JP2003300985A - Cephem compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cephem compound as an antibacterial agent having quality sufficiently satisfiable as a pharmaceutical. <P>SOLUTION: The cephem compound is shown by the general formula (wherein, m is 0-3 except m=0). <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has excellent antibacterial activity and is useful as a medicine for a cephem compound (particularly its crystal).
And the manufacturing method thereof.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 9-100283 describes a cephem compound having excellent antibacterial activity.

[Chemical 3] 7β- [2- (5-amino-1,2,4-thiadiazole-3-
Iyl) -2 (Z) -ethoxyiminoacetamido] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-
Carboxylates are mentioned.

Further, in JP-A No. 11-255772, there is disclosed a formula in which the water solubility of the compound represented by the formula (III) is increased.

[Chemical 4] Represented by 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl) -2 (Z ) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate is described.

[0004]

[Problems to be Solved by the Invention] When used as a medicine, a compound excellent in quality as a medicine such as purity, stability, storability, and easiness of handling is preferable, and an antibacterial agent sufficiently satisfactory as a medicine is provided. There is an object of the present invention to do so.

[0005]

[Means for Solving the Problems] The inventors of the present invention have conducted various studies in view of the above circumstances, and as a result, the compound represented by the formula (III) has an inner salt structure and is stable to solids. and,
Although it was obtained as an amorphous that is not sufficient in terms of quality, its hydrochloride (I) is obtained as a high quality crystal having solid stability superior to that of the compound represented by the formula (III). The present invention was completed based on the heading.

That is, the present invention is (1) General formula

[Chemical 5] [In the formula, m represents 0 to 3. However, the case of m = 0 is excluded. ] (2) The compound according to (1) above, wherein m is 2. (3) The compound according to (1) or (2) above, which is a hydrate; (4) The above description, which is a crystal. (3) The compound described above; (5) The compound described in (4) above, wherein m is 2 and is a dihydrate; (6) Diffraction angles 5.94, 14.1 in powder X-ray diffraction.
4, 17.90, 21.32, the crystal according to (4) above, which has a peak near 23.64.

(7) A pharmaceutical composition comprising the compound according to (1) above; (8) A pharmaceutical composition according to (7) above which is an antibacterial agent; (9) Above (7) which is an anti-MRSA agent. ) The pharmaceutical composition as described above; (10) General formula

[Chemical 6] [In formula, R shows the amino group which may be protected. ] The compound or its salt represented by these is reacted with HCl, The manufacturing method of the compound as described in said (1); (11) Use of the compound as described in said (1) for manufacture of a pharmaceutical. And (12) a method for treating an infectious disease, which comprises administering an effective amount of the compound according to (1) to an infectious disease patient.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) is a compound consisting of one molecule of the compound (III) and 0 to 3 molecules of hydrochloric acid (the case of 0 molecule of hydrochloric acid is not included in the present invention,
Of course, 0.5 molecule of hydrochloric acid per molecule of compound (III) is also included in the present invention). Further, the compound (I) may be a solvate, and may particularly contain water, and in that case, the water may be taken in as crystallization water or simply adhering water. Further, the compound (I) is preferably in crystalline form from the viewpoint of purity and solid stability. Compound (I) is the compound (II) or a salt thereof,
Hydrophilic organic solvent and HCl (hydrochloric acid or hydrogen chloride)
Can be produced from water containing. As the compound (II) or a salt thereof, a lyophilized product of the compound (IV) or a salt thereof synthesized by the method described in JP-A-11-255772 (for example, Example 1) may be used, or A solution containing the corresponding disodium salt, dipotassium salt, diammonium salt, or a solution thereof such as hydrochloric acid,
The compound (IV) obtained by adding sulfuric acid, nitric acid or the like may be used. Furthermore, instead of the compound (II), the compound (II
Although I) may be used, it is more preferable to use the compound (II). The solution containing the disodium salt of compound (IV) may be a reaction solution containing the disodium salt of compound (IV) obtained as a result of various reactions for synthesizing the disodium salt of compound (IV). Alternatively, it may be a solution of crystals of the disodium salt of compound (IV). Examples of the hydrophilic organic solvent include organic acids such as acetic acid and lactic acid, nitriles such as acetonitrile, ketones such as acetone, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran. Etc., and hydrophilic organic solvents such as mixed solvents thereof, and mixed solvents of these and water. Among these, acetic acid, methanol, ethanol, and a mixed solvent of these with water are preferable, and ethanol, acetic acid, and a mixed solvent of these with water are particularly preferable. As the concentration of hydrochloric acid in water containing hydrochloric acid, 12 mol / L to 0.1 mol / L corresponding to concentrated hydrochloric acid can be used, and 12 mol / L to 6 mol / L is preferable.

