WO1993019072A1 - Carbapenem derivative - Google Patents

Abstract

A carbapenem derivative represented by general formula (I) or a salt thereof. It has an excellent antibacterial activity against a wide variety of gram-positive and negative bacteria, thus being useful as an antibacterial agent.

Description

 Technical Documents Lumbane Numerator Technical Field

 TECHNICAL FIELD The present invention relates to a sorbaenem derivative, and more specifically, a 1 S-methylcarbanemine derivative having an S-configuration methyl group introduced at the 1-position of the carbavanene skeleton, and a method for producing the compound An antimicrobial agent containing the compound as an active ingredient. Background art

 Hitherto, a large number of lubavenem compounds having a basic skeleton of carber-2-enem-3-carboxylic acid have been proposed for various antibacterial effects.

 For example, the earliest potent varpenem antibiotics include chenamycin, which is obtained as a fermentation product of Streptomyces cattleya. 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 [Autimi crob. Agents Chemother., 2_ 2, 62 (1982); ibid., 23, 300, (1983)].

Next, imidenem (J. Med. Chem. 2 ^ 1435, (1979)), in which the amino group of the side chain 2 of this chenamycin is formimidylated, has emerged as a practical antibacterial agent. Although the compound has a certain level of excellent antibacterial activity and chemical stability, it is susceptible to degradation inactivation by renal aldehyde oral peptidase (DHP) in vivo. CAutimicrob. Agents Chemother. 12 (SupplD), 1, (1983)], which is a combination formulation of iminenum Z sylastin (IPMZC S) in combination with cilastatin, a type of inhibitor.

 On the other hand, various 1-methyl carbanem compounds having a methyl group introduced at the 1-position of the carbane skeleton have been proposed, including, for example, a substituted thio group at the 2-position of the carbane skeleton. Under development such as Melodynem (SM-7333, Japanese Patent Publication No. 63-555514) and LJC106627 (Japanese Patent Publication No. Hei 1-27779) The compound is known o

 There is also known a compound which discloses a compound having a heterocyclic alkylthio group at the 2-position of a 1-methylcarbapanem skeleton. For example, JP-A-59-89683, JP-A-61-83183, and the like have disclosed in a wide range of disclosures that a 2-position heterocyclic alkylthio group is Although there is a general description to include compounds having a bicyclic heteroaryl group, no specific disclosure is made. Disclosure of the invention

The present invention is structurally different from these compounds, and a nitrogen atom represented by the formula at the 2-position of the 1-methylcarbadium skeleton.

Introducing a Te-ring group into a bicyclic ring containing a molecule, it has superior antibacterial activity compared to known carbanem derivatives, and has clinical utility with excellent DHP stability and pharmacokinetics It provides a compound with a high valency.

That is, the present invention provides a compound represented by the following general formula (I): Derivatives thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, pharmaceutically acceptable hydrates thereof, methods for producing the compounds, and pharmaceutical compositions containing the compounds as active ingredients About.

(The groups in the formula have the following meanings,

: Contains 1 to 3 nitrogen atoms and oxygen atoms

Or a substituted or unsubstituted bicyclic heterocyclic group X, Y condensed with a saturated or unsaturated 5- or 6-membered heterocyclic ring (A 璟) which may contain one sulfur atom: Nitrogen atom or group represented by formula CH = Broken line: One of the broken lines represents a single bond, and the other represents a double bond.

 R: hydrogen atom, negative charge or ester residue The same applies hereinafter.

 FIG. 1 is a graph comparing the distribution of the compound of the present invention and a compound on the market or under development in tissues of a mouse.

 In the figure, the vertical axis represents concentration (s / 1), and the horizontal axis represents time (min).

 Compound of the present invention;-(Compound of Example 4)

1 PM / CS;-□- LJC 10627; — ▽ 一 (Compound described in Japanese Patent Application Laid-Open No. 1-257779)

 SM-7338 ； — △ 一 (CHEMOTHERAPY, 40, S-1, 1 2 3 (Merobenem)

(Reference values of (1992), under iv administration) The present invention will be described in more detail as follows. Examples of the bicyclic heterocyclic group represented by the formula

Examples include the following heterocyclic groups <

(Wherein, R ² is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an acyl lower alkyl group, a carbamoyl lower alkyl group, a carbamoyl group, or a lower alkyl carbamoyl group; R ³ is absent or One or more of the same or different lower alkyl groups, lower alkenyl groups, lower alkynyl groups, hydroxyl lower alkyl groups, rubamoyl lower alkyl groups, halogen atoms, nitro groups, cyano groups, lower alkoxy groups, A substituent selected from a rubamoyl group, a lower alkyl group, a rubamoyl group, and a trihalogenomethyl group.

That is, in the bicyclic heterocyclic group, R ³ is absent or a group selected from the above-listed groups, and is the same or different and has 1 to plural, preferably 1 to 3 substituents. Means a group. Where R ³ is Any ring atom of the bicyclic heterocyclic group may be substituted.

 Unless otherwise specified in the definition of the general formula in this specification, the term “lower” means a straight chain or a functional 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 ibutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amido) ) 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, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3- Dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethylethyl group 1 A monomethylpropyl group and a 1-ethyl-2-methylpropyl group are preferred. Of these groups, a methyl group, an ethyl group, a propyl group, and an isopropyl group are preferable, and a methyl group and an ethyl group are more preferable. It is.

The “lower alkenyl group” is a linear 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, 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, 1-1 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 1-methyl-2-butenyl group, 2-methyl-3-butenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethylaryl group , 1,2-Dimethyl-1 monopropenyl group, 1,2-Dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-hexenyl group , 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,1,1-dimethyl-1-butenyl, 1,1, -dimethyl-2-butenyl, 1, 1 1-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 1-methyl-1 1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-pentenyl , 4-Methyl-1 pentenyl group, 4-methyl 2-pentenyl group, 4-methyl-3 - pentenyl group and the like.

 The “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, 3-butynyl group, 1-methyl-12-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 group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4 Examples include a hexyl group and a 5-hexynyl group.

Examples of the “alkyl lower alkyl group” include, for example, an acetyl group, a propionyl group, a benzoyl group, etc., which are substituted at any position of the lower alkyl group, and include, for example, an acetylmethyl group, an acetylethyl group, an acetylpropyl Group, propionylpropyl group, benzoylmethyl And a propionylethyl group, and more preferably an acetylmethyl group and an acetylethyl group.

 The “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy, and 2-methylbutoxy. , 1,2-dimethylpropoxy, 11-ethylpropoxy, hexyloxy, and the like. Of these groups, methoxy, ethoxy, propoxy, and isopropoxy groups are preferred. Preferred are a methoxy group and an ethoxy group.

 Examples of the “lower alkyl rubamoyl group” include a methylcarbamoyl group, an ethylcarbamoyl group, a propyl rubamoyl group, a 1-methylpropyl rubamoyl group, and an isopropylpropyl rubamoyl group.

 Further, the “lowermoyl lower alkyl group” is a lower alkyl group in which an arbitrary position of the lower alkyl group is substituted with a lower-level alkyl group, for example, a lower-level alkyl group, a lower-level alkyl group, a lower-level alkyl group or the like.

 Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The “ester residue” is an ester residue that is metabolized and hydrolyzed in a living body, and is, for example, a lower alkanoyloxy lower alkyl group, a lower alkenoyl lower alkyl group, or a cycloalkyl carboxy lower alkyl group. , Lower alkenyloxy lower alkyl group, lower alkoxy lower alkanoyloxy lower alkenyl group, lower alkoxy lower alkenyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alk Coxy lower alkoxy lower alkyl group, benzoyl lower alkyl group, 2-oxotetrahydrofuran-5-yl group, 2-oxo-1-5-alkyl-1,3-dioxolen-1-4-alkyl

 (, =)

Methyl group 0, tetrahydrofuranylka

 0

Common ester residues such as a luponyloxymethyl group and a 3-phthalidyl group are exemplified.

 In the above, the lower alkylene group has 1 to 6 carbon atoms, particularly 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.

The typical compounds of the present invention are shown below.

Compound number

These compounds can be synthesized by a method similar to the synthetic route described in the following production methods and Examples.

 The compound of the present invention can form an inner salt with the 3-position carboxy anion depending on the type of the heterocyclic ring as the 2-position substituent. Or a salt with another acid or base depending on the type of the heterocyclic ring which is the substituent at the 2-position, or when the ester residue is replaced. 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 Acid addition salts with organic acids such as acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methsulfonic acid, ethanesulfonic acid, and glumic acid can be mentioned.

 Examples of the salt with a base 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 ordinine. Salt and ammonium salt.

 In addition, the compound of the present invention has a double bond depending on the type of asymmetric carbon atom or substituent, and thus has a plurality of isomers. The present invention includes separated or mixtures of these isomers. Particularly preferred isomers in the kerbaenem ring of the present invention are 1 R, 5 S and 6 S. Furthermore, the compound of the present invention also includes pharmaceutically acceptable solvates or hydrates thereof.

Further, depending on the type of the heterocyclic group which is a substituent at the 2-position of the compound of the present invention, there are tautomers shown below, and any of the isomers is included in the compound of the present invention. It is.

(Manufacturing method)

 Hereinafter, a typical production method of the compound of the present invention will be described.

The compound of the present invention can be synthesized by a conventionally known method other than the following production method.

(First production method)

^

1) removal of protecting groups if desired

(Step 111) 2) Esterification or salt formation as desired

Wherein R ⁴ is a carboxyl-protecting group, and R ⁵ is

 0

 ί

-ΟΡΟ means a group represented by (OPh) ₂ or a group represented by 1 SPh. Hereinafter the same)

 The compound (I) of the present invention can be prepared by reacting the compound represented by the general formula (VI) with diphenylphosphoryl chloride (Step I-1) or oxidizing the compound (VII) using an appropriate oxidizing agent. Then, after the compound (II) is obtained (Step I-12), a substitution reaction with the thiol compound (III) is carried out (Step II), and if necessary, the protecting group is removed. Alternatively, (Step III) can be obtained by subjecting it to a salt formation reaction.

 (Phase I—1 step)

 This step is a step of reacting compound (VI) with diphenylphosphoryl chloride.

 Solvents used for this reaction include ketones such as acetone and methylethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, and a mixed solvent thereof. Good.

In this reaction, a base can be added to promote the reaction. Examples of the base in this case include organic bases such as triethylamine, diisopropylethylamine, DBU, N-methylmorpholine, and quinuclidine; inorganic bases such as hydroxylated lime, sodium hydroxide, and carbonated lime; sodium methoxide; The reaction temperature of _c, which is a metal alcoholate or the like, is set under cooling to room temperature, preferably under cooling. (Step I-2)

 This step is a step of oxidizing compound (VH) to obtain compound (II).

 Oxidation of the compound (νπ) is carried out by halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, tetrabasic carbon, etc., ketones such as acetone and methyl ethyl ketone, acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran The reaction is performed with perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, selenium dioxide, ozone or the like in a solvent such as water, phosphate buffer or the like.

 The reaction temperature is from cooling to heating.

 Here, examples of the carboxyl-protecting group include a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a nitrobenzyl group, a lower alkoxybenzhydryl group and the like.

 Step π

 Next, the obtained compound (π) undergoes a substitution reaction with the compound represented by the general formula (πί).

 The compound (II) may be isolated once, or may be reacted with the compound (III) without isolation after the reaction in the first step.

 Here, as the thiol compound of the compound (III), a monomer represented by the general formula (II) may be reacted, and two molecules of the compound represented by the general formula (III) may be an S—S disulfite. The compound bonded by a sulfide bond may be reacted with a compound that cleaves a disulfide bond, such as trimethylmer.

As the solvent in this step, the solvent described in Step I-11 is preferably used. In this step, the reaction may be performed in the presence of a base, and in this case, the base described in Step I-1 may be used. Examples of the alkali metal represented by M include potassium and sodium.

 Step III

This step is for removing the protecting group when compound (VIII) has a protecting group. That is, when a protecting group of R ^{4 has} a p-nitrobenzyl group, a benzyl group, a benzhydryl group, or the like, the removal of these protecting groups can be achieved by 1) reduction of compound (VIII) using zinc or iron, 2) Liquid reduction or 3) catalytic reduction using palladium monocarbon or palladium hydroxide-carbon.

In the reduction method of 1) above, compound (VIII) is added to a warming solution (an inert solvent is added if necessary), and then an amount of zinc corresponding to the reaction or an excess amount is added, and the mixture is stirred under cooling or heating. Can be done by _c

The reduction method 2) can be carried out by adding compound (VIII) to liquid ammonia, then adding metallic sodium and stirring. The reduction method 3) can be performed under cooling or heating in the presence of a catalyst such as palladium-carbon or palladium hydroxide-carbon. The reaction time of the above reaction varies as appropriate depending on the reaction conditions such as the raw materials and the reaction reagents, but it can be from tens to tens of hours, preferably from tens of minutes to several hours.

2 manufacturing method

R ² one Z (V)

Is

(In the formula, Z represents a halogen atom. The same applies hereinafter.)

