JPH0369353B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel cefem compounds and salts thereof. More specifically, the present invention relates to novel cefem compounds and salts thereof, which are intermediates for producing novel 7-acylamino-3-vinylcephalosporanic acid derivatives and salts thereof having antibacterial activity. . Therefore, an object of the present invention is to provide an antibacterial agent that exhibits excellent antibacterial activity against a large number of pathogenic microorganisms.
To provide a novel cefem compound and its salts, which are intermediates for producing a novel 7-acylamino-3-vinylcephalosporanic acid derivative and its pharmaceutically acceptable salts, which are particularly useful as drugs for oral administration. It is in. The cefem compound (2), which is the object of this invention, is a new compound and can be represented by the following general formula. [In the formula, R ⁴ is an aryl group, R _B is the formula -CH ₂ -X ¹ , -CH ₂ P (R ⁵ ) ₃・X2 or -
CH=P(R ⁵ ) ₃ (in the formula, R ⁵ is an aryl group, X ¹ and X ² are each a halogen), R ¹ is a carboxy group or a protected carboxy group] In the target compounds () and the corresponding raw material compounds (), () and () produced by the following methods 1 to 4, chemical isomers and geometric isomers are determined based on the asymmetric carbon atoms and double bonds in these compounds. There may be one or more pairs of stereoisomers such as isomers, and any of these isomers are intended to be encompassed by this invention. Suitable salts of the object compound () include pharmaceutically acceptable salts, especially the customary non-toxic salts, salts with bases and acid addition salts, i.e. salts with inorganic bases, such as sodium salts, potassium salts, etc. Alkali metal salts such as salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, salts with organic bases such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, organic amine salts such as N,N'-dibenzylethylenediamine salts, hydrochlorides, hydrobromides,
Inorganic acid addition salts such as sulfates and phosphates; organic acids such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, and p-trienesulfonates; Included are carboxylic acid or sulfonic acid addition salts, salts with basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid. In the description above and below, suitable examples included in the various definitions will be explained in detail as follows. The term lower is used to include groups having 1 to 7 carbon atoms, unless otherwise specified. Suitable "protected carboxys" include esterified carboxyls commonly used at the 3- or 4-position of penicillin or cephalosporin compounds. Suitable ester moieties in the esterified carboxy include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary
Lower alkyl esters such as butyl esters, pentyl esters, tertiary pentyl esters, hexyl esters, lower alkenyl esters such as vinyl esters and allyl esters, lower alkyl esters such as ethynyl esters and propynyl esters, methoxymethyl esters, ethoxymethyl esters , lower alkoxy (lower) alkyl esters such as isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, lower alkylthio (such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester) lower) alkyl esters, amino- and carboxy-substituted lower alkyl esters such as 2-amino-2-carboxyethyl ester, 3-amino-3-carboxypropyl ester, 2-tert-butoxycarbonylamino-2-benzhydryloxy Protection such as lower alkoxycarbonylamino and mono (or di or tri) phenyl (lower) alkoxy carbonyl substituted lower alkyl esters such as carbonylethyl ester, 3-tertiary butoxycarbonylamino-3-benzhydryloxycarbonylpropyl ester amino and protected carboxy-substituted lower alkyl esters, 2-iodoethyl esters, 2,
Mono (or di or tri) halo (lower) alkyl ester such as 2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, shisobutyryloxymethyl ester,
Lower alkanoyloxy (lower) alkyl esters such as valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-acetoxypropyl ester, mesylmethyl ester, lower alkanesulfonyl (lower) alkyl ester such as 2-mesylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-
nitrobenzyl ester, phenethyl ester,
Trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4
-dimethoxybenzyl ester, 4-hydroxy-3,5-tertiary butylbenzyl ester, etc.
One or two substituents such as mono (or di- or tri) phenyl (lower) alkyl esters which may have one or more suitable substituents.
