WO1992021681A1

WO1992021681A1 - Novel cephalosporins and processes for preparation thereof

Info

Publication number: WO1992021681A1
Application number: PCT/KR1991/000028
Authority: WO
Inventors: Il Keun Roh; Chi Jang Moon; Sae Choong Park; Myoung Goo Kim; Young Key Choi; Sea Han Oh; Seong Soo Yim; Moo Je Sung; Sang Geun AN
Original assignee: DAE WONG PHARMACEUTICAL Co Ltd; Daewoong Pharmaceutical Co Ltd
Current assignee: DAE WONG PHARMACEUTICAL Co Ltd; Daewoong Pharmaceutical Co Ltd
Priority date: 1991-05-25
Filing date: 1991-10-29
Publication date: 1992-12-10
Anticipated expiration: 1993-11-25
Also published as: KR930009796B1; AU8855191A; KR920021561A

Abstract

The present invention relates to a compound of general formula (I) wherein R1a is hydrogen atom or an amino-protecting group; R1b is a C1-C4 alkyl group or a group of formula (a) wherein R3 and R4, being the same or different from each other, are hydrogen atom or a C1-C4 alkyl group and R5 is hydrogen atom, an alkali metal or a carboxyl-protecting group; R2 is a C1-C4 alkyl group or a C1-C4 alkyl group substituted by a carboxyl group, an amino group or a hydroxyl group; and Q is carbon or nitrogen atom, and a pharmaceutically acceptable salt thereof. The cephalosporin compound according to the present invention shows potent antimicrobial activity and broad antibacterial spectrum against both gram-negative and gram-positive strains. Thus, the compounds are expected to be very useful for treating the intractable infectious diseases caused by these microorganisms.

Description

NOVEL CEPHALOSPORINS AND

PROCESSES FOR PREPARATION THEREOF

Field of the Invention

The present invention relates to a novel cephalosporin and a pharmaceutically acceptable salt thereof, which are useful as an antibacterial agent. The invention also relates to processes for preparing the same and to a pharmaceutical composition containing one or more of the same as an active ingredient.

Background of the Invention

It has been known that a variety of cephalosporin antibiotics, of which 3- and 7-positions in the nucleus (A):

are substituted, show an antimicrobial activity against both gram-negative and gram-positive bacteria and are useful for treating various infectious diseases.

Particularly, the cephalosporins whose 3-position is substituted by quaternary ammonium methyl and 7-position is substituted by a variety of acylamino group exhibit potent antimicrobial activity against those belonging to genera Staphylococcus and Pseudomonas. Among those having zwiterion in their structure, the following compounds have been reported: Cephaloridine in French patent No. 1,384,197; Ceftazidime in USP 4,250,041 and 4,328,453; Cefpimizole in the Journal of Antibiotics, 1983, 242, Cefepime in the Journal of Antibiotics, 1988, 86 and ME-1228. in the Journal of Antibiotics, 1990, 62. Ceftazidime shows relatively weak antibacterial activity against Staphylococcus although it shows an excellent antibacterial activity against Pseudomonas.

It has been known that the cephalosporins whose

3-position is substituted by groups other than quaternary ammonium methyl, for example Cefotaxime in USP 4,152,432 and 4,098,888, Cefmenoxime in USP 4,098,888 and 4,476,122 and Ceftriaxone in USP 4,327,210 have relatively weak antibacterial activity against Staphylococcus when compared with Cefazoline in USP 3,516,997.

Thus, the present inventors have made intensive researches to provide novel cephalosporins having a potent antibacterial activity against both of Staphylococcus and Pseudomonas. As a result thereof, we found that the cephalosporins whose 3-position is substituted by a benzotriazole group and 7-position is substituted by a variety of acylamino groups have a potent antimicrobial activity against Staphylococcus as well as Pseudomonas. Summary of the Invention

An object of the invention is to provide a novel cephalosporin of the formula (I):

wherein,

R_1a is hydrogen atom or an amino-protecting group;

R_1b is a C₁-C₄ alkyl group or a group of the formula: wherein R₃ and R₄, being the same or different

from each other, are hydrogen atom or a C₁-C₄ alkyl group and R₅ is hydrogen atom, an alkali metal or a carboxyl-protecting group;

R₂ is a C₁-C₄ alkyl group or a C₁-C₄ alkyl group substituted by a carboxyl group, an amino group or a hydroxyl group; and

Q is carbon or nitrogen atom,

and a pharmaceutically acceptable salt thereof.

The other object of the invention is to provide processes for preparing the compound of the formula (I).

The another object of the invention is to provide a pharmaceutical composition containing one or more of the compound of the formula (I) as an active ingredient in admixture with a pharmaceutically acceptable carrier or expient.

Detailed Description of the Invention

The novel cephalosporins according to the invention may be represented by the formula (I):

wherei n ,

R_1a is hydrogen atom or an amino-protecting group;

Q is carbon or nitrogen atom.

The compound of the formula (I) may be represented by or .

However, the syn isomer is generally preferred.

The compound of the formula (I) according to the invention may be prepared as a pharmaceutically acceptable salt and may include an inorganic acid salt (e.g., sulfate, hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphate etc.), an organic carboxylic acid salt (e.g., acetate, maleate, tartrate, fumarate, citrate, succinate, malate, lactate, oxalate, etc.), a sulfonic acid salt(e.g., methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), a salt with a basic, or acidic amino acid (e.g., salts with arginine, asparagine, glutamine, lysine, etc.), an inorganic salt, for example, metal salts such as an alkali, metal salt (e.g., sodium, potassium), and an alkaline earth metal salt (e.g., calcium, magnesium), an ammonium salt, and an organic salt (e.g., trimethylamine, triethylamine, pyridine, procaine, picoline, dieyelohexylamine, N-methylglucamine, diethanolamine, triethanolamine, phenylethylbenzylamine, dibenzylethylenediamine, etc.).

For the present invention, an inorganic acid salt such as sulfate or hydrochloride and an organic acid salt such as maleate or fumarate are particularly preferred since they are formed as a stable crystalline salt of the compound (I).

According to the present invention, processes for preparing the compound (I) and a pharmaceutically acceptable salt thereof are provided.

