KR100297468B1 - Penem derivative, its manufacturing method and manufacturing method - Google Patents

Abstract

The present invention relates to penem derivatives of the general formula (I) and salts of pharmaceutically acceptable penem derivatives

Wherein R ₁ is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, optionally protected C ₁ -C ₆ hydroxyalkyl groups, R ₂ Is selected from the group consisting of carboxyl groups esterified with carboxyl groups alone or easily activated in vivo, carboxyl anions, R ₃ is selected from the group consisting of H, optionally substituted C ₁ -C ₄ alkyl groups, R ₄ is H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ hydroxyalkyl, optionally substituted C ₁ -C ₆ mercaptoalkyl, optionally substituted C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ alkyl substituted as quaternary ammonium group, optionally substituted C ₁ -C ₆ carboxyalkyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ Aryl C ₁ -C ₆ alkyl, optionally substituted heterocyclyl C ₁ -C ₆ alkyl, side chain of the native α-amino acid, N in the ring, Selected from the group consisting of saturated or unsaturated C ₃ -C ₇ heterocycles containing heteroatoms of O, S or R ₃ and R ₄ are linked together to form a heterocycle having 3 to 7 atoms, which heterocycle May optionally include heteroatoms such as substituted and saturated or unsaturated heterocycles N, O, S.

R ₅ and R ₆ independent of each other are H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ mercaptoalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ al Kenyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl C ₆ -C ₁₀ aryl, heterocyclyl C ₁ -C Heterocyclic having 3 to 7 atoms selected from the group consisting of C ₁ -C ₆ alkyl carboxyamides having ₆ alkyl, straight or branched alkyl groups (optionally substituted alkyl groups) or R ₅ and R ₆ linked together Which heterocycle is optionally substituted and n is 1, 2 or 3.

Description

[Name of invention]

Penem derivatives and preparation method thereof

[Field of Invention]

The present invention relates to penem derivatives of the general formula (I).

Wherein R ₁ is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, a C ₁ -C ₆ hydroxyalkyl group which may be protected, and R ₂ Is selected from the group consisting of free carboxyl groups or carboxyl groups esterified with groups readily activated in vivo, carboxylated anions, R ₃ is selected from the group consisting of H, C ₁ -C ₄ alkyl which may be substituted, and R is ₄ is H, C ₁ -C ₆ alkyl which may be substituted, C ₁ -C ₆ hydroxyalkyl which may be substituted, C ₁ -C ₆ mercaptoalkyl which may be substituted, C ₁ -C ₆ which may be substituted Aminoalkyl, C ₁ -C ₆ alkyl to be substituted with quaternary ammonium groups, C ₁ -C ₆ carboxyalkyl which may be substituted, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl, optionally substituted heterocyclyl one -C ₁ -C ₆ alkyl, PO heteroatoms of N, O, S in the side chain, a heterocyclic of the natural α- amino acid Selected from a saturated or unsaturated heterocycloalkyl formed of groups that can be, or or R ₃ and the R ₄ is connected is connected with, N, O, or selected, including a heteroatom S, or R ₃ and R ₄ together, N Form a substituted or saturated heterocyclic ring having 3 to 7 atoms which may include heteroatoms of O, S, and R ₅ and R ₆ are each independently H, C ₁ -C ₆ Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ mercaptoalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl C ₆ -C ₁₀ Allyl C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkyl C ₆ -C ₁₀ Allyl, heterocyclyl-C ₁ -C ₆ Alkyl, C with straight chain or branched, substituted alkyl Selected from the group consisting of _1- C ₆ alkyl carboxyamide, or R ₅ and R ₆ are linked together to form a heterocycle having 3 to 7 atoms which may be substituted, n is selected from the group consisting of 1, 2, 3.

[Prior technology]

Compounds known as penems refer to a broad group of compounds with antimicrobial properties.

Bacteria quickly become resistant to the antibiotics used against bacteria, so they are effective against known or unknown infectious bacteria, and have good positivity, low toxicity, and therefore, the development of new compounds that meet pharmacological requirements is very important. Do.

Detailed description of the invention

The present invention is to provide novel penem species compounds with interesting pharmaceutical properties.

Compounds according to the invention have the structure of formula (I) wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and n are as defined above.

From the above formula (I) the compounds according to the invention may consist of a mixture of various optical and geometric isomers as well as respective optical and geometric isomers, which are included within the scope of the invention.