In this production method, a compound represented by the general formula (IV) is reacted with a halogen compound represented by the general formula (V) to obtain a compound represented by the general formula (IX). Or, as desired This is a method in which a compound represented by the general formula (Ia) is obtained by carrying out a sulfurization reaction or a salt formation reaction.

 Here, examples of the halogen atom represented by X include a chlorine atom, a bromine atom and an iodine atom.

 The reaction proceeds without solvent, but is not involved in the reaction, and is preferably performed in an organic solvent. Suitable organic solvents that do not participate in the reaction include benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloromethane, methanol and ethanol.

 Compound (IV) is preferably used in an equimolar amount or a slight excess with respect to compound (V).

 During the reaction, secondary or tertiary bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, dimethylamine, and bases such as carbonated lime, sodium carbonate, and sodium hydrogen carbonate are added. Alternatively, it may be advantageous to increase the amount of compound (V) to promote the reaction smoothly, and this method can be employed if necessary.

 The reaction temperature and reaction time depend on the starting compounds ([V) and

It is appropriately set in consideration of reaction conditions such as the type of (V) and the type of solvent. This reaction is usually performed at room temperature, under heating, or under heating to reflux.

Isolation and purification of the target substance from the reaction solution are performed by a conventional method by appropriately combining extraction with an organic solvent, chromatography, crystallization, and the like. When the compound (I) has an ester residue, the compound (I) is reacted with an esterifying agent such as an alcohol or a halide thereof, a sulfonate, a sulfate, a diazo compound, or the like, or the compound (I) is converted into a salt. If it does, use a conventional salt formation reaction. Can be obtained. Industrial applicability

 The compound of the present invention, its pharmaceutically acceptable salt, its pharmaceutically acceptable solvate, and its pharmaceutically acceptable hydrate are excellent against a wide range of Gram-positive and Gram-negative bacteria. It has excellent antibacterial activity, excellent plasma concentration, distribution in each tissue and stability in each tissue, high urinary excretion rate, and a good pharmacokinetic profile. Therefore, it exhibits an anti-infection activity against various bacteria reflecting the strong antibacterial activity of in vitro, and is useful as an antibacterial agent for the treatment and prevention of infectious diseases targeting a wide range of bacteria. Compound.

 The compounds of the present invention also include compounds that exhibit a good infection protective action against methicillin-resistant Staphylococcus aureus.

 Further, the compound of the present invention is stable against DHP-1, and a stable effect is expected with a single agent without being combined with a DHP-1 inhibitor such as cilastatin.

 The usefulness of the compound of the present invention has been confirmed by the following experiments. In the following confirmation of the pharmacological effects, unless stated otherwise, the 2-position of the compound of the present invention is (1-methylimidazo [1,2-a] pyridine-12-io) methylthio group, This was performed for the carboxy anion at the 3-position.

 (1) Antibacterial activity (inv itro)

The MIC of the compound of the present invention is shown below. Control compound, IP MZC S: Imidenemulastatin • Compound A:

 (Compound disclosed in Example 25 of JP-A-59-89683) • Compound B:

(Compound disclosed in Example 15 of JP-A-63-63680) The compound of the present invention has good antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria. In particular, gram-negative bacteria showed better antibacterial activity than IPM / CS.

(Control) (Control) (Control)

t

CD

* Values described in JP-A-63-63680

(2) Infection protection

 (1) Therapeutic effect on systemic mouse infections caused by Staphylococcus aureus Smith, Escherichia coli NY17, Pseudomonas aeruginosa CAY9246 'Pseudo awake as aeruginosa ATCC 8689, Klebsiella pneumoniae CAY12825

Method: 37 Cells cultured overnight at 37 ° C were suspended in 5% mucin, and 0.5 ml was inoculated intraperitoneally into mice (ICR or ddY, male, 5 weeks old) Caused. Medicine solution 0.2 m 1 to 2 hours post-infection by subcutaneous administration, after mice were observed for survival of 7 days, was calculated ED ₅₀ by Probit method or Weil method.

 Each group consisted of 10 mice, and dissolved in physiological saline using I PMZCS as a comparative drug.

Results: The compounds of the invention against E. coli NY 1 7, showed about fold ED ₅₀ values of I PMZCS. Other bacteria showed almost the same value as IPM / CS.

 ② Therapeutic effect of Escherichia coli CAY19216 on urinary tract infection in mice

Method: Cells cultured overnight at 37 ° C are suspended in physiological saline, and 501 is transurethrally inoculated into mice (ICR, female, 6 weeks old), which have been dehydrated overnight. That caused the infection. At 24 hours after infection, 0.2 ml of the drug solution was subcutaneously administered, and the number of endophytic bacteria in the kidney 30 hours after infection was measured.

 Each group consisted of 4 mice, which were dissolved in saline using I PMZCS as a comparative drug.

Results: The dose of the compound of the present invention was reduced in the number of endophytic bacteria in the kidney, and the therapeutic effect was better than that of IPMZCS. (3) Stability in the organization

 1Z15M phosphate buffer (pH 7) 1.5 times the renal wet weight of ICR male mice and SD male rats was added, and a 40% renal homogenate was prepared using a homogenizer. To 1 volume of 40% kidney homogenate, add drug solution (51 volumes) and incubate for 2 hours at 37. The reaction was performed by adding an equal volume of 100 / gZml cilastatin in 1/15 M phosphate buffer (pH7). This was centrifuged at 3000 rpm for 15 minutes, and the drug concentration in the supernatant was measured by the bioassay method.

 Similarly, a lung homogenate was prepared, and the stability of the drug was measured.

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. The calibration curve was prepared using control plasma or 115 M phosphate buffer (pH 7).

 The compound of the present invention is sufficiently stable even in the absence of cilastatin, and is 2.1 times in the lung and 2.7 times in the kidney compared to IPMZCS.

 (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 a physiological saline solution for injection (2 mgZml), and 1 OmgZkg was administered once intravenously. At predetermined times after drug administration, urine was collected and provided for bioassay.

As a result, about 66% of the dose of the compound of the present invention was excreted in urine by 24 hours after administration. This was about 6 times better than I PMZCS. (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 (1 mgZm 1), and a single dose of 1 Omg / kg was subcutaneously administered. 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 g / m1 cilastatin-containing 1/15 M phosphate buffer (pH7), homogenize with a homogenizer, and centrifuge at 3000 rpm for 15 minutes. The concentration was measured by the bioassay method.

As shown in FIG. 1, the compound of the present invention showed a favorable transition in plasma concentration and a high AUC value even when compared with a compound on the market or under development. In addition, the compound of the present invention showed good distribution in heart, lung, liver, kidney, and spleen tissues, and was 1.3 to 2.1 times at C _max and 1.7 to 2.7 times at AUC, halved compared to I PMZCS. In the period (Tl / 2), the value was superior by 1.6 to 2.4 times.

 (6) Central toxicity test

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

 The drug was dissolved in physiological saline for injection and administered locally in the left ventricle of the mouse at 200 g Zanimal. The administration volume was 201 in each case, and the control group received only saline for injection. The lateral ventricle was injected under anesthesia under vertical anesthesia at 3 mm behind the posterior margin of the left eye and vertically into the skull position 0.5 mm outside the longitudinal midline. Thereafter, behavioral observation was performed for 30 minutes to determine the presence or absence of convulsions and death.

The compound of the present invention showed no effect in all cases when 200 g of Znima1 was administered. — Formulations containing one or more of the compounds represented by the formula (I) as an active ingredient can be prepared using carriers, excipients, and other additives that are usually used in formulation. Is done. Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, arabic gum, olive oil, sesame oil, cocoa butter (1) Ethylene glycol and others commonly used.

 Administration can be in the form of tablets, pills, capsules, granules, powders, liquids, etc., or intravenous injections, intravenous injections, intramuscular injections, etc., non-oral administrations such as suppositories, transdermals, etc. You may. The dosage is appropriately determined depending on the individual case in consideration of the symptoms, age of the administration subject, sex, and the like, but is generally about 250 to 150 Omg per day.

 The compound of the present invention and the method for producing the same 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

(1) 2.0 g (21.2 mmo1) of 2-aminoviridine and 5 Om1 of acetate nitrile and 2.70 g (21.2 mmo1) of 1,3-dichloroacetone ) And stirred at room temperature overnight. The precipitated salt was collected by filtration and dried to obtain 2.96 g of crude 2-chloromethyl-13-hydroimidazo [1,2-a] pyridinium hydrochloride.

Physicochemical properties Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 (5: 3.9 1 (2H, s), 4.8 1 (2H, s),

 7.08 (2H, m), 8.0 1 (1H, m),

 8.2 1 (1 H, m)

Mass spectrometry (EI, m / z): 166 (M ⁺ )

 (2) To 2.96 g (10.8 mmo 1) of the obtained crude 2-chloromethyl-3-hydroimidazo [1,2-a) pyridinium hydrochloride, 100 ml of dimethylformamide was added, and 2.00 g of thioacetic acid potassium salt was added. Was added and stirred at room temperature for 2 hours. The precipitated insolubles were collected by filtration and dried to obtain crude 2-acetylthiomethylimidazo [1,2-a] pyridine 3.14.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMSO- d _e, TMS internal standard)

 5: 2.39 (3H, s), 4.56 (2H, s),

 7.08 (2H, m), 7.68 (1 1, m),

 8.02 (1Η, m), 8.30 (1Η, m)

Mass spec (EI, m / z): 206 (M ⁺ )

 (3) Dissolve 3.14 g of the obtained crude 2-acetylthiomethylimidazo [1,2-a] pyridine in 150 ml of methanol, and cool under ice-cooling a 28% methanol solution of sodium methylate 6.3 m 1 was added dropwise. The mixture was stirred for 1 hour as it was, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, eluted with chloroform (20; 1, V / v), and 0-89 g of 2-mercaptomethylimidazo [1,2-a] pyridine was added. Obtained.

Physicochemical properties

'Nuclear magnetic resonance spectrum (DMSO- d _e, TMS internal standard) d: 4.02 (2H, s), 6.86 (1H, s),

 7.22 (1 H, m), 7.49 (1 H, d, J = 9.1 Hz) 7.86 (1 H, s), 8.50 (1 H, m)

Mass spectrometry value (EI, m / z): 1 64 (M ⁺ )

Reference example 2

HS

(1) 250 ml of acetonitrile was added to 20.0 g (21 Ommo 1) of (i) 2 -aminopyridine, 27.0 g (21 Ommo 1) of 1,3-dichloroacetone was added, and the mixture was stirred overnight at room temperature. The precipitated salt was collected by filtration and dried to obtain 4.70 g of crude 2-chloromethyl-3-hydroimidazo [1,2-a] pyridinium hydrochloride.

Physicochemical properties

Nuclear magnetic resonance spectrum (CD ₃ OD, TMS internal standard)

 5: 3.96 (2H, s), 4.80 (2H, s),

7.08 (2 H, dd, J, = 6.6 Hz, J ₂ = 4.7 Hz),

8.68 (1 H, dd, J , = 6.6 Hz, J 2 = 2.0 Hz), 8.90 (1 H, dd, J j = 4.7 H z, J 2 = 2.0 H z)

(ii) 2-Aminobilimidine 1 09.00 g (1.1 5 mol 1), 50 Om 1 of acetone was added, and 150.00 g (1.1 8 mol 1) of 1,3-dichloroacetone dissolved in 50 Om 1 of acetone was added. The mixture was stirred day and night. The precipitated salt was collected by filtration and dried to obtain crude 2-chloromethyl-3-hydroimidazo [1,2-a] pyrimidinium hydrochloride. Further, the filtrate collected earlier was again stirred for 24 hours. Salt generated as before Was collected by filtration, and the filtrate was stirred for 4 days, and the resulting salt was collected by filtration. All these salts were dried to give 200.87 g of crude 2-chloromethyl-3-hydroimidazo [1,2-a] pyrimidinium hydrochloride.

 2.00 g of 2-chloromethyl-3-hydroimidazo [1,2-a] pyrimidinium hydrochloride was dissolved in 50 ml of ethanol and refluxed for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, and the obtained crystals were dried to obtain 1.9 g of 2-chloromethylimidazo [1,2-a] pyrimidine hydrochloride.