The cephalosporins according to the invention may be prepared by the following processes:

Process 1

According to the present invention, the compound of the formula (I) may be prepared by reacting a compound of the formula (II):

wherein, R_1a, R_1b and R₂ are the same as defined above; L is a leaving group selected from a halogen atom e.g., chlorine, bromine or iodine, or an acetoxy group; and R₆ is hydrogen atom, an alkali metal or a carboxyl-protecting group, with a benzotriazole compound of the formula (III):

wherein, R₂ is the same as defined above.

In order to prepare the compound of the formula (I), the compound (II) in which L is an acetoxy group is condensed with the compound (III) in accordance with a method described in EP 318,552. The compound (II) in which L is a halogen atom may be condensed with the compound (III) in accordance with a method described in Japanese unexamined patent publication Nos. 81-13159, 83-90590 or 84-10593 to give the compound of the formula (I).

in the process for preparing the compound (I), the condensation reaction of the compound (II) in which L is an acetoxy group with the compound (III) can be advantageously carried out in the presence of a polar solvent, for example, water, a phosphate buffered solution, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethylsulfoxide, dioxane, methanol or ethanol, or a mixed solvent thereof with water.

The reaction is preferably carried out at a neutral pH . The reaction temperature is not specifically limited, but usually ranges between room temperature and about 70°C.

The reaction time varies depending the reaction conditions, but is generally 1 to 10 hours.

The reaction may be accelerated by adding a alkali metal halide, for example, sodium iodide, lithium iodide or potassium iodide to the reaction mixture.

The example of the compound (III), which is to be introduced into 3-position of the formula (I) via the substitution reaction of the compound (III) with the compound (II), may include 1-methylbenzotriazole, 1-ethylbenzotriazole, 1 - car b ox yme t h y l be n zot r i a z o l e , 1 - ethoxycarbonyl methyl benzotriazole, 1 -(2-hydroxyethyl) benzotriazole, 1-(2-aminoethyl) benzotriazole and the like. These compounds may be prepared by a known method, for example, the method of Krollpfeiffer, F., Justus. Liebigs. Ann. Chem., 1935, 515 113.

Process 2

The compound of the formula (I) according to the invention may be prepared by acylating a compound of the formula (IV):

wherein, R_1a, R_1b and Q are the same as defined above, or a reactive derivative thereof with a compound of the formula (v):

wherein, R₂ and R₆ are the same as defined above,, and X^⊝ is a halogen atom or an acid residue, and, if necessary, removing any protecting group.

The starting compound (IV) may be obtained by a known method, for example, the method described in the Journal of Antibiotics, Vol. 36, No. 8, p1020 (1983).

The starting compound (V) may be prepared by condensing the compound of the formula(III):

wherein, R₂ is the same as defined above

with a compound of the formula(VI):

wherein, R₆ and L are the same as defined above and R₇ is an acyl, formyl, salicylaldehyde or benzaldehyde group, to obtain a compound of the formula (VII):

wherein, R₂, R₆, R₇ and X^⊝ are the same as defined obove, and removing any amino- or carboxyl-protecting group from the compound (VII).

The compound (VI) may be obtained according to the methods described in Japanese unexamined patent publication

83-72590, Japanese unexamined patent publication No. 83- 154588 or the Journal of Antibiotics, Vol. 39, No. 18, p 1092

(1986).

In the process 2, the acylation reaction can be effected by reacting 1 mole of the compound (V) with 1 to 3 moles of ester of the compound (IV) or the reactive derivative thereof.

Suitable examples of the reactive derivative of the compound (IV) may include acid halides, acid anhydrides, activated amides or activated esters. Preferred examples are acid halides such as acid chloride, acid bromide, mixed anhydrides such as acetic acid, pivalic acid, isopivalic acid, trichloroacetic acid, activated amides such as pyrazole, imidazole, dimethylpyrazole, benzotriazole, and activated esters such as p-nitrophenylester, 2,4-dinitrophenylester, trichlorophenylester, 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphtal imide.

The acylation is preferably conducted in the presence of condensing agents in case that the compound (IV) is in the free acid form. The examples of the condensing agent may include a carbodiimide compound such as N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethyl- car bod i i mi de , N-cyc l ohexy l -N ' - ( 4-di et hyl ami nocyc l ohexyl ) carbodiimide and the like. The acylation also may be conducted in the presence of Vilsmeyer reagents formed from the reaction of an amide compound such as N-methylformamide or N,N-dimethylformamide with a halide compound such as thionyl chloride, phosphorus oxychloride or phosgene.

When an acid halide or acid anhydride is used as a reactive derivative, it is essential to conduct the acylation in the presence of acid condensing agents, for example an organic base such as triethylamine, trimethylamine, ethyldiisopropylamine, N,N-dimethylamine, N-methylmorpholine or pyridine, an alkai metal compound such as hydroxide, carbonate or bicarbonate of sodium, potassium or calcium, and an oxylan such as ethylene oxide or propylene oxide.

The reaction is carried out in the presence of the solvent which does not influence the reaction adversely. The examples of the solvent may include water, acetone, acetonitrile, dioxane, tetrahydrofuran, dichloromethane, chloroform, dichloroethane, N,N-dimethylformaimde or mixtures thereof.

The reaction temperature is not specifically limited, but generally ranges between -30ºC and 40°C.

The reaction time generally ranges between 30 min and 10 hours.

in the above processes for preparing the compound (I), various amino- or carboxyl-protecting groups are employed, which are suitably selected from those used in the field of ß- lactam and peptide synthesis.

Suitable examples of the amino-protecting group may include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t- butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p- nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, trityl or trimethylsilyl group.

Suitable examples of the carboxyl-protecting group may include t-butyl, t-amyl, benzyl, p-nitrobenzyl, p- methoxybenzyl, benzhydryl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, methylthiomethyl, trityl, trichloroethyl, trimethylsilyl, dimethylsilyl or dimethylaminoethyl group.

The protecting group should be removed by a method suitably selected depending on the kind of the protecting group from the methods using an acid, base or hydrazine, which are usually employed in the field of ß-lactam and peptide synthesis.

