JPH08134075A - New carbapenem derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new compound useful as an antibacterial agent against Gram-positive bacteria, Gram-negative bacteria, esp. resistant bacteria such as multiple drug-resistant MRSA and drug-resistant Pseudomonas aeruginosa. CONSTITUTION: This new compound is expressed by formula I (R1 is H or a lower alkyl such as methyl; R2 is a negative electric charge, H, or an ester residue such as a lower alkanoyloxy or a lower alkyl group; A ring is an unsaturated N-contg. 5 to 6-membered heterocycle; dotted lines means that one of them is double bond, the other being single bond; (+) is positive electric charge). The compound of formula I is obtained by reaction of an intermediate expressed by formula II with a thiol compound of formula III followed by either removing the protecting group by reduction or conducting an esterification or salt-forming reaction. The reaction is pref. made in an organic solvent such as acetone in the presence of a base such as trimethylamine under cooling.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carbapenem derivative having excellent antibacterial activity and useful as an antibacterial agent, and salts thereof.

[0002]

2. Description of the Related Art A carbapenem compound is a general term for compounds in which a sulfur atom of a penicillin skeleton is substituted with a carbon atom and an unsaturated bond is at the 2-position. For example, an early carbapenem antibiotic includes thienamycin obtained as a fermentation product of Streptomyces cattleya . Although thienamycin has excellent antibacterial activity against a wide range of Gram-positive and negative bacteria, it has poor chemical stability and has not yet been put to practical use [Antimicrob. Agents Chemoth
er., 22 , 62, (1982); ibid, 23 , 300, (1983)]. Next, imipenem [J. Med. Chem., 22 , 1435, (1979)] in which the amino group on the 2-side chain of thienamycin was formimidylated has appeared as a practical antibacterial agent. Although this compound has excellent antibacterial activity and chemical stability to some extent, it is prone to degradation and inactivation by renal dehydropeptidase (DHP) in vivo and is used in combination with imipenem, which is a kind of DHP inhibitor cilastatin. / Cilastatin (I
PM / CS) is a combination prescription [Antimicrob.Age
nts Chemother., 12 (SupplD), 1, (1983)].

On the other hand, various 1-methylcarbapenem compounds in which a methyl group has been introduced at the 1-position of the carbapenem skeleton have been proposed.
Meropenem having a substituted thio group at the position [SM-733
8, Japanese Patent Publication No. 63-55514], L-627 (Japanese Patent Laid-Open No. 1-25779), which are under development.

[0004]

[Problems to be Solved by the Invention] Currently, penicillin-based
Since β-lactam compounds such as cephalosporins have few side effects, they are widely used as antibacterial agents for treatment, but in recent years, resistant bacteria that have emerged due to the abuse of various known antibiotics, especially high resistance Methicillin-resistant Staphylococcus aureus (MRSA) and resistant Pseudomonas aeruginosa have emerged and have become a serious social problem. Under such circumstances, the development of carbapenem derivatives having excellent antibacterial activity against MRSA, which is a multidrug-resistant bacterium, or resistant bacteria such as resistant Pseudomonas aeruginosa, or a carbapenem derivative having DHP stability and high biological stability. Is requested.

[0005]

MEANS FOR SOLVING THE PROBLEMS The present inventors mean MRSA.
As a result of diligent research aimed at developing a carbapenem derivative having excellent antibacterial activity against such resistant bacteria as well, the carbapenem derivative represented by the following general formula (I) or a salt thereof contains Gram-positive including resistant bacteria such as MRSA. The inventors have completed the present invention by finding that they have an excellent antibacterial activity against Gram-negative bacteria.

[0006]

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(The symbols in the formulas have the following meanings: R ¹ : hydrogen atom or lower alkyl group, R ² : negative charge, hydrogen atom, or ester residue, A ring: unsaturated nitrogen-containing 5 to 6 Member heterocycle, dotted line: either one is a double bond, the other is a single bond, +: positive charge. That is, the present invention provides a compound represented by the above general formula (I) or a salt thereof as a constitution of the invention. For the purpose of provision. The compound (I) of the present invention and a salt thereof have a chemical structural feature in that the ring A is an unsaturated nitrogen-containing 5- to 6-membered heterocycle. Hereinafter, the compound of the present invention will be described in detail. The term "lower" in the definition of the general formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms. Specific examples of the "lower alkyl group" for R ¹ include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, Isopentyl group, neopentyl group, tert-pentyl group,
1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-
Methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2, 3-dimethylbutyl group, 3,3-
Dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,
2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like can be mentioned.

