JPH01242589A - Cephem compound - Google Patents

Abstract

NEW MATERIAL:A compound (salt) expressed by the formula (R<1> is amino or aminoacyl; R<2> is carboxyl or protected carboxyl). EXAMPLE:7-acetamide-3-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester. USE:An antibacterial agent against wide pathogenic fungi containing Gram-posi tive and Gram-negative bacteria. PREPARATION:For example, 7-acetamide-3-vinyl-3-cephem-4-carboxylic acid and p-nitrobenzyl chloride are added to dimethyl sulfoxide and reacted in the presence of triethylamine at 40-45 deg.C for 4.5hr. The reaction mixture is then poured into a large amount of water and the resultant precipitate is filtered and purified using the column chromatography, etc., thus obtaining the objective compound of the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) This invention relates to novel cephem compounds and salts thereof.

(Prior art) A cephem compound having a vinyl group at the 3-position, an acylamino group at the 7-position, and a double bond between the 3-position and the 4-position is described in Japanese Patent Application Laid-open No. 56-86187. It is already well known that the compound represented by the following formula (generic name cefixime) is already commercially available as an orally administrable cephem antibiotic.

(Problems to be Solved by the Invention) The present invention provides a novel cephem compound having antibacterial activity, and also provides a new cephem compound useful for synthesizing the cephem compound represented by the above-mentioned cefixime and other cephem compounds. The purpose is to provide an intermediate.

(Means for solving the problem) The present invention provides a 77J-me compound represented by the following general formula and a salt thereof. However, R1 is an amide group or an acylamino group, and R2 represents a carboxy group or a protected carboxy group.

Here, examples of the salt of compound (I) include conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal rings such as calcium salts and magnesium salts, ammonium salts, and Organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonic acid Organic acid salts such as salts, formates, toluenesulfonic acid salts, inorganic acid salts such as hydrochlorides, hydrobromides, borates, phosphates, salts with amino acids such as arginine, aspartic acid, glutamic acid, etc. can be mentioned.

As mentioned above, in the general formula (I), R1 means an ami7 group or an acylamino group. In this case, the acyl moiety used in the acylamino group is, in penicillin and cephalosporin compounds,
A commonly used acyl moiety can be used as the acylamino group at the 6- or 7-position. To give a preferable example, the acyl moiety is polmyl, acetyl, propionyl,
lower alkanoyl such as butyryl, isobutyryl, valeryl, invaleryl, pivaloyl, hexanoyl,
It is also a heterocyclic acyl group represented by the general formula. However, in formula (11), R3 is an amine group or a protected amine group, R4
It represents a lower alkyl group substituted with hacarpoxy or protected carboxy.

In general formula (n), as the amine protecting group used in R3, an amino protecting group commonly used in penicillin and heptaphalosborin compounds can be used. Examples of suitable amino protecting groups are lower alkali/amino protecting groups such as foamyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.
It is an yl group.

Further, as the carboxy protecting group used in R', a protecting group commonly used as a protecting group for the carboxy group at the 3-position or -position of penicillin and cephalosporin compounds can be used. Suitable carboxyl protecting groups are, for example, substituted or unsubstituted phenyl (lower) alkyl groups such as benzyl, P-nitrobenzyl, phenylpropyl. Suitable lower alkyl groups include:
Straight chain or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl and the like are included.

As mentioned above, R2 represents a carboxy group or a reserved carboxy group, and the protecting group in this case can be the same as the protecting group for R4 described above.

Preferred specific examples of the compound represented by formula (1) according to the present invention include 7-acetamido-8-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester, 7-
Amino-3-vinyl-2-cephem-4-carboxylic acid p
-Nitrobenzyl ester, ? -L:2-(formamidothiazol-4-yl)-2-p-nitrobenzyloxycarbonylmethyloxyiminoacetamide]-3-
Vinyl-2--t'7) Mu-4-carboxylic acid p-nitrobenzyl ester, ? -C2-(2-aminothiazol-4-yl)-2-p-nitrobenzyloxycarbonylmethoxyiminoacetamide)-3-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester,
t-7-(2-(2-7minothiazol-4-yl)-
2-carboxymethoxyiminoacetamide)-3-vinyl-2-cephem-4-carboxylic acid.

(Effects of the Invention) The compound represented by formula (I) according to the present invention is a novel compound, exhibits high antibacterial activity, and inhibits the growth of pathogenic bacteria including Durham-positive bacteria and Durham-negative bacteria. It is useful as an antibacterial agent. That is, the object compound (1) of the present invention and its salts are combined with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external therapeutic use. They can be mixed and used in the form of conventional pharmaceutical preparations. Pharmaceutical preparations include capsules, tablets, dragees,
It may be in a solid form, such as an ointment or a concentrate, or in a liquid form, such as a solution, suspension, or emulsion. If desired, auxiliary agents, stabilizers,
Wetting agents, emulsifiers, buffers may be added, and lactose, 7
Maric acid, citric acid, 1m mineral acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao oil,
Other commonly used additives such as ethylene glycol and the like may also be added.

Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds of this invention can be administered at an average single dose of 10 myy.
, 50rny, 1100rn, 250 town, 500rny, 1
000 was found to be effective in treating pathogenic bacterial infections. -In terms of numbers, 1 takumi/individual ~ about 600 per day
01n! /individual or more may be administered.

Moreover, the object compound (I) of this invention or its salt is:
By subjecting it to oxidation and reduction reactions that are known per se, it can be converted into a cephem antibiotic as disclosed in JP-A-56-86187 (
(see reaction scheme below).

(In the formula, R1 and R2 are the same as above.) In particular, cefixime, which is a useful oral cephem antibiotic, can be synthesized from the following compound (I-a), which is a representative compound of the present invention.

(Cefixime) The oxidation reaction of the target compound (1) can be carried out using a method commonly used for converting -S- to -S-, such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, ozone, and peracetic acid. This can be easily carried out by using an oxidizing agent such as hydrogen oxide or periodic acid.

This oxidation reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrapolydrofuran, ethyl acetate. However, the solvent is not limited to this, and any other solvent can be used as long as it does not adversely affect the reaction. The reaction temperature is not particularly limited, but is preferably cooled or at room temperature.

↑ The reduction reaction following the above oxidation reaction can be carried out using methods commonly used to change -8- to -8-, such as phosphorus trichloride, a combination of stannous chloride and acetyl chloride, and sodium iodide. This can be carried out using a combination of an alkali metal iodide such as an alkali metal iodide and a trihalogenated acetic acid anhydride such as trifluoroacetic anhydride.

This reduction reaction usually involves acetone, dioxane, acetonitrile, N,N-dimethylformamide, benzene,
It is carried out in solvents such as hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, and ethyl acetate. However, the solvent is not limited to those mentioned above, and any other solvent can be used as long as it does not adversely affect the reaction. Although the reaction temperature is not particularly limited, cooling or room temperature is usually selected.

Examples of the cephem compound of formula (1) according to the present invention will be described below.

Example 1 Dimethyl sulfoxide (400 mt'), 7-acetamido-3-vinyl-3-7femu-4-carboxylic acid (3'7.5y), p-nitropenzyl chloride (
28.8g') and triethylamine (23.4d) were added and stirred at 40-45°C for 4.5 hours. This reaction mixture was added to 31ml of water, and the resulting precipitate was collected. The precipitate was subjected to silica gel chromatography and eluted with a 4:1 mixed solution of benzene and ethyl acetate. The solvent of the eluate containing the target product was distilled off to obtain 7-acetamido-8-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester (7,511).

IR (Nujol): also, 1775.1745.
1655.161 Qcm NMR (DMSO-d, δ): 1.94 (3H,
s), 4.99 (IH.

d, J=11Hz), 5.22-5.70 (6H, m
), 6.42 (IH, d d.

J=11Hz, 17Hz), 6.76 (IH, s), 7
．． 63 (2H, d, J=9Hz), 8.23 (2H,
d, J=9Hz), 8.92(LH,d, J=8
Hz) Example 2 Phosphorus pentachloride <7.7 in dichloromethane (40rne)
9) was added thereto, pyridine (3.0 m/) was added dropwise under water cooling, and the mixture was stirred at room temperature for 30 minutes. Example IT to this mixture
Obtained 7-acetamido-3-vinyl-2-cephem-4
-Carboxylic acid p-nitrobenzyl ester (7,59>
was added under water cooling, and stirred for 1.5 hours under water cooling. Methanol (5,; M) was added dropwise to this mixture at -20°C,
The mixture was stirred for 50 minutes while cooling with water.

Water (30ffle) was added to the reaction mixture, and 1
Stirred for 0 minutes. Thereafter, dichloromethane was distilled off, and the resulting aqueous solution was adjusted to pH 8 with 20% potassium carbonate. This aqueous solution was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution. The extract was then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
-Amino-3-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester (4,711) was obtained.

NMR (DM S Odo, 3 houses 4.65 (LH, d,
J = 4Hz), 4.94 (I H,d, J = 1
1 Hz), 4.95-5.53 (2H, m), 5
．． 08(LH.

d, J=4Hz), 5.32(2H,s), 6.39(
LH, d d, J = 11Hz.

