JPH07138264A - Cephalosporin antibiotic and its preparation - Google Patents

Abstract

PURPOSE: To obtain a compound useful as a cephalosporin antibiotic having an excellent antibacterial property particularly to Gram-negative bacteria, such as Pseudomonas bacteria by reacting a specific compound with an intermediate obtained by reacting iodomethylcephem with a specific amine.

CONSTITUTION: A compound represented by formula I, (wherein Q is =N- or CH-; P is an acyclic amine having an N atom and one or two hydroxyl groups or a heteroalicyclic amine). For example, it is obtained by reacting 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[N-methyl-N,N-bis(2- hydroxyethyl)aminyo]methyl-3-cephem-4-carboxylate, or the like with an iodomethylcephem represented by formula II, an acylic amine of P, and a heteroalicyclic amine, and reacting the resuting intermediate with a compound represented by formula III.

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cephasporin compound and a method for producing the same. More specifically, it exhibits a wide range of antibacterial activity, and in particular exhibits excellent activity against Gram-negative bacteria such as Pseudomonas and Enterobacter cloacae P99, and has the following general formula (I) useful as an antibiotic. The present invention relates to a represented cephalosporin compound and a method for producing the same.

[0002]

2. Description of the Related Art Belgian Patent No. 876,538
A ceftazidime represented by the structural formula (A) in which a methyl group having a quaternary ammonium salt at the 3-position of cephalosporin, that is, a pyridiniomethyl group is introduced is described. Compounds of this family are characterized by having a wide range of antibacterial activity and being stable against beta-lactamase. Taking advantage of the development of this compound, an attempt was made to develop an antibiotic having an improved antibacterial activity, and the cefpirome (Dru) represented by the following structural formula (B) was expressed.
gs Future 13, 369-371, 1988) and a structural formula (C) represented by cefepime, German Patent No. 3,30.
No. 7,550) was developed.

[0003]

[Chemical 3]

[0004]

SUMMARY OF THE INVENTION The present invention is to provide a cephalosporin antibiotic having excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria.

[0005]

[Means for Solving the Problems] As a result of research, a cephalosporin compound having an ammoniomethyl group substituted with a hydroxyl group at the 3-position and an aminothiazole group or an aminothiadiazole group at the 7-β position at the same time was found. It has been discovered that, in addition to exhibiting a wide range of antibacterial activity, it exhibits an excellent antibacterial activity particularly against Gram-negative bacteria such as Pseudomonas and Enterobacter cloacae P99.

The present invention has the general formula (I)

[0007]

[Chemical 4]

In the above formula (I), Q is = N- or = CH.
And P is an acyclic amine or a heteroalicyclic amine having one nitrogen atom and one or two hydroxyl groups, and P is, for example, N-methyl-bis (2-hydroxyethyl) amine; Racemic-3,4-trans-dihydroxy-1-methylpyrrolidine; (3S, 4S)-
3,4-dihydroxy-1-methylpyrrolidine; (3
R, 4R) -3,4-Dihydroxy-1-methylpyrrolidine; meso-3,4-dihydroxy-1-methylpyrrolidine; (2S, 4R) -4-hydroxy-1-methyl-
2-pyrrolidinemethanol; 3,4-cis-dihydroxy-1-methylpiperidine; 3,4-trans-dihydroxy-1-methylpiperidine; or tropine.

The above-mentioned cephalosporin compound of the general formula (I) of the present invention is a 7-amino-3- (iodomethyl) -3-cephem-4-carboxylic acid (hereinafter iodomethyl) represented by the general formula (II). Cefem) is reacted with an acyclic tertiary amine or a heteroalicyclic amine represented by the following general formula (III), and the resulting intermediate is represented by 2- (2-) represented by the general formula (IV). Aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetic acid benzothiazolyl-2
-Thioester (Q = CH-; hereinafter referred to as aminothiazole) or 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetic acid benzothiazolyl-2-thioester ( Q = N-; hereinafter referred to as aminothiadiazole).

[0010]

[Chemical 5]

In the general formulas (III) and (IV), P and Q are the same as P and Q in the general formula (I).

The present invention will be described in more detail below.