The "ester residue" in R ² is
Examples thereof include an ester residue that is metabolized and hydrolyzed in the living body, or an ester residue that can be a protective group for a carboxyl group. Examples of the ester residue that is metabolized and hydrolyzed in vivo include a lower alkanoyloxy lower alkyl group, a lower alkenoyl lower alkyl group, a cycloalkyloxycarbonyloxy lower alkyl group, a lower alkenoyloxy lower alkyl group, and a lower alkoxy. Lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxycarbonyloxy lower alkyl group, benzoyloxy lower alkyl group,
Common ester residues such as 2-oxotetrahydrfuran-5-yl group, 2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyl group, tetrahydrofuranylcarbonyloxymethyl group, 3-phthalidyl group, etc. Is mentioned.

Examples of the ester residue which can be a protective group for the carboxyl group include lower alkyl group, lower alkenyl group, halogeno lower alkyl group, lower alkoxybenzyl group, nitrobenzyl group, lower alkoxybenzhydryl group, benzhydryl group. Groups and the like. In the above, a lower alkanoyl group having 2 to 6 carbon atoms (eg acetyl, propionyl, pivaloyl etc.), a lower alkyl group having 1 to 6 carbon atoms (eg methyl, ethyl etc.), a lower alkenoyl group having carbon atoms Numbers 3 to 6 (eg acryloyl,
(Crotonoyl, maleoyl, etc.), cycloalkyl groups having 3 to 8 carbon atoms, especially those having 3 to 6 carbon atoms (eg cyclopropyl, cyclopentyl, cyclohexyl, etc.), alkoxy groups having 1 to 6 carbon atoms, especially Preferable examples include those having 1 to 4 (eg, methoxy, ethoxy, etc.) and lower alkenyl groups having 2 to 6 carbon atoms (eg, vinyl, allyl, 1-propenyl, etc.). Further, examples of the halogen include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the "unsaturated nitrogen-containing 5- to 6-membered heterocycle" represented by ring A include imidazole ring, triazole ring, pyrimidine ring, triazine ring and the like.

The compound (I) of the present invention forms salts with acids and bases. Salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Mention may be made of acid addition salts with organic acids such as maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid and aspartic acid. Examples of salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, methylamine, ethylamine, ethanolamine, diethanolamine,
Examples thereof include salts with organic bases such as procaine, N-methylglucosamine, phenethylbenzylamine, dibenzylethylenediamine, lysine, and ornithine, and ammonium salts. When R ² is a hydrogen atom or an ester residue, although not shown in the general formula, anions in which a proton is removed from the above acid, anions such as p-toluenesulfonate ion and trifluoroacetate ion are It forms a salt with the cation of the heterocycle. Furthermore, the compound (I) of the present invention may be isolated as a hydrate, a solvate such as ethanol, or a crystalline polymorphic substance, and the present invention includes these substances. Since the compound of the present invention has an asymmetric carbon atom, a plurality of isomers exist. The present invention includes separates or mixtures of these isomers. Preferred isomers in the carbapenem ring of the present invention are those having the configurations of 1R, 5S and 6S represented by the following formula.