R represents an optionally protected amino group. In the field of β-lactams and peptides, amino-protecting groups have been thoroughly studied and their protection methods have already been established, and in the present invention, those known as amino-protecting groups are appropriately adopted. sell. Examples of the amino-protecting group include a phosphono group (or a group that can be converted to a phosphono group), a formyl group, a substituted oxycarbonyl group, an optionally substituted C _6-10 aryl-methyl group, and a substituted group. which may be di- C _{6- 10} aryl - methyl, optionally substituted tri C _6-10 aryl - methyl, optionally substituted C _6-10 aryl -
Methylene group, substituted silyl group, formula MOCO- [In the formula, M represents an alkali metal. ] The group etc. which are represented by these are used.

Here, the group which can be converted into a phosphono group means a group which can be converted into a phosphono group by hydrolysis or substitution reaction, and in addition to the protected phosphono group, for example, dihalophosphoryl such as dichlorophosphoryl and the like. Is mentioned. The protected phosphono group is one protected by a protecting group for a phosphono group. In the field of nucleic acid chemistry, a protecting group for a phosphono group has been thoroughly studied, and a method for protecting it has already been established. In the present invention, those known as a protecting group for a phosphono group can be appropriately adopted. Examples of the protected phosphono group include dihalophosphoryl such as dichlorophosphoryl and the like, dialkoxyphosphoryl group such as dimethoxyphosphoryl, diethoxyphosphoryl and dipropoxyphosphoryl, and O-alkylphosphono such as O-methylphosphono and O-ethylphosphono. Groups such as mono- or di-ester phosphono groups, such as diaminophosphoryl, mono- or diamidated phosphono groups such as (amino) (hydroxy) phosphoryl,
For example, (alkoxy) (amino) phosphoryl group such as (methoxy) (amino) phosphoryl, (ethoxy) (amino) phosphoryl, etc., and (alkoxy) such as (methoxy) (morpholino) phosphoryl, (ethoxy) (morpholino) phosphoryl, etc. ) Monomorphized monoamidated phosphono groups such as (morpholino) phosphoryl groups and the like. Among the amino-protecting groups, the phosphono group or a group that can be converted to a phosphono group is phosphono, dialkoxyphosphoryl, O-alkylphosphono, diaminophosphoryl, (amino) (hydroxy) phosphoryl, (alkoxy).
(Morpholino) phosphoryl or dihalophosphoryl is preferable, and phosphono is particularly preferable.

The "substituted oxycarbonyl group" is, for example, a C _1-10 alkoxy-carbonyl group, a C _3-10 cycloalkyloxy-carbonyl group, a C _5-10 bridged cyclic hydrocarbon oxy-carbonyl group, C _{2-. 10} alkenyloxy-carbonyl group, C _6-10 aryloxy-carbonyl group or C _7-19 aralkyloxy-carbonyl group, as well as C _1-6 alkoxy, C _1-6 alkanoyl, C
_1-10 alkanoyloxy, C _1-10 alkoxy-carbonyloxy, C _3-10 cycloalkyloxy-carbonyloxy, substituted silyl group (substituted silyl group described later, eg, trimethylsilyl, tert-butyldimethylsilyl, etc.), C
_1-6 alkylsulfonyl, halogen, cyano, C _1-6 alkyl includes those having 1 to 3 substituents selected from nitro and the like. Specifically, for example, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, etc. Is used.

