JPS638925B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² represents an alkyl group, R ³ represents an acyloxy group or a heterocyclic thio group consisting of a nitrogen-containing five-membered ring; R ⁴ represents a hydrogen atom or a carboxyl protection forming group, respectively. ] The present invention relates to an antibacterial agent containing a 7α-methoxycephalosporin or a non-toxic salt thereof. The aim is to have a broad spectrum antibacterial effect against Gram-positive and Gram-negative bacteria, be stable against β-lactamases, be well absorbed in the body, and have high blood and organ concentrations. 7α- is effective against human and animal diseases.
It is an object of the present invention to provide an antibacterial agent containing methoxycephalosporins or non-toxic salts thereof. The compound of the present invention is structurally characterized in that it has a hydroxyl group at the β-position of the alkanoyl group bonded to the 7-position, and a substituted 2,3-dioxo-1-piperazinecarboxamide group at the α-position. The present invention will be explained in more detail below. In this specification, "alkyl" means methyl,
"Lower alkyl" refers to straight-chain and branched alkyl having 1 to 14 carbon atoms, such as ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl, etc. means a straight chain alkyl of up to 4. In addition, R ³ is "an acyloxy group or a heterocyclic thio group consisting of a nitrogen-containing five-membered ring", and specifically includes acetoxy, propionyloxy, butyryloxy, benzoyloxy, naphthoyloxy, pentanecarbonyloxy, cyclohexanecarbonyloxy, Acyloxy groups such as furoyloxy and senoyloxy; oxazoylthio, thiazolylthio,
Examples include heterocyclic thio groups consisting of a five-membered nitrogen-containing ring such as isoxazolylthio, isothiazolylthio, imidazolylthio, pyrazolylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, and tetrazolylthio. Furthermore, the above R ³ is, for example, a halogen atom, an alkyl group, an aryl group, an alkenyl group, a hydroxyl group, an alkoxy group, an alkylthio group, a nitro group, a cyano group, an alkylamino group, a dialkylamino group, an acylamino group, an acyl group, an acyloxy group. , acylalkyl group, carboxyl group, carbamoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, hydroxyalkyl group, hydroxyiminoalkyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group , a sulfo group, a sulfamoyl alkyl group, a sulfamoyl group, a carbamoyl alkyl group, a carbamoyl alkenyl group, an N-hydroxycarbamoyl alkyl group, or the like. Further, R ₄ is a hydrogen atom or a carboxyl protection forming group, and examples of the carboxyl protection forming group include those conventionally used in the field of penicillin and cephalosporin compounds. These carboxyl protection-forming groups include ester-forming groups that have the property of being eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions;
or ester-forming groups that are easily eliminated in vivo, or other known ester-forming groups such as organosilyl, organic phosphorus, or organotin groups that are easily eliminated when treated with water or alcohol. can be mentioned. Among these types of protection-forming groups, preferable protection-forming groups include the following. (a) Alkyl groups; especially straight-chain or branched C _1-14 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and pentyl. . (b) At least one of the substituents is chloro, bromo,
Fluoro, nitro, carbalkoxy, acyl, alkoxy, oxo, cyano, alkylmercapto, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4
-imidazolyl, phthalimide, acetidino,
aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-lower alkylpiperazino, 2,5-dimethylpyrrolidino, 1,
4,5,6-tetrahydropyrimidinyl, 4-
Methylpiperidino, 2,6-dimethylpiperidino, alkylamino, dialkylamino, acyloxy, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkoxycarbonyloxy or substituted with alkylanilino or chloro, bromo, lower alkyl or lower alkoxy A substituted lower alkyl group that is alkylanilino. (c) Cycloalkyl or lower alkyl-substituted cycloalkyl or [2,2-dilower alkyl-1,3-dioxolan-4-yl]methyl group consisting of 3 to 7 carbon atoms. (d) Alkenyl groups having up to 10 carbon atoms. (e) Alkynyl groups having up to 10 carbon atoms. (f) A substituted phenyl group or a substituent in which the phenyl group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a substituted phenyl group of the formula [In the formula, X is -CH=CH-O-, -CH=CH-S
−, −CH ₂ CH ₂ S−, −CH=N−CH=N−, −
CH=CH−CH=CH−, −CO−CH=CH−CO
-, or -CO-CO-CH=CH-. ] A group represented by or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified in (b) above),
or expression [In the formula, Y is a lower alkylene group such as -(CH ₂ ) ₃ - or -(CH ₂ ) ₄ -. ] A group represented by or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified in (b) above)
Aryl groups such as. (g) An aralkyl group such as benzyl or a substituted benzyl in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (H) furyl, quinolyl, methyl-substituted quinolyl, phenazinyl, 1,3-benzodioxolanyl,
3-(2-methyl-4-pyrrolinyl), 3-(4
-pyrrolinyl) or N-(methylpyridyl)
A heterocyclic group such as or a substituted heterocyclic group in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (li) Alicyclic indanyl or phthalidyl and substituted derivatives thereof in which the substituent is methyl, chloro, bromo or fluoro; alicyclic tetrahydronaphthyl and substituted derivatives thereof in which the substituent is methyl, chloro, bromo or fluoro;
trityl, cholesteryl, bicyclo [4,4,