[0011]

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Production Method A typical production method of the compound of the present invention will be described below.
The compound of the present invention can be synthesized by a conventionally known method other than the following production method or according to the method. First manufacturing method

[0013]

[Chemical 4]

(In the formula, R ¹ , R ² , A ring, dotted line and + have the above-mentioned meanings, R ³ is an ester residue as a protecting group for a carboxyl group, and R ⁴ is a diphenylphosphoryl group or phenyl. Sulfenyl group, X is a halogen atom, Ph
Means a phenyl group. The compound (I) of the present invention is prepared by reacting a known intermediate represented by the general formula (V) with a thiol compound represented by the general formula (VI), then optionally removing a protecting group, or optionally an esterification reaction. Alternatively, it can be produced by subjecting it to a salt formation reaction. Intermediate (V) can be prepared by a known method, that is, 2
It is produced by reacting an -oxocarbapenem derivative with diphenylphosphoryl halide or phenylsulfenyl halide, or by oxidizing a 2-phenylthiocarbapenem derivative. Since these intermediates can be subjected to the next step without isolation, they are shown as a series of reactions from compounds (II) and (IV) in the flow chart.

Examples of the ester residue or halogen atom of the carboxy-protecting group include those mentioned above.
In addition to the monomer represented by the formula, the compound (VI) may be reacted with a compound in which two molecules of the compound (VI) are bound by a disulfide bond (SS) together with a compound that cleaves the disulfide bond such as triphenylmercaptan. Therefore, such a disulfide bond compound is also included.

The thiol etherification reaction is almost the same as when the 2- (diphenylphosphoryl) carbapenem derivative [active intermediate (V)] is used as the starting compound and when the 2-phenylsulfenylcarbapenem derivative is used as the starting compound. It can be carried out. Examples of the solvent used in these reactions include organic solvents inert to the reaction, such as acetone, ketones such as methyl ethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, water or a mixed solvent thereof. It is suitable. Further, a base may be added to accelerate the reaction, and examples of such a base include trimethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, N-methylmorpholine. , Organic bases such as quinuclidine, inorganic bases such as potassium hydroxide, sodium hydroxide and potassium carbonate, and metal alcoholates such as sodium methoxide. The reaction temperature is set under cooling to room temperature, preferably under cooling.

The removal of the protecting group depends on the kind of the protecting group, but when the protecting group is an aralkyl-based protecting group such as p-nitrobenzyl group, benzyl group, benzhydryl group, etc., 1) zinc or iron is used. The protecting group can be eliminated by applying 2) liquid reduction or 3) catalytic reduction using palladium-carbon, palladium hydroxide-carbon or the like as a catalyst. These treatments can be performed by a conventional method, for example, the above 1)
Is carried out by adding the compound (VI) to a buffer solution (adding an inert solvent as necessary), then adding a reaction-corresponding amount or an excess amount of zinc, and stirring the mixture under cooling or heating. be able to. The reduction method of 2) is the compound (V
It can be carried out by adding I) into liquid ammonia, then adding metallic sodium and stirring. Also,
The reduction method 3) can be carried out in the presence of a catalyst such as palladium-carbon or palladium hydroxide-carbon under cooling or heating.

Esterification can also be carried out by a conventional method, including a substituted carbapenemcarboxylic acid or a reactive derivative thereof (for example, its ester, halide, acid anhydride, etc.),
It is carried out by esterification with an alcohol corresponding to an ester residue which is metabolized and hydrolyzed in the living body or a reactive derivative such as a halide thereof, a sulfonate, a sulfate or a diazo compound. In addition, depending on the type of ester residue, it can be produced by previously introducing it instead of the ester residue as a protecting group and subjecting it to the above series of reactions. The salt is formed as an intramolecular salt, or can be produced by subjecting it to a conventional salt-forming reaction.

The starting compound (VI) can be manufactured and obtained by applying the method represented by the following reaction formula.

[0020]

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[0021]

[Chemical 6]

(In the formula, A ring, dotted line, + and X have the above-mentioned meanings, R ⁵ is a protecting group for a mercapto group, M ¹ is an alkali metal, and R ⁶ and R ⁷ are the same or different. A lower alkyl group, R ⁸ a hydroxyl group protecting group, M ² a metal atom such as lithium, R ⁹ a halogen atom or M ² -R ⁹ together with a Grignard reagent, and R ¹⁰ a hydroxyl group activation. the OR ¹⁰ and turned by salifiable group, ^{- -} a group of OR ¹¹ is the anion of the acid used for the removal of the protecting group of mercapto, - means respectively a negative charge).