“Optionally substituted C _6-10 aryl-
Examples of the “methyl group” include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
C _6-10 aryl-methyl group _optionally substituted with one substituent is used, and specifically, for example, benzyl, naphthylmethyl, p-methylbenzyl, p-methoxybenzyl and the like are used. "Di C which may be substituted
_{As the “6-10} aryl-methyl group”, for example, diC optionally substituted with 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like.
_{A 6-10} aryl-methyl group is used, and specifically, for example, benzhydryl, di (p-tolyl) methyl and the like are used. Examples of the “ _optionally substituted tri-C _6-10 aryl-methyl group” include halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
A tri C _6-10 aryl-methyl group which may be substituted with one substituent is used, and specific examples thereof include trityl and tri (p-tolyl) methyl. Examples of the “ _optionally substituted C _6-10 aryl-methylene group” include halogen, nitro, C _1-6 alkyl, C
_A C _6-10 aryl-methylene group optionally substituted with 1 to 3 substituents selected from _1-6 alkoxy and the like is used, and specific examples thereof include benzylidene, p-methylbenzylidene, p- Chlorobenzylidene or the like is used.

A "substituted silyl group", together with a protected amino group, has the formula R ¹ R ² R ³ SiNH-, (R ¹ R ² R ³ S
i) ₂ N- or

[Chemical 7] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4a and R ^5a are each a C _1-6 alkyl group or a C _6-10 aryl group;
_{Represents a} C _1-3 alkylene group (methylene, ethylene, propylene, etc.)]. Preferable examples of the "substituted silyl group" such as trimethylsilyl, tert- butyldimethylsilyl, -Si (CH _{3) 2} C
_{H 2 CH 2 Si (CH 3} ) 2 - , etc. can be used. As the “alkali metal” represented by M, for example, sodium, potassium and the like are preferable, and sodium and the like are particularly preferable. R is preferably a phosphonoamino group, a formylamino group, an amino group or the like.

Compound (I) can be produced by mixing the above and and to form a solution, and isolating from this solution by a usual isolation means such as crystallization. ,
The mixing order of and may be any order. For example, first and may be mixed and then mixed with, and and may be mixed and then mixed, or and may be mixed and then mixed. The reaction temperature is -40 ° C to 60 ° C, preferably 0 ° C to 30 ° C. The reaction time is 20 minutes to 96 hours, preferably 12 hours to 30 hours. In the case of crystallization, the solvent and water are mixed at a volume ratio of usually 1: 0.1 to 10, preferably 1: 0.
5 to 5, particularly preferably about 1: 1. The amount of and used for crystallization is not particularly limited as long as it is within the range of crystallization, but is usually 1
The total amount of and is 2 to 100 parts by weight, preferably 5 to 100 parts by weight, and more preferably 10 to 50 parts by weight with respect to parts by weight. Crystallization can be performed by cooling the solution, reducing the amount of and by reducing the pressure, or by taking a crystallization means such as adding a seed crystal.

The compound (I) thus obtained can be separated from the solution by a conventional separation means (eg, filtration, centrifugation, etc.) and purified by a conventional purification means (eg, washing with a solvent, etc.). it can. The compound (I) thus obtained (in particular, its crystal) is, for example, highly pure, has excellent solid stability and the like and can be stored for a long period of time, and thus can be used in a pharmaceutical preparation. The water content of the crystal of the compound (I) can be changed depending on the degree of drying, and as described above, the water-free crystal is also included in the scope of the present invention. Compound (I) has excellent antibacterial activity, has a broad spectrum of antibacterial activity, and has low toxicity, so humans and mammals (eg, mouse, rat, rabbit, dog,
It can be safely used for the prevention and treatment of various diseases caused by pathogenic bacteria in cats, cattle, pigs, etc., such as respiratory tract infection and urinary tract infection. The bacterium targeted when the compound (I) is used as an antibacterial agent is not particularly limited as long as the compound (I) exhibits antibacterial activity, and a wide range of Gram-positive and Gram-negative bacteria are targeted. However, it shows an excellent antibacterial action against Staphylococcus, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas. Compound (I) (particularly its crystal) has excellent stability and can be administered in the same manner as known penicillin agents and cephalosporin agents. The pharmaceutical composition and antibacterial composition of the present invention may be the compound (I) alone, and is a carrier usually used for a drug (for example, in the case of an injection, a solution and a solubilizing agent, a pH adjusting agent). Etc. may be included.