17Hz), 6.76 (LH, s), 7.61 (2H,
d, J = 9Hz), 8.14 (2H, d, J = 9Hz) Example 3 Dimethylformamide (0,57) and ethyl acetate (2
,0rnl) was added to a mixed solution of phosphorus oxychloride (0rnl) under water cooling.
, 7me) was added dropwise, and the mixture was stirred for 20 minutes under water cooling. This mixed solution was mixed with tetrahydrofuran (25 ml'), and further [2-(2-formamidothiazole-4-
yl)-2-p-nitrobenzyloxycarbonylmethyloxyimino]acetic acid (2,5y) was added under water cooling, and the mixture was stirred for 80 minutes under water cooling. This mixture was mixed with 7-amino-3-vinyl-2-cephem-4-carboxylic 8p-nitrobenzyl ester (2,09) obtained in Example 2 and N-
It was added to ethyl acetate (30+r+e) containing 1-limethylsilyla7adoamide (4,49>) at a temperature of -10°C, and the mixture was stirred for 80 minutes at a temperature of -10 to -5°C to react. A mixed solution of water and ethyl acetate was added to the reaction mixture. The organic solution layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate, and the solvent was evaporated. -(2-formamidothiazol-4-yl)-2-p-nitrobenzyloxycarbonylmethyloxyiminoacetamide]-3-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester (4,479) was obtained. Ta.

IR (Nujol): 1776.1745.1685.
161 Qcm Example 4 7-C2-(2-formamidothiazol-4-yl)-2-p-nitrobenzyloxycarbonylmethyloxyiminoacetamide]-3-vinyl-2 obtained in Example 3
-Concentrated hydrochloric acid (1,1') was added to cephem-4-carboxylic acid p-nitrobenzyl ester (4,47) in a mixed solvent of methanol ('30ml') and tetrahydrofuran (30mt9) and The reaction mixture was stirred for an hour.A mixed solution of ethyl acetate and water was added to the reaction mixture, and the pH was adjusted to 8 with a 20% aqueous potassium carbonate solution.

The organic solvent layer was separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off. -(2-(2-aminothiazol-4-yl)-2-
p-Nitrobenzyloxytriponylmethoxyimide/acetamide)-3-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester (3,891>) obtained.

IR (Nujol): 3440.3300.1770.
1745.1678.1610cm-'NMR(DMS
O-d,, δ): 4.53-5.46 (8H, m),
4.77 (2H, s), 5.58 (LH, d d, J
=4Hz, 8Hz), 6.29 (IH.

d d, J=11Hz, 17Hz), 6.65(LH
, s), 6.78 (IH, s).

7.14 (2H, broads), 7.53 (2H, d
, J=8Hz), 7.57(2H,d, J=8Hz
), 8.07 (2H, d, J=8Hz), 8.1
3 (2H.

d, J=8Hz), 9.52(IH, d, J=
8Hz) Example 5 Methanol (40m'), Tetrahydro7ran (40m')
f'), 7-(2-(2-aminothiazol-4-yl)-2 obtained in Example 4) in a mixed solution of vinegar a(lrnt')
-p-nitrobenzyloxypolonylmethoxyiminoacetamide]-3-vinyl-2-cephem-4-carboxylic acid p-nitrobenzyl ester (3,751') was added, and 10% palladium-carbon was added to the mixed solution. (L
99) was added and the mixture was catalytically reduced at room temperature under atmospheric pressure. Next, the catalyst was removed and the solvent was removed by reducing the pressure of the p liquid.

Ethyl acetate and water were added to the residue thus obtained, and 20
The pH was adjusted to 7 with a solution of % potassium carbonate. After separating the aqueous layer and adjusting the pH to 5 with 10% hydrochloric acid, it was subjected to column chromatography packed with a porous nonionic adsorption resin (trade name: Diaion HP-20, manufactured by Mitsubishi Chemical Corporation). and expanded with water. Both eluted fractions containing the target product were adjusted to pH 2.2 with 10% hydrochloric acid, and extracted with a mixed solution of ethyl acetate and tetrahydrofuran. The extract layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporating the solvent, the resulting residue was triturated with ether, and the precipitate was collected by filtration. -(2-(2-
aminothiazol-4-yl)-2-carpoxymethoxyiminoheptamide)-3-vinyl-2-cephem-
4-carboxylic acid (0,65!;') was obtained.

IR (Nujol): 3300.1760.1675c
m-”NMRCDMSO-d6.5 units 4.51 (2H,
s), 4.87 (IH, d.

J=11Hz), 4.88-5.07 (IH, m),
5.08 (IH, d, J = 17Hz), 5.21 (L
H, s), 5.51 (IH, d d, J=4Hz.

8Hz), 6.24 (IH, dd, J=11Hz, 17
Hz), 6.55 (LH, s), 6.73 (IH, s
), 7.11 (2H, broads), 9.34 (
IH, d, J=8Hz)

Claims (1)

[Claims] 1. A cefem compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ and its salt. However, during the ceremony,
R^1 represents an amino group or an acylamino group, and R^2 represents a carboxyl group or a protected carboxy group. 2. The cefem compound and its salt according to claim 1, wherein R^1 is an acylamino group represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. However, in the formula, R^3 represents an amino group or a protected amino group, and R^4 represents a lower alkyl group substituted with carboxy or protected carboxy. 3. The cefem compound according to claim 2, wherein R^3 is an amino group and R^4 is a carboxymethyl group. 4. The cefem compound according to claim 1, wherein R^1 is an amino group or a lower alkane amide group.