The starting material of the present invention, iodomethylcephem of the general formula (II), is a known compound and can be produced according to the following reaction formula (Japanese Patent 126,492).
issue). That is, it can be easily produced by reacting 7-ACA of the general formula (V) with trifluoromethanesulfonic acid and sodium iodide.

[0014]

[Chemical 6]

In the compound of the general formula (III) used in the present invention, P is racemic-3,4-trans-dihydroxy-1-methylpyrrolidine; (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine ; (3R, 4R)-
3,4-dihydroxy-1-methylpyrrolidine; meso-
3,4-dihydroxy-1-methylpyrrolidine; (2
The compound, S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol, is a novel substance, and its manufacturing method will be described in detail in the following reference examples.

The cephalosporin compound represented by the general formula (I) includes an iodomethylcephem represented by the general formula (II) and a general formula (II
1-10 equivalents of the tertiary amine derivative represented by I) are mixed using a polar organic solvent and reacted at 20 to 25 ° C. for 1 to 12 hours, preferably 1 to 2 hours, and then the resulting intermediate Is reacted with 1 to 3 equivalents, preferably 1 to 2 equivalents of aminothiazole or aminothiadiazole of the general formula (IV) in the same container for 2 to 12 hours, and the reaction product is subjected to silica gel column chromatography. It is obtained by lyophilizing after separating and purifying using. At this time,
N, N-dimethylformamide (DM
Preference is given to using F).

[0017]

[Chemical 7]

[0018]

INDUSTRIAL APPLICABILITY The cephalosporin compound produced by the present invention exhibits high antibacterial activity against a wide range of bacterial species including Gram-positive bacteria and Gram-negative bacteria. Its usefulness was evaluated by investigating the minimum inhibitory concentration using a known compound ceftazidime as a comparative substance. The minimum inhibitory concentration was determined by investigating with Mueller-Hinton Agar by the agar dilution method, culturing 5 × 10 ⁴ cfu strains in a culture dish at 37 ° C. for 24 hours, and the results are shown in Table 1 and The results are shown in Table 2.

[0019]

[Table 1]

[0020]

[Table 2]

Compounds of the Invention Ia: 7-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[N-methyl-N, N-bis (2-hydroxyethyl)
Aminio] methyl-3-cephem-4-carboxylate

[0022]

[Chemical 8]

Ib: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy-1-)
Methylpyrrolidinio) methyl-3-cephem-4-carboxylate

[0024]

[Chemical 9]

Ic: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3S, 4S) -3,4-dihydroxy-1 -Methylpyrrolidinio] methyl-3-cephem-4
-Carboxylate

[0026]

[Chemical 10]

Id: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(3R, 4R) -3,4-dihydroxy-1 -Methylpyrrolidinio] methyl-3-cephem-4
-Carboxylate

[0028]

[Chemical 11]

Ie: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (meso-3,4-dihydroxy-1-methylpyrrolid ide Nio) methyl-3-cephem-4-carboxylate

[0030]

[Chemical 12]

If: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- (2S) -hydroxymethyl- 1-methylpyrrolidinio] methyl-3-
Cephem-4-carboxylate

[0032]

[Chemical 13]

Ig: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy-1-)
Methyl piperidinio) methyl-3-cephem-4-carboxylate

[0034]

[Chemical 14]

Ih: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (3,4-cis-dihydroxy-1-methylpiperidi Nio) methyl-3-cephem-4-carboxylate

[0036]

[Chemical 15]

Ii: 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-tropiniomethyl-3-cephem-4-carboxylate

[0038]

[Chemical 16]

Ij: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [N-methyl-N, N
-Bis (2-hydroxyethyl) aminio] methyl-3
-Cephem-4-carboxylate

[0040]

[Chemical 17]

Ik: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3,4-trans-
Dihydroxy-1-methylpyrrolidinio) methyl-3-
Cephem-4-carboxylate

[0042]

[Chemical 18]

I-1: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(3S, 4S)-
3,4-Dihydroxy-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate

[0044]

[Chemical 19]

Im: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(3R, 4R)-
3,4-Dihydroxy-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate

[0046]

[Chemical 20]

In: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (meso-3,4-) Dihydroxy-1-methylpyrrolidinio) methyl-3-cephem-4-carboxylate

[0048]

[Chemical 21]

Io: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- (2S) -Hydroxymethyl-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate

[0050]

[Chemical formula 22]

