WO1993016080A1 - Novel carbapenem derivative - Google Patents

Abstract

A carbapenem derivative represented by general formula (I) or a salt thereof, wherein (a) represents (un)substituted pyridinium, (b), (c), (d) or (e); R?1 and R2¿ may be the same or different from each other and each represents lower alkyl; n represents an integer of 3 to 7; R represents hydrogen, anionic charge or ester residue; and the wavy line represents either cis or trans form. This compound has an excellent antibacterial activity against a wide variety of bacteria falling under the category of gram-positive and negative bacteria, thus being useful as an antibacterial.

Description

 Description New Features Luba Nem Inductor Technical Field

 The present invention relates to a novel carbanemine derivative, and more particularly, to a 1β-methylcarbapanem derivative having a —configuration methyl group introduced at the 1-position of a carbanemene skeleton, and a method for producing the compound. The present invention relates to an antibacterial agent containing the compound as an active ingredient. Background art

 Conventionally, a large number of compounds having a basic skeleton of carber-2-enem-3 rubonic acid have been proposed for various antibacterial activities.

 For example, one of the earliest potato antibiotics is chenamycin, which is obtained as a fermentation product of Streptomyces catt leya. Although this chenamycin has excellent antibacterial activity against a wide range of Gram-positive and negative bacteria, its chemical stability is poor and it has not yet been put to practical use.

 Next, imidenem, in which the amino group on the 2-position side chain of chenamycin was formimidylated, appeared as a practical antibacterial agent. Although this compound has excellent antibacterial activity and chemical stability to some extent, it is easily degraded and inactivated by renal dehydrobeptidase (DHP) in vivo, and is used in combination with cilastatin, a type of DHP inhibitor. It is formulated with Midianem Z Cilastatin.

On the other hand, various 1-methyl compounds having a methyl group introduced at the 1-position of the carbane skeleton have been proposed, including, for example, a substituted thiol at the 2-position of the carbane skeleton. Such as meronem, LJC10627 (Japanese Patent Laid-Open Publication No. Hei 1-259779) Compounds are known.

 In addition, compounds having a nitrogen atom-containing heterocyclic group at the 2-position of 1-methylcarbapanem skeleton are also known. For example, in Japanese Patent Application Laid-Open No. Among them, some compounds having a substituted heterocyclic alkyl group at the 2-position of the 1-methylcarbapanem skeleton are described, and Japanese Patent Application Laid-Open No. 3-120280 discloses a special compound. Specific examples of the compounds contained in the broad disclosure of Japanese Patent Application Laid-Open No. 6-11511, and their antibacterial activity are disclosed. Furthermore, in JP-A-2-289571, compounds having a vinyl group substituted with an unsaturated heterocyclic group which may be substituted at the 2-position of the 1-methylcarbapanem skeleton are highly antibacterial. It is reported to be active and stable against DHP. Disclosure of the invention

 The present invention differs from these compounds in that 1-propenyl group, which is structurally different from 1-methylcarbane skeleton, is bonded to the nitrogen atom on the heterocycle at the 2-position to form a quaternary ammonium group. By introducing the compound, it provides a highly clinically useful compound that has superior antibacterial activity compared to known lenvanem derivatives and has excellent DHP stability and pharmacokinetics.

 That is, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable hydrate thereof. And a method for producing the compound, and a pharmaceutical composition comprising the compound as an active ingredient.

(The groups in the formula have the following meanings ㊉ /

 — N

 : A substituted or unsubstituted pyridinyl group,

 .

 formula

 ©

Or a group represented ^by- † vJ ^{eH2) n}

 R2

R'R ² same or different lower alkyl group

 n an integer from 3 to 7

 R hydrogen atom, anion charge, ester residue

 Wavy ray cis-form or trans-form)

 The present invention will be described in more detail as follows.

 ㊉ /

As the group represented by the formula -N, a substituent or an unsubstituted, pyr R ¹ or

ここで， 「置換若しくは未置換のピリ ジニゥム基」 における置換 基としては， 例えば， 低級アルキル基， 低級アルケニル基， 低級ァ ルキニル基， 低級アルコキシ基， 低級アルキルチオ基， ハロゲン原 子， 水酸基， アミ ノ基， カルボキシ基， 力ルバモイル基， モノ—若 しくはジー低級アルキルアミ ノ基， ァミノ低級アルキル基， 隣接す る低級アルキル基が一体となり形成される低級アルキレン基， 炭素 数 3〜 6個のシク口アルキル基， ァリール （A r y 1 ) 基， モノ又 はジー置換アミ ノ基， 低級アルコキシカルボニル基， ァシル基， シ ァノ基. ニトロ基， N -低級アルキル置換力ルバモイル基、 スルホ 二ル基， 低級アルキルスルホニル基， スルフィニル基， 低級アルォ ルスルフィニル基， 及びこれらの基で置換されていてもよい低級ァ ルキル基等である。 これらの置換基は， 同一又は異なりてピリ ジニ ゥム基に 1個乃至複数個が， 好ましくは 1個乃至 2個が置換してい てもよい。

Here, examples of the substituent in the “substituted or unsubstituted pyridinium group” include a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a hydroxyl group, and an amino group. Group, carboxy group, carbamoyl group, mono- or di-lower alkylamino group, amino-lower alkyl group, lower alkylene group formed by adjoining lower alkyl group, and 3-6 carbon atoms Alkyl group, aryl (Ary 1) group, mono- or di-substituted amino group, lower alkoxycarbonyl group, acyl group, cyano group. Nitro group, N-lower alkyl-substituted rubamoyl group, sulfonyl group, Lower alkylsulfonyl group, sulfinyl group, lower arylsulfinyl group, and substituted with these groups And a lower alkyl group. These substituents may be the same or different One or more, preferably one or two, may be substituted on the dimethyl group.

 Unless otherwise specified in the definition of the general formulas herein, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, as the “lower alkyl group”, specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amyl group) ) 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 monomethylpropyl group and 1-ethyl-2-methylpropyl group. Of these groups, preferred are methyl group, ethyl group, propyl group and isopropyl group, and more preferred are methyl group and An ethyl group.

The “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, and specifically includes a vinyl group, an aryl group, a 1-propyl group, a 2-propenyl group, a 1-propyl group. —Butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylaryl group, 1—methyl-1-propenyl group, 1-methylaryl group, 1,1-dimethylvinyl Group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 2-methyl-1- Butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-1 Methyl-3-butenyl group, 1,1-dimethylaryl group, 1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2 -Propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1,1,1-dimethyl-1-butenyl group, 1, 1, —Dimethyl-2-butenyl group, 1,1 —Dimethyl-3-butenyl group, 3,3 —Dimethyl-1-butenyl group, 1-Methyl-111-Pentenyl group, 1-Methyl-2-pentenyl group, 1-Methyl--3 —Pentenyl group, 1-methyl-pentenyl group, 4-methyl-1-pentenyl group, 4-methyl-2-pentenyl group, 4-methyl-3.1-pentenyl group and the like.

 “Lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl group , 1-methyl-2-butynyl, 1-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl And a 5_hexynyl group.

The “lower alkoxy group” includes methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentyloxy and the like. Group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group and the like. Of these groups, preferred is , A methoxy group, an ethoxy group, a propoxy group and an isopropoxy group, more preferably a methoxy group and an ethoxy group. Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

 Examples of the “lower alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. .

 Specific examples of the "mono- or di-lower alkylamino group" include, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, and a tert-butylamino group. , Pentyl (amyl) amino group, isopentylamino group, neopentylamino group, tert-pentylamino g, dimethylamino group, getylamino group, ethylmethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group And diisobutylamino groups. Of these groups, preferred are an amino group, a methylamino group, an ethylamino group, a dimethylamino group and a dimethylamino group, and more preferred is a dimethylamino group.