That is, when the compound (VI) uses halogenobutyrolactone (VII) as a raw material, it is
A mercapto protecting group such as p-nitrobenzyl group is introduced by reacting in the same manner as in the thiol etherification of the production method to form a protected mercaptobutyrolactone (IX), and N, O-di-lower alkylhydroxylamine (X) is added to this. Is reacted to cleave the lactone ring and amidate to give an amide compound (XI), which is then treated with t-
O-protected and S-protected amide compound (XIII) was obtained by introducing a protective group for hydroxyl group such as butyldimethylsilyl group, and chloroiodomethane (XIV) substituted with two halogens having different reactivity and bromide. Α-Haloketone compound (XV) and amide compound (XV) using a metal reagent such as lithium (ketone synthesis from amide), reacting with nitrogen-containing heterocyclic amine (XVI), and imidazo condensed nitrogen-containing heterocyclic ring Compound (XVII) and nothing (synthesis of imidazole from α-haloketone). This was treated with an acid such as concentrated hydrochloric acid to remove the protective group of the hydroxyl group and the hydroxypropyl compound (XVII
I), and the hydroxyl group activating group (eg, methanesulfonyl group, p
-Toluenesulfonyl group, etc.) to form an O-activated compound (XX), which is then cyclized by heating to form a tricyclic compound (XXI), which is used to remove a mercapto protecting group such as trifluoromethanesulfonic acid. used is, ^- it can be prepared by removal of the protecting group by treatment with a salt capable of forming acid as OR ^11.

Introduction of a protecting group for a mercapto group by these thioetherification, amidation accompanied by lactone ring cleavage, O
-Introduction of a hydroxyl-protecting group by silylation, synthesis of α-haloketone from amide, synthesis of imidazole from α-haloketone, removal of hydroxyl-protecting group by acid, introduction of hydroxyl-activating group by O-sulfonylation, hydroxyalkyl The synthesis of pyrrolidine from amine and the reaction of removing the protecting group of the mercapto group with acid are all conventional methods, and the conventional methods can be applied.

The reaction product obtained by the above production method is
It is isolated and purified by applying ordinary chemical operations such as extraction, crystallization, recrystallization and various chromatographies. Further, the separation of isomers can be carried out by selecting and reacting an appropriate starting compound in advance, or by utilizing the difference in physicochemical properties between isomers (for example, by applying chromatography etc.). it can.

[0026]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention or a salt thereof has an excellent antibacterial activity against Gram positive bacteria and negative bacteria.
In particular, the antibacterial activity against multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and resistant Pseudomonas aeruginosa (P. aeruginosa) is remarkably excellent. Furthermore, the compound of the present invention is a degrading enzyme dehydropeptidase (DHP-1) in the kidney.
It is stable and has high biological stability. It also has an excellent anti-infective effect. Therefore, the compound of the present invention is useful as an antibacterial agent for preventing / treating various infections and complications caused by resistant bacteria such as gram-positive and negative bacteria, especially MRSA and resistant Pseudomonas aeruginosa. Is. (Antibacterial activity) The MIC of the compound of the present invention is shown below.

[0027]

[Table 1] *: MRSA target compound, IPM / CS: imipenem / cilastatin

A pharmaceutical composition containing, as an active ingredient, one or more of the compounds represented by the general formula (I) and salts thereof is used as a carrier, an excipient, or other additives for usual preparations. The drug is used to prepare tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., and is orally or parenterally administered. The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to whom it is applied.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances may be combined with at least one inert diluent such as lactose,
It is mixed with mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, denbun, polyvinylpyrrolidone, magnesium aluminometasilicate.
According to a conventional method, the composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or aspartic acid. Such a solubilizing agent or solubilizing agent may be contained.
If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water. , Including ethanol. This composition contains a solubilizing or solubilizing agent other than an inert diluent,
It may also contain auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of diluents for non-water-soluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may further contain additives such as isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizing or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

[0031]

EXAMPLES The present invention will be described in detail with reference to the following examples. Needless to say, the present invention should not be limited to the compounds described in the examples. The raw material compounds of the present invention include novel compounds. A reference example is shown to show how to obtain the starting material compound of the present invention. In addition, the numbering of the heterocyclic group in the reference example and the example compound is as follows.