It is preferable to have an arrangement of compounds (5R, 6S) of formula (I).

In the compound of formula (I), it is preferable that R ₁ is α-hydroxyethyl, and it is more preferable that the above-mentioned group is 1R arrangement, that is, the arrangement of α-carbon atoms of the ethyl group is R.

R ₂ is a carboxyl group etherified with a group which is readily activated in vivo selected from the group consisting of a carboxyl anion, a free carboxyl group or a compound of formulas (a) and (b),

Wherein R ₇ and R ₈ are H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl or cycloalkenyl, C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl Is selected from the group consisting of C ₆ -C ₁₀ aryl, m is 0 or 1.

Examples of groups that can be readily activated in vivo include the following:

-Acetoxymethyl [(a): R ₇ = H; R ₈ = CH ₃ ; m = 0]

-Propanoyloxymethyl [(a): R ₇ = H; R ₈ = CH ₂ CH ₃ ; m = 0]

Pivaloyloxymethyl [(a): R ₇ = H; R ₈ = C (CH ₃ ) ₃ ; m = 0]

-1-acetoxyethyl [(a): R ₇ = CH ₃ ; R ₈ = CH ₃ ; m = 0]

-1-acetoxypropyl [(a): R ₇ = CH ₂ CH ₃ ; R ₈ = CH ₃ ; m = 0]

-1-cyclohexylcarbonyloxyethyl [(a): R ₇ = CH ₃ ; R ₈ = cyclohexyl; m = 0]

-Benzoyloxymethyl [(a): R ₇ = H; R ₈ = Ph; m = 0]

-1-benzoyloxyethyl [(a): R ₇ = CH ₃ ; R ₈ = Ph; m = 0]

-Methoxycarbonyloxymethyl [(a): R ₇ = H; R ₈ = CH ₃ ; m = 1]

-1-methoxycarbonyloxyethyl [(a): R ₇ = CH ₃ ; R ₈ = CH ₃ ; m = 1]

Isopropyloxycarbonyloxymethyl [(a): R ₇ = H; R ₈ = CH (CH ₃ ) ₂ ; m = 1]

-1-isopropyloxycarbonyloxyethyl [(a): R ₇ = CH ₃ ; R ₈ = CH (CH ₃ ) ₂ ; m = 1]

-Cyclohexyloxycarbonyloxymethyl [(a): R ₇ = H; R ₈ = cyclohexyl; m = 1]

-Cyclohexylmethyloxycarbonyloxymethyl [(a): R ₇ = H; R ₈ = cyclohex-CH ₂ ; m = 1]

-1-cyclohexyloxycarbonyloxyethyl [(a): R ₇ = CH ₃ ; R ₈ = cyclohexyl; m = 1]

-(2-oxo-1,3-dioxolen-4-yl) methyl [(b): R ₇ = H; R ₈ = H]

-(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl [(b): R ₇ = H; R ₈ = CH ₃ ]

-(5-t-butyl-2-oxo-1,3-dioxolen-4-yl) methyl [(b): R ₇ = H; R ₈ = C (CH ₃ ) ₃ ]

-(5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl [(b): R ₇ = H; R ₈ = Ph]

R ₃ is preferably a methyl or ethyl group which may be substituted. R ₄ is H, optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ mercaptoalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ carboxyalkyl, Preferred are side chains of aryl which may be substituted, for example aryl alkyl such as benzyl, C ₁ -C ₆ alkyl substituted with quaternary ammonium groups, heterocyclyl C ₁ -C ₆ alkyl or natural α-amino acids.

When R ₃ and R ₄ are linked together, they form a substitutable ring having 3 to 7 atoms, in which other heteroatoms other than N may be present, for example 1-pyrrolidine, 1- Azetidine, 1-piperidine, 4-morpholine, 1-piperazine, 4-methyl-piperazine.

R ₅ and R ₆ are H, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl C ₆ -C ₁₀ aryl C _1- Preferred are C ₆ alkylcarboxyamides and R ₅ and R ₆ are joined together to form a substitutable heterocycle having 3 to 7 atoms, for example: : 1-aziridine, 1-azetidine, 1-pyrrolidine, 1-piperidine, 4-morpholine, 1-piperazine, 4-methyl-piperazine.