 The “amino lower alkyl group” is a group in which an amino group is substituted at an arbitrary position of the above lower alkyl group, and specifically, an aminomethyl group, an aminoethyl group, an aminopropyl group , Aminobutyl, aminopentyl and the like.

As the “lower alkylene group formed by integrating adjacent lower alkyl groups”, an alkylene group having 1 to 6 carbon atoms is preferable, and specifically, a methylene group, an ethylene group, a methylmethylene group, a trimethylene group is preferable. Len, dimethylmethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-ethylethylene, 2-ethylethylene, 2,2-dimethylethylene, 1 , 1-dimethylethylene, ethylmethylmethylene, pentamethylene, 1-methyltetramethylene, 2-methyl Tilttramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene Group, 2,3-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1,1,2—trimethylethylene group, getylmethylene group, hexamethylene group, 1-methylpentamethylene group, 1,1 Mono-dimethyltetramethylene group, 2,2-dimethyltetramethylene group, etc., more preferably trimethylene group, dimethylmethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, etc. Is mentioned. These lower alkylene groups are adjacent to and form a pyridinium ring.

 Examples of the "aryl group" include a phenyl group and a naphthyl group.

 Examples of the “mono- or di-substituted amino group” include an amino group having one or two substituents selected from an acyl group, an aralkyl group and the like.

 Examples of the “lower alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and the like.

 Examples of the “acyl group” include an acetyl group, a propionyl group, a benzoyl group and the like.

 The “N—lower alkyl-substituted rubamoyl group” includes, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylpower rubamoyl group, N, N, —dimethylcarbamoyl group or N, N-diethyl And a rucarbamoyl group.

Examples of the “lower alkylsulfonyl group” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group and a butylsulfonyl group. Examples of the “lower alkylsulfinyl group” include a methylsulfinyl group, an ethylsulfinyl group, a butylsulfinyl group and an isopropylsulfinyl group.

 Examples of the “ester residue” include an ester residue which is metabolized and hydrolyzed in a living body, or an ester residue which can serve as a protecting group for a carboxyl group. Examples of the ester residues that are metabolized and hydrolyzed in vivo include lower alkanoyloxy lower alkyl groups, lower alkenyl lower alkyl groups, cycloalkyl carboxy lower alkyl groups, lower alkenoyloxy lower alkyl groups. Alkyl group, 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, 2-oxotetrahydrofuran-5-yl group, 2-oxo-5-alkyl-1,3-dioxolen-4-ylmethyalkyl,

Group, tetrahydrofuranylcarbonyloxime

Common ester residues such as a tyl group and a 3-phthalidyl group are exemplified. Examples of the ester residue which can serve as a protecting group for a carboxyl group include, for example, a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a nitrobenzyl group, a lower alkoxybenzhydryl group, and the like.

In the above, the lower alkylene group has 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms, the lower alkanoyl group has 2 to 6 carbon atoms, and the cycloalkyl group has 3 to 8 carbon atoms. Particularly, those having 3 to 6 carbon atoms are mentioned. -1

 o

 Hereinafter, typical compounds of the present invention will be exemplified.

Fifteen

20

上記化合物のうち， 特に好ましい化合物としては， 1 , 2, 5 , 6, 7 , 8の化合物である。 これらの化合物は， 後記工程図及び実 施例に記載した合成経路と同様の方法によって合成することができ る。 twenty five

Among the above compounds, particularly preferred compounds are 1, 2, 5, 6, 7, and 8 compounds. These compounds are described in the process diagrams and It can be synthesized by a method similar to the synthesis route described in the examples.

 The compound of the present invention has a group represented by the formula 1 NJ which is a substituent at the 2-position and a group represented by the formula 1) which is capable of forming an inner salt by a carboxy anion or an anion at the 3-position. When there is an ion or anion, or when the carboxy anion moiety at the 3-position is substituted with an ester residue, it forms salts with other acids and bases. Salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Examples include acid addition salts with organic acids such as maleic acid, lactic acid, lingic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid.

 Examples of salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolamine; and basic amino acids such as lysine and orditin. Salts with acids include ammonium salt.

 Further, the compound of the present invention has an asymmetric carbon atom and a double bond (a propyl group at the 2-position), and thus has a plurality of isomers. The present invention includes separated or mixtures of these isomers. Particularly preferred isomers in the ring of the present invention are 1 S, 5 R and 6 S, in which the propenyl group at the 2-position has a trans configuration (E). Furthermore, the compound of the present invention also includes pharmaceutically acceptable solvates or hydrates thereof.

 (Manufacturing method)

Hereinafter, the method for producing the compound of the present invention will be described. First manufacturing method

(i) Phosphoric acid esterifying agent

 (ii) Halogen donor _

 No.

1工程

1 process

(II)

 (ΠΙ) (lb)

Removal of protecting groups

 (la)

(Wherein, R ³ represents a carboxyl-protecting group, and X represents a halogen atom. The same applies hereinafter.)

The compound (III) of the present invention is obtained by phosphorylating 3-hydroxy-1-propene-1-ylcarbapanem represented by the general formula (II), followed by halogenation to give the compound represented by the general formula (III). Change the benyl halide (Step 1), and then react the probenyl halide with the corresponding pyridine or bridged ring derivative represented by the general formula (V) to obtain a compound represented by the general formula (lb). The compound can be produced by removing the protecting group R ³ of the compound (deprotection step) if necessary (second step).

In the first step of this method, a phosphate esterifying agent (a reactive derivative of phosphoric acid) is allowed to act under cooling in an inert solvent in the presence of an acid scavenger (such as dimethylaminopyridine). —Phosphoryloxy-1-propene-1-ylcarbapanem compound is obtained, and then the compound is added to an inert solvent. Rogen donors (eg, halogenated compounds such as alkali metals and alkaline earth metals, halogenated silanol compounds such as trialkylsilyl halides, or trialkyltin halides, dialkyltin dihalide tins or monoalkyltin trihalide halides) The reaction is carried out under cooling or at room temperature to produce 3-halogeno-1-propene-1-ylbenzene compound (III).

 Next, the reaction in the second step is carried out by stirring the compound (III) and a corresponding amount or an excess amount of the compound (V) in an inert solvent.

 As the inert solvent, aromatic hydrocarbons such as benzene, toluene and xylene are preferable, but dimethyl ether, dioxane, tetrahydrofuran, cyclohexane, cyclohexane, chloroform, dichloromethane, acetonitrile, dimethyl are preferable. Examples include sulfoxide, N, N-dimethylformamide, hexamethylphosphamide, and ethanol. Also, a mixture thereof may be used.

The first step and the second step may be performed continuously. In addition, in the case where the formula ( ¹⁾ has a substituent R1, the reaction may be performed after the first and second steps are performed.

 The removal of the protecting group can then be carried out by 1) reduction using zinc or iron, 2) liquid reduction or 3) catalytic reduction using palladium-carbon or palladium hydroxide-carbon. it can.

 In the reduction method of 1) above, compound (IV) is added to a buffer solution (an inert solvent is added if necessary), and then an amount of zinc or iron corresponding to the reaction is added, and the mixture is cooled or heated. Can be performed by stirring under o

 2) The reduction method can be performed by adding compound (IV) to liquid ammonia, then adding sodium metal and stirring.

The reduction method in 3) is based on palladium-carbon or palladium hydroxide. It can be performed under cooling or heating in the presence of a catalyst such as carbon. The reaction time of the above reaction varies depending on the reaction conditions such as the raw materials and the reaction reagents, but it is several tens to several tens of hours, preferably several tens to several hours.