Ip: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3,4-trans-
Dihydroxy-1-methylpiperidinio) methyl-3-
Cephem-4-carboxylate

[0052]

[Chemical formula 23]

Iq: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- (3,4-cis- Dihydroxy-1-methylpiperidinio) methyl-3-cephem-4-carboxylate

[0054]

[Chemical formula 24]

Ir: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-tropiniomethyl-3
-Cephem-4-carboxylate

[0056]

[Chemical 25]

Control compound:

[0058]

[Chemical formula 26]

As can be seen from Tables 1 and 2, the cephalosporin compound of the present invention exhibits excellent antibacterial activity against a wide range of bacteria. In particular, Enterobacter bacillus P99 (Ente
For robacter Cloacae P99), the minimum inhibitory concentration of ceftazidime, which is a control drug widely known as a broad-spectrum antibiotic, is 100 μg / ml or more, whereas the compound of the present invention is 1.563-6.25 μg / ml. It exhibits a minimum inhibitory concentration of ml, shows not only 16 times more excellent antibacterial activity than ceftazidime, but also excellent antibacterial activity against Pseudomonas aeruginosa (Pseudomonas aeruginosa). This suggests the fact that the compounds of the present invention are far more extensive and useful than ceftazidime used as a control agent.
Also, an aminothiadiazole derivative (I in which Q is = N- (I
V) is a 7-position substituted cephalosporin compound of I-j to I-r, as compared with the control drug ceftazidime,
The antibacterial activity against Pseudomonas aeruginosa, which is a strain highly resistant to cephalosporin antibiotics, is almost the same, or about twice as excellent.

[0060]

EXAMPLES The following examples explain the present invention in more detail, and for reference, a method for producing an acyclic amine or a heteroalicyclic amine of the general formula (III) will be described in parallel.

Reference Example 1 Synthesis of (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol Trans-4-hydroxy-L-proline (2.5 g,
BF ₃ .Et ₂ O (2.35 ml, 19 mmol) was added dropwise at 15 to 25 ° C. to a solution of 19 mmol) suspended in tetrahydrofuran (25 ml). While refluxing this mixed solution, borane dimethylsulfite (18 ml,
(190 mmol) was added over 10 minutes and then refluxed continuously for 24 hours. The reaction mixture was cooled to 0 ° C., methanol (20 ml) was gradually added, the reaction mixture was concentrated, and a 6N aqueous sodium hydroxide solution (20 ml) was added to the obtained residue, followed by refluxing for 4 hours. The reaction solution was cooled to 15-25 ° C, insoluble material was filtered off and the filtrate was evaporated. Ethanol (50 ml) was added to the obtained residue, and 3
After stirring vigorously for 0 minutes, the mixture was filtered to remove insoluble materials. The filtrate was concentrated and isopropanol (100 ml) was added, and then insoluble material was removed by filtration. The filtrate was concentrated, 35% formaldehyde solution (5 ml) and formic acid (15 ml) were added, and the mixture was refluxed for 16 hours. The reaction mixture was concentrated, methanol (20 ml) and anhydrous sodium carbonate (5 g) were added, and the mixture was stirred at 15 to 25 ° C for 1 hr. The reaction mixture was filtered, the filtrate was concentrated and methylene chloride (20 ml) was added to the resulting residue, and insoluble material was further filtered off. After concentrating the filtrate, vacuum distillation (200-220 ℃
/ 1 mmHg) to give the title compound (950 mg, 30%). ¹ H NMR (CDCl ₃ ) δ: 5.14 (2H, br s), 4.25 (1H, m), 3.5
5 (1H, dd, J = 11.6Hz, 3.9Hz), 3.41 (1H, dd, J = 11.6Hz,
3.9Hz), 3.28 (1H, m), 2.75 (1H, m), 2.37 (3H, s), 2.3
0 (1H, m), 1.72-1.99 (2H, m) [α] =-34 ° (c 0.1, MeOH)