0] Decir et al. The protection-forming groups exemplified above are representative examples, and the protection-forming groups described in the following documents can be arbitrarily selected. U.S. Patent Nos. 3,499,909, 3,573,296 and
No. 3641018: West German Patent Publication No. 2301014,
Nos. 2253287 and 2337105. In addition, examples of the non-toxic salts of cephalosporins represented by the general formula () of the present invention include non-toxic salts with acidic groups and non-toxic salts with basic groups that are conventionally known in the field of penicillin or cephalosporin compounds. . Non-toxic salts of acidic groups include, for example, alkali metal salts such as sodium and potassium; alkaline earth metals such as calcium and magnesium; ammonium salts; procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, trimethylamine,
Triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine,
Examples include salts with nitrogen-containing organic bases such as N-methylmorpholine, diethylamine, and dicyclohexylamine. Non-toxic salts of basic groups include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, and trifluoroacetic acid; methanesulfonic acid, toluenesulfonic acid, Examples include salts with organic sulfonic acids such as naphthalenesulfonic acid. Furthermore, the cephalosporins represented by the general formula () and their non-toxic salts of the present invention include all optical isomers and racemates, as well as all crystal forms and hydrates. Among the compounds of the present invention, preferred examples include the following. ●7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-hydroxypropanamide]-7α-methoxy-3-
[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid and its nontoxic salts 7β-[D-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamide)-β-(S
or R)-hydroxybutanamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,4
-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid and its non-toxic salts●7β-[D-α-(4-n- or iso-propyl-
2,3-dioxo-1-piperazinecarboxamide)-β-(S or R)-hydroxybutanamide]-7α-methoxy-3-[5-(1-methyl-
1,2,3,4-tetrazolyl)thiomethyl]
-△ ³ -Cefem-4-carboxylic acid and its non-toxic salts 7β-[D-α-(4-n- or iso-butyl-2,
3-dioxo-1-piperazinecarboxamide)-β-(S or R)-hydroxybutanamide]
-7α-methoxy-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-△ ³
-Cefem-4-carboxylic acid and its non-toxic salts 7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S
or R)-hydroxybutanamide]-7α-methoxy-3-[2-(5-methyl-1,3,4-thiadiazolyl)thiomethyl]-△ ³ -cephem-
4-Carboxylic acid and its non-toxic salts 7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S
or R)-hydroxybutanamide]-7α-methoxy-3-acetoxymethyl-△ ³ -cephem-4-carboxylic acid and its nontoxic salts●7β-[D-α-(4-methyl-2,3-dioxo -1-piperazinecarboxamide)-β-(S
or R)-hydroxybutanamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,4
-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid and its nontoxic salts●7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S
or R)-hydroxybutanamide]-7α-methoxy-3-[2-(1,3,4-thiadiazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid and its nontoxic salts 7β-[D- α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S
or R)-hydroxybutanamide]-7α-methoxy-3-[5-[1-(2-hydroxyethyl)
-1,2,3,4-tetrazolyl]thiomethyl]-△ ³ -cephem-4-carboxylic acid and its nontoxic salts 7β-[D-α-(4-n-octyl-2,3-
dioxo-1-piperazinecarboxamide)-
β-(S or R)-hydroxybutanamide]-7α
-Methoxy-3-[5-(1-methyl-1,2,
3,4-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid and its non-toxic salt The compound represented by the general formula () or its non-toxic salt can be produced by a conventionally known method such as the following method. Ru. Manufacturing method (1); General formula () (In the formula, R ¹ , R ³ and R ⁴ have the above-mentioned meanings.) The compound represented by the general formula () (In the formula, R ² has the above-mentioned meaning.) A method of reacting a reactive derivative at the carboxyl group of a compound represented by the following. Manufacturing method (2); General formula () (In the formula, R ³ and R ⁴ have the above-mentioned meanings.) The compound represented by the general formula () (In the formula, R ¹ and R ² have the above-mentioned meanings.) A method of reacting a compound represented by the following or a salt thereof or a reactive derivative thereof at a carboxyl group. Manufacturing method 3; General formula () (In the formula, R ¹ , R ² , R ³ and R ⁴ have the above-mentioned meanings.) A cephalosporin represented by the general formula () M ^{1+ -} OCH ₃ () (in the formula , M ¹ means an alkali metal.) A method of reacting methanol with an alkali metal salt represented by the following formula, and then reacting with a halogenating agent. Manufacturing method (4); General formula () (In the formula, R ⁵ represents a group that can be easily replaced by a nucleophile, and R ¹ , R ² and R ⁴ have the meanings described above.) 7α-methoxycephalosporins represented by the general formula ( ) R ³ M ² () (wherein M ² represents a hydrogen atom, an alkali metal or an alkaline earth metal, and R ³ has the meaning described above). In addition, R ⁵ represents a group that can be easily replaced by a nucleophilic reagent, such as halogen atoms such as chlorine and bromine; lower alkanoyloxy groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, and pivaloyloxy; benzoyloxy,
Arylcarbonyloxy groups such as naphthoyloxy; Arylthiocarbonyloxy groups such as thiobenzoyloxy and thionaphthoyloxy; Arylcarbonylthio groups such as benzoylthio and naphthoylthio; Arylthiocarbonylthio such as thiobenzoylthio and thionaphthoylthio group; carbamoyloxy group; thiocarbamoyloxy group; pyridine-N-oxide-2-yl group; pyridazine-N-oxide-6-yl group.