Second manufacturing method

(I)

(I)

 (In the formula, Y means a phenyl group, the lower alkyl group or the lower alkoxy group.)

 The compound (I) of the present invention can be produced by subjecting the phosphorane represented by the general formula (VI) to a Wittig reaction, and then optionally removing a protecting group. The Wittig reaction can be carried out by heating compound (VI) usually in an inert solvent. Suitable examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, but the solvents described in the first production method can also be used.

 The reaction temperature is preferably in the range of 50 to 200 ° C, but the reaction can be adjusted by cooling or heating as appropriate. Next, if necessary, the protective group can be removed in the same manner as in the first production method.

Isolation and purification of the target substance from the reaction solution are carried out in a conventional manner by appropriately combining extraction with an organic solvent, chromatography, crystallization, and the like. When compound (I) has an ester residue, Is carried out by reacting an alcohol or an esterifying agent such as a halide, sulfonate, sulfite, diazo compound or the like by an ordinary method, or, when compound (I) has a salt, by a conventional salt-forming reaction. Can be obtained by adding. Industrial applicability

 The compound of the present invention, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, and its pharmaceutically acceptable hydrate have excellent antibacterial activity and belong to Gram positive and negative Inhibits the growth of a wide range of pathogenic microorganisms. That is, the compound of the present invention has an excellent antibacterial activity equivalent to or higher than imidenem / cilastatin (I PMZC S), which has the highest antibacterial activity as a carbanadem derivative, and a protective effect against infection. .

 In addition, the compound of the present invention is stable against DHP-I in the kidney, and its pharmacokinetics, particularly the excretion pathway, the distribution characteristics in the tissue, etc. are comparable to those of IPM / cs or other active leubadenem compounds. In comparison, it has a much better profile, low toxicity, and can be a clinically useful antibacterial agent without being combined with a DHP inhibitor. In particular, it is expected to have excellent clinical effects as an antibacterial agent for diseases such as urinary tract infections. The usefulness of the compound of the present invention has been confirmed by the following experiments. In the following experiment, among the compounds of the present invention, the 2-position was (E) -31- (pyridine-11-)-1-propene-1-yl and the 3-position was a carboxy anion. Went with things.

 (1) Antibacterial activity (in vitro)

 The compound of the present invention exhibited an antibacterial activity (MIC) equivalent to or higher than that of imidenem / cilastatin (IPMZCS). (2) Therapeutic effect of Staphylococcus aureus Smith on systemic infection in mice

1. Method; Suspend cells cultured at 37 ° C for 24 hours in 5% mucin Then, 0.5 ml of the solution was inoculated intraperitoneally into mice (ICR, male, 5 weeks old) to cause infection. Two hours after infection, 0.27 ml of the drug solution was subcutaneously administered, and after 7 days of survival, the ED50 was calculated by the Probit method.

 Each group consisted of 10 mice, which were dissolved in physiological saline using IPM / CS as a comparative drug.

 2. Result

 The compound of the present invention had a good ED50 value almost equivalent to that of IPMZCS.

 (3) Stability to DH P-I in kidney homogenate

 1.5 times the wet weight of the kidney of ICR male mice and SD male rats was added to a 1/15 M'J acid buffer (pH 7), and a 40% kidney homogenate was prepared using a homogenizer. did. One volume of the drug solution (50 gZm 1) was added to one volume of the 40% kidney homogenate, and the mixture was incubated at 37 ° C for 2 hours. The reaction was stopped by adding an equal volume of 1 Z15M phosphate buffer (pH 7) containing 100 g / m1 cilastatin and allowing to stand on ice. This was centrifuged at 300,000 rpm for 5 minutes, and the drug concentration in the supernatant was measured by the bioassay method. Bioassay method (the same applies hereinafter)

 The bioassay method was performed by the agar well method using B. subtilis ATCC 6633 as a test bacterium and antibiotic medium 1 or citrate medium (pH 6.5) as a medium. Calibration curves were prepared using control plasma or 1 / 15M phosphate buffer (PH7).

 The compound of the present invention was sufficiently stable even in the absence of cilastatin, and was twice as stable in mice and about 10-fold in rats as compared to IPM / CS.

 (4) Urinary excretion rate in rats

 Three SD rats (6 weeks old, male) were used per group.

The compound of the present invention was prepared in physiological saline for injection (2 mg / ml), One OmgZkg was administered once intravenously. After administration of the drug, urine was collected at a predetermined time and used for bioassay.

 As a result, the compound of the present invention exhibited a good urinary excretion rate of about twice that of IPM / CS.

(5) Tissue distribution in mice

 Three ICR mice (6 weeks old, male) were used per group.

 The compound of the present invention was prepared in a physiological saline solution for injection (lmgZml), and 1 Omg / kg was subcutaneously administered once. At a predetermined time after drug administration, blood was killed from the inferior vena cava and the heart, lung, liver, kidney, and spleen were removed. Heparin was added to the blood, the plasma was separated, and used for bioassay. To each tissue, add 3 times the wet weight of 50 βg / m1 cilastatin in 115 M phosphate buffer (pH 7), homogenize with a homogenizer, and centrifuge at 300 rpm for 15 minutes. The drug concentration in the supernatant was measured by the bioassay method.

 Compared to IPM / CS, the compound of the present invention showed about 6-fold better value in Cmax in the kidney, about 9-fold in AUC, and about 3-fold in half-life (T½min) .

 Furthermore, the compound of the present invention showed a favorable value in plasma as compared with I PMZC S.

(6) Serum protein binding

Add the drug to human, rat and mouse serum (final concentration 90%) to a final concentration of 100 μg Zm1, incubate at 37 ° C for 1 hour, The drug concentration in the filtrate obtained by centrifugal ultrafiltration at 100 X g for 30 minutes using S-3 Centrifree (Amicon) was measured by the bioassay method. The protein binding ratio was calculated by the following equation. . A—Additive drug concentration—Drug concentration in filtrate _{1 Λ8} Protein binding rate = X 100

(%) Additive concentration The compounds of the present invention had lower protein binding compared to the values of the compounds on the market or under development of IPM, Merovenem, LJC10627.

(7) Central toxicity test

 Three d dY mice (4 weeks old, male) were used per group.

 The drug was dissolved in physiological saline for injection, and administered locally at 100 zg / animal and 300 g / animal into the left ventricle of the mouse. The administered liquid volume was 20 to 1 in all cases, and the control group received only physiological saline for injection. Intracerebroventricular administration was performed under anesthesia and the drug was injected vertically into the skull position 3 mm behind the posterior margin of the left eye and 0.5 mm outside the longitudinal midline. After that, behavioral observation was performed for 30 minutes to determine the presence or absence of convulsions and death.

 The convulsant-inducing effect of the compound of the present invention was weaker than that of IPM, and there was no death at any dose, confirming that the central toxicity of the compound of the present invention was low.

 Preparations containing one or more of the compounds represented by the general formula (I) as an active ingredient are prepared using carriers, excipients, and other additives that are usually used in formulation. Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, Examples include ethylene glycol and other commonly used ones.

Administration can be either oral administration, such as tablets, pills, capsules, granules, powders, or liquids, or parenteral administration, such as injections such as intravenous and intramuscular injections, suppositories, and transdermal agents. Good. The dose is appropriately determined depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration, but is generally about 250 to 150 Omg per day. BEST MODE FOR CARRYING OUT THE INVENTION

 The compound of the present invention and the method for producing the compound have been described above, and will be described in more detail with reference to the following examples. In addition, since the raw material of the compound of the present invention includes a novel substance, it will be described as a reference example.