Reference Example 2 Synthesis of 3,4-trans-dihydroxy-1-methylpyrrolidine (racemic mixture) Racemic-3,4-trans-diacetoxy-1-methylpyrrolidine (1.5 g, 6.54 mmol) LiAlH ₄ (1.24 g) in tetrahydrofuran (60 ml)
, 32.72 mmol) was gradually added to the suspended solution at a temperature of 0 ° C. The reaction mixture was refluxed for 24 hours, cooled to 0 ° C., and ethyl acetate (2 ml), ethanol (15 ml) and water (10 ml) were added successively with vigorous stirring. The reaction mixture was stirred at 15 to 25 ° C. for 30 minutes, filtered, and washed with a chloroform-ethanol (1: 1) mixed solution (20 ml × 3). The combined filtrate was concentrated and then vacuum distilled (1 mmHg), and the obtained material was recrystallized from chloroform and ethyl acetate to obtain the title compound (427 mg, 57%) as a white solid. mp93-95 ° C ¹ H NMR (CDCl ₃ ) δ: 4.79 (2H, br s), 4.10 (2H, m), 2.94.
(2H, dd, J = 10Hz, 6Hz), 2.47 (2H, dd, J = 10Hz, 4Hz),
2.32 (3H, s)

Reference Example 3 Synthesis of (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine Using (3R, 4R) -3,4-diacetoxy-1-methylpyrrolidine, the method of Reference Example 2 was used. The same procedure was performed to obtain the title compound. mp93-95 ° C. [α] = + 28 ° (c 0.05, MeOH)

Reference Example 4 Synthesis of (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine Similar to Reference Example 2 using (3S, 4S) -3,4-diacetoxy-1-methylpyrrolidine. The title compound was obtained by various methods. mp93-95 ° C. [α] = − 28 ° (c 0.6, MeOH)

Reference Example 5 Synthesis of 1-benzyloxycarbonyl-3-pyrroline 3-pyrroline (2 g, 65%, 18.8 mmol) and anhydrous sodium carbonate (15.33 g, 144.6 mmol) were added to methylene chloride (30 ml). ), And cooled to 0 ° C. to give a solution of benzyl chloroformate (7.4 g, 4
(3.4 mmol) was added slowly. After stirring for 20 minutes, the reaction temperature was raised to 20 ° C. and stirring was continued for 2 hours. The reaction mixture was washed successively with cold water (30 ml) and saturated brine (20 ml), dried over anhydrous magnesium sulfate and evaporated, and the resulting residue was purified by silica gel column chromatography.
The title compound (3 g, 78%) was obtained.

Reference Example 6 Synthesis of meso-1-benzyloxycarbonyl-3,4-dihydroxypyrrolidine N-methylmorpholine monohydrate (479 mg, 3.54 mmol) was dissolved in distilled water (15 ml) and acetone (7 ml). A catalytic amount of osmum tetraoxide and the compound (600 mg, 2.95 mmol) synthesized in Reference Example 3 were added to the solution, and the mixture was stirred overnight. Sodium hydrosulfite (0.1 g) and florisyl (2 g) were added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction solution was filtered, and acetone (1
The filtrate washed with 0 ml × 2) was concentrated to remove acetone. The aqueous solution obtained at this time was saturated with salt, extracted with chloroform (10 ml × 4), dried over anhydrous magnesium sulfate and evaporated, and the obtained residue was purified by silica gel column chromatography to give the title compound (586 mg , 8
3.7%). ¹ H NMR (CDCl ₃ ) δ: 7.36 (5H, s), 5.13 (2H, s), 4.25 (2
H, m), 3.65 (2H, dd, J = 11Hz, 5Hz), 3.44 (2H, dd, J = 11
Hz, 3Hz)

Reference Example 7 Synthesis of meso-3,4-dihydroxy-1-methylpyrrolidine The compound (270 mg, 1.14 mmol) synthesized in Reference Example 4 was dissolved in a 95% ethanol solution to obtain 10% Pd / C.
(27 mg) was added, and the mixture was stirred under hydrogen atmospheric pressure (1 atm) for 6 hours. The reaction solution was filtered and concentrated, to the product obtained was added 35% formaldehyde solution (4.5 ml) and formic acid (5.5 ml), and the mixture was refluxed for 24 hours. The reaction mixture was concentrated, methanol (20 ml) and anhydrous potassium carbonate (2 g) were added, and the mixture was stirred for 1 hr. The reaction mixture was filtered and concentrated, chloroform (10 ml) was added to the obtained residue, the insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (107 mg, 82%). . ¹ H NMR (CDCl ₃ ) δ: 4.17 (2H, m), 2.67 (4H, m), 2.30 (3
H, m)