Each of these groups represented by R ⁵ may be further substituted with various substituents such as a halogen atom, nitro group, alkyl group, alkoxy group, alkylthio group, and acyl group. As the reactive derivative of the carboxyl group of the compound represented by the general formula () or (), reactive derivatives of carboxylic acid that are generally used in the synthesis reaction of acid amide compounds are applied, such as acid halides, acid azides, etc. , mixed acid anhydrides with organic or inorganic acids, active esters, active amides, and the like. As the reactive derivative of the carboxyl group represented by the general formula (), acid halides such as acid chloride and acid bromide, active esters such as dianomethyl ester and trichloromethyl ester, and acid azides are particularly preferred. Furthermore, as the reactive derivative of the carboxyl group represented by the general formula (), acid halides, mixed acid anhydrides, and active acid amides are particularly preferred. Compounds represented by the general formulas () and () can be synthesized according to methods known per se, such as the method described in Journal of the Society of Organic Synthetic Chemistry, Vol. 35, No. 7, pp. 568-574 (1977). can do. Moreover, the compounds represented by the general formulas (), (), and () can be synthesized according to methods known per se. During the reactions of the above production methods (1) to (4), active groups such as amino groups, hydroxyl groups, and carboxyl groups in the raw materials are usually used to protect amino groups, hydroxyl groups, and carboxyl groups. It can be protected with an arbitrary protecting group, and after the reaction, the protecting group can be removed by a conventional method and converted into the desired substituent. Next, embodiments of each manufacturing method will be described. Production methods (1) and (2) can be carried out under substantially similar conditions. That is, compound () or compound () is reacted with an inert solvent such as water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene, toluene. , methylene chloride, chloroform, ethyl acetate, methyl isobutyl ketone, etc., and a reactive derivative at the carboxyl group of the compound () or a salt thereof or a salt thereof. Reactive derivatives at the carboxyl group in the presence or absence of a base from −60 to 80
The reaction is preferably carried out at -40 to 30°C. A reaction time of 5 minutes to 5 hours is generally sufficient. Examples of the base used here include inorganic bases such as alkali hydroxide, alkali carbonate, alkali acetate, trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, etc. and secondary amines such as dicyclohexylamine and diethylamine. When using compound () or a salt thereof as a raw material in production method (2), for example, N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide,
N,N'-diethylcarbodiimide, N,N'-carbonyl (2-methylimidazole), phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, phosphorus oxychloride, phosphorus trichloride, 2-chloro-
1,3,2-dioxaphosphorane, oxalyl chloride, dimethylchloroforminium chloride,
This can be carried out in the presence of a dehydration condensation agent such as dimethylethoxyforminium chloride. Production method (3) involves using a cephalosporin represented by the general formula () obtained by a conventionally known method in a reaction-inert solvent such as tetrahydrofuran, dioxane, dimethyl ether of ethylene glycol, methylene chloride, chloroform, dimethylformamide, It is dissolved or suspended in one or more mixed solvents such as dimethylacetamide, acetonitrile, methanol, etc., an alkali metal salt of methanol () is added together with methanol for reaction, and then a halogenating agent is added for reaction. In this reaction, methanol is preferably used in an excess amount, and the amount of the alkali metal salt of methanol () is preferably 2 to 6 equivalents relative to the cephalosporin of the general formula (). Moreover, the excess amount means 1 equivalent or more with respect to the cephalosporin of formula (). All the above reactions are generally carried out at a reaction temperature of -120 to -10℃.