Reference example 1

ΡΝΒ： パラニ トロべンジル

ΡΝΒ: Parani Trobenzil

(1) To 0.55 ml (8.47 mmol) of propargyl alcohol, 7 mg of 2.2'-azobis (isobutyronitrile) and 3.0 ml (11.l mmol) of hydrogen citry n-butyltin were added, and an argon stream was added. The mixture was stirred at 80 C for 2 hours. After cooling, the mixture was subjected to silica gel column chromatography, eluting with n-hexane and then dichloromethane, and a colorless oil of (E) -3- (tri-n-butyltin) aryl alcohol 2.1 5 g were obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 0.90 (15 5, m), 1.30 (6H, m),

1.50 (6 H, m), 4.14 (2H, d, J = 4 Hz), 6.14 (1 H, dxt, J! = 19.5 Hz, J ₀ = 4 H z), 6.2 1 (1 H, d, J = 19.5 H z)

② (4R) —2-Diazo—4 — [(2R, 3S) -3-((1R) -11-hydroxyl) -1-4-Oxazetidine-2-yl] -13-oxopentanoate Add 0.50 g (1.28 mm o 1) of trobenzil to 5 ml of toluene, and add 2 mg of rhodium (II) acetate dimer at 95 ° C under an argon stream. After stirring for 5 minutes, the toluene was distilled off under reduced pressure.

The obtained crude paranitrobenzil (1 S, 3 R, 5 R, 6 S)- 6 — ((1 R) 1 1 —Hydroxityl) 1 1—Methyl-2—Kisocarbapenamu 3-Dicarboxylate, add 10 ml of acetonitrile, and under a stream of argon at —5 ° C, diisopropylethyla Add 0.55 ml (3.23 mmo1) of min, and add 0.21 ml (1.2811111101) of trifluoromethanesulfonic anhydride at 0 or below, and bring to --5 ° C. And stirred for 10 minutes. 20 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with cold water and then with a cold saturated saline solution.

 This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. Crude paranitrobenzyl (1S, 5R, 6S) -6-((1R) —1—hydroxyl) 1.3 g of trifluoromethanesulfonyloxyl-lubapen-2-emu-3-carboxylate were obtained.

 To this was added 8 ml of 1-methylpyrrolidinone, 60 mg of tri (2-furyl) phosphine (0.26 mm o 1), 0.35 g of zinc chloride (2.56 mm o 1), bis (dibenzylideneacetone) palladium (0) 74 mg (0.128 mmo 1) (E) — 3- (tri-n-butyltin) allyl alcohol 0.49 g (1.41 mmo 1) Was added and washed with 2 ml of 1-methylpyrrolidinone, and the mixture was stirred at room temperature for 1 hour.

 70 ml of ethyl acetate was added to the reaction mixture, which was washed twice with 40 ml of water and then with 40 ml of saturated saline. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. 50 ml of acetonitrile was added to the residue, which was washed twice with 50 ml of n-hexane, and the acetonitrile layer was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography, eluted with dichloromethane-methanol (20: 1, v / v), and pentyl benzyl (1S, 5R, 6S) — 6— ( (1 R) — 1 — Hydroquinethyl 2 — ((E) 1 3 — Hydroxy 1 1 Propene 1 1 1) 1 1-Methylcarbapene 2 — Chem — 3 — Carboxylar 0.19 g of foam was obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 5: 1.2 3 (3 H, d, J = 7 H z),

 1. 3 7 (3 H, d, J = 6 Η ζ),

 3.28 (1 Η, d d, J! = 5 Η ζ 2 Η ζ) 3.43 (1 Η, m),

4.2 1 (1 Η, dd, J ₂ = 8 Η ζ J 2 2 Η ζ)

4.27 (1Η, m), 4.32 (2Η, d, J = 3Η ζ),

5.3 7 (2 Η, A Β q, .1 = 1 3.7 Η ζ,

 △ y = 9 1 ζ ζ),

6 20 (1 Η, dt J 1 = 16 ζ ₂ J ₂ = 5 Η ζ) 7 3 0 (1 Η, d, J = 16 Η ζ),

 7 6 7 (2 Η, d, J = 9 Η ζ),

 8 2 3 (2 Η, d, J = 9 Η ζ)

Example 1

"Θ

① Parani trobenzil (IS, 5 R, 6 S)-6-((1 R)-1-Hydroxicetil) 1 2-((E)-3-Hydroxy 1-Propene 1-1)- 1-Methylcarbamate 2-heme-l-boxylate 0.30 g (0.75 mmo 1) of dichloromethane in 6 ml of solution at 140 ° C under a stream of argon. 4 Add 0.1 g of (N, N-dimethylamino) pyridine, 0.10 g (0.82 mm 0 1) and 0.16 ml of diphenylphosphoric acid chloride (0.79 mm o 1). The mixture was stirred at 20 ° C for 30 minutes.

The reaction mixture was diluted with cold water, cold saturated aqueous sodium bicarbonate solution, cold 0. Washing was performed in the order of IN hydrochloric acid and cold water. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.

(1 S, 5 R, 6 S) — 2— ((E) — 3—diphenylphosphoroxy 1-propene 1-yl) 1 6— ((1 R) 1- 1-hydroxyl) 1-methylcarbabe There was obtained 0.42 g of an oil of 2--2-emu-3-carboxylate.

 To this, 8 ml of dichloromethane was added, and a 2.0 ml solution of 0.165 g (1.10 mmo 1) of sodium iodide in acetone was added at room temperature, and N, N-dimethyl was added. 0.5 ml of formamide was added. After stirring for 5 minutes, 0.18 ml (2.22 mmol) of pyridine was added, and the mixture was stirred overnight at room temperature. The precipitated crystals were separated by filtration, and the filtrate was distilled off under reduced pressure. 50 ml of ethyl acetate was added to the residue (0.80 g), washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue (0.37 g) was washed with getyl ether, and crude (1S, 5R, 6S) -6-((1R) -11-hydroxylethyl) 1-1-methyl-2-([ E) — 3— (Pyridine—1—1—1) —1—propene—1—yl] L-rubapen—2—emu-3-paranitrobenzyl carboxylate ′ 0.35 g of an iodide oil was obtained.

得られた粗 （ 1 S, 5 R, 6 S) — 6— （ （ 1 R) — 1 ーヒ ド 口キシェチル） — 1—メチル一 2— [ (E) — 3— （ピリ ジン— 1 —ィォ） — 1 —プロペン一 1 —ィル] 力ルバペン— 2—ェム一 3一力ルボン酸パラ二トロベンジル ' ヨウ化物の油 0. 3 5 に p H 6. 1の 0. 3 5Mリ ン酸緩衝液 6 m 1， テトラヒ ドロフラ ン 6 m 1， 亜鉛 0. 70 g ( 1 0. 7 mm o 1 ) を加えた。 リ ン 酸二水素ナト リウム水溶液を加えて， p H 6. 1に調整し， 室温 下， 5 0分撹拌した。

The obtained crude (1 S, 5 R, 6 S) — 6— ((1 R) — 1-hide mouth quichetyl) — 1-methyl-1- 2 — [(E) — 3 — (pyridine — 1 —ォ) — 1 — Propene 1 — yl] Power Lubapen — 2 — EM 1 3 力 ト ロ ベ ン ジ ル 二 油 の Oil of iodide 0.35 to 0.35 M at pH 6.1 6 ml of acid buffer, 6 ml of tetrahydrofuran, and 0.70 g (10.7 mmo 1) of zinc were added. Rin The pH was adjusted to 6.1 by adding an aqueous solution of sodium dihydrogen oxide, and the mixture was stirred at room temperature for 50 minutes.