Al (lower) which may have 1 or more substituents
May have one or more suitable substituents such as alkyl ester, phenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc. aryl ester,
Heterocyclic esters such as phthalidyl esters are included. Suitable "halogens" include chloro, bromo, iodo, and the like. Suitable "aryl" include phenyl, tolyl, xylyl, naphthyl, and the like. The object compound () of the present invention and its salts are produced by the method shown in the following reaction formula. [In the formula, R ¹ , R ⁴ , R ⁵ , X ¹ and X ² each have the same meaning as before. ] Methods 1 to 4 for producing the target compound () are explained in detail as follows. Method 1 Compound (-a) or a salt thereof is produced by reacting compound (-a) or a salt thereof with a halogenating agent. Suitable salts for compound () include the same bases as exemplified for compound (). Suitable halogenating agents used in this reaction include phosphorus halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, and phosphorus pentabromide, thionyl halides such as thionyl chloride, and phosgene. Those conventionally used for converting hydroxy groups into halogens are used. This reaction can be carried out with alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide, alkali metal alkanoates such as sodium acetate, trialkylamines such as triethylamine, pyridine compounds such as pyridine, lutidine, and pyrroline, and quinoline. Preferably, the reaction is carried out in the presence of a base such as an organic base such as. This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as methylene chloride, chloroform, ethylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, or a mixture thereof. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. Method 2 Compound (-b) or its salts, compound (
-a) or a salt thereof with a trisubstituted phosphine represented by the formula P(R ⁵ ) ₃ (wherein R ⁵ has the same meaning as above). This reaction is preferably carried out in the presence of a metal halide such as an alkali metal halide such as sodium iodide, potassium iodide, sodium bromide, etc. In this case, the halogen of X ¹ in compound (-a) is In compound (-b), the halogen of the above metal halide may be substituted. This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride, tetrahydrofuran, ethyl acetate, or a mixture thereof. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. Method 3 Compound (-c) or a salt thereof is produced by reacting compound (-b) or a base thereof. This reaction can be carried out using organic bases such as those exemplified in Method 1, or alkali metals such as lithium, sodium, and potassium, alkaline earth metals such as calcium, and alkali metal hydrides such as sodium hydride.
alkaline earth metal hydrides such as calcium hydride;
It is carried out in the presence of an inorganic base such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydrogen carbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate. is preferred. This reaction is usually carried out in a conventional solvent such as acetone, tetrahydrofuran, water, etc. which does not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at a temperature that is slightly warmed. Method 4 Compound (-a) or a salt thereof is prepared by reacting compound (-a) or a salt thereof with a compound () represented by the formula R ⁴ -CHO (wherein R ⁴ has the same meaning as above). This reaction is preferably carried out in the presence of a dehydrating agent such as a molecular sieve. This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as N,N-dimethylformamide. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. In the above methods 1 to 4 and post-treatment of the reaction mixture, if the starting compound or the target compound contains an optical or geometric isomer, it may be converted to another optical or geometric isomer, and in this case, the present invention also applies. shall be included in. The compound () of the present invention is useful as a synthetic intermediate for 7-acylamino-3-vinylcephalosporanic acid, which is useful as an antibacterial agent. This 7-acylamino-3-vinylcephalosporanic acid is produced from the compound () of the present invention, for example, by the method described in Reference Examples below. In order to demonstrate the usefulness of the target compound, the antibacterial activity of representative 7-acylamino-3-vinylcephalosporanic acids produced using the target compound () of the present invention as a raw material compound is measured. is shown below. (1) Test 1: In vitro antibacterial activity [Test compound] 7-[2-(3-methanesulfonamidophenyl)-D-glycinamide]-3-vinyl-3-
Cefem-4-carboxylic acid (compound A) [Test method] In vitro antibacterial activity was measured by the following agar plate multiple dilution method. Trypticase soy broth (bacterial count
One loopful of the test strain cultured overnight in 10 ⁸ /ml) was inoculated onto heart infusion agar (HI agar) containing each concentration of the test compound.