Among the possible substituents, the following are preferred: methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, cyclohexyl, phenyl, benzyl, OH, C ₁ -C ₆ alkoxy, carboxyamide groups (optionally substituted), carboxy Esters, carbamoyloxy.

Among the pharmacologically acceptable salts of the compounds of formula (I) according to the invention are salts which are produced with inorganic bases which are alkali metal hydroxides or alkali metal hydroxides (preferably NaOH, KOH) and, for example, lysine. Salts of organic bases containing amino acids are used together with penicillin and cephalo-sporin. In addition, pharmacologically acceptable salts according to the present invention include zwitterions.

The product of the present invention may be administered in combination with excipients used with penicillin and cephalosporin for the preparation of oral or parenteral preparations or in combination with known antibiotics or inhibitors of β-lactamase. .

The compounds according to the invention have a wide range of antibacterial activity and can be administered in the dosages and dosages already set forth in similar penicillin and antibiotic pharmacies.

The compounds according to the invention can be prepared from hydroxymethyl compounds corresponding to formula (II), wherein R ₁ is as defined above (preferably α-hydroxyethyl) and Y is for example Ester groups such as allyl or p-nitrobenzyl.

Compounds of formula (II) are known and known processes from azetidinone compound (III) or from natural penicillin derivatives (IV) [e.g. Fontana et al., J. Rab. Comp. Radioparm (J. Lab. Comp. Radopharm), 24, 41 (1986); a. second. A. J. Corraz et al., J. et al. Med. J. Med. Chem., 35, 1828 (1992)] (Scheme 1).

Scheme I

Hydroxymethyl penem (II) is suitable sulfonyl chloride under an inert organic solvent such as, for example, dichloromethane or chloroform, for example under an organic base such as triethylamine or N, N-diisopropylethylamine. And react at a temperature of −70 ° C. to 20 ° C. to convert to the corresponding sulfonyl derivative (V), wherein R ₁ and Y are as defined above and Z is an alkyl or aryl group (preferably methyl or ρ-tol) One day). The sulfonyl derivative (V) is, for example, a compound of formula (VI) and a temperature of -20 ° C to 20 ° C under an organic solvent such as dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran or ethyl acetate. In which n, R ₃ , R ₄ , R ₅ and R ₆ are as defined above; The reaction can be carried out with crude or purified sulfonyl derivative (V). Alternatively, this synthesis can be carried out by converting the sulfonyl derivative (V) to the corresponding halide, wherein X is chlorine, bromine or iodine, and the conversion to halide is an inorganic halide. , Preferably via reaction with calcium halides.

Compounds of formula (VII) may be obtained through reaction of a compound of formula (VI) with a halide, where n, R ₃ , R ₄ , R ₅ and R ₆ are as defined above The reaction is carried out at a temperature of -20 ° C to 20 ° C, for example under an organic solvent such as dimethylsulfoxide, dimethylformamide, dioxane, tetrahydrofuran or ethyl acetate; In this case, the reaction is also carried out starting with a separated or naturally occurring halide. In the last step of the invention penem is characterized by conventional methods after separation.

If R ₁ is a hydroxyalkyl group, for example, rho-nitrobenzyloxycarbonyl, allyloxycarbonyl, t-butyldimethylsilyl or trimethylsilyl may be used to protect the alcohol group with a general protecting group and then the reaction may proceed in the order of the reaction. And the protecting group is removed at the end of the reaction sequence. Alternatively the reaction can be carried out with an unprotected alcohol derivative (II) (R ₁ = CH ₃ CHOH-).

Compounds of general formula (I) are finally obtained from the corresponding esters through hydrolysis, hydrogenolysis or other processes.

Compounds of general formula (I) have superior antimicrobial activity against gram-positive bacteria and gram-negative bacteria and anaerobic strains which produce or do not produce β-lactamase compared to conventional β-lactam antibiotics.

Example 1

Allyl (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -phenem- 3-carboxylate

6 g of allyl (5R, 6S) -2-hydroxymethyl-6-[(1R) -1-t-butyldimethyl-silyloxy-ethyl] -phenem-3-carboxylate in 150 ml of anhydrous methylene dichloride ( To 15 mlole), 3.2 ml (23.2 mmoles) of triethylamine and 1.8 ml (23.2 mmoles) of methanesulfonyl chloride were added under a nitrogen atmosphere at 0 ° C. The reaction mixture is stirred at 5 ° C. for 30 minutes. The solution was washed with water, aqueous sodium bicarbonate solution (5%) and again with water. The solution was dried over Na ₂ SO ₄ and evaporated to give a yellow residue.