The compound of the formula (I), when its 3-position is substituted by the compound (III), may exist in the tautomeric forms and the tautomers are recognized to be equivalent to each other. These tautomers are also included within the scope of the invention and the position of the positive charge changes depending on the state of salt, the kind of solvent, the properties of solution, the temperature, the kind of substi tuent and the like. Such tautomeric equlibrium can be represented by the following scheme:

In vitro antibacterial activity of the compound (I) according to the invention against standard test strains and methicillin-resistant Staphylococcus strains was determined by Agar-plate dilution method as described below. That is, two-fold serial dilutions of the antibacterial compounds (1000μg compound/ml) were prepared and dispersed in Muller Hinton Agar in a petr i dish to a concentration of 100-0.002μg/ml. One loopful of the culture broths of the standard test strains(10⁷ CFU/ml) were streaked on the medium and incubated at 37°C for 18 hours. The concentration of the compound (I) at which the strains were not grown was regarded as minimum inhibition concentration (MIC). The results were shown in Tables 1 and 2.

As shown in Tables 1, and 2, the compound (I) of the invention exhibits broader antibacterial spectrum and more potent antibacterial activity against gram-negative and gram- positive strains in comparison with Cefotaxime-Sodium. Particularly, the compound of Example 1 exhibits superior activity against ß-lactamase producing strains such as Pseudomonas aeruginosa and Enterobacter cloacae which have clinical problems in the field of cephem antibiotics as well as show strong activity against gram-positive strains, for example, Staphylococcus aureus which is resistant to the third-generation cephalosporins.

The compounds of Examples 7 and 10 also exhibited excellent antibacterial activity against gram-positive strains as well as against gram-negative strains including Pseudomonas.

Accordingly, the compound of the invention is expected to be very useful for treatment of an intractable infection diseases caused by Staphylococcus or Pseudomonas.

Further, in order to illustrate the usefulness of the compound (I) as a drug, the compounds of Examples 1, 7 and 10 were tested for acute toxicity by using 4 weeks-old male ICR-mouse as a test animal.

The compounds were dissolved in physiological saline and phosphate buffered solution (pH 7.0), or if they were not soluble, suspended in carboxymethyl cellulose or gum Arabic and then mixed with phosphate buffered solution. The solution or mixture was administered to the tested animals intravenously or subcutaneously and, after 1 week, the number of surviving animals was calculated.

The results of the acute toxicity test were shown in Table 3.

As shown in the Table 3, the LD₅₀ of the tested compounds are more than 3000 mg/kg when intravenously administered and more than 5000 mg/kg when subcutaneously administered, so that it was demonstrated that their safety as a drug was very high.

As described above, the compound according to the present invention exhibits potent and broad antibacterial activity against gram-positive strains as well as gram-negative strains including Pseudomonas, while its toxicity is very low.

The compounds of the invention may be administered parenterally for treatment of bacterial infection in human beings in a dose of 50-1000mg, preferably 100-500mg per adult, 2-4 times a day.

The pharmaceutical composition according to the invention contains the compounds (I) as an active ingredient in association with a solid or liquid excipient. The excipient may include those one which are commonly employed in the filed of antibiotic pharmaceutics.

The pharmaceutical composition may be formulated into sol id formulations, for example, tablet, capsule or powder, or liquid formulations, for example, injection solution, suspension or syrup. The liquid formulations are preferred.

The present invention will be described in detail with reference to the following examples, but is not limited thereto.

Reference Example 1

Synthesis of 1-methylbenzotriazole

To 15ml of methanol were added 0.88g(15.8mmol) of potassium hydroxide, and 1.79g(15mmol) of 1H-benzotriazole and 4.67ml(75mmol) of iodomethane were dissolved therein. The solution was refluxed for 3 hours.

The reaction solution was concentrated under reduced pressure and 20ml of water and 20ml of ethyl acetate were added thereto. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The concentrate was purified by silica gel column chromatography using dichloromethane : methanol (9:1) as an eluant. 1.41g(70%) of the desired compound were obtained as white needle crystals.

m.p. : 64 - 67°C TLC (dichloromethane : methanol = 9:1) Rf=0.35

NMR (DMSO-d₆, δ)

4.32 (s, 3H, CH₃), 7.30 - 8.07 (m, 4H, phenyl)

Reference Example 2

Synthesis of 1-ethylbenzotriazole

By following the procedure in Reference Example 1 except that 6ml(75mmol) of iodoethane was employed in place of iodomethane, there were obtained 1.61g(739.) of the desired compound.

m.p. : 52 - 54ºC

NMR (DMSO-d₆, δ)

1.23 (t, 3H, -CH₃), 3.95 (q, 2H, -CH₂ -)

7.30 - 8.07 (m, 4H , phenyl)

Reference Example 3

Synthesis of 1-carboxymethyl benzotriazole

To 20ml of ethanol were added 0.92g(23mmol) of sodium hydroxide,, and 1.18g(10mmol) of 1H-benzotriazole were added thereto. 1.81g(13mmol) of chloroacetic acid were added and the mixture was refluxed for 2 hours. The reaction solution was cooled to room temperature and neutralized with 6N hydrochloric acid. The resulting sodium chloride was removed by filtration and the solution was concentrated under reduced pressure.

The residues obtained were purified by silica gel column chromatography to give 1.26g(71%) of the desired compound, m.p. : 71 - 73ºC NMR (DMSO-d₆, δ)

5.43 (s, 2H, -CH₂-), 7.31 - 8.03 (m, 4H, phenyl)

Reference Example 4

Synthesis of 1-ethoxycarbonylmethyl benzotriazole

By following the procedure in Reference Example 3 except that 1.59g(13mmol) of ethyl chloroacetate were employed in place of chloroacetic acid, there were obtained 1.25g(61%) of the desired compound,

m.p. : 67 - 69ºC

NMR (CDCl₃, δ)

1.24 (t, 3H, -CH₃), 4.17 (q, 2H , -CH₂-)

5.06 (s, 2H, -CH₂-), 7.30 - 8.05 (m, 4H, phenyl)

Reference Example 5

Synthesis of 1-(2-hydroxyethyl)benzotriazole

To 20ml of methanol were added 0.59g(10.5mmol) of potassium hydroxide, and 1.19g(10mmol) of benzotriazole and 1.42ml(20mmol) of 2-bromoethanol were dissolved therein. The solution was refluxed for 5 hours.