Physicochemical properties

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

 5: 4.8 1 (2 H, s),

6.87 (1 H, dd, J, = 6.8 Hz, J ₂ = 4.2 Hz),

7.6 1 (1 H, s),

8.42 (1 H, dd, J , = 6. 8 Hz, J 2 = 2.0 Hz), 8. 5 6 (1 H, dd, J, = 4.2Hz, J 2 = 2. 0Hz) Mass analysis (EI , MZs): 1 6 7 (M ⁺ )

 —— KB r

 Infrared absorption spectrum

max (cm " ¹ ): 1 6 54, 1 5 3 6,

1 3 78, 1 324, 1 1 72, 8 22, 772

 (2) 3.0 g (14.6 mmo, l) of crude 2-chloromethyl-3-hydroimidazo [1,2-a] pyrimidinium hydrochloride obtained in (1) (i) was added to dimethylformate. Mumamide 10 Om 1 and 1.67 g of thioacetic acid potassium salt were added, and the mixture was stirred at room temperature for 2 hours. Dimethylformamide is distilled off under reduced pressure, and the residue is added with chloroform. The insolubles are collected by filtration and dried, and crude 2-acetylthiomethylimidazo [1,2-a] pyrimidine 2.6 7 g were obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (DMSO- _ds , TMS internal standard) (5: 2.39 (3H, s), 4.55 (2H, s),

 7.1 9 (2H, m), 7.80 (1H, s),

(1) (4R) — 2-Diazo 4-— ((2R, 3 S)-3- ((1 R) — 1-hydroxyethyl) 14-oxoazetidine- 12-yl) para-nitrobenzyl 1,3-oxopentanoate 50.8 mg (1.3 Ommo 1) and 5 ml of toluene were added. Under an argon stream, 5 mg of rhodium (II) acetate dimer was added at 95 ° C. After stirring at the same temperature for 10 minutes, toluene was distilled off under reduced pressure.

 The obtained crude paranitrobenzyl (1R, 3R, 5R, 6S) -6-((1R) -1-hydroxyethyl) 1-1-methyl-2-oxocarbazane-13-carboxylate Dissolved in 5 ml of acetonitrile and 0.24 ml of diisopropylethylamine (1.4 mm 01) and 0.27 ml of diphenylphosphoryl chloride (1.4 mmo 1) at −20 under an argon stream. The mixture was stirred for 2.5 hours. At the same temperature, 0.23 ml of diisopropylamine (1.3 mmo1) and 25 mg of 2-mercaptomethylimidazo [1,2-a] pyridine were added, and the mixture was stirred for 1 hour. . The reaction mixture was poured into a large amount of ethyl acetate, and this was washed with water and saturated saline. This was dried over magnesium acetate, filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (30: 1, v / v). Crude paranitrobenzyl (1R, 5S, 6S) — 6— ((1R ) — 1-Hydroxitytyl) 1 2 — [(imidazo [1, 2, a] pyridine-1-2-yl) methylthio]-1-methyl 1-methyl-lubapen-1-2-emucaraboxy xylate 1.09 g was obtained. .

Physicochemical properties

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

 δ: 1.2 7 (3 Η, d, J = 7Hz),

 1.3 5 (3 Η, d, J = 6Hz),

3.28 (1 Η, dd, J, = 5 Ηζ, J ₂ = 2 Η ζ), 3.75 (1 H, m), 4.05 (2 H, AB q, J = 10 Hz)

4.30 (1 H, m),

 5.33 (AB q, J = 13 Hz, Δ v = 90 Hz),

6.78 (m, 1 H), 7.8-8.3 (9 H, m)

 Mass spectrometry value (FAB, Pos, m / z): 509 ((M + 1) +) (2) The obtained crude paranitrobenzyl (1R, 5S, 6S) -6-((1R) — 1-Hydroxyethyl) 1 2— ((imidazo [1,2—a] pyridine-12-yl) methylthio] -11-methylcarbaben-12-hemecarboxylate 1.00 g in 15 ml of tetrahydrofuran Then, 10 ml of a 0.05 M potassium phosphate buffer solution (pH 7) and 0.95 g of 20% palladium hydroxide supported on carbon were added, and the mixture was stirred at room temperature and normal pressure under hydrogen for 5.5 hours.

 After filtering off palladium and distilling off tetrahydrofuran under reduced pressure, the remaining aqueous solution was washed with ethyl acetate and then adsorbed on Diaion HP-20. Elute with water and then 30% methanol, collect the desired fractions, concentrate under reduced pressure, and freeze-dry (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1) 2-[(Imidazo [1,2-a] pyridin-12-yl) methylthio] -11-methylcarbapene-12-em One-pot rubonic acid (113 mg) was obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMSO— _ds , TMS internal standard)

 5: 1. 16 (3H, d, J = 6 Hz),

 1. 1 8 (3Η, d, J = 7 Η ζ),

3.1 9 (1Η, d, J, = 5 Hz, J ₂ = 2 Hz),

3.94 (1H, dd, J) = 6 Hz, J ₂ = 6 Hz),

4.08 (1H, dd, J, = 4Hz, J 2 = 2Hz), 4.2 1 (2H, ABq, J = 14Hz, mm v = 84Hz)

6.88 (1 H, dd, J) = 7 Hz, J ₂ = 7 Hz),

7.23 (1 H, dd, Ji = 8 Hz, J ₂ = 8 Hz),

7.49 (1 H, d, J = 9 Hz), 7.90 (1 H, s),

8.5 1 (1 H, d, J = 7Hz)

Mass spectrometry value (FP os, m / z): 374 ((M + 1) ⁺ )

The crude paranitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-2-[(imidazo [1, 2-a] Pyridine-12-yl) methylthio] -1-Methylcarbapene-2-Emucarboxylate To 825 mg (2.1 3 mm 01), add 15 ml of acetone and 0.85 g of methyl iodide, and overnight at room temperature. Stirred. After evaporating the solvent under reduced pressure, add 15 ml of tetrahydrofuran, 10 ml of 0.05 M phosphate buffer solution (pH 7) and 0.85 g of 20% palladium hydroxide on carbon to the obtained residue, and add room temperature and normal pressure. For 6 hours under hydrogen. The palladium was separated by filtration, and the remaining aqueous solution obtained by distilling off tetrahydrofuran under reduced pressure was washed with ethyl acetate and then adsorbed on Diaion HP-20. Elution was carried out with water and then with 15% aqueous methanol. The desired fractions were collected, concentrated under reduced pressure, and lyophilized to give (1R, 5S, 6S) -6-((1R) -1-hydroxy- Chill) 1 1 1 [(1— 86 mg of methylimidazo [1,2-a] pyridine-12-io) methylthio] -11-methylcarbapene-12-em-carboxylate were obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMS〇— _ds , TMS internal standard)

 5: 0.98 (3H, d, J = 7Hz),

 1.1 2 (3 H, d, J = 6 Hz),

 3.06 (1 H, d, J = 4 Hz), 3.17 (1 H, m),

3.88 (1 H, dd, J, = 6 Hz, J ₂ = 6 Hz),

4.00 (3 H, s),

 4.36 (2H, ABq, J = 15 Hz, mm v = 76Hz),

7.50 (1 H, m), 8.00 (1 H, m),

 8.17 (1H, d, J = 9Hz), 8.36 (1H, s),

8.89 (1 H, m)

Mass spectrometry value (FAB, Pos, m / z): 388 ((M + 1) ⁺ ) Example 3

(1) (4 R) — 2-diazo 4 — ((2 R, 3 S)-3-((1 R) — 1-hydroxyethyl) — 4-oxoazetidine 1 2

—Yl] To 1.016 mg (2.60 mm 01) of paranitrobenzyl-1,3-oxopentanoate, 5 ml of toluene was added, and at 95 under an argon stream, 5 mg of a rhodium (II) acetate dimer was added. At the same temperature 1 0 After stirring for minutes, toluene was distilled off under reduced pressure.

The resulting crude paranitrobenzyl (1R, 3R, 5R, 6S) -6 — ((1R) —1-hydroxyethyl) -1-methyl-2-oxocarbazane-3-carboxylate Add 10 m1 of acetonitrile, and at 120 ° C under an argon stream, 0.48 m1 (1.4 mmo1) of diisopropylethylamine and 0.54 ml (1.4 mmo1) of diphenylphosphoric chloride Was added and stirred at the same temperature for 1 hour. At the same temperature, 2-mercaptomethylimidazo [1,2-a] pyrimidine 64 8 mg dissolved in disopropylamine 0.48m1 (1.4mmo1) and 6m1 dimethylformamide 3. Ommo 1) was added, and the mixture was stirred at the same temperature for 1 hour, and further stirred for 1 hour under ice cooling. The reaction mixture was poured into a large amount of acetic acid Echiru, this water, which was washed _c dried over anhydrous sodium acetate with brine, and filtered, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with chloroform-methanol (30: 1, v / v) to give crude paranitrobenzyl (1R, 5S, 6S) — 6— ((1R) — 1-Hydroxyethyl) 12-[(imidazo [1,2-a] pyrimidine-12-yl) methylthio] -11-methylcarbapene-12-emucarboxylate 898 mg was obtained.

Physicochemical properties

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

 ά: 1.17 (3H, d, J = 6 Hz),

 1.2 3 (3 H, d, J = 7Hz),

3.2 9 (1 H, dd, J, = 6 Hz, J ₂ = 2 Hz), 3.88 (1 H, m), 3.98 (1 H, m),

4.18 (1 H, dd, J, = 9 Hz, J ₂ = 2 Hz), 4.32 (2H, ABq, J = 14Hz, Δ v = 36 Hz), 5.35 (2H, ABq, J = 1 4Hz, Δν = 66Ηζ), 7.05 (1 H, dd, J: = 7Hz, J 2 = 4Hz) ,

7.89 (1 H, d),

 7.96 (4H, ABq, J = 9 Hz, Δ v = 206 Hz),

8.52 (1 H, dd, J , = 4Hz, J 2 = 2 Hz), 8.94 (1 H, dd, J i = 7Hz, J 2 = 2 Hz) Mass spectrometry value (FAB, Po s, mZz) : 5 10 (CM + 1) +) (2) The obtained crude paranitrobenzyl (1R, 5S, 6S) -6 — ((1R) —1-hydroxyethyl) 1-2 — [(imidazo [1, 2-a] pyrimidine-1-yl) methylthio] -11-methylcarbapene 2-heme-carboxylate 51 3 mg in tetrahydrofuran 5 ml, ^ 17 0.05 M potassium phosphate buffer 5 ml 1, carbon 0.51 g of supported 20% palladium hydroxide was added, and the mixture was stirred at room temperature and normal pressure under hydrogen for 5.5 hours. After removing palladium by filtration and distilling off tetrahydrofuran under reduced pressure, the remaining aqueous solution was washed with ethyl acetate and then adsorbed on Dia HP-20. Elute with water and then 20% methanol-water, collect the desired fractions, concentrate under reduced pressure, lyophilize, and (1R, 5S, 6S) -6-((1R) -1-hydroxy 6-Omg of 2-([imidazo [1,2-a) pyrimidine-12-yl) methylthio] -11-methylcarbapene-12-em-carboxylic acid was obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

 d: 1.06 (3H, d, J = 7Hz),

 1.1 5 (3Η, d, J = 6Hz),

3.00 (1 H, dd, J i = 7 Hz, J ₂ = 2 Hz), 3.39 (1 H, m), 3.89 (2 H, m),

 4.0 1 (2 H, ABq, J = 14 Hz, Δν = 52ν),

7.0 1 (1 H, m), 7.8 1 (s, 1 H),

8.48 (1 H, dd, J, = 4 Hz, J ₂ = 2 Hz), 8.94 (1 H, dd, J, = 7 Hz, J ₂ = 2 Hz)) Mass spec (FAB, Pos, m / z): 375 (C + 1) ⁺ ) Example 4

Crude paranitrobenzyl (1R, 5S, 6S) —6 -— ((1R) —1-hydroxyethyl) 1-2 — [(imidazo [1, 2-a] Pyrimidine-1-yl) methylthio] -11-methylcarbapene 2-Emucarboxylate To 628 mg (1.68 mmo 1), 5 ml of acetone and 0.65 mg of methyl iodide were added, and the mixture was heated at room temperature. Stirred overnight. The solvent was distilled off under reduced pressure, and the resulting residue was added with 3 ml of tetrahydrofuran, 3 ml of 0.05M potassium phosphate buffer solution at pH 7 and 0.63 g of 20% palladium hydroxide on carbon, and hydrogenated at room temperature and normal pressure. Stirred for hours. After filtering off the palladium and distilling off tetrahydrofuran under reduced pressure, the remaining aqueous solution was washed with ethyl acetate and then adsorbed on DIAION HP-20. Elute with water, collect the desired fractions, concentrate under reduced pressure, freeze-dry, and purify (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-2- (1-methylimidazo [1, 2-a] Pyrimidine-l- 2-methylthio] -l-methylcarbapene-l- 2-emucarboxylate 96 mg was obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

 d: 1.01 (3H, d, J = 7Hz),

 1.1 2 (3H, d, J = 6Hz),

 3.14 (1 H, m), 3.88 (2 H, m),

 4.00 (3H, s),

 4.34 (2H, AB q, J = 15 Hz, Δν = 54Hz),

7.50 (1 H, dd, = 6 Hz, J ₂ = 4 Hz),

8.32 (1 H, s),

9.06 (1 H, dd, _} = 5 Hz, J ₂ = 2 Hz), 9.37 (1H, d, J = 6 Hz)

 Mass spectrometry value (FAB, Pos, m / z): 388 (CM + 1) +) Reference example 3

(L) To 25.0 g (26.3 mmol) of 2-aminopyrimidine, 300 ml of ethanol, 39.7 g (26.3 mmol) of malondialdehyde bromide and 44.2 g of sodium hydrogen carbonate were added, and the mixture was stirred and refluxed for 7.5 hours. The insoluble material was removed by filtration and the solvent was distilled off. An aqueous solution of sodium hydroxide having a pH of 10 or more was added to the residue, and the mixture was extracted with black hole form. This was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. 5.78 g of Dazo [1,2-a] pyrimidine-3-carboxaldehyde was obtained.