Reference Example 8 Synthesis of 1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine 1,2,3,6-tetrahydropyridine (1.5 g, 1
(8 mmol) in the same manner as in Reference Example 3 to obtain the title compound (1.85 g, 47%). ¹ H NMR (CDCl ₃ ) δ: 7.33 (5H, s), 5.17 (2H, m), 5.17 (2
H, s), 3.97 (2H, m), 3.53 (2H, t, J = 6Hz), 2.10 (2H, m)

Reference Example 9 Synthesis of 1-benzyloxycarbonyl-3,4-cis-dihydroxypiperidine The compound (400 mg, 1.84 mmol) synthesized in Reference Example 6 was prepared in the same manner as in Reference Example 4, and the title was obtained. Compound (4
12 mg, 89%) was obtained (racemic mixture). ¹ H NMR (CDCl ₃ ) δ: 7.30 (5H, s), 5.10 (2H, s), 3.41-
4.10 (6H, m), 1.68 (2H, m)

Reference Example 10 Synthesis of 3,4-cis-dihydroxy-1-methylpiperidine The compound (500 mg, 1.84 mmol) synthesized in Reference Example 7 was treated in the same manner as in Reference Example 5 to give the title compound ( 1
09 mg, 47%) was obtained (racemic mixture). ¹ H NMR (CDCl ₃ ) δ: 3.70 (2H, m), 2.23-2.57 (4H, m),
2.02 (3H, s), 1.63 (2H, m)

Reference Example 11 Synthesis of 1-benzyloxycarbonyl-3,4-trans-dihydroxypiperidine A 35% hydrogen peroxide solution (2 ml) was added dropwise to formic acid (5 ml) at 0 ° C. and the mixture was stirred for 10 minutes. The compound (600 mg, 2.76 mmol) synthesized in Reference Example 6 was added to this solution, the temperature was raised to 25 ° C., and the mixture was stirred for 24 hours. The reaction mixture was concentrated, 2N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred for 30 minutes, then chloroform (10 ml × 2).
It was extracted with. The chloroform solution was dried over anhydrous magnesium sulfate, evaporated, and then purified by silica gel column chromatography to obtain the title compound (403 mg, 58%) (racemic mixture).

Reference Example 12 Synthesis of trans-3,4-dihydroxy-1-methylpiperidine The compound (403 mg, 1.60 mmol) synthesized in Reference Example 9 was prepared in the same manner as in Reference Example 5 to give the title compound (17
4 mg, 83%) was obtained (racemic mixture). ¹ H NMR (CDCl ₃ ) δ: 3.2-3.5 (2H, m), 2.7-3.1 (4H, m),
2.2 (3H, s), 1.8-2.1 (2H, m)

Example 1 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- [N-
Methyl-N, N-bis (2-hydroxyethyl) aminio] methyl-3-cephem-4-carboxylate (I
Preparation of -a) Iodomethylcephem (II, 100 mg, 0.29 mmol) and N-methyldiethanolamine (104 mg, 0.
87 mmol) of N, N-dimethylformamide (4 m
l) and then stirred at 20 to 25 ° C. for 3 hours. Aminothiazole (IV, X = CH; 120 mg,
0.34 mmol) was added and the mixture was stirred for 6 hours. The reaction mixture was subjected to silica gel column chromatography (CH ₃ CN
/ H ₂ O = 5: 1) and the title compound (22 mg, 1
4.7%) was obtained. ¹ H NMR (D ₂ O) δ: 7.07 (1H, s), 5.92 (1H, d, J = 4.9Hz),
5.41 (1H, d, J = 4.9Hz), 4.23, 4.93 (ABq, J = 13.8Hz),
4.04 (3H, s), 3.19 (3H, s) IR (KBr) 3358, 1769, 1614,
1537 cm ^-1