The reaction solution was concentrated under reduced pressure and 30ml of water and 30ml of ethyl acetate were added thereto. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residues were purified by silica gel column chromatography using dichloromethane-methanol (9:1) as an eluant and concentrated under reduced pressure to give 0.83g(51%) of an oily desired compound.

TLC (dichloromethane: methanol=9:1) Rf=0.6

m.p. : 58 - 63ºC

NMR (CDCl₃, δ)

4.24 (t, 2H, -CH₂-), 4.85 (t, 2H, -CH₂-)

7.26 - 7.91 (m, 4H , phenyl)

Reference Example 6

Synthesis of 1-(2-aminoethyl)benzotriazole

By following the procedure in Reference Example 5 except that 4.1g(20mmol) of 2-bromoethylamine were employed in place of 2-bromoethanol, there were obtained 0.89g(55%) of the desired compound.

m.p. : 65 - 67ºC

NMR (DMSO-d₆, δ)

4.21 (t, 2H, -CH,-), 4.64 (t, 2H , -CH₂-)

7.27 - 7.89 (m, 4H , phenyl)

Example 1

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4- yl)-2-methoxyiminoacetamido]-3-[(1-methylbenzotriazol- 3-ium)methyl]-ceph-3-em-4-carboxylate

In a mixture of 10ml of acetonitrile and 15ml of water were dissolved 6.69g(50mmol) of lithium iodide and the solution was heated to 67-70ºC.

2.40g(18mmol) of 1-methylbenzotriazole and 4.77g(10mmol) of sodium (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-ceph-3-em-4-carboxylate were added and the mixture was reacted at 74-75ºC for 20 min while adjusting the reaction mixture to pH 6.5-7.0.

After the reaction, the solution was cooled to room temperature and stirred for 30 min while adjusting to pH 1-1.5 with 3N hydrochloric acid. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The concentrate was passed through the columns packed with aluminium oxide and silica gel, respectively. The columns were eluted with 80% aqueous acetonitrile. The eluates obtained were concentrated under reduced pressure.

Then, the concentrate was dissolved in a small amount of water and passed through a column packed with Diaion HP-20(Mitsubishi). The column was eluted with 15% aqueous acetonitrile, and the fractions containing the desired compounds were concentrated under reduced pressure and freeze-dried to give 1.27g(24%) of the desired compound in a pale yellow amorphous form,

m.p. : 146ºC (dec.)

Rf = 0.3 (80% aqueous acetonitrile)

MS (FAB, M+1) : 529

NMR (DMSO-d₆, δ)

3.33 (m, 2H, C-2), 3.82 (s, 3H, -OCH₃)

4.65 (s, 3H, -CH₃), 5.18 (d, 1H, C-6)

5.90 - 6.07 (m, 3H , C-3 , C-7)

6.75 (s, 1H, thiazole), 7.38 - 8.05 (m, 4H, phenyl) Example 2

Synthesis of ( 6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-methoxyiminoacetamido]-3-[(1-ethylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate

By following the procedure in Example 1 except that 2.65g( 18mmol ) of 1-ethylbenzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 1.14g(213.) of the desired compound.

m.p. : 153°C (dec.)

NMR (DMSO-d₆, δ)

1.23 (t, 3H, -CH₃), 3.45 (m, 2H, C-2)

3.82 - 3.94 (m, 5H, -0CH₃, -CH₂-)

5.07 (d, 1H, C-6), 5.52 (d, 1H, C-7)

6.05 (m, 2H, C-3), 6.87 (s, 1H, thiazole)

7.35 - 8.02 (m, 4H, phenyl)

Example 3

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-methoxyiminoacetamido]-3-[(1-carboxymethylbenzotriazol- 3-ium)methyl]-ceph-3-em-4-carboxylate

By following the procedure in Example 1 except that 3.19g( 18mmol ) of 1-carboxymethylbenzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 0.86g(15%) of the desired compound.

m.p. : 152ºC (dec.)

NMR (DMSO-d₆ + D₂O, δ)

3.41 - 3.55 (m, 2H, C-2), 3.91 (s, 3H, -OCH₃) 5.01 (d, 1H, C-6), 5.42 (s, 2H, -CH₂- )

5.57 (d, 1H, C-7), 5.98 (m, 2H, C-3)

6.78 (s, 1H, thiazole), 7.36 - 8.03 (m, 4H, phenyl) Example 4

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- methoxyiminoacetamido]-3-[(1-ethoxycarbonylmethyl- benzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate By following the procedure in Example 1 except that 3.69g(18mmol) of 1-ethoxycarbonylmethylbenzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 1.02g(17%) of the desired compound,

m.p. : 150ºC (dec.)

NMR (DMSO-d₆, δ)

1.23 (t, 3H, -CH₃), 3.35 (m, 2H, C-2)

3.92 (s, 3H, -OCH₃), 4.18 (q, 2H, -CH₂-)

4.98 (d, 1H, C-6), 5.11 (s, 2H, -CH₂-)

5.53 (d, 1H, C-7), 6.01 (d, 2H, C-3)

6.81 (s, 1H, thiazole), 7.37 - 8.04 (m, 4H, phenyl) Example 5

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-methoxyiminoacetamido]-3-[(1-(2-hydroxyethyl)

benzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate By following the procedure in Example 1 except that 3.26 (20mmol) of 1-(2-hydroxyethyl)benzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 0.84g(15%) of the desired compound. m.p. : 153°C (dec.)

NMR (DMSO-d₆ + D₂O, δ)

3.38 (m, 2H, C-2), 3.88 (s, 3H, -OCH₃)

4.31 (t, 2H, -CH₂-), 4.83 - 5.07 (m, 3H, -CH₂-, C-7) 5.54 (d, 1, C-6), 6.02 (d, 2H, C-3)

6.74 (s, 1H, thiazole), 7.35 - 8.01 (m, 4H, phenyl) Example 6

Synthesis of (6R,7R)-7-[(z)-2-(2-aminothiazol-4-yl)- 2-methoxyiminoacetamido]-3-[(1-(2-aminoethyl)

benzotri azol -3- ium )methy l ] -ceph-3-em-4-carboxyl ate

By following the procedure in Example 1 except that 3.24g(20mmol) of 1-(2-aminoethyl)benzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 1.01g(18%) of the desired compound.

m.p. : 151ºC (dec.)