Physicochemical properties

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

(5: 7.23 C 1 H, dd, J, = 4.2 Hz, J ₂ = 6.8 Hz), 8.53 (1 H, s),

8.85 (1 H, dd, J, = 2.0 Hz, J ₂ = 4.3 Hz)

9.75 (1 H, dd, J, = 2.0 Hz, J ₂ = 6.8 Hz) 9.99 (1 H, s)

 (2) Dissolve 5.77 g (39.2 mmol) of imidazo U, 2-a] pyrimidine-3 monocarboxaldehyde obtained in (1) in 200 ml of ethanol, and add 2.23 g (1.5%) of sodium borohydride under ice-cooling. eq v.)), and the mixture was stirred as it was for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (9: 1, v / v) to give 3-hydroxymethylimidazo [1,2-a] pyrimidine 1.88 g of 1-3-carboxyaldehyde were obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 5: 4.83 (2H, d (b r), J = 5 Hz),

 , 5.32 (1 H, t (b r), J = 5 Hz),

7.10 (1 H, dd, J, = 4.2 Hz, J ₂ = 6.8 Hz)

7.67 (1 H, s),

8.56 (dd, J, = 2.0 Hz, J ₂ = 4.2 Hz)

8.85 (1 H, dd, J, = 2.0 Hz, J ₂ = 6.8 Hz) Mass spectrometry (EI, m / z): 14.9 (M ⁺ ) (3) Dissolve 1.68 g (11.3 mm 01) of 3-hydroxymethylimidazo [1,2-1a] pyrimidine-3-carboxaldehyde obtained in (2) in 50 ml of thionyl chloride, Stirred. The thionyl chloride is distilled off, and the residue is washed with diethyl ether. 3-Chloromethylimidazo [1,2-a] pyrimidine hydrochloride

2.1 5 g were obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

 d: 5.41 (2H, s),

7.7 8 (1 H, dd, Ji = 4.2 Hz, J ₂ = 6.8 Hz)

8.46 (1 H, s),

9.1 2 (1 H, dd, Jx = 2.0 Hz, J ₂ = 4.2 Hz)

9.43 (1 H, dd, i = 2.0 Hz, J ₂ = 6.8 Hz)

(4) 3-chloromethylimidazo [1,2-a] pyrimidine hydrochloride 2.01 (9.85mmo1) obtained in (3) was added to dimethylformamide 20m1, thioacetate potassium salt 1.15 g, triethylamine 1.37 ml was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in 2 Oml of methanol. Under ice-cooling, 3.8 ml of a 28% methanol solution of sodium methylate was added dropwise, and the mixture was stirred for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1, v / v) to give 3-mercaptomethylimidazo [1,2-a] pyrimidine 674 mg I got

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

d: 1.80 (1H, t (br), J = 7Hz), 4. 1 1 (2 H, d (br), J = 7Hz),

6.98 (1 H, dd, J, = 4.1 Hz, J ₂ = 6.8 Hz)

7.71 (1 H, s), 8.5 -8.7 (2 H, m),

Mass spectrometry (EI, m / z): 1 65 (M ⁺ )

Reference example 4

(1) 5.0 g of 1-amino-4 pyridazine in methanol

The mixture was dissolved in 100 ml, and triethylamine (6.0 ml) and 10% paradigm carbon (2.5 g) were added, followed by stirring under hydrogen at room temperature and normal pressure for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1, v / v) to obtain 8.76 g of crude 1-aminopyridazine.

Physicochemical properties

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

 5: 6.38 (2H, b r s),

6.80 (1 H, dd, J, = 1.5 Hz, J ₂ = 9.1 Hz) 7.24 (1 H, dd, J, = 4.4 Hz, J ₂ = 9.0 Hz)

8.40 (1 H, dd, J) = 1.5 Hz, J ₂ = 4.4 Hz) Mass spec (EI, m / z): 95 (M ⁺ )

(2) Dissolve 8.67 g of the crude 1-aminobiridazine obtained in (1) in a mixed solvent of ethanol 8 Om 1 and acetonitrile 8 Om 1, add 1,3-dichloroacetone 7 g, and reflux under 2.5 hours. The stirred _t solvent was distilled off under reduced pressure, and the residue was diluted to form 10 Om 1 and water 10 Om 1 Was added. The organic layer was separated, and the aqueous layer was extracted three times with 4 ml of form-form. After the combined organic layers were dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1 (vv)) to give 2-cyclomethylmethylimidazo [1,2-b) pyridazine 0.87 g.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

 d: 4.80 (2H, d, J = 0.5 Hz),

7.06 (1Η, dd, J! = 4.4Hz, J ₂ = 9.3 Hz)

7.93 (1 H, dd, J, = 1.9 Hz, J ₂ = 10 Hz)

8.0 1 (1 H, s),

8.3 1 (1 H, dd, J, = 1.5 Hz, J ₂ = 4.4 Hz) Mass spec (EI, m / z): 1 67 (M +)

 (3) Using 2-chloromethylimidazo [1,2-b] pyridazine 0.87 g obtained in (2), the same procedure as in (2) of Reference Example 1 was carried out. The product was further subjected to silica gel chromatography and eluted with methylene chloride-ethyl acetate (1: 1, vZv) to obtain 0.98 g of 2-acetylthiomethylimidazo [1,2-b] pyridazine.

Physicochemical properties

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

 (5: 2.35 (3H, d, J = 2.8Hz),

 4.32 (2 H, s),

7.00 (1 H, dd, J, = 4.5 Hz, J ₂ = 9.3 Hz) 7.9 (1 H, dd, J, = 1.5 Hz)

 7.92 (1 H, s),

8.27 (1 H, dd, J, = 1.5 Hz, J ₂ = 4.9 Hz) Mass spec (EI, m / z): 207 (M ⁺ )

Reference example 5

(1) In the same manner as in (2) of Reference Example 4, using 2.00 g (15.4 mmo 1) of 1-amino-4-cyclopyridazine, 6-chloro-2-chloromethylimidazo [1,2-b] 1.03 g of pyridazine were obtained.

Physicochemical properties

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

 (5: 4.77 (2H, d, J = 0.7Hz),

 7.08 (1 H, d, J = 14.4 Hz),

7.87 (1 H, dd, J, = 0.4 Hz, J ₂ = 14.4 Hz)

7.96 (1 H, d, J = 0.5 Hz)

 Mass spectrometry value (E I, m / z): 201 ((M-1) +),

 203 ((M + 1) +),

 (2) 6-chloro-1-imidazo obtained from (1) [1,2-! )] Using 1.03 g of pyridazine in the same manner as in (2) of Reference Example 1, 0.88 g of 2-acetylthiomethyl-6-chloroimidazo [1,2-b] pyridazine was obtained.

Physicochemical properties

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

 0: 2.37 (3H, s), 4.28 (2H, s),

7.03 (1 H, d, J = 9.6 Hz), 7.83 (1 H, dd, J, = 0.6 Hz, J ₂ = 9.4 Hz) Mass spec (EI, mZz): 24 1 (M ⁺ )

Reference example 6

 Tf OH: trifluoromethanesulfonic acid

(1) 10.0 g (77.2 mmo 1) of 3-amino-6-chloropyridazine was dissolved in 240 ml of acetonitrile, and 17.5 g (100.4 mmo 1) of 2-bromomalonaldehyde was dissolved in 200 ml of acetonitrile. After adding 270 ml of ethanol, the mixture was stirred at room temperature for 3 hours.

 16.8 g (200.7 mmo 1) of sodium hydrogen carbonate was added thereto, and the mixture was stirred at 70 ° C for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (chloroform / methanol) to obtain 13.28 g (73.1 mm 01) of 6-chloroimidazo [1,2-b] pyridazine-13-carbaldehyde. Was.

Physicochemical properties

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

 d: 7.35 (1 H, d, J = 5 Hz),

 8.07 (1 Η, d, J = 5 Hz),

 8.4 1 (1 H, s),

 10.36 (1H, s)

Mass spec (EI, m / z): 18 1 (M ⁺ )

 KB r

Infrared absorption spectrum (cm " ¹ ); 2752, 1 662 1 5 2 8, 1 5 0 8, 1 4 4 8, 1 3 0 0, 1 1 7 0, 1134, 74 6

 (2) 6-Chloroimidazo [1,2-b] pyridazine-3-carbaldehyde 9.93 g (54.7mmo 1), 5% palladium on carbon 2.5 g, triethylamine 7.6m 1 (54.7mm o 1) To 1,

4 In addition to 600 ml of dioxane, the mixture was stirred for 6 hours under a hydrogen atmosphere. Thereafter, cerite filtration was performed, and the solvent was distilled off under reduced pressure. The residue was subjected to liquid separation with ethyl acetate and water, the ethyl acetate layer was dried over anhydrous magnesium sulfate, magnesium sulfate was distilled off, and ethyl acetate was distilled off under reduced pressure to obtain a crude imidazo [1, 2-b 4.48 g (30.4 mmo 1) of pyridazine-1 3-carbaldehyde were obtained.

Physicochemical properties

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

δ: 7.35 (1 Η, dd, J, = 9.5 Hz, J ₂ = 4.5 Hz) 8.1 2 (1 H, dd, J, = 9.5 Hz, J ₂ = 1.5 Hz)

8.44 (1 H, s),

8.5 9 (1 H, dd, J, = 4.5 Hz, J ₂ = 1.5 Hz) 10.34 (1 H, s)

Mass spectrometry value (EI, m / z): 1 4 7 (M ⁺ )

Infrared absorption spectrum (cm ^-1 ); 3 10 8, 3 0 5 2,

 max

 1 6 6 8, 1 5 20, 1 2 9 2, 1 1 7 8, 8 1 6, 8 0 8, 744

(3) Imidazo [1,2-b] pyridazine-3-carbaldehyde 4.48 g (30.4mmo1) was dissolved in methanol 250ml and sodium borohydride dissolved in methanol 50ml 2 30 g (60.8 mm 01) was added dropwise under ice cooling. 10 minutes After stirring, the pH was adjusted to 2 with an aqueous solution of IN hydrochloric acid, and the mixture was stirred for 30 minutes. Thereafter, the pH was adjusted to 9 with potassium carbonate, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to give crude 3-hydroxymethylimidazo [1,2-b] pyridazine 4.50 g (30.2 mm 01) was obtained.

Physicochemical properties

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

 d: 5.08 (2H, s),

7.04 (1H, dd, Ji = 9.3Hz, J 2 = 4.6 Hz) 7.73 (1H, s),

7.94 (1 H, dd, J! = 9.3 Hz, J ₂ = 1.7 Hz)

8.35 (1H, dd, Jj = 4.6 Hz, Jz = 1.7Hz) Mass spec (EI, mXz): 149 (M ⁺ )

 KB r

 Infrared absorption spectrum (cm-1);

 max 3 140, 1 4 16

1 362, 1 3 12, 1298, 1 1 30, 1 098, 1042,

792, 734, 5 12

 (4) 3-Hydroxyimidazo [1,2-b] pyrimidine (1.55 g, 10.4 mmo 1) was dissolved in thionyl chloride (20 ml), and the mixture was stirred at 50 for one day and night. The thionyl chloride was directly distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (form-form / methanol).

1.72 g (10.3 mm 01) of 3-chloromethylimidazo [1,2-b] pyrimidine was obtained.

Physicochemical properties

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

 (J: 5.26 (2H, s),

7.76 (1H, dd, J, = 9.3 Hz, J ₂ = 4.4 Hz) 8.3 8 (1 H, s),

8.4 8 (1 H, dd, Ji = 9.3 Hz, J ₂ = 1.5 Hz)

9. 0 2 (. 1 H, dd, J, = 4.4 Hz, J 2 = 1 5 Hz) Mass spectrometry value (FAB, P os, m / z): 1 6 8 ((M + 1) +) Infrared absorption Spectrum (cm " ¹ ); 3 0 72, 1 6 4 6,

 ma

 1 4 34, 1 3 9 4, 1 3 8 0, 1 3 0 4, 8 32, 8 0 6, 7 0 8

 (5) To 3-87-chloromethylimidazo [1,2-b] pyridazine was added 5 ml of tetrahydrofuran and dissolved in 2.87 g (17.lmmo 1). Thereto was added 0.822 g of sodium hydride (60%) under ice-cooling, and further dissolved in 10 ml of tetrahydrofuran. 4-Methoxy Ichii Toluenethiol (90%) 2.75 ml was added dropwise. After stirring for 20 minutes, a saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted with a chloroform solution. The port-form layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (formaldehyde Z methanol) to give 2.74 g (9.6 Ommo 1) of 3- (4-methoxybenzylthiomethyl) imidazo [1,2-b] pyridazine. .

