JP3009329B2 - Cephalosporin antibiotic and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cefasporin compound and a method for producing the same. More specifically, it exhibits an antibacterial activity in a wide range, and particularly exhibits excellent activity against Gram-negative bacteria such as Pseudomonas and Enterobacter cloche P99, and is useful in the following general formula (I). The present invention relates to a cephalosporin compound represented and a method for producing the same.

[0002]

2. Description of the Related Art Belgian Patent No. 876,538 discloses that
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 broad spectrum of antibacterial activity and being stable to beta-lactamases. With the development of this compound, attempts have been made to develop antibiotics having improved antibacterial activity, and ceppirome (Dru) represented by the following structural formula (B)
gs Future 13, 369-371, 1988) and cefepime represented by the structural formula (C).
No. 7,550).

[0003]

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[0004]

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

[0005]

As a result of research, a cephalosporin compound having an ammoniomethyl group substituted with a hydroxyl group at the 3-position and simultaneously having an aminothiazole group or an aminothiadiazole group at the 7-β position has been obtained. It has been found that it exhibits a broad antibacterial activity and, in particular, an excellent antibacterial activity against Gram-negative bacteria such as Pseudomonas bacteria and Enterobacter cloche P99.

The present invention relates to a compound of the formula (I)

[0007]

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(In the above formula (I), Q is ＮN- or ＣC
H- and P is N-methyl-bis (2-hydroxyethyl) amine; racemic-3,4-trans-dihydroxy-1-methylpyrrolidine; (3S, 4S) -3,
4-dihydroxy-1-methylpyrrolidine; (3R, 4
R) -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 or 3,4-transdihydroxy-1-methylpiperidine).

The cephalosporin compound of the above general formula (I) of the present invention is a compound of the formula (II) 7-amino-3- (iodomethyl) -3-cephem-4-carboxylic acid (hereinafter iodomethyl) Cefem) 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- 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]

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

Hereinafter, the present invention will be described in more detail.

The iodomethylcephem of the general formula (II) which is a starting material of the present invention is a known compound and can be produced according to the following reaction formula (Japanese Patent No. 126,492).
issue). That is, it can be easily produced by reacting trifluoromethanesulfonic acid and sodium iodide with 7-ACA of the general formula (V).

[0014]

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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 production method is described in detail in the following Reference Examples.

The cephalosporin compound of the general formula (I) is prepared by combining iodomethylcephem of the general formula (II) with the general formula (II)
1-10 equivalents of a tertiary amine derivative represented by I) are mixed using a polar organic solvent, and the mixture is reacted at 20 to 25 ° C. for 1 to 12 hours, preferably 1 to 2 hours. Is reacted with 1 to 3 equivalents, desirably 1 to 2 equivalents of aminothiazole or aminothiadiazole of the general formula (IV) for 2 to 12 hours in the same vessel without separation, followed by silica gel column chromatography from the reaction product. And then freeze-dried. At this time,
N, N-dimethylformamide (DM
It is desirable to use F).

[0017]

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[0018]

Industrial Applicability The cephalosporin compound produced by the present invention has 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 investigated by agar dilution using Mueller-Hinton Agar, and 5 × 10 ⁴ cfu strains were cultured in a culture dish at 37 ° C. for 24 hours. The results are shown in Tables 1 and 2. The results are shown in Table 2.

[0019]

[Table 1]

[0020]

[Table 2]

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

[0022]

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

[0024]

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

[0026]

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

[0028]

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

[0030]

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

[0032]

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

[0034]

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

[0036]

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

[0038]

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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]

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

[0042]

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Il: 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]

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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]

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

[0048]

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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]

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

[0052]

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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]

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

[0056]

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Control compound:

[0058]

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As can be seen from Tables 1 and 2, the cephalosporin compounds of the present invention exhibit excellent antibacterial activity against a wide range of bacteria. In particular, enterobacter cloche P99 (Ente), a strain that is highly resistant to cephalosporin antibiotics
robacter Cloacae P99), whereas the minimum inhibitory concentration of the control drug ceftazidime, which is 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 0.1 ml, and exhibits not only superior antibacterial activity 16 times or more than ceftazidime, but also excellent antibacterial activity against Pseudomonas aeruginosa (Pseudomonas). This suggests that the compounds of the present invention are much more extensive and useful than ceftazidime used as a control agent.
In addition, aminothiadiazole derivatives wherein Q is = N- (I
V) The cephalosporin compounds of Ij to Ir substituted at the 7-position were compared with the control drug ceftazidime,
The antibacterial activity against Pseudomonas aeruginosa, which is a strain having a high resistance to cephalosporin antibiotics, is almost the same or shows about twice as good results.

[0060]

The following examples illustrate the present invention in more detail, and further provide a method for producing an acyclic amine or a heteroalicyclic amine of the general formula (III) for reference.