 This was filtered through celite with water and ethyl acetate, and the aqueous layer was further washed with ethyl acetate. This was subjected to resin column chromatography on Amberlite I R 120B (manufactured by Organo Co., Ltd.) of 80 ml and eluted with 100 ml of water. This was concentrated under reduced pressure to 10 ml, adsorbed on Diaion HP-20 (80 ml), eluted with water, then with 10% acetate-water, and the desired fraction was collected and concentrated under reduced pressure. , Freeze-dried and dried (IS, 5 R, 6 S) — 6— ((1 R) 1 1 — hydroxyethyl) — 1 methyl 1 2 — [(E) — 3— (pyridin 1 1 Ye) — 1 propene— 1 — yl] kyrubapene—2—hem—3-—yield 50 mg.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMS 0- d _6, TMS internal standard) 5: 1. 0 0 (3 H, d, J = 7 H z),

 1 1 4 (3 H, d, J = 6 H z),

 3 00 (1 H, dd, J! = 7 Hz, J = 2.4 Hz), 3 1 1 (1 H, m), 3.90 (2 H, m), 5 3 5 (2 H, d, J = 6 H z),

5 92 (1 H, dt J _l = 17 H z J ₂ = 7 H z) 7 6 4 (1 H, d, J = 17 H z),

 8 1 7 (2 H, t, J = 7 H z),

 8 6 1 (2 H, t, J = 8 H z),

 9 0 9 (2 H, d, J = 6 H z)

Mass analysis (FAB, P os, m / z): 3 2 9 (M + + 1) Example 2

. I㊀

① Parani trobenzil (IS, 5R, 6S)-6-((1R)-1-hydroxyl) — 2— ((E) 13-hydroxyl 1-propene 1-yl) — 1-Methylcarbapene-1-heme-3-carboxylate To a solution of 0.30 g (0.75 mmo 1) of dichloromethane in 6 ml of methane at 140 ° C under a stream of argon. Then, 0.10 g (0.82 mm 0 1) of 4- (N, N-dimethylamino) pyridine and 0.165 ml (0.79 mmo 1) of diphenylphosphoric acid chloride were added. The mixture was stirred at 0 ° C for 1 hour.

 The reaction solution was washed with cold water, a cold saturated aqueous sodium hydrogen carbonate solution, cold 0.1 N hydrochloric acid, and cold water in this order. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. Crude paranitrobenzyl (1S, 5R, 6S) —2 — ((E) —3-diphenylphosphoroxy) 1 1-propene—1—yl) —6 — ((1 R) —1-hydroxyl) 1-Methylcarbapene—2-Emuu 3-Carboxylate An oil of 0.445 g was obtained.

 To this was added 8 ml of dichloromethane, and at room temperature, a 2.0 ml solution of 0.165 g of sodium iodide (1.0 mm 0 1) in acetone was added, and N, N-dimethylform was added. 0.2 ml of amide was added. After stirring for 20 minutes, 0.26 ml (2.22 mmo 1.) of 2,3-cyclopentenoviridine was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were separated by filtration, and the filtrate was distilled off under reduced pressure. 50 ml of dichloromethane was added to the residue (0.80 g), washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.

The residue (0.45 g) was washed with getyl ether, and the crude (1S, 5 R, 6 S) — 2— [(E) — 3— (2,3-cyclopentenoviridine 1 1 — io) — 1-propene — 1-yl] — 6— ((1 R) — 1 —Hydroxityl) — 1-Methylcarbane—2—Em—3—Paraditrobenzyl rubrate. 0.37 g of iodide oil was obtained.

Physicochemical properties

Mass analysis (FAB, P 0 s, m / z): 5 0 4 (M + + 1)

②

得られた粗 （ I S, 5 R, 6 S) - 2 - [ (E) — 3— (2， 3—シクロペンテノ ビリ ジン一ィォ] — 6— ( ( 1 R) — 1 —ヒ ドロキシェチル） — 1 ーメチルカルバべン— 2—ェムー 3—カル ボン酸パラ二トロベンジル ' ヨウ化物の油 0. 3 6 gに p H 6. 1の 0. 3 5 Mリ ン酸緩衝液 6m l , テ トラヒ ドロフラン 6m l， 亜鉛 0. 7 0 g ( 1 0. 7 mm o l ) を加えた。

The crude (IS, 5R, 6S) obtained-2-[(E) — 3— (2,3-cyclopentenoviridine) — 6 — ((1R) — 1 — hydroxyxetil) — 1-Methylcarbaben-2-emup 3-paranitrobenzyl carboxylate '0.36 g of oil in 0.36 g of 0.35 M phosphate buffer with a pH of 6.1 6 ml, tetrahydrofuran 6 m l, zinc 0.70 g (10.7 mmol) was added.

The pH was adjusted to 6.1 by adding an aqueous solution of sodium dihydrogen phosphate, and the mixture was stirred at room temperature for 30 minutes. This was filtered through celite with water and ethyl acetate, and the aqueous layer was further washed with ethyl acetate. This was applied to a resin column chromatograph of Amberlite IR120B (manufactured by Organo) of 60 ml and eluted with 140 ml of water. This was concentrated under reduced pressure to 15 ml, adsorbed on Diaion HP-20 (100 ml), eluted with water and then with 10% aqueous acetate-water, and the target fraction was collected and depressurized. Concentrate, freeze-dry, and (1 S, 5 R, 6 S) — 2-[(E) 1 3 — (2,3-cyclopentenoviridine 1 1 — io) 1 1 — Pup pen — 1 — 1-6-((1R) -1-Hydroxitytyl) 1-Methylcarbapene-1-Em-3-3-carboxylate 38mg I got

Physicochemical properties

Nuclear magnetic resonance spectrum (DMS 0-d ₆ , TMS internal standard) 6: 1.00 (3H, d, J = 7Hz),

 1. 1 4 (3 H, d, J = 6 Η ζ),

 2.2 3 (2 Η, t, J = 7 Η ζ),

3.0.0 (1 Η, d, J = 5 Η ζ), 3.13 (5 Η, m) 3.91 (2 Η, m), 5.2 4 (2 Η, d, J = 6 Η ζ) 5. 7 9 (1 Η, dt, J ₁ = 17 Η ,, J ₂ = 7 Η ζ) 7.59 (1 1, d, J = 16 1 Η),

 7.89 (1 Η, t, J = 6.5 Η ζ),

 8.3 9 (1 Η, t, J = 8 Η ζ),

 8. 7 6 (1 Η, d, J = 6 Η ζ)

 Mass spectrometry value (FAB, Pos, m / z): 36 9 (M ++ 1) Example 3

· I㊀

① Paranitrobenzyl (IS, 5R, 6S)-6-((1R)

 1-Hydroxyschetyl) — 2 — ((E) -1-3-Hydroxyl 1—Propene-1—yl) 1-1-Methylcarbapene-1 2-Em—3 — Powerboxylate 0.30 g (0 75 mm o 1) in a dichloromethane solution of 6 ml of methane under argon flow. At C, 4 — (N, Ν'-dimethylamino) pyridine 0.10 g (0.82 mmo 1), diphenyluric acid chloride 0.165 ml (0.79 mmo 1) Was added and stirred at 13 CTC for 40 minutes.

The reaction solution was washed with cold water, a cold saturated aqueous solution of sodium hydrogen carbonate, cold 0.1 N hydrochloric acid, and cold water in this order. This is anhydrous magnesium sulfate , Filtered, and the solvent was distilled off under reduced pressure. Crude paranitrobenzil (1S, 5R, 6S) —2 -— [(E) —3-diphenylphosphoryloxy-1-propene-1 —Yl] — 6— ((1 R) 1 1 —Hydroxitytyl) 1 1 —Methylcarbapene 1 2 —Em— 3—Carboxylate oil 0.45 g was obtained.