[0032]

[Chemical 7]

Reference Example 1

[0034]

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Α-Bromo-γ-butyrolactone 10.0
25 ml of dimethylformamide was added to ml (121 mmol).
0 ml, 4-methoxy-α-toluenethiol 18.5
ml (133 mmol) and potassium carbonate 20.0 g (1
45 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The insoluble material was filtered off, and dimethylformamide was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated.
The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (12: 1, v / v), α
26.9 g of-(p-methoxybenzyl) thio-γ-butyrolactone was obtained.

Mass spectrometric value (EI, m / z): 238 (M
⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.85-2.20 (1H, m), 2.30-2.
80 (1H, m), 3.31 (1H, dd, J = 4.6)
Hz, 8.6 Hz), 3.77, 4.08 (2H, AB
q, J = 13.5 Hz), 3.79 (3H, s), 4.
20-4.65 (2H, m), 6.85, 7.32 (4
H, ABq, J = 8.8 Hz) Reference Example 2

[0037]

[Chemical 9]

11.8 g (121 mmol) of N, O-dimethylhydroxylamine hydrochloride was added to 30 parts of dichloromethane.
It was suspended in 0 ml and 116 ml of 1.05N trimethylaluminum / hexane solution was added dropwise. After stirring for 15 minutes at room temperature, a dichloromethane (80 ml) solution of 26.2 g (110 mmol) of α- (p-methoxybenzyl) thio-γ-butyrolactone was added dropwise. After refluxing for 1 hour, 1N hydrochloric acid was slowly added, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, chloroform-ethyl acetate (1: 1, v / v).
Eluted with N-methoxy-N-methyl-4-hydroxy-2- (p-methoxybenzyl) thiobutyramide 2
9.8 g was obtained.

Mass spectrometric value (FAB, Pos., M /
z): 300 ((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.65-2.45 (2H, m), 3.20 (3)
H, s), 3.50-3.90 (2H, m), 3.65.
(3H, s), 3.78 (5H, s), 3.98 (1
H, t, J = 7.3 Hz), 6.83, 7.25 (4
H, ABq, J = 8.8 Hz) Reference Example 3

[0040]

[Chemical 10]

N-methoxy-N-methyl-4-hydroxy-2- (p-methoxybenzyl) thiobutyramide 3
To a solution of 5.9 g (120 mmol) of dimethylformamide (250 ml) was added 19.0 g (126 mmol) of t-butyldimethylchlorosilane, and the mixture was stirred at room temperature for 2 hours. Dimethylformamide was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed 3 times with water and once with saturated brine. After drying over anhydrous magnesium sulfate, N-methoxy-N
-Methyl-4- (t-butyldimethylsilyl) oxy-
2- (p-methoxybenzyl) thiobutyramide 43.
2 g was obtained.

Mass spectrometric value (FAB, Pos., M /
z): 414 ((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 0.03 (6H, s), 0.87 (9H, s),
1.65-2.40 (2H, m), 3.19 (3H,
s), 3.40-4.10 (3H, m), 3.63 (3
H, s), 3.78 (5H, s), 6.81, 7.25.
(4H, ABq, J = 8.6Hz) Reference Example 4

[0043]

[Chemical 11]

N-methoxy-N-methyl-4- (t-butyldimethylsilyl) oxy-2- (p-methoxybenzyl) thiobutyramide 5.00 g (12.1 mmo)
l), chloroiodomethane 1.32 ml (18.2 mm
ol) and lithium bromide 1.05 g (12.1 mmol)
To a tetrahydrofuran (50 ml) solution of was added dropwise 18.1 ml of 1.07N methyllithium-diethyl ether solution at -70 ° C. After stirring at the same temperature for 30 minutes, 1N hydrochloric acid was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (20: 1, v / v) to give 5- (t-butyldimethylsilyl) oxy-1-.
Chloro-3- (p-methoxybenzyl) thiopentane-
4.56 g of 2-one was obtained.