NMR (DMSO-d₆ + 20% DCl, δ)

3.57 (m, 2H, C-2), 4.01 (s, 3H, -OCH₃)

4.24 (t, 2H, -CH₂-), 4.84 - 5.15 (m, 3H, -CH₂-, C-6) 5.67 (d, 1H, C-7), 6.01 (m, 2H, C-3)

7.01 (s, 1H, thiazole), 7.47 - 8.11 (m, 4H, phenyl) Example 7

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-carboxymethoxyiminoacetamindo]-3-[(1- methylbenzotriazol-3-ium)methyl]-ceph-3-em-4- carboxylate

To a mixture of 9ml of acetonitrile and 15ml of water were dissolved 5.35g(40mmol) of lithium iodide, 1.06g(8mmol) of 1-methylbenzotriazole were added thereto and the mixture was heated to 68ºC.

2g(4mmol) of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- carboxymethoxyiminoacetamido]-3-acetoxymethyl-ceph-3-em-4- carboxylic acid were added and the mixture was reacted at 70- 72ºC for 1.5 hours while adjusting to pH 6.5-7.0.

After the reaction, the solution was cooled to room temperature and adjusted to pH 1.5 with 3N hydrochloric acid. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure and then subjected to aluminium oxide column chromatography using 80% aqueous acetonitrile as an eluant. The eluates were concentrated under reduced pressure.

Thus obtained concentrate was dissolved in a small amount of water and passed through a column packed with Diaion HP-20. The fractions containing the desired compound were concentrated under reduced pressure and freeze-dried to give 0.35g(15%) of the desired compound,

m.p. : 158ºC (dec.)

Rf : 0.25 (80% aqueous acetonitrile)

NMR (DMSO-d₆, δ)

3.48 (m, 2H, C-2), 4.31 (s, 3H, -CH₃)

4.65 (s, 2H, -CH₂-), 5.12 (d, 1H, C-6)

5.53 (d, 1H, C-7), 6.03 (m, 1H, C-3)

6.78 (s, 1H, thiazole), 7.36 - 8.03 (m, 4H, phenyl) Example 8

Synthesis of ( 6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-carboxymethoxyiminoacetamido]-3-[(1-(2-hydroxyethyl) benzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate By following the procedure in Example 7 except that

1.30g(8mmol) of 1-(2-hydroxyethyl)benzotriazole were employed in place of 1-methylbenzotriazole, there were obtained

0.41g(17%) of the desired compound.

m.p. : 160°C (dec.)

NMR (DMSO-d₆ + D₂O, δ)

3.51 (m, 2H, C-2), 4.31 (t, 2H , -CH₂-)

4.63 (s, 2H, -CH₂-), 4.83 - 4.96 (m, 3H, -CH₂-, C-6)

5.60 (d, 1H, C-7), 6.02 (m, 2H, C-3)

6.75 (s, 1H, thiazole), 7.35 - 8.02 (m, 4H, phenyl)

Example 9

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- carboxymethoxyiminoacetamido]-3-[(1-(2-aminoethyl) benzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate By following the procedure in Example 7 except that

1.30g(8mmol) of 1-(2-aminoethyl)benzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 0.36g(15%) of the desired compound.

m.p. : 155°C (dec.)

NMR (DMSO-d₆ + D₂O, δ)

3.51 (m, 2H, C-2), 4.27 (t, 2H, -CH₂-)

4.63 (s, 2H, -CH₂-), 4.84 - 5.01 (m, 3H, -CH₂-, C-6) 5.59 (d, 1H, C-7), 5.91 (m, 2H, C-3)

6.75 (s, 1H, thiazole), 7.44 - 8.07 (m, 4H, phenyl) Example 10

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-(2-carboxyprop-2-oxyimino)acetamido]-3-[(1- methylbenzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate In a mixture of 10ml of acetonitrile and 15ml of water were dissolved 5.35g(40mmol) of lithium iodide, 1.06g(8mmol) of 1-methylbenzotriazole were added thereto and the mixture was heated to 65-68ºC.

2.11g(4mmol) of (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- (2-carboxyprop-2-oxyimino)acetamido]-3-acetoxymethyl-ceph-3- em-4-carboxylic acid were added and the mixture was reacted at 70-72ºC for 2 hours while adjusting to pH 6.5-7.0.

After the reaction, the solution was cooled to room temperature and adjusted to pH 1-1.5 with 3N hydrochloric acid. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure and then purified by aluminium oxide column chromatography using 80% aqueous acetonitrile as an eluant. The eluates were concentrated under reduced pressure.

Thus obtained concentrate was dissolved in a small amount of water and passed through a column packed with Diaion HP-20. The fractions containing the desired compound were concentrated under reduced pressure and freeze-dried to give 0.43g(18%) of the desired compound. m.p. : 155°C (dec.)

MS (FAB, M+1) ; 601

NMR (DMSO-d₆, δ)

1.50 (s, 6H, CH₃-C-CH₃), 3.45 (m, 2H, C-2)

4.32 (s, 3H, -CH₃), 5.09 (d, 1H, C-6)

5.58 - 6.08 (m, 3H, C-3, C-7)

6.78 (s, 1H, thiazole), 7.35 - 8.02 (m, 4H, phenyl) Example 11

Synthesis of ( 6R,7R)-7-[(Z)-2-(2-aminothiazol-4- yl)-2-carboxyprop-2-oxyiminoacetamido]-3-[(1- carboxymethylbenzotriazol-3-ium)methyl]-ceph-3- em-4-carboxylate

By following the procedure in Example 10 except that 1.42g(8mmol) of 1-carboxymethylbenzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 0.33g(13%) of the desired compound,

m.p. : 160ºC (dec.)

NMR (D₂O, δ)

1.49 (s, 6H, CH₃-C-CH₃), 3.47 (m, 2H, C-2)

5.12 (d, 1H, C-6), 5.43 (s, 2H, -CH₂-)

5.57 - 6.15 (m, 3H, C-3, C-7)

6.81 (s, 1H, thiazole), 7.34 - 8.01 (m, 4H, phenyl) Example 12

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-carboxyprop-2-oxyimi noacetami do]-3-[(1 -(2- hydroxyethyl)benzotriazol-3-ium)methyl]-ceph-3-em- 4-carboxylate

By following the procedure in Example 10 except that 1.30g(8mmol) of 1-(2-hydroxyethyl)benzotriazole were employed in place of 1-methylbenzotriazole, there were obtained 0.40g(16%) of the desired compound,

m.p. : 158ºC (dec.)