 To this, 8 ml of dichloromethane was added, and a solution of 0.165 g (1.1 l Ommol) of sodium iodide in 2.5 ml of acetonitrile was added at room temperature, and N, N-dimethylformamide was added. 0.3 ml was added. After stirring for 15 minutes, 0.25 g (2.22 mmo 1) of 1,4-diazabicyclo [2,2,2] octane was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were separated by filtration, and the filtrate was distilled off under reduced pressure to give crude (IS, 5R, 6S) -12-[(E) -3-[(1,4-diazabicyclo (2,2,2) octane). ) 1 1 1 io] — 1 — propene 1 1 yl] — 6 — ((1 S) 1 1 — hydroxicetyl) — 1-methylcarbapene — 2 — emu 3 — p-nitrobenzyl carboxylate 0.85 g of the compound oil was obtained.

得られた粗 （ 1 S, 5 R, 6 S) — 2— [ (E) — 3— [ ( 1， 4—ジァザビシクロ [2, 2, 2] オクタン） 一 1 —ィォ] 一 1 一プロペン— 1 一ィル] 一 6— ( ( 1 R) — 1 —ヒ ドロキシェチ ル） — 1 ーメチルカルバペン一 2—ェム— 3—カルボン酸パラ二 トロベンジル. ヨウ化物の油 0. 85 gに pH 6. 1の 0. 35M リン酸緩衝液 6m l , テトラヒ ドロフラン 6m l , 亜鉛 0. 90 g ( 1 3. 7 mm o 1 ) を加えた。

The obtained crude (1 S, 5 R, 6 S) — 2— [(E) — 3— [(1,4-diazabicyclo [2, 2, 2] octane) 1 1 — io] 1 1 1 propene — 1 yl] 1 6— ((1 R) — 1 —hydroxyl) — 1-Methylcarbapene 1-2 — hem — 3-nitrobenzyl carboxylate. To 0.85 g of iodide oil 6 ml of 0.35 M phosphate buffer having a pH of 6.1, 6 ml of tetrahydrofuran, and 0.90 g (13.7 mmo 1) of zinc were added.

Adjust the pH to 6.1 with an aqueous solution of sodium dihydrogen phosphate. The mixture was stirred at room temperature for 20 minutes. This was filtered through celite with water and ethyl acetate, and the aqueous layer was further washed with ethyl acetate. This was applied to a resin column chromatography of Amberlite IR120B (manufactured by Organo) of 80 ml, and eluted with 100 ml of water. This was concentrated under reduced pressure to 10 ml, adsorbed on Diaion HP-20 (100 ml), eluted with water, then with 10% aqueous acetate-water, and the target fraction was collected and decompressed. Concentrate, freeze-dry, and (1 S, 5 R, 6 S) — 2-[(E) 13 (1,4-diazabicyclo [2, 2, 2] octane) 1 1 1] — 1 Propene-1 1-yl] — 6 — ((1 R) 1 1—Hyd mouth quichetyl) 1 1—Methylcarbapene 1—2-emu-3-carboxylate 77 mg was obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMS 0 - d _6, TMS internal standard)

 5: 1.06 (3 H, d, J = 6 H z),

 1.16 (3 H, d, J = 6 Η ζ), 3.00 (8 H, m),

3.25 (6 Η, m), 3.93 (4 Η, m), 5.64 (1 Η, dt, JJ = 16 Η Η, J ₂ = 7 Η ζ), 7.66 (1 Η, d, J = 16 Η ζ)

 Mass spectrometry value (FAB, Pos, / z): 36 2 (M + + 1) Example 4

① パラニトロべンジル （ 1 S, 5 R, 6 S) — 6— （ （ 1 R) — 1 ーヒ ドロキシェチル） 一 2— ( (E) 一 3—ヒ ドロキン一 1一 プロペン一 1 —ィル） — 1 ーメチルカルバペン一 2—ェムー 3— 力ルボキシラー ト 0. 3 0 g (0. 7 5 mm o 1 ) のジクロロメ タン 6m l溶液に， アルゴン気流下， — 4 0°Cにて， 4一 （N, N—ジメチルァミノ） ピリジン 0. 1 0 g (0. 8 2 mm o 1 ) , ジフエニルリ ン酸クロリ ド 0. 1 6 5 m l (0. 7 9 mm o 1 ) を加え， 一 2 0。Cにて， 1時間撹拌した。 これにジクロロメタン 4 0 m l を加え， 冷水， 冷飽和塩化ナ ト リウム水溶液の順に洗浄 した。 これを無水硫酸マグネシウムにて乾燥し， 濾過し， 溶媒を 減圧留去し， 粗パラニトロべンジル （ 1 R, 5 R, 6 S) - 2 - ( ( E) — 3—ジフエニルホスホリルォキシ— 1 一プロペン— 1 —ィル） 一 6— ( ( 1 R) — 1 —ヒ ドロキシェチル） — 1 ーメチ ルカルバペン— 2—ェム一 3—カルボキシラー 卜の油 0. 4 6 g を得た。

① Paranitrobenzyl (1 S, 5 R, 6 S) — 6 — ((1 R) — 1-hydroxyl) 1 2 — ((E) 1 — 3 — Hydroquinine 1 — 1 Propene 1 — 1) — 1-Methylcarbapene 1—2-Emu3—Carboxylate 0.30 g (0.75 mmo 1) in 6 ml of dichloromethane in a stream of argon at —40 ° C. One (N, Add 0.10 g (0.82 mmo1) of N-dimethylamino) pyridine and 0.165 ml (0.79 mmo1) of diphenylphosphoryl chloride, and add 20. The mixture was stirred at C for 1 hour. To this was added 40 ml of dichloromethane, and the mixture was washed with cold water and a cold saturated aqueous sodium chloride solution in that order. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. Crude paranitrobenzyl (1R, 5R, 6S) -2- (E) —3-diphenylphosphoryloxy 1 1-Propene—1—yl) 1—6 — ((1R) —1—Hydroxitytil) —1-Methylcarbapene—2-hem-13—Carboxylate Oil 0.46 g was obtained.

 To this was added 8 ml of dichloromethane, 0.18 g (2.22 mmol) of pyridine was added at room temperature, and a solution of 0.165 g (1.10 mmol) of sodium iodide in 2.0 ml of acetonitrile was added. In addition, 0.5 ml of N, N-dimethylformamide was added. This was stirred at room temperature for 3 hours. To this was added 40 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue (0.42 g) was washed with getyl ether. The residue was subjected to Diaion HP-20 (70 ml) and eluted with water and then with 20% acetonitrile-water. The desired fractions are collected, concentrated under reduced pressure, and lyophilized (1S, 5R, 6S) -6-((lR) -l-hydroxyxetyl) 1 1-methyl-2-[(E) -3 -(Pyridin-1-yl) — 1 —Propene — 1-yl] Power Lappaen — 2-Am — 3-Paraditrobenzyl carboxylate 'Iodide oil 70 g.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMS 0—d ₆ , TMS internal standard) 6: 1.13 (3 H, d, J = 7 Hz),

1.16 (3 H, d, J = 6Η ζ), 3.30 (1Η, m), 3.47 (1Η, m), 3.99 (1Η, m), 4 2 0 (1 H, dd, J ₂ = 9 Hz, J ₂ = 3 Hz) 5 41 (2H, AB, J = 14 Hz, Δ = 49.3 Hz) 5 4 5 (2 H, d , J = 6 H z),