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 15-25 ° C. to a solution of (19 mmol) in tetrahydrofuran (25 ml). While refluxing this mixed solution, borane-dimethyl sulfite (18 ml,
(190 mmol) over 10 minutes and then refluxed for 24 hours. After the reaction mixture was cooled to 0 ° C., methanol (20 ml) was gradually added, and the reaction solution was concentrated. A 6N aqueous sodium hydroxide solution (20 ml) was added to the resulting residue, and the mixture was refluxed for 4 hours. The reaction solution was cooled to 15-25 ° C., the insoluble material was removed by filtration, and the filtrate was evaporated. Ethanol (50 ml) was added to the resulting residue, and 3
After vigorous stirring for 0 minutes, the mixture was filtered to remove insoluble substances. After concentrating the filtrate and adding isopropanol (100 ml), further insoluble substances were removed by filtration. After the filtrate was concentrated, a 35% formaldehyde solution (5 ml) and formic acid (15 ml) were added, and the mixture was refluxed for 16 hours. After concentrating the reaction mixture, methanol (20 ml) and anhydrous sodium carbonate (5 g) were added, and the mixture was stirred at 15 to 25 ° C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated, methylene chloride (20 ml) was added to the residue obtained, and the insoluble material was further removed by filtration. After concentrating the filtrate, vacuum distillation (200-220 ° C)
/ 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) was LiAlH ₄ (1.24 g) in tetrahydrofuran (60 ml)
, 32.72 mmol) was added slowly at a temperature of 0 ° C. After the reaction mixture was refluxed for 24 hours, it was cooled to 0 ° C., and ethyl acetate (2 ml), ethanol (15 ml), and water (10 ml) were sequentially added with vigorous stirring. The reaction mixture was stirred at 15 to 25 ° C. for 30 minutes, filtered, and washed with a mixed solution of chloroform and ethanol (1: 1) (20 ml × 3). After concentrating the combined filtrate, vacuum distillation (1 mmHg) was performed, and the obtained substance was recrystallized from chloroform and ethyl acetate to obtain the title compound as a white solid (427 mg, 57%). mp 93-95 ° C ¹ H NMR (CDCl ₃ ) δ: 4.79 (2H, brs), 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 same procedure was performed to obtain the title compound. mp 93-95 ° C. [α] = + 28 ° (c 0.05, MeOH)

Reference Example 4 Synthesis of (3R, 4R) -3,4-dihydroxy-1-methylpyrrolidine Same as Reference Example 2 using (3S, 4S) -3,4-diacetoxy-1-methylpyrrolidine The title compound was obtained in a similar manner. mp 93-95 ° 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 combined with methylene chloride (30 ml). Benzyl chloride formate (7.4 g, 4 g).
(3.4 mmol) was added slowly. After stirring for 20 minutes, the reaction temperature was raised to 20 ° C. and stirred for 2 hours. The reaction solution was washed successively with cooling water (30 ml) and saturated saline (20 ml), dried over anhydrous magnesium sulfate and evaporated, and the residue obtained 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). To the resulting solution, a catalytic amount of osmum tetraoxide and the compound synthesized in Reference Example 3 (600 mg, 2.95 mmol) were added, and the mixture was stirred overnight. Sodium hydrosulfite (0.1 g) and florisil (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 a salt, extracted with chloroform (10 ml × 4), dried over anhydrous magnesium sulfate and evaporated, and the residue obtained 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, and 10% Pd / C
After adding (27 mg), the mixture was stirred under hydrogen atmospheric pressure (1 atm) for 6 hours. The reaction solution was filtered and concentrated. A 35% formaldehyde solution (4.5 ml) and formic acid (5.5 ml) were added to the obtained product, and the mixture was refluxed for 24 hours. After concentrating the reaction mixture, methanol (20 ml) and anhydrous potassium carbonate (2 g) were added, and the mixture was stirred for 1 hour. The reaction solution was filtered and concentrated. Chloroform (10 ml) was added to the residue obtained, and the insoluble material was removed by filtration. 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 give 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 synthesized in Reference Example 6 (400 mg, 1.84 mmol) was prepared in the same manner as in Reference Example 4 to give the title 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 synthesized in Reference Example 7 (500 mg, 1.84 mmol) was prepared in the same manner as in Reference Example 5 to give the title compound ( 1
(09 mg, 47%) (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 stirred for 10 minutes. The compound synthesized in Reference Example 6 (600 mg, 2.76 mmol) was added to this solution, and the temperature was raised to 25 ° C., followed by stirring for 24 hours. The reaction mixture was concentrated, a 2N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred for 30 minutes, and then chloroform (10 ml × 2)
Extracted. The chloroform solution was dried over anhydrous magnesium sulfate and 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 subjected to the same method as in Reference Example 5 to give the title compound (17
(4 mg, 83%) (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, 0.1 mg).
87 mmol) with N, N-dimethylformamide (4m
After adding to l), the mixture was stirred at 20 to 25 ° C for 3 hours. The aminothiazole (IV, X = CH; 120 mg,
0.34 mmol) and stirred for 6 hours. The reaction mixture is subjected to silica gel column chromatography (CH ₃ CN
/ H ₂ O = 5: 1) to give the title compound (22 mg, 1
4.7%). _{^{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 (Ij) Iodomethylcephem (II, 100 mg, 0.29 mmol) and N-methyldiethanolamine (104 mg,
(0.87 mmol) was added to N, N-dimethylformamide (4 ml) and then stirred at 20-25 ° C for 3 hours.
Add aminothiadiazole (IV, X = N; 60) to the reaction mixture.
mg, 0.17 mmol) and stirred for 18 hours.
Silica gel column chromatography (CH ₃ CN / H
₂ O = 5: 1) to give the title compound (10 mg, 10
%). _{^{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-methoxyiminoacetamido] -3- (3
4-trans-dihydroxy-1-methylpyrrolidinio) methyl-3-cephem-4-carboxylate (I
Preparation of -b) Example 1 using racemic-3,4-trans-dihydroxy-1-methylpyrrolidine synthesized in Reference Example 2.
In a similar manner to the above, the title compound (18%) was obtained. _{^{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
Production of (S, 4S) -3,4-dihydroxy-1-methylpyrrolidinio] methyl-3-cephem-4-carboxylate (Ic) 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,
2s) IR (KBr) 3320, 1775, 1661, 1615, 1535cm ^-1