Example 2 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [N-methyl-N, N Preparation of -bis (2-hydroxyethyl) aminio] methyl-3-cephem-4-carboxylate (I-j) Iodomethylcephem (II, 100 mg, 0.29 mmol) and N-methyldiethanolamine (104 mg,
0.87 mmol) was added to N, N-dimethylformamide (4 ml), and the mixture was stirred at 20 to 25 ° C for 3 hr.
Aminothiadiazole (IV, X = N; 60
(mg, 0.17 mmol) and stirred for 18 hours,
Silica gel column chromatography (CH ₃ CN / H
₂ O = 5: 1) and the title compound (10 mg, 10
%) Was obtained. ¹ H NMR (D ₂ O) δ: 5.92 (1H, d, J = 4.9Hz), 5.41 (1H, d,
J = 4.9Hz), 4.25, 4.93 (ABq, J = 13.8Hz), 4.11 (3H, s),
3.16 (3H, s) IR (KBr) 3321, 1767, 1674, 1617, 1524cm ^-1

Example 3 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (3,3
4-trans-dihydroxy-1-methylpyrrolidinio) methyl-3-cephem-4-carboxylate (I
-B) Production Using racemic-3,4-trans-dihydroxy-1-methylpyrrolidine synthesized in Reference Example 2, Example 1
The title compound (18%) was obtained in a similar manner to. ¹ H NMR (D ₂ O) δ: 7.02 (1H, s), 5.88 (1H, d, J = 4.8Hz),
5.37 (1H, d, J = 4.8Hz), 4.00 (3H, s), 3.22 (3H, s) IR (KBr) 3408, 1769, 1617, 1535cm ^-1

Example 4 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy Production of -1-methylpyrrolidinio) methyl-3-cephem-4-carboxylate (Ik) Using racemic-3,4-trans-dihydroxy-1-methylpyrrolidine synthesized in Reference Example 2, The title compound (16.6%) was obtained in the same manner as in Example 2. ¹ H NMR (D ₂ O) δ: 5.91 (1H, d, J = 4.8Hz), 5.36 (1H, d,
J = 4.8Hz), 4.00 (3H, s), 3.23 (3H, s) IR (KBr) 3410, 1769, 1617, 1526cm ^-1

Example 5 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(3
S, 4S) -3,4-Dihydroxy-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate (Ic) was synthesized in Reference Example 2 (3S, 4S)-.
The title compound was obtained in the same manner as in Example 1 using 3,4-dihydroxy-1-methylpyrrolidine. ¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.89 (1H, d, J = 4.7Hz),
5.38 (1H, d, J = 4.7Hz), 4.02 (3H, s), 3.24, 3.27 (3H,
2 s) IR (KBr) 3320, 1775, 1661, 1615, 1535cm ^-1

Example 6 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(3S, 4S) -3 , 4-dihydroxy-
1-Methylpyrrolidinio] methyl-3-cephem-4-
Production of Carboxylate (I-1) Using (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Reference Example 2, the title compound was obtained in the same manner as in Example 2. ¹ H NMR (D ₂ O) δ: 5.93 (1H, d, J = 4.7Hz), 5.39 (1H, d,
J = 4.7Hz), 4.12 (3H, s), 3.25, 3.28 (3H, 2 s) IR (KBr) 3322, 1771, 1616, 1524cm ^-1

Example 7 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(3
R, 4R) -3,4-Dihydroxy-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate (Id) synthesized in Reference Example 2 (3R, 4R)-
The title compound was obtained in the same manner as in Example 1 using 3,4-dihydroxy-1-methylpyrrolidine. ¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.89 (1H, d, J = 4.7Hz),
5.38 (1H, d, J = 4.7Hz), 4.02 (3H, s), 3.24, 3.27 (3H,
2 s) IR (KBr) 3320, 1775, 1661, 1615, 1535cm ^-1

Example 8 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-[(3R, 4R) -3 , 4-dihydroxy-
1-Methylpyrrolidinio] methyl-3-cephem-4-
Production of Carboxylate (Im) Using (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Reference Example 2, the title compound was obtained in the same manner as in Example 2. ¹ H NMR (D ₂ O) δ: 5.89 (1H, d, J = 4.7Hz), 5.36 (1H, d,
J = 4.7Hz), 4.09 (3H, s), 3.24 (3H, s) IR (KBr) 3322, 1771, 1616, 1524cm ^-1

Example 9 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (meso-3,4-dihydroxy-1-methylpyrrolidinio) ) Methyl-3-cephem-4-carboxylate (Ie)
Production of Meso-3,4-dihydroxy-1-synthesized in Reference Example 5
The title compound (20%) was obtained in the same manner as in Example 1 using methylpyrrolidine. ¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.90 (1H, d, J = 4.8Hz),
5.39 (1H, d, J = 4.8Hz), 4.02 (3H, s), 3.12 (3H, s) IR (KBr) 3455, 1769, 1615, 1535cm ^-1