The reaction is preferably carried out at -100 to -50°C, and a reaction time of 5 to 30 minutes is sufficient. Thereafter, the reaction is stopped by making the reaction system acidic. The halogenating agent that can be used in this method is:
Generally known as a positive halogen source, it is any halogen compound capable of supplying a positive halogen atom, such as Cl ⁺ , Br ⁺ or I ⁺ . Specifically, for example, halogens such as chlorine and bromine; N-haloimides such as N-chlorosuccinimide and N-bromosuccinimide; N- such as N-chloroacetamide and N-bromoacetamide;
Haloamides; N-halosulfonamides such as N-chlorobenzenesulfonamide and N-chloro-p-toluenesulfonamide; 1-halobenzotriazoles; 1-halotriazines; tert.-butylhypochlorite, tert. -organic hypohalogenites such as butyl iodide; halohydantoins such as N,N-dibromohydantoin; and the like. A preferred halogenating agent is tert.-butylhypochlorite. For cephalosporins represented by the general formula (), the halogenating agent is
A sufficient amount is used to provide an equivalent amount of positive halogen. Suitable acids for terminating the reaction are also those which, when added to the cold reaction mixture, do not cause the reaction mixture to solidify or freeze into a heavy viscous mixture. For example, 98% formic acid, glacial acetic acid, trichloroacetic acid, methanesulfonic acid, etc. can be used. After the reaction has stopped, in order to remove excess halogenating agent, treatment with a reducing agent such as trialkyl ester of phosphorous acid or sodium thiosulfate is recommended. In addition, in order to carry out the manufacturing method (4), R ⁵ in the formula ()
is a heterocyclic aromatic amine having a thio group on the carbon atom adjacent to the N-oxide group in the molecule. When using a compound represented by the general formula () other than a compound having an N-oxide thio group as a raw material, for example, water , methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, 2-methoxyethanol, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, dichloroethane, chloroform , in one or a mixed solvent of two or more solvents inert to the reaction such as dichloromethane,
Compounds represented by general formula () and general formula ()
React with the compound represented by The above reaction is preferably carried out in a highly polar solvent such as water, in which case it is advantageous to maintain the pH value of the reaction solvent between 2 and 10, especially between 4 and 8, and with a buffer such as sodium phosphate. Add the agent to achieve the desired
It can be reacted by adjusting the pH value. Although the reaction conditions are not particularly limited, the reaction is usually carried out within the range of 0 to 100°C over several hours to several tens of hours. In addition, in the formula (), when R ⁵ is a heterocyclic aromatic amine N-oxide thio group having a thio group on the carbon atom adjacent to the N-oxide group in the molecule, in the above inert solvent, the general formula () A compound represented by the formula () is reacted with a compound represented by the general formula () in the presence of a divalent copper compound. In this reaction, the compound represented by the general formula () is methyl alcohol,
It is particularly useful when using alcohols such as ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, benzyl alcohol, and ethylene glycol. If it is used also as a reaction solvent, the reaction will proceed smoothly. Examples of divalent copper compounds used in this method include copper chloride, copper bromide, copper fluoride, copper nitrate, copper sulfate, copper borate, copper phosphate, copper cyanide, copper formate, and copper acetate. , copper propionate, copper citrate, copper tartrate, copper benzoate, copper salicylate, and other inorganic or organic divalent copper compounds. The amount of the divalent copper compound to be used is preferably 1/2 mole or more based on the compound represented by the general formula (). The reaction temperature and reaction time depend on the compound represented by the general formula (), the divalent copper compound used, and the type of the compound represented by the general formula (), but generally the reaction temperature is 0 to 100%. ℃
The range and reaction time are appropriately selected from several minutes to several days. Furthermore, in the case of a compound of the general formula () where R ¹ is a carboxyl protection forming group, a compound of the general formula () where R ¹ is a hydrogen atom or a non-toxic salt thereof; a general formula where R ¹ is a hydrogen atom; In the case of a compound of (), a compound of general formula () or a non-toxic salt of a compound of general formula () in which R ¹ is a carboxyl protecting group; can be converted into free compounds by conventional methods. The conditions for the above-mentioned production method are not limited to these, but can be appropriately selected depending on the type of reaction reagent. 7α-Methoxycephalosporin () and its non-toxic salts are isolated and collected from the reaction mixture according to conventional methods. In addition, 7α represented by the general formula () of the present invention
The method for producing -methoxycephalosporins and their non-toxic salts is not limited to the production method described here, but can also be produced by applying other conventionally known methods. Next, the pharmacological effects of representative compounds of the present invention will be shown. (1) Antibacterial activity Japanese Society of Chemotherapy (Chemo therapy) No. 16
Volume 98-99 (1968)] Based on Heart
A bacterial solution cultured in Infusion broth (manufactured by Eiken Kagaku Co., Ltd.) at 37℃ for 20 hours was inoculated into Heart Infusion agar medium (manufactured by Eiken Kagaku Co., Ltd.), and after culturing at 37℃ for 20 hours, the presence or absence of bacterial growth was observed. The minimum concentration at which bacterial growth was inhibited was defined as the MIC (mcg/ml). However, the amount of inoculated bacteria is 10 ⁴ pieces/plate (10 ⁶ pieces/plate)
ml). Compound A; 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-
7α-methoxy-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-
△ Sodium salt of ³ -cephem-4-carboxylic acid. Compound B; 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-
Sodium salt of 7α-methoxy-3-[2-(1,3,4-thiadiazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid. Compound C; 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-
Sodium salt of 7α-methoxy-3-[5-(1-hydroxyethyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylic acid. Compound D; 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)-β-(R)-hydroxybutanamide]-
7α-methoxy-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-
△ Sodium salt of ³ -cephem-4-carboxylic acid. Compound E; 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-
7α-Methoxy-3-acetoxymethyl-△ ³
-Sodium salt of cefem-4-carboxylic acid

【table】

[Table] (2) Blood concentration 20mg/Kg was intramuscularly injected into rats (3 rats were used), and K.pneumoniae ATCC-
10031 and the paper disk method.

[Table] (3) Infection prevention effect A group of 5 4-week-old ICR mice (male) was used, and a predetermined amount of pathogenic bacteria suspended in 5% mucin was inoculated intraperitoneally, and 1 hour after inoculation. After administering the following drugs subcutaneously, the infection prevention effect was measured.