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 (5: 3.68 (2H, s), 3.80 (3H, s),

 4.00 (2H, s),

 6.84 (2H, d, J = 8.8 Hz),

7. 0 3 (1 H, dd , J, = 9.3 Hz, J 2 = 4.4 Hz) 7.24 (2H, d, J = 8.8 Hz),

7.67 (1 H, s), 7.94 (1 H, d, J = 9.3 Hz),

 8.37 (1 H, d, J = 4, 4 Hz)

 Mass spectrum (E I, m / z): 285 (M +)

 KB r

 Infrared absorption spectrum

max (cm- ¹ ); 3056, 2948,

1 6 12, 1 5 1 4, 1 350, 1 300, 1 250, 1236, 1 172, 1 142, 1 040, 8 1 0, 758

 (6) Dissolve 2.74 g (9.60 mm o 1) of 3- (4-methoxybenzylthiomethyl) imidazo [1,2-b] pyridazine in 7.69 ml of anisol and 30 ml of trifluoroacetic acid, and add trifluoromethanesulfone under ice-cooling. 1.03 ml (12.0 mm 01) of the acid was added dropwise. After stirring under ice cooling for 1.5 hours, trifluoroacetic acid was distilled off under reduced pressure while cooling to 15 or less. Getyl ether was added to the residue, and amorphous crude 3-mercaptomethylimidazo [1,2-b] pyridazinium trifluoromethanesulfonate (1.50 g, 4.74 mm 01) was obtained.

Physicochemical properties

Nuclear ^ care resonance spectrum (DMSO- d _6, TMS internal standard)

 d: 3.28 (1 H, t, J = 7.8 Hz),

 4.1 9 (2H, d, J = 7.8 Hz),

7.85 (1 H, dd, J, = 9.3 Hz, J ₂ = 4.4 Hz), 8.26 (1 H, s),

 8.50 (1 H, d, J = 9.3Hz),

 9.07 (1 H, d, J = 4.4 Hz)

 Mass spec (EI, m / z): 165 (M +)

 KB r

 Infrared absorption spectrum (cm—υ; 3 1 32, 1 394

 m & χ

1 278, 1240, 1 1 78, 1 030, 8 1 8, 642 Reference Example 7

(1) 9.11 g (65.6 mmol) of bromoacetic acid and 11.4 ml of 4-methoxya-toluenethiol were added to 150 ml of a 1 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 4 hours. After the aqueous solution was washed with ethyl acetate, concentrated hydrochloric acid was added to adjust the pH to 1, followed by extraction with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1-2.9 g of 4-methoxybenzylmercaptoacetic acid.

Physicochemical properties

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

 (5: 3.10 (2H, s), 3.80 (3H, s),

 3.8 2 (2H, s),

6.8 5, 7.2 6 (4H, AB q, J = 8.8 Hz) Mass spectrometry (EI, m / z): 2 1 2 (M ⁺ )

(2) 1.05 g of aminoguanidine hydrochloride was added to 2.0 g (9.4 2 mm 01) of 4-methoxybenzylmercaptoacetic acid obtained in (1), and the mixture was stirred for 15 hours with TC (2 hours). After returning to room temperature, adding a large amount of black-mouthed form, drying over anhydrous sodium sulfate _c which was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, the solvent was distilled off under reduced pressure, and 5-amino-3 There was obtained 2.09 g of (4-methoxybenzylthiomethyl) -11,2,4-triazole.

Physicochemical properties Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

 d: 3.31 (2H, brs), 3.35 (2H, s),

 3.71 (2 H, s), 3.74 (5 H, s),

 5.85 (1 H, b rs),

6.87, 7.27 (4H, AB q, J = 8.9Hz), mass spectrometry (EI, m / z): 250 (M ⁺ )

 (3) 2.56 g of 5-amino-3- (4-methoxybenzylthiomethyl) 1-1,2,4-triazole obtained in (2) and 6 ml of malonaldehyde, tetramethyl acetal in 30 ml of acetic acid In addition,

The mixture was stirred at 120 ° C for 15 hours. After cooling to room temperature, a large amount of chloroform was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform monoethyl acetate (1: 1, / V) to give 3- (4-methoxybenzylthiomethyl) 1-1,2,4-triab [1 , 5-a] pyrimidine 2.48 g was obtained. Physicochemical properties

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

 d: 3.79 (3H, s), 3.84 (2 H, s),

 3.85 (2 H, s),

 6.84, 7.35 (4 H, ABq, J = 8, 6Hz),

7.09 (1 H, dd, J, = 5.2 Hz, J ₂ = 5.9 Hz),

8.7-8.9 (1 H, m)

Mass spec (EI, mZz): 286 (M ⁺ )

 (4) 3- (4-methoxybenzylthiomethyl) obtained in (3) — 1,2,4-trizolo [1,5-a] pyrimidine 3.50 g

(12.2mmo1) and anisol 3.5m1 in trifluoroacetic acid 50 The mixture was dissolved in ml and stirred under reflux for 5 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to gel chromatography, and the residue was taken out with formaldehyde (20: 1, v / v) to give 3-mercaptomethyl-1,2,4-triazolo [1,5-a] pyri. 1.90 g of midine were obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 <5: 2.27 (1 H, t, J = 8.4 Hz),

 4.03 (2H, d, J = 8.1 Hz),

7.1 5 (1 H, dd, J, = 4.8 Hz, J ₂ = 6.6 Hz) 8.7 -8.9 (2H, m)

Mass spectrometry (EI, m / z): 166 (M ⁺ )

Reference Example 8

(1) To 3.00 g (31.2 mm 01) of 3-amino-1,2,4-triazine, add 7.90 g (62.4 mm 01) of 60 ml of benzene and 1,3-dichloro-1--2-propanone and add a Dean-Stark trap. The mixture was stirred at 100 ° C for one day and night. After that, water was added, and the mixture was extracted with a black hole form. After drying over anhydrous magnesium sulfate and filtration, the chloroform was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol) to give 2-chloromethylimidazo [1,2-b] [1,2,4] triazine 251 mg (1.49 Ol).

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 d: 4.84 (2H, s), 8.03 (1H, s),

 8.37 (1 H, d, J = l.8 Hz),

 8.48 (1Η, d, J = l.8Hz)

Mass spec (EI, m / z): 168 (M ⁺ )

 (2) 2-Chloromethylimidazo [1,2-b] [1,2,4] Triazine 51 9mg (3.06mmo 1) is dissolved in dimethylformamide 25ml, and thioacetate potassium salt 703mg is dissolved therein. (6.12 t), and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (form-form Z methanol) to give 2-acetylthiomethylimidazo [1, 2-b] [1, 2, 4] triazine 569 mg ( 2.73 mm o 1) was obtained.

Physicochemical properties

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

 ά: 2.38 (3Η, s), 4.37 (2Η, s),

 7.94 (1 H, s),

 8.35 (1 H, d, J = 2.0 Hz),

 8.45 (1 H, d, J = 2.0 Hz)

 Mass spec (E I, m / z): 208 (M +)

 Reference Example 9

(1) 2-aminothiazole 20.5 g (205 mmo 1) and 1,

28 g of 3-dichloroacetone was added to 200 ml of acetone, and the mixture was stirred at room temperature for 4 days. The precipitated solid was collected by filtration, further added with 40 Oml of acetonitrile, and stirred under reflux for 3 hours. After returning to room temperature, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and a 1N aqueous sodium hydroxide solution was added to adjust the pH to 10. After extraction with chloroform and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) to give 7.84 g of 5- (chloromethyl) imidazo [2,1-b] thiazole.

Physicochemical properties

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

 5: 4.67 (2H, d, J = 0.6 Hz),

 6.84 (1 Η, d, J = 4.6 Hz),

 7.38 (1 H, d, J = 4.7Hz),

 7.49 (1 H, s)

Mass spec (EI, mZz): 172 (M ⁺ )

 (2) Using 8.0 1 g (46.4 mmo 1) of 5- (chloromethyl) imidazo [2,11-b] thiazole obtained in (1),

In a similar manner to (2), 8.1—2 g of 5- (acetylthiomethyl) imidazo [2,11b] thiazole was obtained.

Physicochemical properties

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

 d: 2.35 (3H, s)

 4.1 7 (2H, d, J = 0.4 Hz),

6.78 (1 H, d, J = 4.4 Hz), 7.34 (1 H, d, J = 4.5 Hz),

 7.39 (1 H, s)

Mass spec (EI, m / z): 21 2 (M ⁺ )

Reference example 10

 PNZ: p-nitrobenzoyloxycarbonyl group

 (1) 1.31 g (7.82 mmo 1) of 2-chloromethylimidazo [1,2-a] pyrimidine obtained in (1) (ii) of Reference Example 2 was dissolved in dimethylformamide 1 Om 1 and -Methoxy-α-toluenethiol (1.5 ml) and potassium carbonate (1.6 g) were added, and the mixture was stirred at room temperature for 30 minutes. The solvent was also reduced. After evaporation, the residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1, v / v) to give 2- (4-methoxybenzylthiomethyl) imidazo [1,2 — A] Pyrimidine (1, 45 g) was obtained.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

 d: 3.78 (5H, s)

 3.82 (2H, d, J = 0.5 Hz),

 6.82, 7.28 (2Η, ABq, J = 8.7Hz),

6.85 (1 Η, dd, Ji = 4.1 Hz, J ₂ = 6.8 Hz):

7.47 (1 H, s),

8.39 (1H, dd, Ji = 2.0Hz, J 2 = 6.8 Hz) 8.52 (1 H, dd, J, = 2.0 Hz, J 2 = 4.2 Hz) Mass spectrometry value (EI, m / z): 285 (M ⁺ )

 (2) The 2— (4—me obtained in (1)

To 1.44 g of imidazo [1,2-a] pyrimidine was added 40 ml of dioxane and 50 Omg of lithium borohydride, and the mixture was stirred at 60 ° C for 20 minutes. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1, v / v) to obtain 2- (4-methoxybenzylthiomethyl) -1,5,6 7,53-mg of 7,8-tetrahydroimidazo [1,2-a] pyrimidine was obtained.

Physicochemical properties

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

 5: 1.9-2.3 (2H, m), 3.7-3.9 (4H, m),

 3.7 9 (5H, s), 6.29 (1H, s),

 6.8 2, 7.25 (4 H, AB q, J = 8.8 Hz)

Mass spec (EI, mZz): 289 (M ⁺ )

 (3) 4.7-g of 2- (4-methoxybenzylthiomethyl: -5,6,7,8-tetrahydroimidazo [1,2—a] pyrimidine obtained in (2) was treated with methylene chloride 6 Om Dissolve in ice-cooled solution and add 3.5 ml of triethylamine and paranitrobenzyloxycarbonyl chloride under ice-cooling

5.30 g was added, and the mixture was stirred at room temperature for 2 hours. After water was added and the organic layer was separated, the aqueous layer was extracted three times with methylene chloride. The collected organic layer was dried using anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography to form ethyl monoacetate (1:

Eluted with 1, vZv), and 1.89 g of the starting compound was recovered. 2- (4-Methoxybenzylthiomethyl) -18- (412-trobenzylyloxycarbonyl) -1,5,6,7,8-tetrahydro 3.09 g of imidazo [1,2-a] pyrimidine was obtained. Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 d: 2.0 -2.3 (2 H, m), 3.78 (5 H, s),

 3.8 -4.1 (4H, m), 5.42 (2 H, s),

 6.58 (1 H, s),

 6.82, 7.26 (4 H, AB q, J = 8.9 Hz),

7.77, 8.1 9 (4H, ABq, J = 9.0 Hz) Mass spectrometry (EI, m / z): 468 (M ⁺ )

 (4) 2- (4-Methoxybenzylthiomethyl) -18- (412-trobenzoyloxycarbonyl) -1,5,6,7,8-tetrahydroimidazo obtained in (3) [1,2 — A] Pyrimidine (3.04 g, 7.77 mmo 1) was dissolved in trifluoroacetic acid (15 ml), and under ice cooling, 2.5 ml of anisol and 0.76 ml of trifluoromethanesulfonic acid were added. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and crude 2-mercaptomethyl-18- (4-nitrobenzyloxycarbonyl) -1,5,6,7,8-tetrahydroimidazo [1,2- a] Pyrimidine / trifluoromethanesulfonate (4.08 g) was obtained.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 d: 2.1 -2.5 (2H, m), 3.74 (5H, s),

 4.0 -4.3 (4H, m), 5.55 (2H, s), 6.86 (1H, s),

7.67, 8.22 (4 H, AB q, J = 8.9 Hz) Mass analysis value (FAB, P os, mZz): 349 (CM + 1) ⁺ ) Reference Example 1 1 H

(1) 23.7 g of 2-aminothiazoline was added to 28 Om1 of ethanol, 32.2 g of bromoacetic acid was added, and the mixture was heated under reflux overnight. Precipitated conclusion

 HB was collected by filtration to obtain 3.7 g of 2,3,5,6-tetrahydroimidazo [2,1-b] thiazol-6-one.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (D ₂ 0, TMS internal standard)