The crude product was dissolved in dimethylsulfoxide (150 mL) and sarcosinamide hydrochloride [Marvel et al., J. et al. In 40 mL dimethylsulfoxide. Am. Chem. Prepared by the method described in J. Am. Chem. Soc., 68, 1685 (1946). A solution containing 2.4 g (19.3 mmoles) and 2.8 ml (20.1 mmoles) of triethylamine was added to the solution. . 2.8 mL (20.1 mmol) triethylamine is added to the solution and the mixture is stirred at room temperature for 4 hours. The mixture was left at room temperature overnight, poured into ice and water and extracted twice with ethyl acetate. The organic extract was washed with water, dried over Na ₂ SO ₄ and the solvent was evaporated in vacuo. This crude product was purified by column chromatography (silica gel; ethyl acetate / cyclohexane 70:30 v / v) to give a pale yellow solid having a melting point of 118 ° C to 119 ° C.

Example 2

Allyl (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxyl Rate

Tetrahydrofuran (200 mL) allyl (5R, 6S) -2-[[N- (2-acetamido) -N-methyl])-aminomethyl] -6-[(1R) -1-t- In a solution of butyl-dimethylsiloxyethyl] -phenem-3-carboxylate (4 g; 8.5 mmol), 2.9 ml (50.7 mmol) of acetic acid and tetrabutylammonium fluoride (1M solution of tetrahydrofuran; 25 ml, 25 mmol) Was added at room temperature.

The mixture was stirred at room temperature for 24 hours, concentrated to 50 ml, diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate solution (5%), dried and evaporated. The residue was crystallized with ethyl ether, washed with ethyl ether on a filter and dried in vacuo to give a yellow solid having a melting point of 83-85 ° C.

Example 3

(5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Allyl (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) to 60 mL of anhydrous tetrahydrofuran and 60 mL of anhydrous methylene dichloride 80 mg (0.30 mmole) of triphenylphosphine and tetrakis (triphenylphosphine) filadium (0) 335 mg in a solution of 1-hydroxyethyl] -phenem-3-carboxylate 1 g (2.8 mmoles) (0.29 mmole) and 0.24 mL (4.2 mmoles) of acetic acid were added at 35 ° C to 40 ° C under a nitrogen atmosphere.

The mixture was stirred at 35 ° C.-40 ° C. for about 1 hour. The solution was concentrated to 50 mL and ethyl ether was added with stirring. : The precipitate was filtered under nitrogen atmosphere, washed with ethyl ether and dried under vacuum. The product was purified by reverse phase column chromatography (LiChroprep Rp-18 ^R ; water / acetone 95; 5 v / v) and the obtained product was a white solid with a molecular weight of 315.35 and dissolved. The point was 92 degreeC-95 degreeC.

Example 4

Allyl (5R, 6S) -2-[[N-prolineamido) -methyl] -6-[(1R) -1-t-butyl-dimethylsilyloxyethyl] -phenem-3-carboxylate

2 g of allyl (5R, 6S) -2-hydroxymethyl-6-[(1R) -1-t-butyldimethylsilyloxy-ethyl] -phenem-3-carboxylate in 60 ml of anhydrous methylene dichloride ) Was added 1.0 ml (7.2 mmoles) of triethylamine and 0.6 ml (7.7 mmoles) of methanesulfonyl chloride at 0 ° C. under a nitrogen atmosphere.

The mixture was stirred at 5 ° C. for 30 min, then washed with water, aqueous sodium bicarbonate solution (5%) and again with water. The solution was dried over Na ₂ SO ₄ and evaporated to give a yellow residue.

The crude product was dissolved in dimethylsulfoxide (60 mL), 0.7 g (6 mmole) of prolineamide and 0.7 mL (5 mmole) of triethylamine were added to the solution, stirred at room temperature for 2 hours, and then at room temperature overnight. Left for a while. The solution was poured into water and ice and extracted twice with ethyl acetate. The organic extract layers were collected together, washed with water, dried over Na ₂ SO ₄ and evaporated under vacuum. The product was purified by column chromatography (silica gel; ethyl acetate) to give a pale yellow wax (wax).