The compound and composition of the present invention can be formulated into a pharmaceutical preparation by a conventional method. When administered as an injection,
The dose is, for example, usually 0.3 to 80 mg / day, more preferably 1 to 40 mg / day, as Compound (I) per 1 kg of body weight of humans and animals infected with the above-mentioned pathogenic bacteria, and usually 1 It is administered in 2 to 3 divided doses daily. When used as an injection, the compound (I) crystals and a solution (for example, distilled water, physiological saline, 5% glucose solution, etc.) are usually provided separately in a package, and the compound (I) is supplied at the time of use. The crystals are dissolved in a solution and administered. In addition, compound (I)
It is also possible to administer it by mixing it with a medical infusion such as replacement fluid. Such injections are usually pH adjusting agents (eg, alkali metal or alkaline earth metal carbonates, phosphates, acetates, citrates (eg, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, carbonate). Carbonate such as potassium hydrogen, calcium carbonate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate Such as phosphates, sodium acetate, potassium acetate, calcium acetate and other acetate salts, disodium citrate, sodium citrate, sodium dihydrogen citrate, calcium citrate and other citrate salts); basic amino acids ( (Eg, L-arginine, L-lysine, etc.); or N
-Methylglucamine and the like are used, and among them, those containing alkali metal or alkaline earth metal carbonates and basic amino acids are preferable). These pH regulators are used to adjust the pH of the injection solution at the time of use.
Is 4 to 10, preferably 4.5 to 8.5, and more preferably 5.0 to 8.
An amount such that it is 0, more preferably 5.0 to 7.5
Used in such an amount that These pH regulators
Usually, it is packaged in a state of being dissolved in a solution, but it may be packaged by mixing with the crystal of compound (I), or provided separately from the crystal of compound (I) and the solution. The three parties may be mixed and used at the time of use. Furthermore, the above-mentioned injection can be prepared by adding a solubilizing agent having reducing property,
The stability of the injection solution at the time of use can be increased. Examples of the solubilizing agent having a reducing property include sodium sulfite, sodium hydrosulfite, sodium hydrogen sulfite, sodium pyrosulfite, and L-cysteine. These reducing agents are usually 0.001 equivalent to 2.0 equivalents, preferably 0.01 to the main drug.
0.5 equivalent, more preferably 0.05 to 0.2 equivalent is used. These reducing solubilizers are usually
Although it is packaged in a state of being dissolved in a solution, it may be packaged by mixing with the crystal of compound (I), or may be packaged by mixing with a pH adjusting agent. Crystals of p
The H regulator and the solution may be separately packaged and provided, and they may be mixed before use. The content of the compound (I) crystals in the injectable preparation is 80 to 2000 mg, preferably 100 to 1000 mg, more preferably 200.
To 800 mg. The proportion of the solution in the injection is 10 to 50 with respect to the crystal 1 of the compound (I) in a weight ratio.
It is 0, preferably 20 to 300. The ratio of the pH adjusting agent is usually 1.0 to 3.0 equivalents to 1 equivalent of the compound (I).

Of the compounds (I), the compounds in which m is 2 and the crystals thereof are preferred. More preferably, m is 2, and the compound is a dihydrate. In powder X-ray diffraction, the diffraction angles were 5.94, 14.14, 17.90, 21.
A compound having a peak around 32, 23.64 ° is particularly preferable. “Near” at the diffraction angle is ± 0.2
Means °. Further, the compound (I) of the present invention is a compound useful as an antibacterial agent as described above.
Formula described in 255772

[Chemical 8] Represented by 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β- [2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl) -2 (Z ) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate can be usefully used as a standard compound used for evaluation of drug efficacy of the compound as an active main compound.

General formula used in the method of the present invention

[Chemical 9] [In formula, R shows the amino group which may be protected. The compound represented by the above formula can be synthesized by a general organic synthesis means. For example, the above-mentioned JP-A-9-10
It can be synthesized by the method described in JP-A No. 0283 or JP-A No. 11-255772.