After 20 hours of incubation at 37°C, the minimum inhibitory concentration (MIC) was determined in μg/ml. [Test results]

[Table] (2) Test 2: Measurement of serum levels after oral administration of antibiotics to rats [Test compound] Compound A [Test animal] 6-week old male rats, SD strain, weight 160 to 230 g each [Test method] Test compound A (100%
mg/Kg) was administered orally. Rats were anesthetized with chloroform at specified time intervals, and blood samples were collected from the heart. The antibiotic level in each serum sample was measured by the disk method using a standard solution made from rat serum. [Test results]

[Table] (3) Test 3: Protective effect against experimental mouse infection [Test compound] Compound A [Test animal] 4-week old male mouse, ICR strain, body weight 20.0 each
±1.5g [Test method] 1.3 x ¹⁰⁴ pathogenic microorganisms suspended in 2.5% mucin were injected intraperitoneally. One hour after injection, Compound A was administered orally. This mouse 4
A day later, the animals were determined to be alive or dead, and the _ED50 value was calculated. [Test results]

[Table] 7- obtained from the object compound of this invention ()
When administering acylamino-3-vinyl-cephalosporanic acid for therapeutic purposes, it may contain the above-mentioned compound as a main ingredient and be accompanied by a pharmaceutically acceptable carrier, such as an organic compound suitable for oral, parenteral, or topical use. Alternatively, they can be administered in the form of conventional preparations with inorganic, solid or liquid excipients. Such preparations include solids such as tablets, granules, powders, and capsules, as well as liquids, suspensions, syrups, emulsions,
Includes liquids such as lemonade. Furthermore, if necessary, adjuvants,
Stabilizers, wetting agents, and other commonly used additives such as lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, and ethylene glycol. can be contained. The dosage of 7-acylamino-3-vinyl-cephalosporanic acid varies depending on the patient's age, condition, type of disease, and type of compound administered, but is generally administered to the patient in an amount of 1 mg to about 4000 mg or more per day. Can be administered. The average dose for one time is about 50 mg, 100 mg, 250 mg, 500 mg,
1000mg, 2000mg can be used to treat diseases caused by pathogenic microorganisms. Next, the present invention will be explained in detail using examples. Production example of raw material compound 1 7-(5-amino-5-carboxypentanamide)-3-hydroxymethyl-3-cephem-
Benzoyl chloride (42.1 g) was added to a solution of sodium 4-carboxylate (118.6 g) in water (1000 ml) and acetone (600 ml) at 10°C with stirring under ice cooling, and the reaction mixture was diluted with 20% sodium carbonate aqueous solution to pH 6. Adjust to .5 to 7.5 while applying.
After continuing to stir at the same temperature for 1 hour, the reaction mixture was adjusted to pH 6.0 with concentrated hydrochloric acid, the acetone was distilled off, and the mixture was washed with ethyl acetate (500 ml). Add ethyl acetate (300ml) to the aqueous solution, add diphenyldiazomethane and ethyl acetate solution until the starting compound disappears on thin layer chromatography, and PH with concentrated hydrochloric acid.
Adjust to 3.0. The ethyl acetate layer is separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Dissolve the residue in acetone (400 ml) and drop the solution into diisopropyl ether (4000 ml). When the precipitated crystals are collected by filtration and dried, 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (mp100-110°C) is obtained. 224.8g). IR (Nujiyor): 3270, 1770, 1730, 1660,
1640cm ^-1 NMRδppm (DMSO-d ₆ ): 1.3-2.7 (6H, m),
3.38 (1H, s), 3.63 (2H, m), 4.27 (2H, d,
J = 5Hz), 4.67 (1H, m), 5.15 (1H, d, J
= 5Hz), 5.77 (1H, dd, J = 5Hz, 8Hz),
6.87 (1H, s), 6.95 (1H, s), 7.43 (25H,
m), 7.97 (1H, m), 8.87 (1H, m) Production example 2 Pyridine (10.3 g) was added dropwise to a suspension of 5-phosphorus chloride (27.0 g) and methylene chloride (200 ml) at 0°C. , stir for 20 minutes at 5°C. 7 for this
-(5-Benzamide-5-benzhydryloxycarbonylpentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (21.0 g) was added in one portion at -40°C, and at -30°C. Stirring is continued for 1 hour and at -10°C for a further 1 hour. Methanol (100 ml) cooled to -40°C was added to the reaction mixture at -40°C in one portion, and the mixture was stirred at -10°C for 1 hour. The solvent was distilled off, methylene chloride (100 ml), water (30 ml) and diisopropyl ether (100 ml) were added to the residue, and the mixture was stirred for a while under ice cooling. Collect the precipitated crystals by filtration, suspend in ethyl acetate (300 ml), and adjust the pH to 8.0 with an aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. When the solvent is distilled off, mp135-140℃
(Decomposition) of 7-amino-3-chloromethyl-3-
Cefem-4-carboxylic acid benzhydryl ester (2.8 g) is obtained. IR (nujiol): 3400, 1760, 1725, 1650 cm ^-1 NMRδppm (DMSO-d ₆ ): 3.60 (2H, q, J = 17
Hz), 4.38 (2H, s), 4.85 (1H, d, J=5
Hz), 5.05 (1H, d, J=5Hz), 6.95 (1H,
s), 7.4 (10H, m), 8.8 (2H, m) Production example of target compound 1 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (8.0
Molecular sieves (10 g) and benzaldehyde (2.1 g) were added to a solution of (g) in N,N-dimethylformamide (40 ml), and the mixture was heated at 40°C.
