KR20000002217A - Novel cephalosporin antibiotics and manufacturing method of it - Google Patents

Abstract

PURPOSE: Novel cephalosporin compound(I) wherein, R1 is hydrogen or protecting group; R2 is hydrogen, C1-C4 alkyl or substituted alkyl; R3 is hydrogen or derivatives of carboxyl group; R4 is cyclized aromatic group) and its pharmaceutically permitted salt are manufactured. CONSTITUTION: 48.70g of 7-Phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid paramethoxy benzyl ester is 500 ml of suspended in aceton, in which of 34.00g triphenylphospine and 15.00g of sodium iodide are added to the suspension, stirred for 30 minutes at 30-35°C. The filtrated liquid is condensed under reduced pressure to give 80.00g of paramethoxybenzyl 7β-(2-phenylacetamido)-3-triphenylphosphonio methyl-3-cephem-4-carboxylate.

Description

New cephalosporin antibiotics and preparation method thereof

The present invention relates to a novel cephalosporin-based compound represented by the general formula (I), a pharmaceutically acceptable salt and a method for producing the same. These compounds exhibit a wide range of antibacterial properties and can be useful for cephalosporin-based medicines.

Wherein R ₁ is hydrogen, amino acid (alanine, glycine, leucine, valine) or a protecting group generally used in penicillin or cephalosporin compounds, and trityl, tert-butoxy-carbonyl (t-BOC), benzyl, Chloroacetyl, trichloroacetyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, formyl, trifluoroacetyl and the like,

R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or a substituted alkyl group, which is alkoxycarbonylmethyl, carbo-methylmethyl, 1-carboxyethyl, 1-carboxy-1-methylethyl, and a cycloalkyl group having 3-7 carbon atoms. ,

R ₃ is a derivative of hydrogen or a carboxyl group, which is a group mainly forming an ester or a group useful as an atom or a carboxy protecting group for forming a salt. Examples of the salts include inorganic salts and organic salts.

Representative inorganic salts include sodium and potassium salts,

Examples of organic salts include salts of alkylamines (lower alkylamines such as methylamine, diethylamine, and triethylamine), salts of aromatic amines (salts such as aniline, dimethylaniline, etc.) and salts of aromatic bases (picolin, lutidine, Salts of quinoline).

Carboxylic protecting groups are those that can be introduced or removed in the field of penicillin or cephalosporin compounds without particularly adversely affecting other parts of the molecule,

For example, alkyl esters including substituted 1-8 carbon atoms (ethyl, methoxymethyl, ethyl, methoxyethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl ester) or phenyl Esters of nil, benzyl, cyanobenzyl, halobenzyl, methylbenzyl, nitrobenzyl, para-methoxybenzyl, phenylbenzyl.

Carboxylic derivatives useful as pharmaceuticals are metal salts or pharmaceutically useful esters, which are used as oral or injectables, and show an antibiotic effect. Specifically, alkyl esters having 1 to 3 carbon atoms are substituted.

For example, alkanoyloxyalkyl esters (more specifically acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxyethyl, tetrahydrofuryl, tetrahydropyranyl ester), alkoxy having 3 to 8 carbon atoms Formyloxyalkyl esters (ethoxycarbonyloxyesters), substituted aralkyl esters of 7 to 15 carbon atoms (phenacyl, indanyl esters), and 2-alkenyl esters (allyl, 2-oxo-1,3- Dioxol-4-ylmethyl esters).

R ₄ is a naphthyl group, methylbenzo [b] thiophene group, nitrothiophene group, 2-chloro-3,4-dimethoxybenzyl group, 1,4-dioxane benzyl group, 1-phenoxybenzyl group, 3 -Phenylethynylthiophene group, 2-phenylethynylthiophene group, 2-methylimidazole group, and the like.

Known β-lactam compounds are described in Japanese No. 124790/80, No.76088 / 84 U.K. No.2128990 is closely related to the cephalosporin-based compounds disclosed in the patent application.