Example 10 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (meso-3,4-dihydroxy) Preparation of -1-methylpyrrolidinio) methyl-3-cephem-4-carboxylate (In) Meso-3,4-dihydroxy-1-synthesized in Reference Example 5
The title compound (7%) was obtained in the same manner as in Example 2 using methylpyrrolidine. ¹ H NMR (D ₂ O) δ: 5.90 (1H, d, J = 4.7Hz), 5.38 (1H, d,
J = 4.7Hz), 4.10 (3H, s), 3.27 (3H, s) IR (KBr) 3345, 1771, 1613, 1528cm ^-1

Example 11 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(4
R) -Hydroxy- (2S) -hydroxymethyl-1-
Production of methylpyrrolidinio] methyl-3-cephem-4-carboxylate (If) (2S, 4R) -4-hydroxy-synthesized in Reference Example 1.
The title compound (16%) was obtained in the same manner as in Example 1 using 1-methyl-2-pyrrolidinemethanol. ¹ H NMR (D ₂ O) δ: 7.02 (1H, s), 5.87 (1H, d, J = 4.7Hz),
5.38 (1H, d, J = 4.7Hz), 4.00 (3H, s), 3.17 (3H, s) IR (KBr) 3320, 1771, 1617, 1535cm ^-1

Example 12 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-[(4R) -hydroxy- ( Production of 2S) -Hydroxymethyl-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate (Io) (2S, 4R) -4-hydroxy-synthesized in Reference Example 1.
The title compound (10%) was obtained in the same manner as in Example 2 using 1-methyl-2-pyrrolidinemethanol. ¹ H NMR (D ₂ O) δ: 5.92 (1H, d, J = 4.9Hz), 5.40 (1H, d,
J = 4.9Hz), 4.11 (3H, s), 3.19 (3H, s) IR (KBr) 3364, 1769, 1617, 1537cm ^-1

Example 13 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (3,3
4-cis-Dihydroxy-1-methylpiperidinio] methyl-3-cephem-4-carboxylate (I-g)
Production of 3,4-cis-dihydroxy-1-synthesized in Reference Example 8
The title compound (13.7%) was obtained in the same manner as in Example 1 using methylpiperidine. ¹ H NMR (D ₂ O) δ: 7.01 (1H, s), 5.87 (1H, d, J = 4.7Hz),
5.37 (1H, d, J = 4.7Hz), 3.99 (3H, s), 3.06, 3.19 (3H,
2 s), 2.10 (2H, m) IR (KBr) 3322, 1771, 1618, 1537cm ^-1

Example 14 7-[(Z) -2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-cis-dihydroxy Production of -1-methylpiperidinio) methyl-3-cephem-4-carboxylate (Ip) 3,4-cis-dihydroxy-1-synthesized in Reference Example 8
The title compound (20.9%) was obtained in the same manner as in Example 2 by using methylpiperidine. ¹ H NMR (D ₂ O) δ: 5.91 (1H, d, J = 4.9Hz), 5.40 (1H, d,
J = 4.9Hz), 4.07 (3H, s), 3.35, 3.98 (2H, ABq, J = 13.3H
z), 3.06, 3.19 (3H, 2 s), 2.10 (2H, m) IR (KBr) 3320, 1771, 1617, 1524cm ^-1

Example 15 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3- (3,3
4-trans-dihydroxy-1-methylpiperidinio) methyl-3-cephem-4-carboxylate (I
-H) Production Using 3,4-trans-dihydroxy-1-methylpiperidine synthesized in Reference Example 10, the title compound (20%) was obtained in the same manner as in Example 1. ¹ H NMR (D ₂ O) δ: 7.04 (1H, s), 5.90 (1H, d, J = 4.8Hz),
5.40 (1H, d, J = 4.8Hz), 4.02 (3H, s), 3.13, 3.19 (3H,
2 s) IR (KBr) 3387, 1771, 1615, 1526cm ^-1

