 1 , in the presence of a solvent, with a compound of formula(III) wherein: R 1 and R 2 have the same meanings as defined above. 12. A process for isolating the compounds of the formulas - 63 - wherein: R 1 , R 2 , R a , R b and Q have the same meanings as defined in claim 1, which comprises isolating said compounds of formulas(I-S) and (I-R) with an eluent from a mixture thereof. 13. The process of claim 12 wherein said eluent is a mixture of ammonium phosphate buffer and acetonitrile. 14. A pharmaceutical composition comprising a therapeuti- cally effective amount of a cephaiosporin compound according to any one of claims 1 to 10.

Inventors: BANG CHAN SIK, KIM WON SUP, KIM YONG ZU, LIM JONG CHAN, OH HUNG SEUNG, YEO JAE HONG, YIM HYEON JOO, BANG, CHAN, SIK, KIM, WON, SUP, KIM, YONG, ZU, LIM, JONG, CHAN, OH, HUNG, SEUNG, YEO, JAE, HONG, YIM, HYEON, JOO
Applicants: LUCKY LTD, LUCKY LTD.
Application year: 1991
Main classification: C07D501
IPC codes: A61K31, A61P31, C07D501