(J: 3.56 (2H, t X d, J _t = 8 Hz, J _d = 1 Hz), 4.14 (2H, s),

4. 1 4 (2H, txd, J t = 8Hz, J d = 1 Hz) Mass spectrometry value (EI, m / z): 1 42 (M +)

 (2) To 35 ml of phosphorus oxychloride was added 3.3 g of 2,3,5,6-tetrahydroimidazo [2,1-b] thiazolu-l-6-one, and the mixture was heated under reflux for 2.5 hours. The phosphorus oxychloride was distilled off under reduced pressure. 200 ml of water was added to the residue, and the mixture was made basic by adding aqueous ammonia, and extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 2.73 g of an oil of 6-chloro-2,3-dihydroimidazo [2,11b] thiazole.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 5: 1.80 (2H, m), 2.20 (2H, m),

 4.90 (1 H, s)

Mass spectrometry (EI, m / z): 160 (M ⁺ , C 1 = 35) (3) To 65 ml of N, N-dimethylformamide, add 0.40 g of 6-chloro-2,3-dihydroimidazo [2,1-b] thiazole, and in step 5, add 0.75 ml of phosphorus oxychloride. The mixture was stirred at 50 ° C for 2 hours. The solvent was distilled off under reduced pressure, 100 ml of water was added to the residue, and the mixture was extracted with dichloromethane. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 0.50 g of crystals of 6-chloro-5-formyl-2,3-dihydroimidazo [2,11b] thiazole. Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 5: 3.88 (2H, t, J = 8 Hz),

 4.52 (2 Η, t, J = 8Hz),

 9.6 1 (1 Η, s)

Mass spectrometry (Ε I, m / z): 188 (Μ ⁺ , C 1 = 35)

(4) Add 0.50 g of 6-chloro-5-formyl-1,2,3-dihydroimidazo [2,1-b] thiazol to 25 ml of ethanol. To the mixture was added 5 Omg of sodium borohydride, and the mixture was stirred at room temperature for 40 minutes. The solvent _c was distilled off under reduced pressure, 100 ml of water was added to the residue, and extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 0.47 g of 6-chloro-5-hydroxymethyl-2,3-dihydroimidazo [2,1-1b] thiazole.

Physicochemical properties

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

<5: 3.80 (2H, t X d, J _t = 8 Hz, J _d = 1 Hz),

4.24 (2 H, t xd, J _t = 8 Hz, J _d = 1 Hz),

4.58 (2 H, s)

Mass spectrometry value (FAB, Po s, mZz): 19 1 C (M + 1) +) (5) 6-chloro-5-hydroxymethyl-2,3-dihydroimidazo [2,1-b] thiazol in 5 ml of thionyl chloride

0.20 g was added, and the mixture was stirred at 50 ° C for 1 hour. Thionyl chloride was distilled off under reduced pressure, and 6-chloro-5-chloromethyl-2,3-dihydro

[2, 1-b] Thiazolyl hydrochloride was obtained.

Physicochemical properties

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

 5: 3.90 (2H, m), 4.25 (2H, m),

 4.8 1 (2H, s)

(6) 0.10 g of 6-chloro-5-chloromethyl-2,3-dihydroimidazo [2,1-b] thiazole was added to 4 ml of dimethylformamide, and 0.15 g of potassium thioacetate was added. The stirred _c- dimethylformamide was distilled off under reduced pressure, 50 ml of ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate, treated with activated carbon, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. I left. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate (10: 1) to give 5-acetylthiomethyl-6-chloro 2,3-dihydroimidazo [2,1- b] 3 Omg of thiazole was obtained.

Physicochemical properties

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

 d: 2.37 (3H, s),

3.75 (2H, t X d, J _t = 6 Hz, J _d = 1 Hz), 4.10 (2 H, s),

4.14 (2H, txd, J _t = 6 Hz, J _d = 1 Hz), mass spectrometry value (FAB, Pos, m / z): 249 ((M + 1) +) (7) 5-Acetylthiomethyl-6-chloro-2,3-dihydroimidazo [2,1-b] thiazole 0.20 g was added to methanol 10 ml, 1N sodium hydroxide aqueous solution 0.80 ml was added, and the mixture was added at room temperature. Stir for 30 minutes. 30 ml of water was added to the residue obtained by evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid was added to adjust the pH to 5, and the mixture was extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 0.13 g of 6-chloro-5-mercaptomethyl-2,3-dihydroimidazo [2,1-b] thiazol.

Physicochemical properties

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

 5: 185 (1H, t, J = 7Hz),

 3.70 (2Η, d, J = 7Hz),

3.80 (2H, t xd, J _t = 7 Hz, J _d = 1 Hz),

4.23 (2H, t xd, J t = 7Hz, J d = 1 Hz) Mass spectrometry value (EI, m / z): 206 (M +)

Example 5

(1R, 5 S, 6 S) — 6— ((1 R) — 1-hydroxyethyl) 1 2— [(1-ethylimidazo [1, 2-a] pyrimidine-2-io) methylthio] 1 1— Methylcarbapene 1-2-em 3- 3-carboxylate

In the same manner as in Example 4, synthesis was performed using methyl iodide instead of methyl iodide.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 <5: 1.03 (3H, d, J = 7Hz),

 1.1 3 (3H, d, J = 7Hz),

 1.46 (3H, t, J = 7Hz),

 3.1 0 (2H, m), 3.88 (3H, m),

 3.98 (1 H, m),

 4, 38 (2H, AB q, J = 15 Hz, mm v = 53 Hz)

4.98 (1 H, broads.),

7.70 (1H, dd, J, = 7Hz, J ₂ = 4 Hz),

8.3 1 (1 H, s),

 9.07 (1 H, d, J = 4 Hz),

 9.34 (1 H, d, J = 7 Hz)

 Mass spectrometry value (FAB, Pos, m / z): 403 ((M + 1) +)

 KB

Infrared absorption spectrum (cm " ¹ ); 3448, 1750 1 642, 1 596, 1 392

Example 6 (1R, 5 S, 6 S) — 6— ((1 R) — 1-hydroxyethyl)-2-[(1-acetonylimidazo [1, 2- a] pyrimidine-1 2 — io) Methylthio] 1-Methylcarbapene 1- 2-Em- 1 3-force Ruboxylate

In the same manner as in Example 4, synthesis was performed using 1-bromo-2-propanone instead of methyl iodide.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 δ: 1.02 (3Η, d, J = 7Hz),

 1.12 (3Η, d, J = 6Hz),

 2.38 (3H, s), 2.50 (3H, s),

 3.09 (2H, m), 3.88 (1H, m),

 3.97 (1H, d, 8Hz),

 4.32 (2H, ABq, J = 15 Hz, Δν = 35 Hz) 7.75 (1H, m), 8.39 (1 H, s),

 9.06 (1 H, d, J = 4Hz),

 9.40 (1 H, d, J = 7 Hz)

Mass spectrometry value (FA B, Pos' mZz): 431 ((M + 1) ⁺ )

 KB i

Infrared absorption spectrum (cm ^-1 ); 3456, 1 750 1 74 0, 1 6 4 4, 1 5 9 8, 1 5 4 6, 1 3 9 4

Example 7

Crude paranitrobenzyl (1R, 5S, 6S) obtained in (1) of Example 3—6-((1R) -1-hydroxyethyl) —2 _ [(imidazo [1, 2-a] pyrimidine-1-yl) methylthio] -1 1-methylcarbapene 2-emmu-3-carboxylate 50 Omg (0.98 1 mmo 1) with 5 m 1 of acetonitrile and 50 Omg of acetoamide iodide The mixture was stirred overnight at room temperature. The mixture was further stirred at 50 ° C for one day. Thereafter, the same treatment as in Example 4 was carried out, and (1R, 5S, 6S) —2-[[(1-1 (aminocarbonylcarbonylmethyl) imidazo [1,2—a] pyrimidine-1--2-yl] Methylthio] -1-6-((1R) -1-hydroxyethyl) -1-methylcarbapene-2-emup 3-potassium propyloxylate 37 mg was obtained.

Physicochemical properties

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

 5: 1.04 (3H, d, J = 6.7Hz),

 1. 1 2 (3H, d, J = 6.1 Hz),

 3.0 8 (1 H, d, J = 2.5 Hz),

 3.86 (1 H, d q),

 3.96 (1 H, d, J = 7.5 Hz),

4.1 8, 4.31 (2H, AB q, J = 15 Hz), 5.21, 5.27 (2H, ABq, J = 17Hz),

7.75 (1H, dd, J, = 4.5 Hz, J ₂ = 6.4 Hz)

8.30 (1 H, s),

 9.08 (1H, d, J = 4.3Hz),

 9.41 (1 H, d, J = 6.1 Hz)

Mass spectrometry value (F Po s, m / z): 432 ((M + 1) ⁺ ) Example 8

(1) Using 3-mercaptomethylimidazo [1,2-a] pyrimidine 60 Omg (3.64 mmo 1), the same procedure as in (1) of Example 1 was carried out, and paranitrobenzyl (1R, 5S, 6 S) -6-((1R) -11-hydroxyethyl) -12-[(imidazo [1,2-a] pyrimidine-13-yl) methylthio] -11-methylcarbapene-12- 1.24 g of m-one 3-carboxylate was obtained.

Physicochemical properties

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

 <5: 1.25 (3H, d, J = 6.5 Hz),

 1.36 (3Η, d, J = 6.0 Hz),

 2.58 (1 H, b r s),

 3.28 (1 H, d, J = 5.5 Hz),

3.5 -3.6 (1 H, m), 4.2 -4.3 (2 H, m), 4.3 1, 4.53 (2H, ABq, J = 14.5 Hz), 5.18, 5.44 (2H, ABq, J = 1 Hz),

6.9 -7.1 (1 H, m),

 7.60, 8.19 (4H, AB q, J = 8.5 Hz), 7.83 (1H, s), 8.5 -8.7 (2H, m)

Mass spectrometry value (FAB, Pos, m / z): 5 10 ((M + 1) ⁺ ) (2) No. Lanitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-2-[(imidazo [1,2-a] pyrimidin-3-yl) methylthio] Using 607 mg of 11-methylcarbapene-12-ammon-3-carboxylate, the procedure of (1R, 5S, 6S) —6 — ((1R ) — 1-Hydroxytyl) — 2 — ((imidazo [1,2-a] pyrimidin-3-yl) methylthio] -11-methylcarbapen-2-em-carboxylic acid 130 mg was obtained.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMSO- d _e, TMS internal standard)

 <5: 1.1 2 (3H, d, J = 7.5Hz),

 1.37 (3Η, d, J = 6.5 Hz),

3.22 (1 H, dd, J, = 2.5 Hz, J ₂ = 6.0 Hz): 3.4 (1 H, brs), 3.65 (1 H, dq),

3.95 (1 H, dd, J '= 6.0 Hz, J ₂ = 6.0 Hz) 4.1 1 (1 H, dd, J) = 2.5 Hz, J ₂ = 9.5 Hz

4.56, 4.63 (2H, ABq, J = 15Hz), 7.1 -7.3 (1H, m), 7.79 (1H, s), 8.60 (1H, d, J = l.5Hz),

8.96 (1 H, d, J = 6.0 Hz) Mass spectrometry value (FAB, Pos, m / z): 375 ((M + 1) +)

Paranitrobenzyl (1 R, 5 S, 6 S) — 6— ((1 R) — 1 — hydroxyethyl) 1-2 — ((imidazo [1, 2-a] pyrimidin-1 3-yl) [Methylthio] -11-methylcarbapene-12-em-1-carboxylate Using 607 mg, and in the same manner as in Example 2, (1R, 5S, 6S) -6-((1R)- 1-Hydroxyethyl) —2-([1-methylimidazo [1,2-a] pyrimidine-13-yl) methylthio] -1-methylcarbapene-2-emup-3-carboxylate 6 Omg was obtained.

Physical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 d: 0.93 (3 H, d, J = 7.5 Hz),

 1.12 (3 H, d, J = 6.0 Hz),

 , 3.02 (1 H, d, J = 9.0 Hz),

3.05 -3.07 (1 H, m), 3.80 -3.95 (1 H, m) 3.95 to 4.00 (1 H, m), 3.99 (3 H, s), 7.76 (1 H, dd, Jj = 4.0 Hz, J ₂ = 7.0 Hz), 8.35 (1 H, s),

9.12 (1 H, dd, J, = 2.0 Hz, J ₂ = 4.0 Hz), 9.75 (1 H, d, J = 6.0 Hz)

Mass spectrometry value (FAB, Pos, m / z): 389 ((M + 1) ⁺ ) Example 10

(1) (4 R) — 2-diazo-4 — ((2 R, 3 S)-3-((1 R) — 1-hydroxyethyl) 1-4 — oxoazetidine 1-2 yl) 1 3 — To 1.84 g (4.73 mmo 1) of paraditrobenzyl oxopentanoate, 10 ml of toluene was added, and 5 mg of a rhodium (U) acetate dimer was added at 90 ° C. in an argon stream. After stirring at the same temperature for 10 minutes, toluene was distilled off under reduced pressure.