NMR ( D₂O , δ )

1.50 (s, 6H, CH₃-C-CH₃), 3.41 (m, 2H, C-2)

4.33 (t, 2H, -CH₂-), 4.84 - 5.11 (m, 3H , -CH₂-, C-6) 5.53 (d, 1H, C-7), 6.01 (m, 2H, C-3)

6.82 (s, 1H, thiazole), 7.35 - 8.01 (m, 4H, phenyl) Preparation Example 1

Synthesis of 4-methoxybenzyl 7ß-(2- hydroxybenzylideneamino)-3-chloromethyl-ceph-3- em-4-carboxylate

In 50ml of methanol were dissolved 4.05(10mmol) of 4-methoxybenzyl 7ß-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride and 1.28ml(12mmol) of sal icylaldehyde and 1.39ml(10mmol) of triethylamine were added thereto.

The mixture was stirred for 5 hours. The resulting precipitates were filtered, washed with 50ml of methanol and dried to give 4.26g(90%) of the desired compound.

NMR (DMSO-d₆, δ)

3.7 (d, 2H, C-2), 3.77 (s, 3H, -OCH₃)

4.53 (s, 2H), 5.22 (s, 2H )

5.35 (d, 1H), 5.66 (d, 1H) 6.85 - 7.58 (m, 8H , phenyl), 8.75 (s, 1H)

Preparation Example 2

Synthe si s of 4- methox ybenzy l 7ß- ( 2 - hydroxybenzylideneamino)-3-[(1-methylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate iodide

To 50ml of acetone were added 4.73g(10mmol) of 4-methoxybenzyl 7ß-(2-hydroxybenzylideneamino)-3-chloromethyl-ceph-3-em-4-carboxylate prepared in Preparation Example 1 and

1.6g(10.7mmol) of sodium iodide were added thereto. The mixture was stirred for 3 hours in the dark and concentrated under reduced pressure to evaporate acetone.

To thus obtained concentrate were added 4.8ml of acetone and 4.05g(30mmol) of 1-methylbenzotriazole and the mixture was stirred at 20-25°C for 24 hours.

50ml of acetone were added to the reaction solution and the insolubles were filtered off. After a mixture of 500ml of di isopropyl ether and 500ml of diethyl ether was added to the filtrate, the precipitates formed were filtered and dried to give 5.93g(85%) of the desired compound.

NMR (DMSO-d₆, δ)

3.76 (s, 5H, -OCH₃, C-2), 4.31 (s, 3H, -CH₃)

5.27 (s, 2H, ), 5.43 (d, 1H, C-6)

5.82 (d, 1H, C-7), 6.2 (dd, 2H, C-3)

6.8 - 7.6 (m, 8H, phenyl)

8.0 - 8.33 (m, 4H, benzotriazole), 8.83 (s, 1H) Preparation Example 3

Synthesis of 4-methoxybenzyl 7ß-am ino-3- [ ( 1 - methylbenzotriazol-3-ium)methyl]-ceph-3-em-4- carboxylate iodide hydrochloride

In 25ml of acetone were dissolved 6.99g(10mmol) of 4- methoxybenzyl 7ß-(2-hydroxybenzylideneamino)-3-[(1- methylbenzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate iodide prepared in Preparation Example 2 and 10ml of cone, hydrochloride were gradually added at 0-5ºC.

100ml of isopropyl alcohol were added to the reaction solution, and the resulting precipitates were filtered and dried to give 4.69g(73%) of the desired compound.

NMR (DMSO-d₆, δ)

3.74 (s, 5H, -OCH₃, C-2), 4.29 (s, 3H, -CH₃)

5.2 (bs, 2H, ), 5.4 (s, 2H , C-6, C-7)

5.95 (dd, 2H, C-3), 6.8 - 7.3 (m, 4H , phenyl)

8.0 - 8.27 (m, 4H, benzotriazole)

Preparation Example 4

Synthesis of 4-methoxybenzyl (6R,7R)-7-[(Z)-2-(2- aminothiazol-4-yl)-2-methoxyiminoacetamindo]-3-[(1- methylbenzotriazol-3-ium)methyl]-ceph-3-em-4- carboxylate iodide

To a mixture of 1.12ml(12mmol) of phosphorous oxychloride and 40ml of ethyl acetate were added 2.21g(11mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and the mixture was stirred at 2-6ºC for 30 min.

Additional 1.12ml(12mmol) of phosphorous oxychloride were added thereto and the mixture was stirred at 4-6°C for 30 min. 0.93ml(12mmol) of N,N-dimethylformamide were added to the reaction solution and the mixture obtained was stirred at the same temperature for 1 hour.

Thus obtained solution was added to a solution of 6.30g(10mmol) of 4-methoxybenzyl 7ß-amino-3-[(1-methylbenzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate iodide-HCl prepared in Preparation Example 3 and 14.8ml(60mmol) of N,O-bistrimethylsilylacetamide in 40ml of ethyl acetate at -10 - -5ºC and the mixture was stirred at -5°C for 30 min.

To the reaction solution were added 100ml of ethyl acetate and 50ml of water and the mixture was adjusted to pH 6-7 with sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added 300ml of diisopropyl ether, and the resulting precipitates were filtered and dried to give 6.06g(78%) of the desired compound.

NMR (DMSO-d₆, δ),

3.28 - 3.7 (m, 5H , C-2, -OCH₃)

3.9 (s, 3H, -OCH₃), 4.31 (s, 3H, -CH₃)

5.1 (q, 2H, ), 5.35 (d, 1H, C-6)

5.66 (d, 1H C-7), 5.9 ( dd , 2H , C-3)

6.8 - 7.3 (m, 5H, phenyl, thiazole-H)

8.0 - 8.3 (m, 4H, benzotriazole)

Example 13

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol- 4-yl)-2-methoxyiminoacetamido]-3-[(1- methylbenzotriazol-3-ium)methyl]-ceph-3-em-4- carboxylate

In a mixture of 15ml of trifluoroacetic acid and 7.5ml of anisole were dissolved 7.7g(10mmol) of 4-methoxybenzyl (6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl )-2- methoxyiminoacetamido]-3-[(1-methylbenzotriazol-3-ium)methyl]- ceph-3-em-4-carboxylate iodide prepared in Preparation Example 4, and the solution was stirred at 35ºC for 4 hours.