[Table] (4) Acute toxicity The acute toxicity (LD50 value) of compound A is 5g/Kg
That is all (ICR mouse ♀-iV administration). The 7α-methoxycephalosporin and its salts represented by the general formula () of the present invention are:
It is generally administered to humans and animals in the free acid form, as well as in the form of non-toxic salts or physiologically acceptable esters. The compound is formulated into a dosage form commonly used for penicillin or cephalosporin drugs, such as tablets, capsules, syrups, and injections, and is administered orally or parenterally. For administration to humans, intravenous (including drip) or intramuscular injections are particularly suitable. The antibacterial agent of the present invention can also be used in combination with a solid or liquid carrier or diluent commonly used in known antibiotic injections. Injectable forms also include powders that are dissolved in a suitable vehicle, such as sterile water, physiological saline, etc., before use. Furthermore, when the antibacterial agent of the present invention is used as an injection, other drugs such as a local anesthetic such as lidocaine hydrochloride may be used in combination. In addition, the dosage of the antibacterial agent of the present invention varies depending on the person or animal; for example, in the case of humans, the dose depends on the age,
It is selected as appropriate depending on the type or symptoms of the infectious disease. For example, in the case of injections, it is generally appropriate for an adult to use a titer of 0.5 to 10 g per day in several doses. Next, Examples and formulation examples of the compounds of the present invention are shown. Example 1 (1) 2.0 g of D-threonine is suspended in 50 ml of methylene chloride, 6.58 ml of trimethylchlorosilane is added, and 7.01 ml of triethylamine is added dropwise at 0 to 5°C. After gradually raising the temperature and reacting at 20℃ for 1.5 hours,
4-ethyl-2,3-dioxo- at 5-10℃
5.9 g of a mixture of 1-piperazine carbonyl chloride and triethylamine hydrochloride [4-ethyl-
2,3-dioxo-1-piperazinecarbonyl chloride content 58.55% (weight/weight)] was added, and the reaction was continued at 20°C for 1 hour, and then the solvent was distilled off. Add 30 ml of water, adjust the pH to 7.5 with sodium bicarbonate, wash with 50 ml of ethyl acetate, add 50 ml of acetonitrile, and adjust the pH to 1.5 with 2N hydrochloric acid.
After adding salt to saturate the mixture, separate the acetonitrile layer. The aqueous layer was further extracted four times with 50 ml of acetonitrile, and the acetonitrile layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate.
After distilling off the solvent under reduced pressure, the residue is recrystallized from n-butanol to give D-
α-(4-Ethyl-2,3-dioxo-1-piperazinecarboximide)-β-(S)-hydroxybutyric acid 3.6g (yield 75%)
get. IR (KBr) cm ^-1 ; νC=O1740, 1710, 1670 NMR (DMSO- _d6 ) ppm value: 1.11 (3H, t, _CH3 ), 1.13 (3H, d, _CH3 ), 3.28-3.75 (4H , m, CH ₂ × 2), 3.78-4.30 (4H, m, CH ₂ , CH × 2) (2) D-α-(4-ethyl-2,3-dioxo-
1-Piperazinecarboxamide)-β-(S)-
Suspend 1.0 g of hydroxybutyric acid in 15 ml of methylene chloride, add 0.38 ml of 1-methylmorpholine to dissolve it, add 0.35 ml of ethyl chlorocarbonate at -15 to -20°C, and dissolve at the same temperature.
Incubate for 1.5 hours. Then, diphenylmethyl=7β-amino-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-△ ³
- Add 1.67 g of cefem-4-carboxylate and keep at the same temperature for 1 hour, and then at -10~0℃ for 1.5
Allow time to react. The solvent was distilled off under reduced pressure, 30 ml of water and 30 ml of ethyl acetate were added to the residue, and the mixture was stirred.
If you remove the white crystals that precipitate, the melting point is 121-125℃.