Example 5

Allyl (5R, 6S) -2-[(N-prolineamido) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate

Tetrahydrofuran (70 ml) allyl (5R, 6S) -2-[(N-prolineamido) -methyl] -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -phenem-3 To a solution of carboxylate (1.3 g; 2.62 mmol) were added 0.9 ml of acetic acid (15.7 mmol) and 2.5 g (7.9 mmol) of tetrabutylammonium fluoride trihydrate at room temperature.

The mixture was stirred at room temperature for 16 hours, diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate solution (5%), dried and evaporated.

The compound was purified by column chromatography (silica gel; ethyl acetate) and the purified compound was yellow oil.

Example 6

(5R, 6S) -2-[(N-Prolineamido) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

To 100 ml of anhydrous tetrahydrofuran (5R, 6S) -2-[(N-prolineamido) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-allyl carboxylate ( In a solution of 0.93 g; 2.4 mmol, triphenylphosphine 130 mg (0.50 mmol), tetraalkis (triphenylphosphine) palladium (0) 560 mg (0.48 mmol), and acetic acid (0.27 ml; 4.7 mmol) It was added under nitrogen atmosphere at room temperature.

The mixture was stirred at room temperature for 30 minutes and then diluted with ethyl ether and the precipitate was filtered under nitrogen, washed with ethyl ether and dried under vacuum. The crude product was purified by reverse phase column chromatography (Lycroprep RP-18 ^R ; water / acetone 95: 5 v / v), and the purified product had a melting point of 133 ° C to 135 ° C and a molecular weight of 341.38. It was a white solid.

Example 7

(5'-Methyl-2'-oxo-1 ', 3'-dioxolen-4'yl) -methyl (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -Aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate

To dimethylformamide (15 mL) (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -106 mg (1.0 mmol) of anhydrous sodium carbonate was added to a solution of 261 mg (0.83 mmol) of penem-3-carboxylic acid under normal temperature and nitrogen atmosphere.

The mixture was stirred at room temperature for 3 hours and cooled to 0 ° C., followed by addition of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one 192 mg (1.0 mmole) for 2 hours at room temperature. Reacted. The solution was diluted with ethyl acetate, washed with water, dried over Na ₂ SO ₄ and evaporated. The residue was precipitated from chloroform / cyclohexane, dissolved in water and freeze dried.

The crude product was purified by HPLC (column Hypersil 10 ODS ^R , 10 μm, 25 cm × 20 mm, mobile phase: water / acetonitrile 40/60, flow rate 10 ml / min) and purified product The yield of was 105 mg (yield 30%) and molecular weight was 427.43.

HPLC (analysis); Column: Hypersil 5 ODS ^R , 5 μm, 25 cm × 4.6 mm, UV detector: 220 and 320 nm, mobile phase: water / acetonitrile (40/60), flow rate: 1 ml / min, t _R = 5.8 min, lambda _max = 325 nm.

Example 8

Sodium (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxyl Rate

Allyl (5R, 6S) -2-[[N- (2-acetamido) -N-methyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] to 10 ml of anhydrous tetrahydrofuran. Triphenylphosphine 35 mg (0.13 mmol), tetraalkis (triphenylphosphine) palladium (O) and sodium 2-ethylhexanoate 326 mg (1.96 mmol) in a solution of penem-3-carboxylate Was added at room temperature and under nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes.

The solution was concentrated to give a raw product, which was then purified by HPLC (column hypersil 10 ODS ^R , 10 μm, 25 cm × 20 mm, mobile phase: water / acetonitrile 90/10, flow rate: 20 mL / min) and the yield of purified product was 235 mg (yield 54%) and molecular weight was 338.34.

HPLC (analysis), column: Hypersil 5 ODS ^R , 5 μm, 25 cm × 4.6 mm, UV detector: 220 and 320 nm, mobile phase: water / acetonitrile (95/5), flow rate: 1 ml / min, t _R = 4.0 min.