The Japanese patent filed above also has a β-substituted vinyl group as a side chain at the 3-position of the cefe nucleus, like the compound of the present invention. However, the cephalosporin-based compounds of the present invention have a different structure from those of the compounds mentioned in the above patents with various substituents introduced at the β-position of the 3-position vinyl group.

In general, third-generation cephalosporin-based compounds are widely active against various G (+) and G (-) bacteria, and these various types of semi-synthesized cephalosporin-based compounds have already been used commercially. Although it has been widely used clinically as a therapeutic agent for various diseases or mixed infections, it is degraded by β-lactamase produced by several bacterial resistant strains and shows weak activity.

In contrast, the cephalosporin-based compounds of the present invention show strong activity against G (+) staphylococcus aureus strains, while not losing activity against various G (+) and G (-) bacteria.

In the general structural formula (I) of the compound of the present invention, two isomers of cis and trans may exist according to the three-dimensional structure of the double bond in the ethenyl group of the cephalosporin derivative. All isomers are included within the scope of the present invention.

The production method of the alkenyl cephalosporin antibiotic of the present invention is as follows.

1) First, a 3-cepm derivative (R ₃ = protecting group) of general formula (IV) is prepared by Wittig reaction between a phosphonium salt of general formula (II) and an aldehyde compound of general formula (III). In this Wittich reaction, an organic solvent and water may be used as a solvent, or a solvent mixed with an organic solvent and water may be used, but various organic solvents may be used, but dichloromethane, chloroform, carbon tetrachloride, ethyl ether and tetrahydro Furan, methanol and the like are preferable, and these solvents may be used alone or mixed with water. In the case of a mixed solvent, the ratio with water may be from 1:10 to 10: 1 (organic solvent: water). A ratio of 2: 1 to 4: 1 is appropriate. Many bases can be used as the base, but for example, lower alkylamines such as triethylamine, diisopropylethylamine and dibi oil.

Organic bases such as morpholine and lithium carbonate ( ), Sodium carbonate ( ), Calcium carbonate ( ), Cesium carbonate ( ), Sodium hydroxide ( ), Potassium hydroxide ( , Or a base such as a strong base . , , , Lithium diisopropylamide ( ), Sodium hydride ( ), Potassium Hydride ( ) Are all possible.

In the present invention, sodium carbonate ( ), Potassium carbonate ( ) Is most suitable, and the temperature can be from 0 ℃ to 100 ℃, but about 0 ~ 30 ℃ is most suitable.

2) The following reaction conditions are required to obtain General Formula (V), which is a 7-aminocepem compound by grinding an amide bond from a compound of Formula (IV).

First, in order to obtain imido chloride, phosphorus contaminants ( ) And pyridine are reacted with the general formula (IV) compound which is an amide compound. In this case, although a conventional solvent is used, it is preferable to use a halohydrocarbon solvent such as methylene chloride and chloroform.

Treatment of the obtained amino chloride compound with an alcohol such as methanol, ethanol, propanol or butanol yields a 7-amino-3-cepem compound of general formula (V) through an acid hydrolysis process. The reaction time in this process is about 10 to 90 minutes, and the reaction temperature is preferably -60 to 20 ° C.

3) The alkenyl cephalosporin-based antibiotic of the present invention of general formula (I) is prepared by acylating a compound of general formula (V) and an acid compound of general formula (VI). In this acylation reaction, when the compounds of formula (VI) are activated and reacted, the reaction solvents usable are water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran and ethyl acetate. , N, N-dimethylformamide, pyridine and the like are useful and react in the presence of organic or inorganic bases.

Examples of bases that can be used are alkali metal hydroxides, alkali metal acetates, tri (lower) alkylamines, pyridine, N-lower alkylmorpholines, N, N-di- (lower) alkylbenzylamines, N, N-di -(Lower) -ethylaniline, and the like, and the reaction temperature is generally about -20 to 30 ° C.