6 4 9 (1 H, dt, J _d = 16 H z J. = 6 H z) 7 2 3 (1 H, d, J = 16 H z),

 7 7 3 (2 H, d J = 9 H z),

 8 1 9 (2 H, t J = 7 Hz),

 8 2 5 (2 H, d J = 9 H z),

 8 6 5 (1 H, t J = 8 H z),

 9 0 7 (2 H, d J = 5 H z)

 Mass spectrum (FAB, Pos, m / z): 464 (M +)

②

(IS, 5 R, 6 S) 1-6 ((1 R)-1-hydroxyl) 1-1-Methyl-2-[(E) 1-3-(Pyridine 1-1)-1-Propene-1 1-yl] caproluvene-1-heme-3-nitrobenzyl 3-carboxylate. Iodide oil 0.22 to 116.1 0.35M phosphate buffer 10m 1, tetrahydrofuran 10ml, zinc 0.44 g (6.73 mm o 1) was added. An aqueous solution of sodium dihydrogen phosphate was added to adjust the pH to 6.1, and the mixture was stirred at room temperature for 1 hour. Further, 0.10 g (1.53 mm 01) of zinc was added, and the mixture was stirred at room temperature for 30 minutes. This was filtered through celite with water and ethyl acetate, and the aqueous layer was further washed with ethyl acetate. This was subjected to resin column chromatography on Amberlite IR120B (manufactured by Organo) with 60 ml, and eluted with 200 ml of water.

This was concentrated under reduced pressure to 10 ml, and Diaion HP-20 (50 ml) And eluted with water, then with 10% methanol-water. The desired fractions are collected, concentrated under reduced pressure, lyophilized, and crude (1S, 5R, 6S) -6-((1R) -11-hydroxyethyl) -1-methyl-2--2-[(E) 1 3— (pyridin 1 1—Io) —1 1 Propene—1—Il] Cal Bapen 1—2—Em 1—3-Rubon xylate 72 2 mg was obtained. 65 mg of this was used for high performance liquid chromatography (HP LC) (support: YMC packed column ODS, 20 mm x 250 mm) Solvent:

Preparative purification was performed at 5% acetonitrile flow rate: 9.9 ml / min. The desired fractions are collected, concentrated under reduced pressure, lyophilized, and (IS, 5R,

6 S) — 6— ((1 R) — 1-hydroxyl) 1 1 — Methyl — 2— [(E) — 3— (Pyridine 1 1 — Io) 1 1 1 Propene 1 1-yl] There were obtained 28 mg of l-lubapen-2-emomu 3-carboxylate.

 The physicochemical properties of this compound were consistent with those of Example 1.

Example 5

① p-Nitrobenzyl (IS, 5R, 6S) — 6— (1R) -1-hydroxyl — 2 — ((E) —3-hydroxy-1—pronil) 1 N, N-Dimethylaminopyridine (167 mg) was added to 75 ml of a dichloromethane solution containing 500 mg of 2-l-emu-3-carboxylate in dichloromethane at -40 ° C under argon atmosphere. While maintaining the temperature, a solution of 500 mg of diphenylphosphoryl chloride in 2 ml of dichloromethane was added dropwise. After stirring at the same temperature for 30 minutes, 250 ml of ethyl acetate was added, washed with a phosphate buffer and a saturated saline solution at pH 7.0, and dried over anhydrous magnesium sulfate. Distill solvent A 5 ml acetonitrile solution of the residue obtained after the addition was added at room temperature under an argon atmosphere to 1.16 g of 4-methylpyridine to which 196 mg of sodium iodide had been added. After stirring at the same temperature for 30 minutes, the solvent was distilled off, and then 50 ml of toluene was added and distilled off. The residue was subjected to silanized silica gel column chromatography.

The fraction eluted with% acetonitrile-water was concentrated to give 144 mg of a pale yellow solid.

(2) To 100 mg of the solid obtained in the previous section, 2 ml of tetrahydrofuran and 6 ml of pH 6.1 phosphate buffer were added, and 200 ml of zinc dust was added with stirring at room temperature. After stirring at the same temperature for 1 hour, the zinc was filtered off using celite. The solution treated with Amberlite 1 RA-120 B resin substituted with Na ion was concentrated under reduced pressure, and subjected to HP-20 resin column chromatography. The fraction eluted with 10% acetonitrile water Is freeze-dried to obtain amorphous (1S, 5R, 6S) -6-((1R) — 1-hydroxyxyl) — 1-methyl— 2-— ((E) — 3-— (4-methyl-1 I-Pyridinio) 1 1-Propenyl] L-lubapen 1 2-Emu 3-carboxylate 58 mg was obtained.

Physicochemical properties

 Mass spec (mZz): 343 (M + 1)

Infrared absorption spectrum max (KB r) cm " ¹ : 3480 (OH),

 1 75 2 (C = 0), 1 6 1 0 (C = 0)

Nuclear magnetic resonance spectrum (DMS 0 - d _6, TMS internal standard)

 δ: 0.99 (3 H, d, J = 7 H z),

 1.15 (3 H, d, J = 6 H z),

 2.5 1 (3 H, s), 3.00 (1 H, d, J = 7H z),

3.10 (1 H, dt, J, = 14 Hz, J ₂ = 7 Hz), 3.86 6 3.93 (2 H, m),

 5.2 4 (2 H, d, J = 7 H z),

5. 82— 5. 89 (1 H, m), 7.65 (1 H, d, J = 1 6.0 Hz)

 7.98 (2 H, d, J = 6 H z),

 8.89 (1H, d, J = 6Hz)

 The compound of Example 6 was obtained in the same manner as in Example 5.

Example 6

( I S, 5 R, 6 S) — 6— ( ( 1 R) — 1—ヒ ドロキシェチル）

(IS, 5 R, 6 S) — 6— ((1 R) — 1—Hydroxyshetil)

— 2— [(E) — 3— (4-Methoxy-1- 1-pyricinio) 1 1-Propenyl] 1-1-Methylcarbapene 2- 2-Em-3-3-carboxylate

Physicochemical properties

 Mass spec (m / z): 359 (M + 1)

Infrared absorption spectrum max (KB r) cm- ¹ : 3432 (OH),

 1 7 5 0 (C = 0), 1 6 46 (C = 0)

Nuclear magnetic resonance spectrum (DMS 0—d ₆ , TMS internal standard) δ: 0.995 (3Η, d, J = 6Η ζ),

 1 1 5 (3 Η, d, J = 7 Η ζ),

 3 0 1 (1 Η, d, J = 6 Η ζ),

3 1 1 (1Η, dt, J, = 1 1Η, J ₂ = 6Η), 387-3.93 (2Η, m), 4.09 (3Η, s), 5 1 6 (2 Η, d, J = 6 Η ζ),

 55.86 (1 Η, d t, J, = 13.2 Hz,

 J 2 = 5.2 Η ζ),

 7.62-7.65 (3 Η, m),

8. 8 6 (2 Η, d, J = 6 Η ζ) Example 7

① p — Nitrobenzil (1 S, 5 R, 6 S) — 6 — ((1 R) — 1 — hydroxyxetyl) 1 2 — ((E) 1 3 — hydroxy 1 1-propionyl) — Dissolve 0.50 g (1.24 mmol) of 1-ketolubapen-12-hem-3-carboxylate in 15 ml of dichloromethane and place the mixture in an argon atmosphere. At C, add 0.23 g (1.86 mmo 1) of 4-dimethylaminopyridine and 0.31 'ml (1.49 mm 01) of phenylphosphorinol chloride in order. The mixture was stirred at the same temperature for 30 minutes. Then, the reaction solution was heated to 15 ° C, and 0.46 g (3.72 mmo 1) of 4-dimethylaminopyridine, 28 g (l. 86 mmo 1) of sodium iodide were obtained. ) In 1.38 ml of acetonitrile was sequentially added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was washed five times with getyl ether. The residue obtained is dried in vacuo, dissolved in 10% aqueous acetonitrile, applied to an HP-20 column chromatograph, and the fraction eluted with 30% aqueous acetonitrile is lyophilized. , P—Nitrobenzyl (1S, 5R, 6S) — 6 — ((1R) — 1 — Hydroxyshetyl) 1 2 — ((E) — 3 — (4 — Dimethylamino 1 — Lisinone 1 —Provenyl) 1 1 Lubapen 1 2 —Emu 3 —Carboxylate salt 0.21 g was obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (DM S 0—d ₆ , TMS internal standard)