The reaction solution was concentrated under reduced pressure and 500ml of diethyl ether were added thereto. The resulting precipitates were filtered and water was added to the solid. After adjusting to pH 4-4.5, the solution was passed through a column packed with Diaion HP-20 and the column was eluted with 12% aqueous ethanol. The eluates were concentrated under reduced pressure and freeze-dried to give 3.8g(72%) of the desired compound.

The NMR spectra were identical with those of the product obtained in Example 1.

Preparation Example 5

Synthesis of 7ß-amino-3-[(1-methylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate

In a mixture of 15ml of trifluoroacetic acid and 7.5ml of anisole were dissolved 6.29g(10mmol) of 4-methoxybenzyl 7ß- amino-3-[(1-methylbenzotriazol-3-ium)methyl]-ceph-3-em-4- carboxylate iodide hydrochloride prepared in Preparation Example 3 at 0-5°C and the solution obtained was stirred at 30-35ºC for 4 hours. The reaction solution was concentrated under reduced prossure and 500ml of diisopropyl ether were added thereto. The resulting precipitates were filtered and dried.

After adding water to the precipitates, the solution obtained was subjected to Diaion HP-20 column chromatography using 15% aqueous ethanol as an eluant. The fractions containing the desired compound were concentrated under reduced pressure and freeze-dried to give 2.17g(63%) of the desired compound.

NMR (DMSO-d₆, δ)

3.7 (d, 2H, C-2), 4.30 (s, 3H, -CH₃)

5.2 (S, 2H, C-6, C-7), 6.0 (dd, 2H, C-3)

7.9 - 8.4 (m, 4H, benzotriazole)

Example 14

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- methoxyiminoacetamido]-3-[(1-methylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate

To a mixture of 1.12ml (12mmol) of phosphorous oxychloride and 40ml of ethyl acetate were added 2.21g(11mmol) of (Z)-2- (2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and the mixture was stirred at 2-6ºC for 30 min. Additional 1.12ml(12mmol) of phosphorous oxychloride was added and the resulting mixture was stirred at 4-6ºC for 30 min.

To the solution were added 0.93ml(12mmol) of N,N- dimethylformamide and the mixture was stirred at the same temperature for 1 hour to give a solution.

3.45g( lOmmol ) of 7ß-amino-3-[(1-methylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate prepared in Preparation Example 5 and14.8ml(60mmol) of N,O-bistrimethylsilylacetamide were dissolved in 40ml of ethyl acetate, and the above solution was gradually added thereto at -10 - -5ºC. The resulting mixture was stirred at -5ºC for 30 min.

After completion of the reaction 10ml of methanol were added and the solution was concentrated under reduced pressure. Water was added to the residues and the pH was adjusted to 4-4.5. The solution was purified by Diaion HP-20 column chromatography using 12% aqueous ethanol as an eluant. The eulates were concentrated under reduced pressure and freeze-dried to give 3.96g(75%) of the desired compound.

The NMR spectra were the same as those of the product obtained in Example 1.

Preparation Example 6

Synthesis of 4-methoxybenzyl (6R,7R)-7-[(Z)-2-(2- tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3- [(1-methylbenzotriazol-3-ium)methyl]-ceph-3-em-4- carboxylate iodide

0.63g(3mmol) of phosphorous pentachloride were suspended in 15ml of dichloromethane and then cooled to -30ºC. 1.2g(2.5mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-2- methoxyiminoacetic acid hydrochloride were gradually added thereto and the mixture was stirred at -20 15°C for 2 hours to give a solution.

To 30ml of acetonitrile were added 1.73g(2.75mmol) of 4-methoxybenzyl 7ß-amino-3-[(1-methylbenzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate iodide hydrochloride prepared in Preparation Example 3 and 2.22ml (9mmol) of N,O-bistrimethylsilylacetamide were added thereto. Then, the resulting mixture was stirred at 10-15ºC for 1.5 hours.

To the solution obtained were gradually added the solution prepared in the above at -30 25°C and the mixture was stirred at -20 - -15°C for 1.5 hours, after which 20ml of water and 40ml of ethyl acetate were added. The organic layer was separated, washed with saturated sodium bicarbonate and with saturated brine and dried over anhydrous magnesium sulfate.

The solids were filtered off and the filtrate was concentrated under reduced pressure. The precipitates formed by addition of dichloromethane and diethyl ether were filtered and dried to give 1.54g(55%) of the desired compound.

NMR (DMSO-d₆, δ)

3.6 - 3.8 (m, 2H, C-2), 3.83 (s, 3H) 3.87 (s, 3H), 4.21 (s, 3H)

5.25 - 5.3 (m, 3H), 5.6 - 5.9 (m, 3H)

6.8 (s, 1H, thiazole-H), 6.9 - 7.5 (m, 19H)

7.6 - 7.9 (m, 4H)

Example 15

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-methoxyiminoacetamido]-3-[(1-methylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate

2ml of trifluoroacetic acid and 1ml of anisole were added to 1.0g(1mmol) of 4-methoxybenzyl (6R,7R)-7-[(Z)-2-(2- tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(1- methylbenzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate iodide prepared in Preparation Example 6, and the mixture was stirred at 15 - 20ºC for 2 hours and concentrated under reduced pressure to remove trifluoroacetic acid. The precipitates formed by addition of diisopropyl ether were filtered and dissolved in 5ml of methanol. The insolubles were filtered off and the filtrate was concentrated under reduced pressure.

To the residue was added a small amount of water and the pH was adjusted to 4-4.5. The solution was purified by Diaion HP-20 column chromatography using 12% aqueous ethanol as an eluant. The fractions containing the desired compound were concentrated under reduced pressure and freeze-dried to give 0.38g(72%) of the desired compound.

The NMR spectra were the same as those of the product obtained in Example 1.