Mass spectrometric value (EI, m / z): 403 (M
⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 0.03 (6H, s), 0.88 (9H, s),
1.50-2.35 (2H, m), 3.55-3.80
(3H, m), 3.79 (5H, s), 4.29 (2
H, s), 6.70, 7.20 (4H, ABq, J =
8.8 Hz) Reference example 5

[0046]

[Chemical 12]

A solution of 5- (t-butyldimethylsilyl) oxy-1-chloro-3- (p-methoxybenzyl) thiopentan-2-one (18.3 g, 45.3 mmol) in acetone (100 ml) was added with sodium iodide (10). 0.0 g
(68.0 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. After removing the insoluble matter by filtration, 4.31 g of 2-aminopyrimidine
(45.3 mmol) was added and the mixture was refluxed for 2 hours. Diisopropylethylamine 9.50 ml (54.4 mmol)
Was added, the mixture was refluxed for 2 hours, and then acetone was distilled off under reduced pressure. Water was added to the residue, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was subjected to column chromatography, and eluted with chloroform-methanol (60: 1, v / v), 2- [3- (t-butyldimethylsilyl) oxy-1- (p- 5.99 g of methoxybenzyl) thiopropyl] imidazo [1,2-a] pyrimidine were obtained.

Mass spectrometry value (FAB, Pos., M /
z): 444 ((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: -0.01 (6H, s), 0.85 (9H, s),
2.00-2.55 (2H, m), 3.50-3.80
(2H, m), 3.72 (2H, s), 3.77 (3
H, s), 4.19 (1H, t, J = 8.6 Hz),
6.70-6.90 (1H, m), 6.77, 7.22
(4H, ABq, J = 8.6Hz), 7.30 (1H,
s), 8.37 (1H, dd, J = 2.2, 6.8H)
z), 8.54 (1H, dd, J = 2.2, 4.2H
z) Reference example 6

[0049]

[Chemical 13]

2- [3- (t-butyldimethylsilyl)
Oxy-1- (p-methoxybenzyl) thiopropyl]
6.98 g of imidazo [1,2-a] pyrimidine (15.
Under ice cooling, 5.24 ml of concentrated hydrochloric acid was slowly added to a solution of 7 mmol) in acetonitrile (100 ml). After stirring for 45 minutes under ice cooling, saturated aqueous sodium hydrogen carbonate solution was added, and acetonitrile was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was subjected to column chromatography, and chloroform-methanol (6
0: 1, v / v) to elute 2- [3-hydroxy-1
There were obtained 4.06 g of-(p-methoxybenzyl) thiopropyl] imidazo [1,2-a] pyrimidine.

Mass spectrometric value (FAB, Pos., M /
z): 330 ((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.10-2.35 (2H, m), 3.0 (1H,
brs), 3.60-3.80 (2H, m), 3.72.
(2H, s), 3.76 (3H, s), 4.18 (1
H, t, J = 7.5 Hz), 6.78, 7.19 (4
H, ABq, J = 8.8 Hz, 6.86 (1H, d
d, J = 4.0, 6.7 Hz), 7.48 (1H,
s), 8.36 (1H, dd, J = 2.0, 6.7H)
z), 8.53 (1H, dd, J = 2.0, 4.0H
z) Reference example 7

[0052]

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A solution of 967 mg (2.94 mmol) of 2- [3-hydroxy-1- (p-methoxybenzyl) thiopropyl] imidazo [1,2-a] pyrimidine in dichloromethane (20 ml) was cooled with ice to obtain triethylamine (0.1 ml).
45 ml (3.24 mmol) was added, and methanesulfonyl chloride 0.25 ml (3.24 mmol) was slowly added dropwise. After stirring for 1.5 hours under ice cooling, water was added and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give crude 2- [3- (methanesulfonyl) oxy-1- (p-methoxybenzyl) thiopropyl] imidazo [1,2-a] pyrimidine 1.22 g.
I got

Mass spectrometric value (FAB, Pos., M /
z): 408 ((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.30-2.65 (2H, m), 2.94 (1)
H, s), 3.65-3.85 (2H, m), 3.76.
(3H, s), 4.00-4.50 (3H, m), 6.
78, 7.21 (4H, ABq, J = 8.8Hz),
6.89 (1H, dd, J = 4.2, 6.7Hz),
7.49 (1H, s), 8.44 (1H, dd, J =
2.0, 6.7 Hz), 8.56 (1H, dd, J =
2.0, 4.2 Hz) Reference Example 8