Diphenylmethyl = 7β-[D-
α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-△ ³
2.5 g (yield 95%) of -cephem-4-carboxylate are obtained. IR (KBr) cm ^-1 ; νC=O1785, 1720, 1680 NMR (DMSO- _d6 ) ppm value, 1.00 (3H, t, _CH3 ), 1.16 (3Hd, _CH3 ), 3.4-4.0 (10H, m , CH ₂ × 4, CH × 2), 3.85 (3H, s, CH ₃ ), 4.25 (2H, q, CH ₂ ), 5.10 (1H, d, CH), 5.8 (1H, m, CH), 6.85 (1H, s, CH), 7.2~7.45 (10H, s,
C ₆ H ₅ ×2), 8.91 (1H, s, NH), 9.26 (1H,
s, NH) (3) Diphenylmethyl = 7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-3-[5-( 1-methyl-1,2,3,4
1.0 g of -tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylate is dissolved in 30 ml of dry methylene chloride and 2 ml of dry tetrahydrofuran and cooled to -70°C. Methanol solution of lithium methoxide (1.66 mmole/ml) at the same temperature
Add 3.55 ml and stir for 3 minutes, then add 0.18 ml of tert-butyl hypochlorite and stir at the same temperature for 15 minutes. Next, 0.39 ml of acetic acid is added and the temperature is raised to room temperature. After distilling off the solvent under reduced pressure, add 20 ml of ethyl acetate and 20 ml of water to dissolve the residue, and adjust the pH to 6.5 with aqueous sodium bicarbonate. The organic layer is separated, washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. If the residue is purified by silica gel column chromatography (eluted with benzene:ethyl acetate = 1:2), diphenylmethyl = 7β
-[D-α-(4-ethyl-2,3-dioxo-
1-Piperazinecarboxamide)-β-(S)-
Hydroxybutanamide]-7α-methoxy-3-
0.6 g (yield: 40.8%) of [5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylate is obtained. IR (KBr) cm ^-1 , 1780, 1710, 1670 NMR (CDCl ₃ ) ppm value: 1.20 (3H, t _D CH ₃ ), 1.25 (3H, d, CH ₃ ),
3.5 (3H, s, CH ₃ ), 3.79 (3H, s, CH ₃ ),
3.2~4.0 (8H, m, CH ₂ × 4), 4.3~4.6 (4H,
m, CH ₂ , CH×2), 5.02 (1H, s, CH),
6.85 (1H, s, CH), 7.2~7.4 (10H, s,
C ₆ H ₅ ×2), 8.52 (1H, s, NH), 9.55 (1H,
d, NH) (4) Diphenylmethyl = 7β-(D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-7α-methoxy-3- [5-(1-methyl-
1,2,3,4-tetrazolyl)thiomethyl]
-△ ³ -Cefem-4-carboxylate 0.5g
Dissolve in 5 ml of anisole, add 5 ml of trifluoroacetic acid under ice cooling, and stir at the same temperature for 30 minutes.
The solvent was distilled off under reduced pressure, and the residue was diluted with 10% ethyl acetate.
ml, add 10 ml of water, and then add saturated sodium bicarbonate solution under stirring to bring the pH to 6.5 and dissolve. Separate the aqueous layer and add 10ml of methyl acetate to 2N
- Adjust the pH to 2.0 with hydrochloric acid and separate the organic layer. The aqueous layer is further extracted twice with 10 ml of methyl acetate, combined with the organic layer, and washed with saturated brine. After drying with magnesium sulfate, the solvent is distilled off under reduced pressure and the residue is treated with ether.
7β-[D-α-
(4-Ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-7α-methoxy-3-[5-(1-
Methyl-1,2,3,4-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid 0.25
g (yield 63.3%). IR (KBr) cm ^-1 ; νC=O1770, 1705, 1675 NMR (DMSO-d ₆ ) ppm value; 1.10 (3H, t, CH ₃ ), 1.15 (3H, d, CH ₃ ),
3.40 (3H, s, CH ₃ ), 3.93 (3H, s, CH ₃ ),
3.5~4.0 (8H, m, CH ₂ × 4), 4.1~4.4 (4H,
m, CH ₂ , CH×2), 5.03 (1H, s, CH),
9.2 (2H, d, NH x 2) The following compound is obtained in the same manner. ●7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β
-Hydroxypropanamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,4-
Tetrazol) thiomethyl]-△ ³ -Cefem-
4-Carboxylic acid Melting point 125-130℃ (decomposed) IR (KBr) cm ^-1 ; νC=O1780, 1720, 1710,
1670 NMR (DMSO- _d6 ) ppm value; 1.15 (3H, t, _CH3 ), 3.30-4.10 (10H,
m, CH ₂ ×5), 3.45 (3H, s, CH ₃ ),
3.95 (3H, s, CH ₃ ), 4.33 (2H, ABq,
CH ₂ ), 4.50 (1H, m, CH), 5.05 (1H,
s, CH), 9.30 (2H, bs, NH x 2) ●7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β
-(S)-Hydroxybutanamide]-7α-methoxy-3-[2-(1,3,4-thiadiazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid Melting point 108-112℃ (decomposition) IR ( KBr) cm ^-1 ; νC=O1780, 1720, 1680 NMR (DMSO- _d6 + _D2O ) ppm value; 1.02-1.39 (6H, m, _CH3 ×2), 3.50 (3H,
s, CH ₃ ), 3.3-4.5 (12H, m, CH ₂ ×5,
CH×2), 5.05 (1H, s, CH), 9.42 (1H,
s, CH) ●7β-[D-α-(4-n-octyl-2,3
-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-
7α-methoxy-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-