Here, activation of the carboxylic acid of general formula (VI) may include activation processes that are typically used for cephalosporin synthesis. Examples of the activated derivatives include acid anhydrides such as symmetrical or mixed anhydrides. At this time, the compound forming the carboxylic acid and the acid anhydride of the general formula (VI) may be inorganic acids (phosphoric acid, sulfuric acid, halogen acid, carbonyl half acid, etc.), organic acid (alkanoic acid, araalkanoic acid, sulfonic acid), molecular acid anhydride (Anhydrides with ketene, isocyanate, etc.), acid halides, alkenyl esters (vinyl esters, isopropenyl esters) which are reactive esters, aryl esters (pyridyl esters, benzotriazolyl esters), n-hydroxy-oxy compounds Esters, diacylhydroxylamine esters (N-hydroxysuccinimide esters, N-hydroxyphthalamide esters), thioesters (aralkylthiol esters, thiol esters with hetero rings), or reactive amides (Imidazole, triazole, amide with 2-ethoxy-1,2-dihydroquinoline, diacylanilide).

In addition, in the acylation reaction, acylation reaction can be directly induced by using a binding aid in an organic acid or salt state.

For example N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholino-ethylcarbodiimide, N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide, N , N-carbonylbis (2-methylimidazole), pentamethyleneketene-N-cyclohexylamine, ethoxyacetylene, ethylpolyphosphate, phosphorochlorochloride, thionyl chloride, oxalyl chloride, triphenyl The method by phosphine is mentioned.

4) Finally, to remove the R ₃ protecting group attached to the carboxyl group of cephalosporin of general formula (I), reacting these compounds in the presence of a base or an acid, R ₃ is a hydrogen atom of general formula (I) Compounds can be prepared.

The acid used at this time is preferably a Lewis acid such as acetic acid, formic acid, trifluoroacetic acid or aluminum chloride, and the addition amount is suitably 1 to 1000 times the acid in a large amount relative to the cephalosporin-based compound of general formula (I). 5 to 100 times is good.

Examples of the representative compounds having the structure of formula (I) obtained in the present invention are as follows.

Example 1

Preparation of para-methoxybenzyl 7β- (2-phenylacetamido) -3-triphenylphosphoniomethyl-3-cepem-4 -carboxylate

The solution was suspended in 500 ml of acetone and stirred. Then, 34.00 g (130.00 mmol) of triphenylphosphine and 15.00 g (100.00 mmol) of sodium iodide were added thereto and maintained at 30-35 ° C. The reaction mixture is stirred for 30 minutes to complete the reaction. The precipitate produced during the reaction was filtered and the filtrate was concentrated under reduced pressure to obtain 80.00 g (95%) of the title compound.

This compound is used without further purification.

Example 2

Preparation of para-methoxybenzyl 7β- (2-phenylacetamido) -3- [2- (naphth-2-yl) vinyl] -3-cepem-4 -carboxylate

30.00 g (36.00 mmol) of para-methoxybenzyl 7β- (2-phenylacetamido) -3-triphenylphosphoniomethyl-3-cepem-4-carboxylate iodide were added to 500 ml of methylene chloride. After dissolving, 5% sodium bicarbonate solution is added to adjust the pH to 8.5 or more and 2-naphthaldehyde is added to the reaction mixture. The mixture is stirred for 7 hours at room temperature. The reaction is completed. The mixture is washed with water and brine and the organic layer is separated with anhydrous magnesium sulfate. After drying, the mixture was distilled under reduced pressure, concentrated, and then separated by column chromatography using a solvent of ethyl acetate and chloroform (1: 5) to obtain 5.40 g (25%) of the title compound.

Example 3

Preparation of para-methoxybenzyl 7-amino-3- [2- (naphth-2yl) vinyl] -3-cefe-4-carboxylate hydrochloride

3.80 g (18.00 mmol) of phosphorus pentachloride was dissolved in 50 ml of methylene chloride, cooled to 0-5 ° C., then 1.47 g (19.00 mmol) of pyridine was added dropwise and stirred for 1 hour while maintaining at 0-5 ° C. 5.40 g (9.14 mmol) of methoxybenzyl 7β- (2-phenylacetamido) -3- [2- (naphth-2-yl) vinyl] -3-cef-4-carboxylate were added dropwise; After stirring for 1.5 hours while maintaining 0-10 ° C., the mixture was cooled to −35 ° C., and 26.35 g (356.00 mmol) of isobutanol were added all at once and stirred for 1 hour and 15 minutes below −10 ° C. The reaction mixture was concentrated under reduced pressure, and then 4.51 g (97%) of the title compound was obtained using isopropyl ether and ethyl acetate.