[0055]

[Chemical 15]

2- [3- (methanesulfonyl) oxy-
1- (p-methoxybenzyl) thiopropyl] imidazo [1,2-a] pyrimidine 1.20 g (2.94 mmo
30 ml of acetone was added to l), and the mixture was heated under reflux for 15 hours. Acetone was distilled off under reduced pressure, and 7- (p-methoxybenzyl) thio-8,9-dihydro-7H-pyrrolo [1 ',
2 ': 3,4] imidazo [1,2-a] pyrimidinium methanesulfonate 1.15 g was obtained.

Mass spectrometric value (FAB, Pos., M /
z): 312 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.37 (3H, s), 2.55-3.50 (2
H, m), 3.75 (3H, s), 4.97 (2H,
s), 4.54 (2H, t, J = 7.3 Hz), 4.7
5-4.95 (1H, m), 6.90, 7.35 (4
H, ABq, J = 8.5 Hz), 7.73 (1H, d
d, J = 4.7, 6.8 Hz), 8.30 (1H,
s), 9.08 (1H, dd, J = 2.0, 4.7H)
z), 9.34 (1H, dd, J = 2.0, 6.8H)
z) Reference example 9

[0058]

Embedded image

7- (p-methoxybenzyl) thio-8,
1.11 g (2.72 mmol) of 9-dihydro-7H-pyrrolo [1 ', 2': 3,4] imidazo [1,2-a] pyrimidinium methanesulfonate was added to anisole-2.
It was dissolved in a mixed liquid of 5 ml and 10 ml of trifluoroacetic acid, and 0.5 ml of trifluoromethanesulfonic acid was added under ice cooling. The mixture was stirred under ice cooling for 30 minutes, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the oily residue, and the mixture was stirred and left standing, and then the upper layer diethyl ether was decanted.
The same operation was repeated 3 times, and diethyl ether was completely removed under reduced pressure to obtain crude 7-mercapto-8,9-dihydro-7H-.
Pyrrolo [1 ', 2': 3,4] imidazo [1,2-a]
Pyrimidinium trifluoromethanesulfonate 99
8 mg was obtained.

Mass spectrometric value (FAB, Pos., M /
z): 192 Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.50-2.80 (1H, m), 3.00-3.
45 (1H, m), 4.05 (1H, brd), 4.4
0-4.70 (2H, m), 4.70-5.05 (1
H, m), 7.70 (1H, dd, J = 2.8, 6.8)
Hz), 8.23 (1H, d, J = 1.1 Hz), 9.
05 (1H, dd, J = 1.8, 2.8 Hz), 9.3
1 (1H, dd, J = 1.8, 6.8 Hz) Example 1

[0061]

[Chemical 17]

P-nitrobenzyl (1R, 5S, 6
S) -2-Diphenoxyphosphoryloxy-6-
[(R) -1-hydroxyethyl] -1-methyl-1-
Carbapen-2-em-3-carboxylate 1.53
g in 30 ml of acetonitrile solution under ice-cooling, 7-mercapto-8,9-dihydro-7H-pyrrolo [1 ', 2':
972 mg of 3,4] imidazo [1,2-a] pyrimidinium trifluoromethanesulfonate and 0.64 ml of diisopropylethylamine were added, and the mixture was stirred under ice cooling for 3 hours. The solvent was distilled off, and p-nitrobenzyl (1R,
5S, 6S) -2- [8,9-Dihydro-7H-pyrrolo [1 ′, 2 ′: 3,4] imidazo [1,2-a] pyrimidine-7-io] thio-1-[(R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3
2.97 g of crude carboxylate trifluoromethanesulfonate salt are obtained.