The following compounds were also obtained by following the methods set forth in Examples 3, 6, 7, and 8 and using the appropriate reagents:

(5R, 6S) -2-[(N-Methyl-phenylalanineamido) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 405.47

MS (FAB): m / z 406 (M + H ⁺ )

HPLC, phase: water / acetonitrile (80/20); t _R = 5.7 min

(5R, 6S) -2-[(3'-Carboxamido-piperidin-1'-yl) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxyl mountain

Molecular Weight = 355.412

[Two diastereoisomers (A) and (B) are obtained; These isomers are separated by HPLC (preparation), phase: water / acetonitrile (95/5); Column hyperseal 10 ODS ^R , 10㎛, 25㎝ × 20㎜, Flow rate: 20mL / min]

HPLC (analysis): t _{R (A)} = 8.2 min; t _{R (B)} = 9.9 min

(5R, 6S) -2-[(N, N-Diacetamido) -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 358.37

MS (FAB): m / z 359 (M + H ⁺ )

¹³ C NMR (50MHz, D ₂ O) δ (ppm) Signal Characteristics: 56.0, 61.1, 66.8, 69.1, 74.0

(5R, 6S) -2-[(N-Methyl-N- (3'-propionamido) -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 329.37

HPLC (analysis): t _R = 5.0 min, lambd _amax = 314 nm

(5R, 6S) -2-[(N-methyl-N- (4'-methyl-1'-piperazine) aminocarboxymethyl-aminomethyl] -6-[(1R) -1-hydroxyethyl]- Penem-3-carboxylic acid

Molecular Weight = 398.48

¹³ C NMR (50 MHz, D ₂ O) δ (ppm) Signal Characteristics: 46.3, 47.4, 59.9, 67.9, 69.0, 74.6

(5R, 6S) -2-[(N-Methyl-N- (2'-acetamido) -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 329.37

HPLC (analysis): t _R = 4.8 min; lambd _amax = 310 nm

(5R, 6S) -2-[(N-methyl-N- (N, N'-dimethyl) acetamido] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3 -Carboxylic acid

Molecular Weight = 343.40

HPLC (analysis): t _R = 9.1 min; lambd _amax = 315 nm

(5R, 6S) -2-[(2'-Carboxamido-piperidin-1'-yl) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxyl mountain

Molecular Weight = 355.411

[Two diastereomers (A) and (B) are obtained; These isomers are separated by HPLC (preparation), phase: water / acetonitrile (99/1); Column hyperseal 10 ODS ^R , 10 μm, 25 cm × 20 mm, flow rate: 20 ml / min]

HPLC (analysis): t _{R (A)} = 9.1 min; t _{R (B)} = 11.0 min

(5R, 6S) -2-[(4'-Carboxamido-piperidin-1'-yl) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxyl mountain

Molecular Weight = 355.412

Melting Point = 136 ℃ ~ 137 ℃

(5'-Methyl-2'-oxo-1 ', 3'-dioxolen-4'-yl) methyl (5R, 6S) -2-[(N-prolineamido) methyl] -6-[(1R ) -1-hydroxyethyl) -phenem-3-carboxylate

Molecular Weight = 453.470

MS (EI): m / z 453 (M ⁺ )

HPLC: phase; Water / acetonitrile (20/80), t _R = 4.2 min; lambd _amax = 325 nm

Acetoxymethyl (5R, 6S) -2-[(N-methyl-N- (2-acetamido)]-aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3- Carboxylate

Molecular Weight = 387.41

HPLC, phase: water / acetonitrile (50/50), t _R = 3.0 min

MS (TS): m / z 388 (M + H ⁺ )

(5R, 6S) -2-[(2'-Carboxamido-aziridin-1'-yl) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 313.33

HPLC: phase; Water / acetonitrile (98/2), t _R = 1.8 min; lambd _amax = 306 nm

MS (FAB): m / z 314 (M + H ⁺ )

(5R, 6S) -2-[[N '-(D-Prolineamido)]-methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 341.38

HPLC, phase: water / acetonitrile (95/5), t _R = 4.4 min

MS (FAB): m / z 342 (M + H ⁺ )

(5R, 6S) -2-[[N-methyl- (N'-glycineamido) -glycyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-car Acid

Molecular Weight = 372.40

HPLC: phase; Water / acetonitrile (95/5), t _R = 3.4 min; lambd _amax = 308 nm

MS (FAB): m / z 373 (M + H ⁺ )

Acetoxymethyl (5R, 6S) -2-[(N-prolineamido) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate

Molecular Weight = 413.449

HPLC, phase: water / acetonitrile (50/50), t _R = 11.1 min; lambd _amax = 328 nm

MS (TS): m / z 414 (M + H ⁺ )

(5R, 6S) -2-[[(2'S, 4'R) -2'-Carboxamido-4'-hydroxy-pyrrolidin-1'-yl] -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid

Molecular Weight = 357.38

HPLC, phase: water (100%), t _R = 2.0 min; lambd _amax = 306 nm

MS (FAB): m / z 358 (M + H ⁺ )

(5R, 6S) -2-[[(N- (2S) -2-propionamido-N-methyl] -aminomethyl] -6-[(1R) -1-hydroxyethyl] -phenem-3- Carboxylic acid

Molecular Weight

Melting Point = 105 ° C (dec.)