 The obtained crude paranitrobenzyl (1 R, 5 S, 6 S)-6-

((1 R) — 1-Hydroxyethyl) 1-Methyl-2-oxo-force Lubapenham 3- 3-carboxylate, add 1 Oml of acetonitrile, and diisopropylethyla at 120 ° C under a stream of argon 0.87 m 1 (4.9 mm 01) of min and 102 ml (4.9 mmo 1) of diphenyl phosphate chloride were added, and the mixture was stirred at the same temperature for 1 hour. At the same temperature, 2-acetylthiomethylimidazo [1,2-b] pyridazine 0.98 g of a 10% methanol solution of 10 ml of methanol was added under ice-cooling to a 28% methanol solution of sodium methylate 0 .92 ml were added, and the solution stirred as it was for 15 minutes was added. After stirring under ice cooling for 1 hour, the reaction mixture was poured into a large amount of acetic acid Echiru, this water, this _c was washed with saturated brine and dried over anhydrous sodium acetate, filtered, vacuum distillation of the solvent Leave Was. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (40: 1, v / v). Paranitrobenzyl (1R, 5S, 6S) — 6— ((1R) — 1— Hydroxyethyl) 1-2-((imidazo [1, 2-b] pyridazine-1-2-yl) methylthio]-1 -methylcarbapene-1-2-emu 3-carboxylate

L 69 g was obtained.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

 d: 1.32 (3H, d, J = 7.5 Hz),

 1.35 (3 Η, d, J = 6.0 Hz),

3.28 (1H, dd, Jj = 4.3Hz, J 2 = 7.0Hz),

3.70 -3.75 (1 H, m),,

 4.1 8, 4.34 (2H, ABq, J = 15Hz),

4.1 9 (1 H, d, J = 2.0 Hz),

 4.2 -4.3 (1 H, m),

 5.23, 5.49 (2 H, ABq, J = 14Hz),

7.07 (1H, dd, Ji = 4.5 Hz, J 2 = 9.5 Hz),

7.64, 8.20 (4H, ABq, J = 9.5 Hz),

7.92 (1 H, d, J = 9.5 Hz),

 7.93 (1 H, s),

8.3 1 (1 H, dd, J, = 1.3 Hz, J ₂ = 4.8 Hz) Mass spectrometry (FAB, Pos, m / z): 5 10 (CM + 1) +)

(2) Paranitrobenzyl (1R, 5S, 6S) -16-((1R) -1-hydroxyethyl) 1-2-[(imidazo [1,2-b ] Pyridazine-1-yl) methylthio] 1-1-methyl-l-bapene 2-em-31-carboxylate 49 Omg (0.962 (1 mmol) and (1R, 5S, 6S) — 6— ((1R) — 1-hydroxyl) 1 2-— ((imidazo [ 1,2-b] pyridazine-12-yl) methylthio] -11-methylcarbapene-12-emu-3-carboxylic acid / sodium salt 114 mg was obtained.

Physicochemical properties

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

 <5: 1.05 (3 H, d, J = 7.6 Hz),

 1.15 (3H, d, J = 7.2Hz),

3.0 1 (1 H, dd, J, = 2.8 Hz, J ₂ = 6.8 Hz),

3.3 1 -3.38 (1H, m), 3.85 -3.90 (2H, m) 3.96, 4.09 (2H, ABq, J = 14Hz), 7.19 (1H, dd, J, = 4.2 Hz, J ₂ = 9.4 Hz), 8.04 (1 H, d, J = 9.2 Hz),

 8.1 6 (1 H, s),

8.46 (1 H, dd, J, = 1.0 Hz, J ₂ = 4.6 Hz) Mass spectrometry (FAB, Pos, m / z): 375 ((M-22) ⁺ ),

 397 ((M + 1) +), 4 19 ((+ 23) +) Infrared absorption spectrum

max (cm " ¹ ); 3460, 1 758, 1 594, 1 404 Example 1 1

No, ° Lanitrobenzil (1 R, 5 S, 6 S) — 6— ((1 R) — 1-hydroxyethyl) —2— 〔(Imidab [1,2—b] pyridazin-2-yl ) Methylthio] 1-Methylcarbapene-2-emou 3-carboxylate To 65 Omg (I.28mmo1), 5 ml of acetonitrile and methyl lm1 were added, and the mixture was stirred at room temperature for 2 days. Thereafter, the same treatment as in Example 4 was carried out, and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-2-[(1-methylimidazo [1,2-b 58 mg of pyridazinium-1-yl) methylthio] -11-methylcarbapene-12-emm-3-carboxylate were obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

 d: 0.99 (3H, d, J = 7.5Hz),

 1.1 1 (3H, d, J = 6.0 Hz),

3.07 (1 H, dd, J, = 2.5 Hz, J ₂ = 6.5 Hz), 3.12 (1 H, dq), 3.86 (1 H, dq),

3.95 (1 H, dd, J, = 2.5 Hz, J ₂ = 9.5 Hz),

4.08 (3 H, s),

 4.25, 4.36 (2 H, ABq, J = 15Hz),

7.92 (1H, dd, Ji = 4.5 Hz, J ₂ = 9.5 Hz), 8.77 (1 H, s),

 8.83 (1 H, d, J = 9.5 Hz)

 9.02 (1H, d, J = 4.0Hz)

 Mass spec (FAB, Pos, m / z): 389 ((M + 1)

 KB i

 Infrared absorption spectrum; 3428, 1 752, 1 5 94

1 398

Example 1 2

(1) 2-Acetylthiomethyl-6-chloroimidazo [1,2-b) Pyridazine 803 mg, and the same procedure as in (1) of Example 10 was carried out. Paranitrobenzyl (1R, 5S , 6S) -6-((1R) -1-Hydroxyethyl) -1-2-((6-Imidab [1,2-b] pyridazine-12-yl) methylthio] -1-1-Methylcarba Pen O 2-hem-3-potoxyloxylate 56 Omg was obtained.

Physicochemical properties

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

 (5: 1.3 1 (3H, d, J = 7.3Hz),

 1.35 (3Η, d, J = 6.4Hz),

3.28 (1Η, dd, J, = 2.4 Hz, J ₂ = 6.8 Hz): 3.70 (i H, dq),

4.13, 4.3 1 (2H, AB q, J = 1.9 Hz), 4.1 8 (1H, dd, Ji = 2.7 Hz, J ₂ = 9.0 Hz),

4.25 (1 H, dq, J, = 6.4 Hz, J ₂ = 6.4 Hz),

5.22, 5.49 (2 H, ABq, J = 13.9 Hz), 7.08 (1 H, d, J = 9.3 Hz),

 7.64, 8.21 (4H, ABq, J = 8.8Hz),

7.83 (1 H, d, J = 9.3 Hz),

 7.89 (1 H, s)

 Mass spectrometry value (FAB, Pos, m / z): 544 ((M + 1) +) (2) No. Lanitrobenzyl (1 R, 5 S, 6 S) -6-((1 R) — 1-hydroxyethyl) 1-2— [(6-Chloroimidazo [1, 2—b] pyridazine-1-yl ) Methylthio] Using 1-methylcarbaben-2-emeu 3-carboxylate 55 Omg, the same procedure as in Example 11 was carried out to give (1R, 5S, 6S) -6-((1R) -1-H Droxityl) 1-2-[(6-Chloro-1-methylimidazo [1,2-b] pyridazinyl-2-yl) -methylthio] -1-methyl-l-rubapen-l- 2-emu-3-carboxylate 37 mg was obtained. Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 δ: 1.02 (3Η, d, J = 6.5 Hz),

 1.1 2 (3H, d, J = 5.0Hz),

3.1 0 (2H, dd, J! = 3.0 Hz, J ₂ = 6.0 Hz),

3.1 3 (1H, dq), 3.88 (1H, dq),

3.98 (1 H, dd, J, = 3.0 Hz, J ₂ = 9.5 Hz), 4.10 (3 H, s),

 4.24, 4.32 (2 H, ABq, J = 15.3 H z),

8.14 (1 H, d, J = 9.5 Hz), 8.8 1 (1 H, s),

 8.94 (1 H, d, J = 9.5 Hz)

 Mass spec (FAB, Pos, m / z): 4 2 3 ((M + 1)

 KB i

 Infrared absorption spectrum; 34 5 2, 1 75 2, 1 5 9 6

1 3 9 2

Example 13

Using 3-mercaptomethylimidazo [1,2-b] pyridazinamide trifluorofluorosulfonate and 3 equivalents of diisopropylethylamine, in the same manner as in Example 3 (1), paramethoxybenzyl (1R, 5S, 6S) — 6— ((1R) — 1-hydroxyethyl) 1-1-methyl-2-— ((imidazo [1, 2-b] pyridazine-3-ylmethyl) thio] 3-carboxylate was synthesized.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 5: 1.3 1 (3H, d, J = 7.3 Hz),

 1.36 (3H, d, J = 6.4 Hz),

 3.3 0 (1 H, m),

3.6 2 (1 H, dt, J, = 7.3 Hz, J ₂ = 2.0 Hz) _;

4.2 5 (2H, m), 4.51 (2H, ABq, J = 1.2 Hz, mm v = 38.1 Hz),

5.34 (2 H, ABq, J = 13.7 H z, Δν = 109.4Ηζ),

7.09 (1 H, dd, Jj = 9.3 Hz, J ₂ = 4.4 Hz),

7.62 (2H, d, J = 8.8 Hz),

 7.75 (1 H, s),

7.97 (1 H, dd, J ! = 9.3 Hz, J 2 = 1.5 Hz), 8.1 7 (2H, d, J = 8.8 Hz),

8.38 (1H, dd, J, = 4.4Hz, J 2 = 1.5Hz) Mass spectrometry value (FAB, P os, m / z): 5 1 0 (CM + 1) +)

 KB

 Infrared absorption spectrum 3408, 2948, 1 772

1708, 1 524, 1 348, 1 142, 756

 Paramethoxybenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-1-methyl-1-2-((imidazo [1,2-b [Pyridazine-1-ylmethyl) thio] l-lubapen-2-heme-3-carboxylate and (1R, 5S, 6S) -6-(( 1R) -1 -Hydroxyethyl) 1-methyl-2-[(imidazo [1,2, -b] pyridazine-13-ylmethyl) thio] l-lubapen-12-em-13-carboxylic acid was synthesized.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMSO— _ds , TMS internal standard)

 d: 0.90 (3H, d, J = 7.3Hz),

 1.1 3 (3Η, d, J = 6.4Hz),

2.96 (1 H, dd, J: = 6.8 Hz, J ₂ = 2.4 Hz),

3.1 9 (1 H, dt, J, = 7.3 Hz, J ₂ = 1.4 Hz), 3.89 (2H, m),

4. 3 1 (2H, AB q , J = 13. 7 H z, Δ v = 99. 1 Hz), 7.22 (1 H, dd, J, = 9.3Hz, J 2 = 4.4Hz),

7.72 (1 H, s),

8.1 1 (1 H, dd, J, = 9.3 Hz, J ₂ = 1.5 Hz),

8.5 8 (1 H, dd, Ji = 4.4 Hz, J ₂ = 1.5 Hz) Mass spectrometry value (FAB, Ne g, m / z): 3 7 3 ((M- 1) +)

 KB i

 Infrared absorption spectrum (cm-; 3456, 1750,

1 6 22, 1 4 0 2, 1 35 2, 8 3 6, 7 0 2

Example 14

Paramethoxybenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-1-methyl 2-([imidab) obtained in (1) of Example 13 [1,2—b] pyridazine-1-ylmethyl: thio] Lubapen-2-emu-3-carboxylate (1R, 5S, 6S) —6 — (( 1 R) — 1-Hydroxitytyl) 1-methyl-2-([1-methylimidazo [1, 2-b] pyridazine-13-io) methylthio] .

Physicochemical properties

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) 5: 0.93 (3 H, d, J = 6.8 Hz),

 1. 1 2 (3H, d, J = 6.3Hz),

3.0 4 (1 H, dd, Ji -6.8 Hz, J ₂ = 2.9 Hz) 3.16 (1 H, m), 3.88 (1 H, m),

 3.9 8 (1 H, m), 4.10 (3 H, s),

 4.34 (2H, AB q, J = 14.6, Δv = 64.0), 5.1 1 (1H, broads),

7.97 (1 H, dd, J, = 9.3 Hz, J ₂ = 4.4 Hz)

8.4 9 (1 H, s),

 8.8 1 (1 H, d, J = 9.3 Hz),

 9.14 (1 H, d, J = 4.4 Hz),

Mass spectrometry value (FAB, Pos, mZz): 389 ((M11) ⁺ )

 KB]

 Infrared absorption spectrum; 3424, 1 754, 1 5 9 6 1 3 8 6, 8 0 8

Example 15

(1) Using 3-mercaptomethyl-1,2,4-triazolo [1,5—a] pyrimidine (1.90 g, 11.4 mmo 1), the same procedure as in (1) ′ of Example 1 was carried out. Paranitrobenzyl (1R, 5S, 6S) -1-6-((1R) -1-hydroxyethyl) 1-2-[(1,2,4-triazolo [1,5-a] pyrimidine-1 3-yl) methylthio] 4.91 g of 1-methylcarbapene-2-emou 3-carboxylate was obtained.