Stir for 40 minutes. Add sodium iodide (2.9
g) and triphenylphosphine (10.1 g) and stirred at 40°C for 1 hour. The reaction mixture was mixed with diisopropyl ether (200 ml) and ethyl acetate (100 ml).
ml), the precipitated crystals are collected by filtration and dried, resulting in [4-benzhydryloxycarbonyl-7-benzylideneamino-3-cephem-3-yl]methyl at mp150-158℃ (decomposition). -Triphenylphosphonium iodide (16.9 g) is obtained. IR (nujiol): 1780, 1705, 1635 cm ^-1 NMRδppm (DMSO-d ₆ ): 3.67 (2H, m), 5.2
(2H, m), 5.58 (1H, d, J=5Hz), 5.82
(1H, d, J=5Hz), 6.30 (1H, s), 7.2−
8.3 (30H, m), 8.70 (1H, s) Example 2 [4-Benzhydryloxycarbonyl-7-
benzylideneamino-3-cephem-3-yl]
To a solution of methyl-triphenylphosphonium iodide (16.9 g) in methylene chloride (200 ml) and water (100 ml) was added 36% formaldehyde aqueous solution (48 ml), and the mixture was diluted with sodium carbonate.
Adjust to PH9.0. After stirring the mixture at room temperature for 1 hour,
The organic layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off to obtain 7-benzylideneamine-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (8.6 g), mp 124-132°C. IR (nujiol): 1770, 1710, 1630 cm ^-1 NMRδppm (DMSO-d ₆ ): 3.75 (2H, q, J = 18
Hz), 5.1−5.8 (4H, m), 6.75 (1H, dd, J=10
Hz, 18Hz), 6.93 (1H, s), 7.1−8.0 (15H, m),
8.58 (1H, s) Reference Example 1 In a suspension of 7-benzylideneamino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (8.6 g) and anisole (10 ml),
Trifluoroacetic acid (10 ml) is added dropwise at −20° C., the reaction mixture is gradually brought to room temperature under stirring and stirred at room temperature for half an hour. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml) and diluted with 20% aqueous sodium carbonate.
Adjust to PH7.5. The aqueous layer is separated, washed with ethyl acetate (100 ml), adjusted to pH 7.2 with concentrated hydrochloric acid, and subjected to column chromatography on alumina (10 ml). Elute with a 15% aqueous sodium chloride solution, collect the compound containing the target compound, and dilute to pH3.3 with concentrated hydrochloric acid.
Adjust to. The precipitated crystals are collected by filtration, washed with acetone and dried.
-Amino-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) is obtained. IR (nujiol): 1800, 1605 cm ^-1 NMRδppm (D ₂ O + NaHCO ₃ ): 3.67 (2H, s),
4.8−5.8 (5H, m), 6.88 (1H, dd, J=12Hz,
18Hz) Reference example 2 2-(3-methanesulfonamidophenyl)-D
- Glycine (2.44g) and methylene chloride (25g)
ml) of suspension, add 5 to 10 ml of hydrogen chloride gas.
Bubble for 5 minutes at °C. Add phosphorus pentoxide (3.1g),
The mixture is stirred for 5 hours at 0-10°C. The precipitated solid was collected by filtration, washed with methylene chloride (5 ml) and dried to give a residue (2.7 g). This residue was added to a solution of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (1.8 g) and trimethylsilylacetamide (6.3 g) in methylene chloride (30 ml) at -15°C with stirring. and continue stirring at -5 to 0°C for 3 hours. Add water (30 ml) to the reaction mixture and shake briefly. The aqueous layer was separated, adjusted to pH 5 with a 20% aqueous sodium carbonate solution, concentrated to dryness under reduced pressure, and the resulting solid was collected using a nonionic adsorption resin "Diaion HP-20" (120
ml) for chromagraphy. After washing with water, elute with 30% isopropyl alcohol, collect fractions containing the target compound, and concentrate under reduced pressure. Lyophilization of the residue gives 7-[2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylic acid (0.47 g). IR (Nujiyor): 3300-3150, 1760, 1685,
1605cm ^-1

Claims (1)

[Claims] 1 formula [In the formula, R ⁴ is an aryl group, R _B is the formula -CH ₂ -X ¹ , -CH ₂ P (R ⁵ ) ₃・X2 or -
CH=P(R ⁵ ) ₃ (in the formula, R ⁵ is an aryl group, X ¹ and X ² are each a halogen), R ¹ is a carboxy group or a protected carboxy group] A compound represented by or its salts.