Example 16

Synthesis of (6R,7R)-7-[(Z)-2-(5-amino-1,2,4- thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)

acetamido]-3-[(1-methy!benzotriazol-3-ium)methyl]- ceph-3-em-4-carboxyl ate

By following the procedure in Example 10 except that

1.83g(4mmol) of (6R,7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-acetoxymethyl-ceph-3-em-4-carboxylic acid were employed, there were .obtained

0.36g(15%) of the desired compound.

m.p. : 153°C (dec.)

NMR (DMSO-d₆, δ)

1.50 (d, 6H), 3.86 - 4.10 (m, 2H)

4.22 (s, 3H), 5.05 (d, 1H)

5.65 - 5.92 (m, 3H), 7.5 - 8.1 (m, 4H)

Example 17

Synthesis of (6R,7R)-7-[(Z)-2-(5-amino-1,2,4- thiadiazol-3-yl)-2-methoxyiminoacetamido]-3- [(1-methylbenzotriazol-3-ium)methyl]-ceph-3-em- 4-carboxylate

In a mixture of 1ml of acetonitrile and 1.5ml of water were dissolved 0.67g(5mmol) of lithium iodide and the solution was heated to 65 - 67ºC.

0.24g(1.8mmol) of 1-methylbenzotriazole and 0.46g(1mmol) of (6R,7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- methoxyiminoacetamido]-3-acetoxymethyl-ceph-3-em-4-carboxylic acid were added to the solution and the mixture was reacted at 70ºC for 1 hour while adjusting to pH 6.8-7.1. After completion of the reaction, the reaction solution was cooled to room temperature and stirred for 30 min while adjusting to pH 1-1.5 with 3N hydrochloric acid. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The concentrate was passed through columns packed with aluminium oxide and silica gel and the columns were eluted with 80% aqueous acetonitrile. The eluates were concentrated under reduced pressure.

The concentrate obtained was dissolved in a small amount of water and the solution was purified by Diaion HP-20 (Mitsubishi) column chromatography using 15% aqueous ethanol as an eluant to give 0.12g(23%) of the desired compound in a colorless amorphous form,

m.p. : 150ºC (dec.)

NMR (DMSO-d₆, δ)

3.8 - 4.0 (m, 2H), 4.02 (s, 3H)

4.21 (s, 3H), 5.06 (d, 1H)

5.68 - 5.92 (m, 3H), 7.6 - 8.1 (m, 4H)

Example 18

Synthesis of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)- 2-methoxyiminoacetamido]-3-[(1-methylbenzotriazol-3- ium)methyl]-ceph-3-em-4-carboxylate sulfate

In 1.5ml of water were dissolved 0.35g(0.66mmol) of ( 6R, 7R )-7-[(Z )-2-( 2-aminothiazol-4-yl )-2-methoxyiminoacetamido]-3-[(1-methylbenzotriazol-3-ium)methyl]-ceph-3-em-4-carboxylate prepared in Example 1, and the solution was cooled to 5°C and stirred at the same temperature for 30 min while adjusting to pH 1-1.5 with 6N sulfuric acid.

15ml of isopropyl alcohol were added thereto and the mixture was stirred at 0-5ºC for 3 hours. The precipitates obtained were filtered, washed with isopropyl alcohol and diethyl ether and dried to give 0.39g(94%) of the desired compound as white crystals,

m.p. : 160°C (dec.)

MS (FAB, M+1) : 627

NMR (DMSO-d₆, δ)

3.34 (q, 2H, C-2), 3.83 (s, 3H, -OCH₃)

4.31 (s, 3H, -CH₃), 5.02 (d, 1H, C-6)

5.8 - 5.94 (m, 3H, C-3, C-7)

6.74 (s, 1H, thiazole-H), 7.21 (bs, 2H)

8.02 - 8.52 (m, 6H), 9.6 (d, 1H)

Claims

What is claimed is :

1. A compound of the formula (I):

wherein,

R_1a is hydrogen atom or an amino-protecting group;

from each otehr, are hydrogen atom or a C₁-C₄ alkyl group, and

R₅ is hydrogen atom, an alkali metal or a carboxyl-protecting group;

R₂ is a C₁-C₄ alkyl group or a C₁-C₄ group substituted by a carboxyl group, an amino group or a hydroxyl group; and

Q is carbon or nitrogen atom,

and a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R_1a is hydrogen atom, R_1b is methyl group or COOH and R₂ is a

C₁-C₄ alkyl group or a C₁-C₄ alkyl group substituted by a carboxyl group, an amino group or a hydroxyl group, and a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, which is an alkali metal salt, an alkaline earth metal salt, a basic salt, an organic acid salt or an inorganic acid salt.

4. A process for preparing a compound of the formula (I):

wherein,

R_1a is hydrogen atom or an amino-protecting group;

from each other, are hydrogen atom or a C₁-C₄ alkyl group and

R₅ is hydrogen atom, an alkali metal or a carboxyl-protecting group;

Q is carbon or nitrogen atom,

and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula (II):

wherein,

R_1a, R_1b and Q are the same as defined above;

R₆ is hydrogen atom, an alkali metal or a carboxyl- protecting group; and

L is an acetoxy group or halogen atom,

with a compound of the formula (III):

wherein, R₂ is the same as defined above, and, if necessary, removing the amino-protecting group or the carboxyl-protecting group.

5. A process for preparing a compound of the formula (I):

wherein, R_1a is hydrogen atom or an amino-protecting group;

from each other, are hydrogen atom, a C₁-C₄ alkyl or a carboxyl-protecting group;

Q is carbon or nitrogen atom,

and a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula (VI):

wherein,

R₆ is hydrogen atom, an alkali metal or a carboxyl-protecting group; and

R₇ is a formyl, salicylaldehyde or benzaldehyde group, with a compound of the formula (III):

wherein, R₂ is the same as defined above

to give a compound of the formula (V):

wherein, R₂ and R₆ are the same as defined above,

reacting the compound of the formula (V) or a reactive derivative thereof with a compound of the formula (IV):

wherein, R_1a, R_1b and Q are the same as defined above, and, if necessary, removing the amino-protecting group or the carboxyl-protecting group.

6. A pharmaceutical composition which comprises a pharmaceutically effective amount of one or more of the compounds (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, in association with a pharmaceutically acceptable carrier or excipient.