Example 4

Para-methoxybenzyl 7- (2-methoxyamino-2- (2-aminothiazol-4-yl) acetamido-3- [2- (naphth-2-yl) vinyl] -3-cepem Preparation of 4-carboxylate

2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid was dissolved in 15 ml of dimethylformamide, cooled to 0 ° C., and then 6-trifluoromethyl-1-methanesulfonyl-1,2, 1.60 g (5.69 mmol) of 3-benzotriazole was added thereto, triethylamine was added dropwise, stirred for 30 minutes, and para-methoxybenzyl 7-amino-3- [2- (naphth-2-yl) vinyl] 1.70 g (3.34 mmol) of -3-cef-4-carboxylate hydrochloride were added thereto, and the mixture was kept at 0-5 ° C., stirred for 1 hour, and further reacted at room temperature for 1 hour, followed by pouring into water: ethyl acetate (1: 1). Pour 5% sodium bicarbonate solution to adjust the pH to 7.5, wash with water and brine, separate the organic layer, dry over anhydrous magnesium sulfate, filter and concentrate, and use chloroform: methanol (20: 1) and column chromatography. Isolate with to give the title compound 0.75g (35%).

Example 5

7- [2-methoxyamino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (naphth-2-yl) vinyl] -3-cepem-4-car Preparation of Acids

0.70 g (1.09 mmol) was suspended in 7.55 g (69.82 mmol) of anisole and stirred, and maintained at 0 ° C., followed by addition of 11.19 g (98.13 mmol) of trifluoroacetic acid and stirring for 1 hour to complete the reaction. . The reaction mixture was poured into isopropyl ether to crystallize. The precipitate was filtered and dried under reduced pressure to obtain 0.40 g (70%) of the title compound.

Example 6

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (3-methylbenzo [b] thiophen-2-yl) vinyl]- Preparation of 3-cepem-4-carboxylic acid

Para-methoxybenzyl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (3-methylbenzo [b] thiophen-2- (1) vinyl] -3-cef-4-carboxylate 0.21 g (0.32 mmol) was suspended in 2.20 g (20.34 mmol) of anisole and stirred, and then maintained at 0 ° C. and 3.30 g (28.94 trifluoroacetic acid). mmol) was added and stirred for 1 hour to complete the reaction. The reaction mixture was poured into isopropyl ether to crystallize, and the precipitate was filtered and dried under reduced pressure to obtain 0.12 g (69%) of the title compound.

Example 7

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (2-nitrothiophen-2-yl) vinyl] -3-cepem- Preparation of 4-carboxylic Acid

Para-methoxybenzyl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (2-nitrothiophen-2-yl) vinyl] 1.97 g (3.00 mmol) of 3-cefe-4-carboxylate was suspended in 20.65 g (190.96 mmol) of anisole, stirred, and maintained at 0 ° C., and 30.80 g (270.00 mmol) of trifluoroacetic acid was added thereto. Addition and stirring for 1 hour completes the reaction. The reaction mixture was poured into isopropyl ether to crystallize. The precipitate was filtered and dried under reduced pressure to obtain 1.00 g (62%) of the title compound.

Example 8

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (2-chloro-3,4-dimethoxybenz) vinyl] -3- Preparation of Cefem-4-carboxylic Acid

0.47 g (6.71 mmol) was suspended in anisole 4.67 g (43.46 mmol), the mixture was stirred and maintained at 0 ° C., followed by addition of 6.90 g (60.52 mmol) of trifluoroacetic acid and stirring for 1 hour to complete the reaction. . The reaction mixture was poured into isopropyl ether to crystallize. The precipitate was filtered and dried under reduced pressure to obtain 0.13 g (33%) of the title compound.