Example 6 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-
Production of carboxylate (I-1) The title compound was obtained in the same manner as in Example 2 using (3S, 4S) -3,4-dihydroxy-1-methylpyrrolidine synthesized in Reference 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) (3R, 4R)-synthesized in Reference Example 2.
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,
2s) 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)
Preparation 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 Production 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-methoxyiminoacetamido] -3-[(4
R) -Hydroxy- (2S) -hydroxymethyl-1-
Preparation 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- ( Preparation 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-methoxyiminoacetamido] -3- (3,3
4-cis-dihydroxy-1-methylpiperidinio] methyl-3-cephem-4-carboxylate (Ig)
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,
2s), 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 Preparation 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 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-methoxyiminoacetamido] -3- (3,3
4-trans-dihydroxy-1-methylpiperidinio) methyl-3-cephem-4-carboxylate (I
Preparation of -h) 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 Preparation of -1-methylpiperidinio) methyl-3-cephem-4-carboxylate (Iq) Example 2, using 3,4-trans-dihydroxy-1-methylpiperidine synthesized in Reference Example 10. The title compound (9%) was obtained in the same manner as described above. _{^{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

Reference Example 17 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-tropiniomethyl-3-cephem-4-carboxylate (I
Preparation of -i) The title compound (13.7%) was obtained in the same manner as in Example 1 using tropine. _{^{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

Reference Example 18 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3-tropiniomethyl-3-cephem Preparation of -4-carboxylate (Ir) The title compound (18.4%) was obtained in the same manner as in Example 2 using tropine. _{^{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, 1526cm ^-1

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Lee Jae-rung 78-4 Aooka Apartment 102-4, Samseong-dong, Gangnam-gu, Seoul, Republic of Korea (72) Inventor U Ginlan Jamsil, Seocho-gu, Seoul, Republic of Korea Dong 58-16 Shinpanura Hanshin apartment 315-708 (56) References JP-A-1-308288 (JP, A) JP-A-60-97983 (JP, A) JP-A-62-123189 (JP, A) JP-A-61-176593 (JP, A) JP-A-59-219292 (JP, A) JP-A-60-197693 (JP, A) JP-A-4-334387 (JP, A) (58) (Int.Cl. ⁷ , DB name) C07D 501/00-501/62 A61P 31/04 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A cephalosporin compound represented by the general formula (I) : In the above formula, Q is = N- or = CH-, and P is N-
Methyl-bis (2-hydroxyethyl) amine; racemic
Lock-3,4-trans-dihydroxy-1-methylpi
Loridine; (3S, 4S) -3,4-dihydroxy-1
-Methylpyrrolidine; (3R, 4R) -3,4-dihydrido
Roxy-1-methylpyrrolidine; meso-3,4-dihydride
Roxy-1-methylpyrrolidine; (2S, 4R) -4-
Hydroxy-1-methyl-2-pyrrolidinemethanol;
3,4-cis-dihydroxy-1-methylpiperidine or
Is 3,4-transdihydroxy-1-methylpiperi
Jin . 2. A compound represented by the general formula (IV) obtained by reacting an iodomethylcephem represented by the general formula (II) with an acyclic amine or a heteroalicyclic amine of the general formula (III) 2. The method according to claim 1, wherein
For producing the cephalosporin compound of the general formula (I) : In the formula, Q and P are the same as in claim 1 .