Pivaloyloxymethyl (5R, 6S) -2-[(N-prolineamido) -methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate

Molecular Weight = 455.17

Melting Point = 51 ℃ ~ 55 ℃

Pivaloyloxymethyl (5R, 6S) -2-[(N-acetamido) -N-methyl] -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate

Molecular Weight = 429.16

Melting Point = 50 ℃ ~ 53 ℃

The operating conditions of HPLC (analysis) are as follows (unless otherwise reported):

Column Hypersil 5 ODS ^R , 5 μm, 25 cm × 4.6 mm, UV detector: 220 and 320 nm, phase; Water / acetonitrile (95/5), flow rate: 1 mL / min.

Claims (8)

Penem derivatives of the general formula (I) here, R ₁ is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, a C ₁ -C ₆ hydroxyalkyl group which may be protected, R ₂ is selected from the group consisting of a carboxylated anion, a free carboxyl group, and a carboxyl group esterified with a group selected from the group consisting of compounds of the general formulas (a) and (b) below, Wherein R ₇ and R ₈ are H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl or cycloalkenyl, C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl Is selected from the group consisting of C ₆ -C ₁₀ aryl, m is 0 or 1, R ₃ is selected from the group consisting of H, C ₁ -C ₄ alkyl which may be substituted, R ₄ is H, C ₁ -C ₆ alkyl which may be substituted, C ₁ -C ₆ hydroxyalkyl which may be substituted, C ₁ -C ₆ mercaptoalkyl which may be substituted, C ₁ -C which may be substituted ₆ aminoalkyl, C ₁ -C ₆ alkyl substituted with quaternary ammonium groups, C ₁ -C ₆ carboxyalkyl which may be substituted, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ allyl, C ₆ -C ₁₀ Allyl C ₁ -C ₆ alkyl, substituted heterocyclyl-C ₁ -C ₆ alkyl, side chain of the natural α-amino acid, saturated or unsaturated hetero, which may contain heteroatoms of N, O, S in the heterocycle Selected from the group consisting of cycles, or Or R ₃ and R ₄ are joined together to form a substitutable saturated or unsaturated heterocycle having 3 to 7 atoms which may include heteroatoms of N, O, S, R ₅ and R ₆ are independently of each other H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ mercaptoalkyl, C ₁ -C ₆ aminoalkyl, C ₂ -C ₆ Alkenyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ allyl, C ₆ -C ₁₀ allyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl C ₆ -C ₁₀ aryl, heterocyclyl-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl carboxyamide having linear or branched substituted alkyl, or Or R ₅ and R ₆ are joined together to form a hetero group having 3 to 7 atoms which may be substituted, n is selected from the group consisting of 1, 2, 3. The penem derivative according to claim 1, having an arrangement of (5R, 6S). 3. The penem derivative according to claim 2, wherein R ₁ is an α-hydroxyethyl group, wherein the α-carbon atom of the ethyl group has an R configuration. The compound according to claim 3, wherein R ₂ is selected from the group consisting of a carboxylated anion, a free carboxyl group, and a carboxyl group esterified with a group selected from the group consisting of compounds of the following general formulas (a) and (b): Wherein R ₇ and R ₈ are H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl or cycloalkenyl, C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl Is selected from the group consisting of C ₆ -C ₁₀ aryl groups, m is 0 or 1, R ₃ is selected from the group consisting of methyl which may be substituted and ethyl which may be substituted, R ₄ is H, optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ mercaptoalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ carboxyalkyl, C ₆ -C ₁₀ allyl, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl which may be substituted, C ₁ -C ₆ alkyl substituted with quaternary ammonium groups, heterocyclyl C ₁ -C ₆ alkyl or natural α -Selected from the group consisting of side chains of amino acids, Or R ₃ and R ₄ are joined together to form 1-aziridine, 1-pyrrolidine, 1-azetidine, 1-piperidine, 4-morpholine, 1-piperazine, 4-methyl-1-pipe To form a ring selected from the group consisting of lazine, R ₅ and R ₆ are groups consisting of H, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ allyl, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl C ₆ -C ₁₀ aryl