 6: 1.1 1 (3 H, d, J = 7.3 H z),

 1.16 (3 H, d, J = 6.3 H z),

3.18 (6H, s), 3.98 (1H, m), 4.19 (1 H, dd, J, = 9.3 Hz, J ₂ = 1 Hz), 4.98 (2 H, d, J = 5.9 Hz),

 5.33 (1H, d, J = 14.2Hz),

 5.4.6 (1 H, d, J = 1 3.7 H z),

 6.38 (1H, m), 7.07 (2H, m),

7.5 9 (1 H, m),

 7.70 (2H, d, J = 8, 8Hz),

 8.2 5 (4 H, m)

 ② p-Nitrobenzyl (IS, 5R, 6S) -6-((1R) —1-hydroxyl) obtained in 1) —2 — ((E) 1-3— (4-dimethylamino 1—) Pyridinone 1 -probenyl) 1 1 lubapen 2 -am-3 -carboxylate chloride 0.20 g of tetrahydrofuran 6 ml and phosphate buffer (pH = 6.1) ) After dissolving in 10 ml, 0.4 g of zinc dust was added while stirring at room temperature, and the pH of the reaction mixture was maintained at 6.1 by adding an aqueous solution of sodium dihydrogen phosphate. The reaction solution was filtered, the filtrate was washed with ethyl acetate, and the resulting aqueous layer was replaced with sodium ion. 40 ml) and eluted with 200 ml of water.The resulting aqueous solution was concentrated under reduced pressure to about 30 ml, and the solution was subjected to HP-20 The fraction eluted with 10% acetonitrile-water is freeze-dried, and (1S, 5R, 6S) —6 — ((1R) —1—hydroxyxethyl 1) 2-((E)-3-(4-dimethylamino 1-1 -pyridinio 1-1-propionyl)-1-force lubapen-2-emu 3-1-carboxylate 51 mg was obtained.

Physicochemical properties

 Mass spec (mZ z): 3 7 2 (M + 1)

Infrared absorption spectrum (L max (KB r) cm— ¹ ): 1 752,

1 654 Nuclear magnetic resonance spectrum (DMS 0-d ₆ , TMS internal standard) δ 0.98 (3 Η, d, J = 67 Hz),

 1. 1 4 (3 Η, d, J 6 • 1 Hz),

 2.98 (1 Η, b r ― d J = 4.9 Hz),

3.18 (6Η, s), 3 • 8 7 (1H, m),

3.89 (1 Η, m),

 4.87 (2 Η, d, J 6 1 H z),

 5. 7 6 (1Η, m)

 7.05 (2 Η, d, J 7 3 H z),

 7.49 (1 Η, b r d J = 1 5.9 Hz)

8.26 (2 Η, d, J79Hz)

Formulation example

 —In the general formula (I), a compound in which the 2-position is (E) 3— (pyridin-11-)-11-propene-11-yl and the 3-position is carboxy anion is used.

(Tablets)

 Compound of the present invention 250 mg Lactose 52 mg Microcrystalline cellulose 35 mg Hydroxypropyl cellulose lOmg Magnesium stearate 3 mg

1 tablet: 350 mg The above ingredients are mixed and compressed into tablets by a conventional method, and then, if necessary, sugar-coated or film-coated by a conventional method to obtain sugar-coated or film-coated tablets. Agent)

Compound of the present invention 250 _mg corn starch 33 mg magnesium stearate 2 mg

1 capsule: 285 mg Mix the above ingredients and fill it into a normal hard gelatin capsule to make a capsule.

 (Dry syrup)

 Compound of the present invention 200 mg Sucrose 790 mg Hydroxypropyl cellulose 5 mg Flavor 5 mg Total: l OOOmg The above ingredients are mixed to form a dry syrup.

(freeze drying)

 An appropriate amount of water for injection is added to 10 g of the compound of the present invention to make a volume of 100 ml, and the solution is filtered through a membrane filter.

 Fill a vial with 2.5 ml of the aqueous solution (containing 250 mg of the compound of the present invention) and freeze-dry. Before use, add about 2 to 4 ml of water for injection to make an injection.

(Powder filling)

 One vial is filled with 250 mg of the sterilized compound of the present invention as powder. Before use, add about 2 to 4 ml of water for injection to make an injection.

Claims

o Scope of billing 1. A compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable hydrate thereof.

(The groups in the formula have the following meanings.  ): Substituted or unsubstituted pyridinyl group,, 5 or

R ¹ , R ² : same or different lower alkyl group  n: an integer from 3 to 7 R: hydrogen atom, anion charge, ester residue ⁰ wavy line: cis or trans) 2. Formula 1! ^) Represents an unsubstituted or lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkoxy group, lower alkylthio group, halogen atom, hydroxyl group, amino group, carboxy group, carbamoyl group, mono- Or a di-lower alkylamino group, an amino5 lower alkyl group, a pyridinum group substituted with a lower alkylene group formed by forming an adjacent lower alkyl group together, or a group represented by the formula:

A compound according to claim 1 3. The group represented by the formula (1) is unsubstituted or replaced by a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, or a lower alkylene group formed integrally with an adjacent lower alkyl group. Or a group represented by the formula

 The compound according to claim 1  4. The compound according to claim 1, wherein the group represented by formula (I) is an unsubstituted pyridinium group.  5. (IS, 5R, 6S) — 6— ((1 R) — 1—hydroxy) — 1 — Methylone 2 — [(E) — 3— (Pyridine 1) 1 1— 2. The compound according to claim 1, which is a propene-2-yl-3-ene-3-carboxylate.  6. A compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable hydrate thereof.

(The groups in the formula have the following meanings.  Resin group, ㊉ "Λ㊉, Group

R ¹ , R ² : same or different lower alkyl group  n: an integer from 3 to 7 R: hydrogen atom, anion charge, ester residue Wavy line: cis body or transformer body, etc.)  In the method of manufacturing  a) Compound represented by general formula (Π)

(Wherein, R ³ represents a carboxyl-protecting group; the same shall apply hereinafter) to the compound represented by the formula (III), wherein (i) a phosphate esterifying agent and (ii) a halogen donor are reacted. After the compound shown,

(Wherein X represents a halogen atom; the same applies hereinafter).  Reacting a compound represented by the general formula (V) (wherein

Represents a substituted or unsubstituted pyridinum group R ¹ . )

Whether the protecting group is removed by a conventional method, esterification by a conventional method, or subject to salt formation reaction by a conventional method b) For the compound represented by the general formula (VI)

(Wherein, Y represents a fuunyl group, a lower alkyl group or a lower alkoxy group; the same applies hereinafter).  After the Wittig reaction, a method comprising removing the protecting group if necessary, esterifying by a conventional method, or subjecting to a salt formation reaction by a conventional method.  7. An antibacterial agent comprising, as an active ingredient, the compound according to claim 1, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable hydrate thereof. .  8. The compound according to claim 1, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable hydrate thereof and a pharmaceutically acceptable salt thereof. Pharmaceutical composition comprising carrier