△ ³ -Cefem-4-carboxylic acid Melting point 113-115℃ (decomposed) IR (KBr) cm ^-1 ; νC=O1780, 1660-1720 NMR (CD ₃ COCD ₃ ) ppm value; 0.80-1.60 (18H, m, CH ₂ ×6, CH ₃ ×
2), 3.30~4.50 (12H, m, CH ₂ × 5, CH
×2), 3.48 (3H, s, CH ₃ ), 3.95 (3H,
s, _CH3 ), 5.00 (1H, s, CH), 8.37
(1H, s, NH), 9.40 (1H, d, NH) ●7β-[D-α-(4-n-butyl-2,3-
dioxo-1-piperazinecarboxamide)
-β-(S)-hydroxybutanamide]-7α-
Methoxy-3-[5-(1-methyl-1,2,
3,4-tetrazolyl)thiomethyl]-△ ^3-
Cefem-4-carboxylic acid Melting point 125-133℃ (decomposed) IR (KBr) cm ^-1 ; νC=O1785, 1710, 1680 NMR (DMSO-d ₆ ) ppm value; 0.80-1.60 (10H, m, CH ₂ × 2, CH ₃ ×
2), 3.20~4.40 (12H, m, CH ₅ × 5, CH
×2), 3.41 (3H, s, CH ₃ ), 3.94 (3H,
s, _CH3 ), 5.08 (1H, s, CH), 9.27
(1H, s, NH), 9.30 (1H, d, NH) ●7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β
-(R)-Hydroxybutanamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,
4-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid Melting point 144-150℃ (decomposition) IR (KBr) cm ^-1 ; νC=O1780, 1735-1660 NMR (CD ₃ COCD ₃ :DMSO-d ₆ =4:1)
ppm value; 0.96 ~ 1.37 (6H, m, CH ₃ × 2), 3.30 ~
4.92 (12H, m, CH ₂ × 5, CH × 2), 3.54
(3H, s, CH ₃ ), 4.04 (3H, s, CH ₃ ),
5.10 (1H, s, CH), 9.23 (1H, bs,
NH), 9.46 (1H, d, NH) Example 2 (1) D-α-(4-ethyl-2,3-dioxo-
1-Piperazinecarboxamide)-β-(S)-
4.5 g of hydroxybutanoic acid is suspended in 45 ml of methylene chloride, and 1.60 g of N-methylmorpholine is added and dissolved. This solution is cooled to -20°C, 1.78g of ethyl chlorocarbonate is added, and the mixture is reacted at -13 to -16°C for 1.5 hours. Then at -30℃ diphenylmethyl = 7β-amino-
3-acetoxymethyl-△ ³ -cephem-4-
Add 6.50 g of carboxylate. −10〜−
After reacting at 15°C for 30 minutes and at -10 to 0°C for 30 minutes, the solvent was distilled off under reduced pressure. Add and dissolve 50 ml of ethyl acetate, 50 ml of methyl acetate and 40 ml of water to the residue. The organic layer is separated, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethanol = 60:1)
If it is separated and purified using white powder diphenylmethyl =7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β
8.2 g (yield: 78.2%) of -(S)-hydroxybutanamide]-3-acetoxymethyl- ^{Δ 3} -cephem-4-carboxylate was obtained. IR (KBr) cm = ¹ ; νC = O1780, 1705, 1670 (2) Diphenylmethyl obtained in (1) = 7β-[D-α-
Dissolve 8.0 g of (4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-3-acetoxymethyl- ^Δ3 -cephem-4-carboxylate in 80 ml of methylene chloride. , 26 ml of a methanol solution of lithium methoxide (content of lithium methoxide: 1.51 mmol/ml) is added at -70°C. −65～
After stirring at -70°C for 3 minutes, 1.60 g of tert.-butyl hypochlorite was added, the mixture was allowed to react at the same temperature for 15 minutes, and then 3 ml of acetic acid was added. After the reaction solution was gradually heated to 0° C., the solvent was distilled off under reduced pressure. Add 100 ml of ethyl acetate and 50 ml of water to the residue.
The organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. If the residue is separated and purified by silica gel column chromatography (eluent: ethyl acetate), a white powder of diphenylmethyl 7β-[D-α-(4-
Ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-7α-methoxy-3-acetoxymethyl-△ ³ -cephem-4-carboxylate 2.65
g (yield 31.8%) was obtained. IR (KBr) cm ^-1 ; 1780, 1740, 1710, 1680 (3) Diphenylmethyl obtained in (2) = 7β-[D-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-7α-methoxy-3-acetoxymethyl-△ ³ -cephem-4-carboxylate (2.65 g) on ice Add 26 ml of anisole and 26 ml of trifluoroacetic acid while cooling, and react at the same temperature for 30 minutes. After the reaction, the solvent is distilled off under reduced pressure, the residue is washed with diethyl ether, and the melting point is
A white powder of 7β-[D
-α-(4-ethyl-2,3-dioxo-1-
2.0 g (yield: 97.6%) of piperazinecarboxamide)-β-(S)-hydroxybutanamide]-7α-methoxy-3-acetoxymethyl-Δ ³ -cephem-4-carboxylic acid was obtained. IR (KBR) cm ^-1 ; νC=O1780, 1605, 1670 NMR (CD ₃ COCD ₃ :DMSO−d ₆ =4:1)
ppm value; 0.85-1.45 (6H, m, CH ₃ × 2), 2.03 (3H,
s, CH ₃ ), 3.15-4.95 (12H, m, CH ₂ ×5,
CH×2), 3.48 (3H, s, CH ₃ ), 5.06 (1H,
s, CH), 8.84 (1H, s, NH), 9.34 (1H,
d, NH) Example 3 7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)
-Hydroxybutanamide]-7α-methoxy-3-
Acetoxymethyl-△ ³ -cephem-4-carboxylic acid 0.71g and 1-(2-hydroxyethyl)-5-
Dissolve 0.22 g of mercapto-1H-tetrazole in 24 ml of nitromethane and react at 80°C for 5 hours.