Example 16 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3,4-trans-dihydroxy Production of -1-methylpiperidinio) methyl-3-cephem-4-carboxylate (Iq) Using 3,4-trans-dihydroxy-1-methylpiperidine synthesized in Reference Example 10, Example 2 The title compound (9%) was obtained by a method similar to. ¹ H NMR (D ₂ O) δ: 5.94 (1H, d, J = 4.9Hz), 5.41 (1H, d,
J = 4.9Hz), 4.10 (3H, s), 3.19 (3H, s) IR (KBr) 3312, 1773, 1615, 1534cm ^-1

Example 17 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-tropiniomethyl-3-cephem-4-carboxylate (I
-I) Production Using tropine, the title compound (13.7%) was obtained in the same manner as in Example 1. ¹ H NMR (D ₂ O) δ: 7.02 (1H, s), 5.87 (1H, d, J = 4.8Hz),
5.35 (1H, d, J = 4.8Hz), 4.00 (3H, s), 2.93, 3.00 (3H,
2 s) IR (KBr) 3368, 1765, 1617, 1534cm ^-1

Example 18 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-tropiniomethyl-3-cephem- Preparation of 4-carboxylate (Ir) Using tropine, the title compound (18.4%) was obtained in the same manner as in Example 2. ¹ H NMR (D ₂ O) δ: 5.89 (1H, d, J = 4.6Hz), 5.36 (1H, d,
J = 4.6Hz), 4.09 (3H, s), 2.92, 3.00 (3H, 2 s) IR (KBr) 3412, 1773, 1672,
1526 cm ^-1

 ─────────────────────────────────────────────────── ───Continued from the front page (72) Inventor Lee Yong Yi, 5 Cave, Yangcheon-gu, Seoul 173, Seoul, South Korea 109-418 Hesan apartment 109-418 (72) Inventor Lee, 1 South Samseong-dong, Gangnam-gu, Seoul, Republic of Korea 78-4 Aooka Apartment 102-703 (72) Inventor Yuan Ganlan 58-16 Seoin-dong, Seocho-gu, Seoul, Republic of Korea Shinbanura Hanshin Apartment 315-708

Claims (8)

[Claims] 1. A cephalosporin compound represented by the general formula (I). [Chemical 1] In the above formula, Q is = N- or = CH-, and P is an acyclic amine or heteroalicyclic amine having one nitrogen atom and one or two hydroxyl groups. 2. P is N-methyl-bis (2-hydroxyethyl) amine; racemic-3,4-trans-dihydroxy-1-methylpyrrolidine; (3S, 4
S) -3,4-Dihydroxy-1-methylpyrrolidine;
(3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine; meso-3,4-dihydroxy-1-methylpyrrolidine; (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol; 3 The cephalosporin compound according to claim 1, which is 3,4-cis-dihydroxy-1-methylpiperidine; 3,4-trans-dihydroxy-1-methylpiperidine; or tropine. 3. The method according to claim 1, wherein Q is = CH-.
The cephalosporin compound described. 4. The cephalosporin compound according to claim 1, wherein Q is ═N—. 5. An iodomethylcephem represented by the general formula (II) is reacted with an acyclic amine or a heteroalicyclic amine represented by the general formula (III), and the produced intermediate is a compound represented by the general formula (IV). 2. The reaction with
A method for producing a cephalosporin compound represented by the general formula (I): [Chemical 2] In the formula, Q and P are the same as described above. 6. P is N-methyl-bis (2-hydroxyethyl) amine; racemic-3,4-trans-dihydroxy-1-methylpyrrolidine; (3S, 4
S) -3,4-Dihydroxy-1-methylpyrrolidine;
(3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine; meso-3,4-dihydroxy-1-methylpyrrolidine; (2S, 4R) -4-hydroxy-1-methyl-2-pyrrolidinemethanol; 3 The method for producing a cephalosporin compound according to claim 5, wherein the compound is 4,4-cis-dihydroxy-1-methylpiperidine; 3,4-trans-dihydroxy-1-methylpiperidine; or tropine. 7. The cephalosporin according to claim 5, wherein 1-10 equivalents of the acyclic amine or the heteroalicyclic amine of the general formula (III) is added to the iodomethylcephem of the general formula (II). Method for producing compound. 8. The method for producing a cephalosporin compound according to claim 5, wherein N, N-dimethylformamide is used as a solvent.