[0019]

The present invention will be described in more detail with reference to the following examples, which are merely illustrative and do not limit the present invention, and may be varied without departing from the scope of the present invention. In the following Reference Examples and Examples, room temperature means 10 to 30 ° C. ¹ H-NMR spectrum is tetramethylsilane (CDCl ₃ , DMSO-d ₆ ) or sodium 3- (trimethylsilyl) propionate-2,2,3,3-d ₄ (D ₂ O) as internal standard, It was measured using Gemini-200 (200MHz), and all δ values are shown in ppm. The symbols used in the examples have the following meanings. s: singlet d: doublet t: triplet q: quartet ABq: AB type quartet dd: double doublet m: multiplet J: Coupling constant

Reference Example 1. 3- [4- (1-methyl-4-pyridini
E) -2-thiazolylthio] -7β- [2- (5-phosphonoamino-1,
2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetate
Toamido] -3-cephem-4-carboxylate / monoacetic acid
Medium 3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate 100 mg (0.151 mmol) in distilled water for injection (0.
It was suspended in a mixed solution of 5 ml) and acetic acid (0.5 ml), and sonicated to dissolve it. This solution was allowed to stand overnight at room temperature. The precipitated crystals were crushed with a spatula and collected by filtration. Distilled water for injection
It was washed with 1.2 ml. Using Molecular Sieves 3A (1/16) as a desiccant, dry under reduced pressure to a constant weight,
Seed crystals were obtained. Yield 79 mg (73%). Melting point: 221-223 ° C (decomposition) AnalCalcd for C ₂₄ H ₂₅ N ₈ O ₁₀ S ₄ P ・ 1.0H ₂ O: C 37.79, H
3.57, N 14.69, P 4.06.Found: C 37.97, H 3.30, N 1
4.37, P 3.88. ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7Hz), 1.91 (3H,
s), 3.58,3.95 (2H, ABq, J = 17Hz), 4.17 (2H, q, J = 7Hz),
4.34 (3H, s), 5.32 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5 & 8H
z), 8.51 (2H, d, J = 6Hz), 8.99 (3H, m), 9.30 (1H, m),
9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3202, 1755, 1668,1
645, 1537, 1392, 1273, 1039.

Example 1. 7β- [2- (5-amino-1,2,4-thio)
Asiazol-3-yl) -2 (Z) -ethoxyiminoacetami
De] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio]
-3-cephem-4-carboxylate dihydrochloride 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
-2 (Z) -Ethoxyiminoacetamido] -3-cephem-4-carboxylate monoacetic acid solvate 2.0 g (2.69 mmol)
It was dissolved in a mixed solution of 30 ml of 6N hydrochloric acid and 30 ml of ethanol, and stirred at room temperature for 20 hours. After stirring for 15 minutes under ice cooling, the mixture was allowed to stand for 30 minutes. The precipitated crystals were collected by filtration, washed with 20 ml of ethanol, and dried under reduced pressure to give the title compound. Yield 1.2
2 g (67%). Anal Calcd for C ₂₂ H ₂₂ N ₈ O ₅ S ₄ Cl ₂・ 2.0H ₂ O: C 37.03, H
3.67, N 15.70, Cl 9.94. Found: C 37.16, H 3.81, N1
5.70, Cl 9.70. ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7Hz), 3.60, 4.00
(2H, ABq, J = 18Hz), 4.17 (2H, q, J = 7Hz), 4.34 (3H, s), 5.
35 (1H, d, J = 5Hz), 5.96 (1H, dd, J = 5 & 8Hz), 8.20 (2H, br
s), 8.57 (2H, d, J = 7Hz), 9.02 (2H, d, J = 7Hz), 9.08 (1
H, s), 9.70 (1H, d, J = 8Hz) .IR (KBr) cm ^-1 : 3264, 1755, 1674, 1645, 1556, 1537,
1456, 1373, 1300, 1045.

Example 2. 7β- [2- (5-amino-1,2,4-thio)
Asiazol-3-yl) -2 (Z) -ethoxyiminoacetami
De] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio]
-3-cephem-4-carboxylate dihydrochloride 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
2.0 g (2.92 mmol) of -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate was dissolved in a mixed liquid of 50 ml of 6N hydrochloric acid and 50 ml of ethanol, and the mixture was stirred at room temperature for 20 hours. The precipitated crystals were collected by filtration, washed with 20 ml of ethanol,
Drying under reduced pressure gave the title compound. Yield 1.09 g (55
%). The same spectrum data as in Example 1 was given.