After the reaction, the solvent is distilled off under reduced pressure, and 20 ml of ethyl acetate and 20 ml of acetone are added to the residue to dissolve it. Next, diphenyldiazomethane was added to this solution until the reddish-purple color no longer disappeared, and then the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform:ethanol = 20:1) to obtain a pale yellow powder. Add 3.5ml of anisole to this powder under ice cooling.
Add 3.5 ml of trifluoroacetic acid and react at the same temperature for 30 minutes. After the reaction, the solvent was distilled off under reduced pressure,
If the residue is washed with ethyl acetate, the melting point
7β-[D
-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-hydroxybutanamide]-7α-methoxy-3-[5-[1-
0.28 g (yield: 34%) of (2-hydroxyethyl)-1,2,3,4-tetrazolyl]thiomethyl]-Δ ³ -cephem-4-carboxylic acid was obtained. IR (KBr) cm ^-1 ; νC=O1780, 1710, 1675 NMR (CD ₃ COCD ₃ :DMSO−d ₆ =4:1) ppm
Value; 0.9-1.4 (6H, m, CH ₃ × 2), 3.47 (3H, s,
CH ₃ ), 3.20-4.60 (16H, m, CH ₂ × 7, CH ×
2), 5.03 (1H, s, CH), 9.01 (1H, s,
NH), 9.31 (1H, d, NH) Example 4 D-α-(4-ethyl-2,3-dioxo-1
-piperazinecarboxamide)-β-(S)-t-
Dissolve 0.20 g of butoxybutyric acid in 7 ml of anhydrous methylene chloride and add oxalyl chloride under ice cooling.
After adding 0.10 g and 1 drop of dimethylformamide, the mixture was allowed to react at room temperature for 30 minutes. The solvent of the reaction solution was distilled off under reduced pressure. The residue was dissolved in anhydrous methylene chloride 8
ml and cool the solution to -50°C. Diphenylmethyl=7β-amino-7α-
Methoxy-3-[5-(1-methyl-1,2,3,
After adding 0.3 g of 4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylate and further 0.1 ml of dimethylaniline, the mixture was allowed to react at -20°C overnight. The solvent is distilled off from the reaction solution under reduced pressure, and the residue is dissolved in 10 ml of water and 15 ml of ethyl acetate.The ethyl acetate layer is separated, washed thoroughly with water, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (eluent; benzene:ethyl acetate = 2:1).
If separated and purified using
7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-
t-butoxybutanamide]-7α-methoxy-3-
0.31 g (yield 63%) of [5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylate is obtained. Next, this was dissolved in a mixed solvent of 2 ml of anisole and trifluoroacetic acid, and reacted at room temperature for 30 minutes. After drying the reaction solution under reduced pressure, 10 ml of ethyl acetate was added to the residue.
If you stir for a while, collect the precipitated crystals, and dry them,
7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)-
Hydroxybutanamide]-7α-methoxy-3-
0.21 g (yield: 55.7%) of [5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ ³ -cephem-4-carboxylic acid is obtained. The melting point (decomposition), IR spectrum, and NMR spectrum of this product matched those of the sample shown in Example 1. Formulation example 1 7β-[D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-β-(S)
-Hydroxybutanamide]-7α-methoxy-3-
Sodium bicarbonate was added to [5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-△ ³ -cephem-4-carboxylic acid and treated by a conventional method,
Obtain the lyophilized sterilized sodium salt. Dissolve 1 g (potency) of the sodium salt in 20 ml of physiological saline to obtain an injection solution. Formulation Example 2 1 g (potency) of the same compound as Formulation Example 1 was added to 0.5 (W/
V%) When dissolved in 4 ml of a solution containing lidocaine hydrochloride, a ready-to-use injection solution can be obtained. Formulation Example 3 1 g (potency) of the same compound as in Formulation Example 1 is dissolved in 20 ml of 5% glucose solution to obtain an injection solution. In addition, if other compounds of the present invention are operated in the same manner as in the above-mentioned formulation examples, freeze-dried products of each compound (sodium salt) and injection solutions can be obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² represents an alkyl group, R ³ represents an acyloxy group or a heterocyclic thio group consisting of a nitrogen-containing five-membered ring, and R ⁴ represents a hydrogen atom or a carboxyl protection forming group. ] An antibacterial agent containing a 7α-methoxycephalosporin or a non-toxic salt thereof. 2 7α-Methoxycephalosporin or its non-toxic salt is 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)
-β-(S)-hydroxybutanamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,4-
Tetrazolyl)thiomethyl]-△ ³ -Cefem-4
- The antibacterial agent according to claim 1, which is a carboxylic acid or a non-toxic salt thereof. 3 7α-Methoxycephalosporin or its non-toxic salt is 7β-[D-α-(4-ethyl-2,
3-dioxo-1-piperazinecarboxamide)
-β-(S)-hydroxypropanamide]-7α-methoxy-3-[5-(1-methyl-1,2,3,4
-tetrazolyl)thiomethyl]-△ ³ -cephem-
The antibacterial agent according to claim 1, which is 4-carboxylic acid or a nontoxic salt thereof.