Mass spectrometric value (FAB, Pos., M /
z): 536 nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.10-1.40 (6H, m), 2.60-2.
80 (2H, m), 3.30-3.50 (2H, m),
3.65-3.80 (1H, m), 4.00-4.10.
(1H, m), 4.45-4.60 (2H, m), 5.
10-5.50 (3H, m), 7.14, 7.25 (4
H, ABq), 7.60-7.80 (1H, m), 8.
46, 8.39 (1H, 2s), 9.05-9.10.
(1H, m), 9.30, 9.35 (1H, m) Example 2

[0064]

Embedded image

P-nitrobenzyl (1 obtained in Example 1)
R, 5S, 6S) -2- [8,9-Dihydro-7H-pyrrolo [1 ', 2': 3,4] imidazo [1,2-a] pyrimidine-7-io] thio-1-[( R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylate / trifluoromethanesulfonate crude product 2.91 g, tetrahydrafuran 15 ml
And 0.35N potassium phosphate buffer (pH = 6.
1) It was dissolved in 15 ml, 2.91 g of zinc powder was added, and the mixture was stirred at room temperature for 40 minutes. Further, 3.50 g of zinc powder was added, the mixture was stirred at room temperature for 1.5 hours, and then the zinc powder was filtered off. Tetrahydrofuran was distilled off under reduced pressure, and the remaining aqueous solution was washed with ethyl acetate. Concentrate the aqueous solution and use DIAION HP
It was subjected to -20 column chromatography, and the fractions eluted with water-methanol (9: 1 to 7: 1) were collected, concentrated, lyophilized, and (1R, 5S, 6S) -2- [8,9-dihydro. -7H-Pyrrolo [1 ', 2': 3,4] imidazo [1,2-a] pyrimidine-7-io] thio-1-
[(R) -1-hydroxyethyl] -1-methyl-1-
615 mg of crude carbapen-2-em-3-carboxylate was obtained. Further, 615 mg of the obtained crude product was subjected to HPLC [water-acetonitrile (97: 3, v / v)].
And the diastereomer was collected. Reversed phase HPLC
The higher polar isomer eluting first was designated as A and the other as B, and the respective fractions were collected. Lyophilize to give isomer A 39.
0 mg, 50.9 mg of isomer B, a mixture of AB 33.
9 mg was obtained.

Isomer A mass spectrometric value (FAB, Pos., M / z): 401
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.13 (3H, d, J = 6.4 Hz), 1.14.
(3H, d, J = 6.0 Hz), 2.60-2.70
(1H, m), 3.05-3.20 (3H, m), 3.
90-4.00 (1H, m), 4.06 (1H, dd,
J = 3.2, 10.0 Hz), 4.40-4.55 (2
H, m), 5.15-5.25 (1H, m), 7.68
(1H, dd, J = 4.4, 6.8Hz), 8.36
(1H, s), 9.03 (1H, dd, J = 1.2,
4.4 Hz), 9.42 (1H, dd, J = 1.2,
6.8 Hz) Isomer B mass spec (FAB, Pos., M / z): 401
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.07 (3H, d, J = 6.8 Hz), 1.15
(3H, d, J = 6.0 Hz), 2.50-2.65
(1H, m), 3.05-3.30 (3H, m), 3.
90-4.00 (1H, m), 4.25 (1H, dd,
J = 2.0, 9.2 Hz), 4.45-4.60 (2
H, m), 5.00-5.05 (1H, m), 7.68
(1H, dd, J = 4.4, 6.8Hz), 8.37
(1H, s), 9.02 (1H, dd, J = 1.6,
4.4 Hz), 9.41 (1H, dd, J = 1.6,
6.8 Hz)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI technical display location C07D 487: 04 487: 14) (72) Inventor Tomio Shinki 2-5 Ninomiya, Tsukuba, Ibaraki Prefecture 9 Rumi Tsukuba 316 (72) Inventor Kiyoshi Washizaki 1-11-30 Fujimi, Ageo City, Saitama Prefecture

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (The symbols in the formulas have the following meanings: R ¹ : hydrogen atom or lower alkyl group, R ² : negative charge, hydrogen atom, or ester residue, A ring: unsaturated nitrogen-containing 5- or 6-membered heterocycle , Dotted line: Carbapenem derivative or salt thereof represented by either one of double bond and the other of single bond, +: positive charge.