Selected from Or R ₅ and R ₆ are joined together to form 1-aziridine, 1-azetidine, 1-pyrrolidine, 1-piperidine, 4-morpholine, 1-piperazine, 4-methyl-1-piperazine Phenem derivative forming a ring selected from the group consisting of. The process of claim 4 wherein the substituents are methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, cyclohexyl, phenyl, benzyl, OH. Phenem derivative selected from the group consisting of C ₁ -C ₆ alkoxy, carboxyamide group which may be substituted, carboxyester. The penem derivative according to claim 5, wherein the penem derivative is selected from the group consisting of: (5R, 6S) -2- (N- (2-acetamido) -N-methyl) -aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2-((N-Prolineamido) -methyl) -6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (N-Methyl-phenylalanineamido) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (3'-Carboxamido-piperidin-1'-yl) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (N, N-Diacetamido) -aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2-N-Methyl-N- (3'-propionamido) -aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (N-Methyl-N- (4'-methyl-1'-piperazine) -aminocarboxymethyl) -aminomethyl-6-[(1R) -1-hydroxyethyl]- Penem-3-carboxylic acid, (5R, 6S) -2- (N-ethyl-N- (2'-acetamido))-aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (N-Methyl-N- (N ', N'-dimethyl) acetamido) -aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3- Carboxylic Acid, (5R, 6S) -2- (2'-Carboxamido-piperidin-1'-yl) methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (4'-Carboxamido-piperidin-1'-yl) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5'-Methyl-2'-oxo-1 ', 3'-dioxolen-4'-yl) methyl (5R, 6S) -2- (N-prolineamido) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate, Acetoxymethyl (5R, 6S) -2- (N-methyl-N- (2-acetamido))-aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxyl Rate, (5R, 6S) -2- (2'-Carboxamido-aziridin-1'-yl) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- (N- (D-Prolineamido))-methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- [N-Methyl- (N'-glycineamido) -glycyl] -aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid , Sodium (5R, 6S) -2- (N-methyl-N- (2-acetamido))-aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate, Acetoxymethyl (5R, 6S) -2- (N-prolineamido) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate, (5'-Methyl-2'-oxo-1 ', 3'-dioxolen-4'-yl) methyl (5R, 6S) -2- (N- (2-acetamido) -N-methyl]- Aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylate, (5R, 6S) -2-[(2'S, 4'R) -2'-Carboxamido-4'-hydroxy-pyrrolidin-1'-yl] -methyl-6-[(1R) -1 -Hydroxyethyl] -phenem-3-carboxylic acid, (5R, 6S) -2- [N- (2S) -2-Propionamido-N-methyl] -aminomethyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid , Pivaloyloxymethyl (5R, 6S) -2- (N-prolineamido) -methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-carboxylic acid, and Pivaloyloxymethyl (5R, 6S) -2- (N-acetamido) -N-methyl-6-[(1R) -1-hydroxyethyl] -phenem-3-pivaloyloxymethyl carboxyl Rate. The hydroxymethyl penem of the following formula (II) was reacted with sulfonyl chloride at a temperature of -70 ° C to 20 ° C in the presence of an organic base in an inert organic solvent to obtain the sulfonyl derivative (V) below. Was reacted at a temperature of -20 ° C to 20 ° C with a compound of the following general formula (VI) to obtain a penem derivative of formula (VII), and hydrolysis or hydrogenolysis of the penem derivative (VII). A method for producing a penem derivative according to claim 1, which is composed of a compound of formula (I). Wherein R ₁ is as defined above and Y is an ester group Wherein R ₁ and Y are as defined above and Z is an alkyl or aryl group Wherein n, R ₃ , R ₄ , R ₅ and R ₆ are as described above. Wherein n, Y, R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as described above. The method according to claim 7, wherein the sulfonyl derivative of formula (V) is converted to the corresponding halide by reacting with an inorganic halide, followed by the method described in claim 7 Method of producing a penem derivative to produce a compound. Wherein R ₁ , Y and Z are as described above. Where X is selected from the group consisting of chlorine, bromine, iodine