Example 3. 7β- [2- (5-amino-1,2,4-thio)
Asiazol-3-yl) -2 (Z) -ethoxyiminoacetami
De] -3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio]
-3-cephem-4-carboxylate dihydrochloride 3- [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -7β
-[2- (5-phosphonoamino-1,2,4-thiadiazol-3-yl)
2.0 g (2.69 mmol) of -2 (Z) -ethoxyiminoacetamido] -3-cephem-4-carboxylate / monoacetic acid solvate was suspended in 20 ml of ethanol, and 20 ml of concentrated hydrochloric acid was added and dissolved under ice cooling. . The mixture was stirred under ice cooling for 1 hour and at 10 ° C. for 20 hours.
The mixture was allowed to stand for 1 hour under ice cooling, and the precipitated crystals were collected by filtration, washed with 6 ml of water, and dried under reduced pressure to give the title compound. Yield 1.2
1 g (67%). The same spectrum data as in Example 1 was given.

Test Example 1. Stability test 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamide] -3-obtained in Example 1
Crystals of [4- (1-methyl-4-pyridinio) -2-thiazolylthio] -3-cephem-4-carboxylate / dihydrochloric acid and the method described in Example 13 of JP-A No. 9-100283 are used. Synthesized amorphous 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 (Z) -ethoxyiminoacetamide]-
3- [4- (1-Methyl-4-pyridinio) -2-thiazolylthio] -3-
10 mg of each sample of cephem-4-carboxylate was placed in a colorless glass bottle, and the stability when stored at 60 ° C was examined (up to 4 weeks). The content at each storage point was determined as a sample solution by dissolving the sample in the mobile phase to make 10 mL and further diluting the solution 5 times with the mobile phase. It was analyzed under the following HPLC conditions, and it was determined from the ratio of the peak area of the initial product (cryopreserved) to that of the sample. * HPLC condition detector: UV254nm Column: YMCProC18 150 × 4.6mm Mobile layer A: 0.1mol / LAcONH ₄ / MeCN (960: 65) Mobile layer B: 0.1mol / LAcONH ₄ / MeCN (1: 9) Gradient: 0 → 10min B: 0%, 10 → 20min B; 0 → 25%, 20 → 25min B: 25% Column temperature: 40 ℃ Flow rate: 1mL / min Injection volume: 10μL

As shown in Table 1 below, the amorphous form showed coloration and decomposition tendency over time, while the 2HCl crystal was stable with almost no decomposition.

[Table 1]

[0026]

The compound of the present invention has an excellent antibacterial action, as well as purity, stability (particularly solid stability), storability,
It is very useful as an antibacterial agent because of its excellent quality as a drug such as ease of handling.

[Brief description of drawings]

1 is a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of the compound obtained in Example 1. FIG. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity.

Continued front page    F term (reference) 4C075 BB02 CC02 CC30 CD04 DD54                       EE18 FF01 GG01 HH01 KK01                       LL03 MM63                 4C086 AA01 AA02 AA03 AA04 CC11                       MA04 MA66 NA03 ZB35

Claims (12)

[Claims] 1. A general formula: [In the formula, m represents 0 to 3. However, the case of m = 0 is excluded. ] The compound represented by these. 2. The compound according to claim 1, wherein m is 2. 3. The compound according to claim 1, which is a hydrate. 4. The compound according to claim 3, which is a crystal. 5. The compound according to claim 4, wherein m is 2 and the compound is a dihydrate. 6. Diffraction angles of 5.94 and 1 in powder X-ray diffraction
The crystal according to claim 4, which has peaks near 4.14, 17.90, 21.32 and 23.64. 7. A pharmaceutical composition comprising the compound according to claim 1. 8. The pharmaceutical composition according to claim 7, which is an antibacterial agent. 9. The pharmaceutical composition according to claim 7, which is an anti-MRSA agent. 10. A general formula: [In formula, R shows the amino group which may be protected. ] The compound or its salt represented by these is made to react with HCl, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 11. Use of a compound according to claim 1 for the manufacture of a medicament. 12. A method for treating an infectious disease, which comprises administering an effective amount of the compound according to claim 1 to an infectious disease patient.