Example 9

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1,4-dioxanebenz-6-yl) vinyl] -3- Preparation of Cefem-4-carboxylic Acid

0.37 g (5.69 mmol) was suspended in 3.94 g (36.45 mmol) of anisole and stirred, and then maintained at 0 ° C., followed by addition of 5.84 g (51.22 mmol) of trifluoroacetic acid and stirring for 1 hour to complete the reaction. . The reaction mixture was poured into iso-propyl ether to crystallize, and the precipitate was filtered and dried under reduced pressure to obtain 0.03 g (9.9%) of the title compound.

Example 10

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (1-phenoxybenz-3-yl) vinyl] -3-cepem- Preparation of 4-carboxylic Acid

0.29 g (0.42 mmol) was suspended in 2.90 g (26.82 mmol) of anisole and stirred, and then maintained at 0 ° C., followed by addition of 4.30 g (37.71 mmol) of trifluoroacetic acid and stirring for 1 hour to complete the reaction. . The reaction mixture was concentrated under reduced pressure, and then separated by column chromatography using ethyl acetate: methanol (4: 1) to obtain 0.12 g (49%) of the title compound.

Example 11

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-[[2- (2-phenylethynyl) thiophen-5-yl] vinyl]- Preparation of 3-cepem-4-carboxylic acid

0.22 g (0.31 mmol) was suspended in 2.10 g (19.42 mmol) of anisole and stirred, and maintained at 0 ° C., followed by addition of 3.20 g (28.07 mmol) of trifluoroacetic acid and stirring for 1 hour to complete the reaction. . The reaction mixture was poured into isopropyl ether to crystallize, and the precipitate was filtered and dried under reduced pressure to obtain 0.02 g (11%) of the title compound.

Example 12

7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (2-methylimidazol-4-yl) vinyl] -3-cepem Preparation of 4-carboxylic Acid

0.30 g (0.50 mmol) was suspended in 3.48 g (32.18 mmol) of anisole and stirred, and then maintained at 0 ° C. 5.17 g (45.34 mmol) of trifluoroacetic acid was added and stirred for 1 hour to complete the reaction. . The reaction mixture was poured into isopropyl ether to crystallize. The precipitate was filtered and dried under reduced pressure to obtain 0.05 g (20%) of the title compound.

Example 13

In Vitro Activity Measurements for Pharmacological Studies on Compounds of the Invention and Dilution in Solid Media.

A series of dishes were prepared, each containing a sterile nutrient medium containing the compound to be studied by weight in equal parts and inoculated with various strains in each dish.

After incubation at 37 ° C. for 18 hours during the incubation period, bacterial growth inhibition and absence of growth were assessed as minimum inhibitory concentration (MIC) (expressed as μl / cm ² ).

The result is expressed as MIC ₅₀ , which means the minimum concentration of antibiotic that can inhibit 50% of the tested strains.

The result is as follows.

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Claims (3)

New cephalosporin-based compounds, pharmaceutically acceptable salts and isomers thereof represented by the following general formula (I) In general formula (I), R <_1> is hydrogen, an amino acid (alanyl, glycyl, royl, valel), trityl, tert-butoxycarbonyl group, or formyl group, R <_2> is hydrogen, C1-C4 Alkyl group, alkoxycarbonylmethyl group, carboxymethyl group, 1-carboxyethyl group, 1-carboxy-1-methylethyl group R ₃ is hydrogen, Na, K, paramethoxybenzyl group, R ₄ is naphthyl group, methylbenzothiophene group, Nitrothiophene group, 2-chloro-3,4-dimethoxybenzyl group, 1,4-dioxane-benzyl group, 1-phenoxybenzyl group, 3-phenylethynylthiophene group, 2-phenylethynyl thi Opene group and 2-methylimidazole group. After reacting the aldehyde compound of general formula (III) with the phosphonium salt of general formula (II) to obtain a 3-cefem compound of general formula (IV), the compound (IV) is subjected to deacylation reaction. To prepare 7-amino-3-cepem derivatives Wherein R ₃ and R ₄ are the same as defined in claim 1, respectively. Method for preparing a new cephalosporin-based compound of general formula (I) by acylation reaction of a compound of general formula (VI) and a compound of general formula (V) Wherein R ₂ , R ₃ and R ₄ are the same as defined in claim 1, respectively.