Physicochemical properties ''

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 5: 1.33 (3H, d, J = 7.3 Hz),

 1.3 8 (3Η, d, J = 6.3 Hz),

3.3 1 (1 H, dd, = 2.4 Hz, J ₂ = 6.4 Hz),

4.07 (1H, dq),

 4.16, 4.4 0 (2H, AB q, J = 14.7 Hz), 4.2-4.4 (2H, m),

 5.2 0, 5.4 6 (2 H, A B q, J = 13.7 H z),

7.15 (1 H, dd, J, = 3.9 Hz, J ₂ = 6.8 Hz),

7.6 2, 8. 19 (4 H, dd, J = 9.0 Hz),

 8.75 -8.8 5 (2 H, m)

Mass spectrometry (FAB, Pos, m / z): 5 1 1 ((M + 1) ⁺ )

(2) Paranitrobenzyl (1R, 5S, 6S) -16-((1R) -1-hydroxyethyl) 1-2-[(1,2,4-triazolo) obtained in (1) [1,5-a] Pyrimidine-1-yl) methylthio] Using 1-methylcarbapene-12-emu-3-carboxylate (500 mg), the same procedure as in (2) of Example 1 was carried out. (1 R, 5 S,

6 S) — 6— ((1 R) — 1-hydroxyethyl) — 2— [(1,2,4-triazolo [1, 5-a] pyrimidine-3-yl) methylthio] — 1 There was obtained 139 mg of 2-methylcarbapene-2-emu-3-carboxylic acid / sodium salt.

Physicochemical properties

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) δ: \. Π (3H, d, J = 7.0 Hz),

 1.18 (3H, d, J = l.0 Hz),

3.2 2 (1 H, d, Jj = 2.3 Hz, J ₂ = 6.8 Hz),

3.8 5 (1 H, d q), 3.95 (1 H, d q),

4. 1 3 (1 H, dd , Jj = 2.3Hz, J 2 = 9.3Hz),

4.27, 4.40 (2 H, AB q, J = 14.0 Hz),

7.37 (1 H, dd, Jj = 4.5 Hz, J ₂ = 6.5 Hz),

8.8 8 (1 H, d d),

9.3 8 (1 H, dd, J, = 2.0 Hz, 7.0 Hz) Mass spectrometry value (FAB, Pos, m / z): 376 ((M + 1) ⁺ ) Example 16

Example 15 Paranitrobenzyl (1R, 5S, 6S) —6 — ((1R) —1-hydroxyethyl) 1-2 — [(1,2,4-1) Triab mouth [1,5-a] Pyrimidine-3-yl) methylthio] 1-methylcarbapene-12-emu 3-carboxylate 505 mg was dissolved in 15 ml of methylene chloride and cooled on ice. 0.34 ml of methyl trifluoromethanesulfonate was added, and the mixture was stirred as it was for 1 hour. Thereafter, the same treatment as in Example 2 was carried out, and (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-2-[(4-methyl-1,2,4-triazolo) [1,5-a] Pyrimidine-13T) methylthio] -1-methylcarbapene-2-em-3-carboxylate 64 mg Obtained.

Physicochemical properties

Nuclear magnetic resonance spectra (D ₂ 0, TSP internal standard)

 <5: 1.26 (3H, d, J = 7.3Hz),

 1.28 (3H, d, J = 6.4 Hz),

 3.22 (1 H, d d), 3.3 -4.4 (3 H, m),

4.1 1 (, s),

 4.43, 4.62 (2 H, AB q, J = 15.6 Hz),

7.9 1 (1 H, dd, J, = 4.4 Hz, J ₂ = 6.8 Hz)

9.30 (1 H, d, J = 2.8Hz),

 9.44 (1 H, d, J = 2.8 Hz)

 Mass spectrometry value (FAB, Pos, m / z): 390 ((M + 1) +) Example 17

(1) Using 2-acetylthiomethylimidazo [1,2-b] [1,2,4] triazine in the same manner as (1) of Example 10 to prepare paramethoxybenzyl (1R, 5S, 6). S) — 6— ((1R) — 1-hydroxyshethyl) 1- 1-methyl- 2— [(Imidazo [1, 2, 4-b] [1, 2, 4] triazine-6-ylmethyl) thio] 1-1-methylcarbapene _2-emm-1-3-carboxylate was synthesized.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard) : 1.32 (3H, d, J = 7Hz),

 1.34 (3H, d, J = 6 Hz),

3.22 (1 H, dd, J, = 7 Hz, J ₂ = 3 Hz), 3.9 1 (1 H, m), 4.20 (2 H, m),

 4.28 (2 H, AB q, J = 14 Hz, Δν = 27Ηζ),

5.38 (2H, AB q, J = 1 3 Hz, mm v = 26Hz),

7.67 (2H, d, J-8 Hz), 7.95 (1H, s),

8.23 (2H, d, J = 8Hz),

 8.39 (1 H, d, J = 2 H z),

 8.47 (1 H, d, J = 2 H z)

 Mass spectrometry value (FAB, Pos, m / z): 5 11 (CM + 1) +) (2) Paramethoxybenzyl (1R, 5S, 6S) obtained in (1) — 6— (( 1 R) — 1-Hydroxyethyl) 1 1-Methyl 1 2 1 [(Imidazo [1, 2-b] [1, 2, 4] Triazine-6-ylmethyl) thio] 1 1-Methylcarbapene 1 2 — (1R, 5S, 6S) —6 — ((1R) —1-hydroxyethyl) 1-2—using を am-1-carboxylate in the same manner as in (2) of Example 3 [(Imidab [1,2-b] [1,2,4] triazine-6-ylmethyl) thio] 11-methylcarbapene-12-em-3-carboxylic acid was synthesized.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 5: 1.04 (3H, d, J = 6.7Hz),

 1.1 4 (3Η, d, J = 6.8 Hz),

 3.00 (1 H, m), 3.20 (1 H, m),

3.88 (2H, m), 4.05 (2H, AB q, J = 14.7 Hz, Δv-70.2 Hz),

8.2 5 (1 H, s),

 8.5 3 (1 H, d, J = 2.4 Hz),

 8.62 (1 H, d, J = 2.4 Hz)

 Mass spectrometry value (FAB, Pos, mZz): 398 ((M + Na) +) Example 18

Example 17 Paramethoxybenzyl (1R, 5S, 6S) —6-((1R) -1-hydroxyethyl) obtained in (1) of 11-Methyl 2-([imidazo [ 1,2-b] [1,2,4] triazine-6-ylmethyl) thio] 1-1-methylcarbapene-2-hemo-3-carboxylate, using methyl iodide in the same manner as in Example 4. Instead of using 1 equivalent of methyl trifluoromethanesulfonate-(1 R, 5 S, 6 S) — 6— ((1 R) — 1-hydrid α-xitytyl) 1 1—methyl 1 2— [[(5 —Methylimidazo [1,2-b] [1,2,4] triazine-1-6-) methyl] thio] l-lubapen-1 2-hemo-3-carboxylate was synthesized.

Physicochemical properties

Mass spectrometry value (FAB, Pos, m / z): 389 (M ⁺ )

 KB

 Infrared absorption spectrum (cm-; 34 2 8, 1 7 5 4

1 5 9 8, 1 3 9 6, 1 2 9 0 Example 19

(1) 5- (Acetylthiomethyl) imidazo [2,1-b] thiazole was used in the same manner as (1) in Example 10 using 2.50 g of paranitrobenzyl (1R, 5S , 6 S) — 6— ((1 R) — 1-hide mouth quichetil) 1 2— [(imidazo [2, 1 1 b] thiabour-5-yl) methylthio] 1 1-methylcarbapene 1 2 2.50 g of lipoxylate were obtained.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 d: 1.30 (3H, d, J = 6.5 Hz),

 1.36 (3H, d, J = 7.0 Hz),

3.27 (1 H, dd, J x = 2.5 Hz, J ₂ = 6.3 Hz), 3.3 -4.2 (3H, m),

 4.04, 4.16 (2H, ABq, J = 14.8 Hz), 5.22, 5.49 (2H, ABq, J = 13.8Hz),

6.75 (1 H, d, J = 4.4 Hz),

 7.3 -7.5 (1H, m), 7.37 (1H, s), 7.64, 8.09 (4H, ABq, J = 8.8Hz)

(2) Paranitrobenzyl (1R, 5S, 6S) -1 6 — ((1R) —1-hydroxyethyl) 1-2 — [(imidab)

[2, 1-b] 1-methyl-thio] (LR, 5S, 6S) -6-((1R) -1) in the same manner as in (1) of Example 1 using 50 lmg of l-lubapen-2-hem-3-carboxylate —Hydroxyethyl) —2-((imidazo [2,1—b] thiazo-l-uyl-5-methyl) methylthio] -l-l-methylcarbaben-2-em-l-l-capronic acid 44 mg was obtained. .

Physicochemical properties

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

 5: 1.05 (3H, d, J = 7.0 Hz),

 1.1 5 (3Η, d, J = 6.1 Hz),

 3.0 1 (1 H, d d), 3.37 (1 H, d q), 3.7— 4.0 (2H, m),

 3.83, 3.94 (2 H, ABq, J = 14.1 Hz),

6.93 (1 H, d), 7.22 (1 H, d),

 7.46 (1 H, s)

Mass spectrum (FAB, Pos, m / z): 380 ((M-2) ⁺ )

 402 ((M + l) +) Example 20

Paranitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) 1-2-[(imidazo [2,1- b] thia.zolyl 5-yl) methylthio] 1-1-methylcarbapene-2-hem-3-carboxylate 500 mg (1R, 5S, 6S) -6-((1) —1-hydroxyethyl) —2 -— ((6-methylimidazo [2,1-b] thiazole-5— Yl) methylthio] 1-methylcarbene pent-2-em-3-carboxylate 69 mg was obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

 <5: 0.98 (3H, d, J = 7.4 Hz),

 1.12 (3Η, d, J = 6.4Hz),

 3.05 (1Η, dd), 3.1 1 (1Η, dq), 3.8-4.0 (2Η, m), 3.94 (3Η, s), 4.14, 4.32 (2Η, ABq, J = 14Hz).

7.72 (1Η, d, J = 4.0 Hz),

 8.14 (1Η, s),

 8.24 (1Η, d, J = 4.ΟΗζ)

Mass spectrometry value (FAB, Pos. MZz): 394 ((M + 1) ⁺ ) Example 21

(1) Crude 2-mercaptomethyl-8- (4-dinitrobenzoylcarboyl) — 5,6,7,8-tetrahydroimidazo [1,21a] pyrimidine monotrifluoromethanesulfonate 4.00 g and diisopropylethylamine 5.4 ml, and in the same manner as in Example 1, (1), paranitrobenzyl (1R, 5S, 6S) -6-((1R) 1-1-hydroxyethyl) 1-2- [C (4-nitrobenzoylcarbonyl) -1,5,6,7,8-tetrahydromidazo [1,2-a] piperazine-12-yl] methylthio] There was obtained 34 mg of 11-methylcarbapene-12-em-3-carboxylate.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 <5: 1.30 (3H, d, J = 7.4Hz),

 1.35 (3Η, d, J = 6.4 Hz),

 2.1 -2.2 (2H, m),

 3.25 (1 H, d d, J = 2.4 Hz, J = 6.8 Hz),

3.73 (1 H, d q), 3.9 -4.0 (4 H, m),

3.95, 4.13 (2H, AB q, d = 14.1 Hz),

4.2 -4.3 (2H, m),

 5.23, 5.5 2 (2H, AB q, d = 13.8 Hz), 6.64 (1H, s),

 7. 6 6, 8.2 1 (4 H, AB q, d = 8.8 Hz), ― 7.70, 8.23 (4 H, AB q, d = 8.8 Hz),

Mass spectrometry value (FAB, Pos, m / z): 693 ((M + l) ⁺ ) (2) Paranitrobenzyl (1R, 5S, 6S) obtained from (1) — 6 — ((1 R) — 1-hydroxyethyl) 1 2— [(4-nitrobenzyloxycarbonyl) 1,5,6,7,8-tetrahydroimidab [1,2-a] piperazine 1-2-yl] methylthio] 1-1-methylcarbapene-12-em-3-carboxylate Performing in the same manner as in Example 2 using 720 mg, (1R, 5S, 6S) -6 -((1R) — 1-Hydroxyethyl) 1-2- ((1-Methyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrimidine-12-yl) [Tylthio] 21-methylcarbapene-2-em-3-carboxylate 21 mg was obtained.

Physicochemical properties

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

 δ: 1.0 S (3Η, d, J = 7.3Hz),

 1.1 4 (d, J = 7.6Hz),

 1.9 -2.0 (2H, m), 3.07 (1H, dd), 3.24 (1H, dq), 3.8 -3.9 (6H, m), 3.86, 3.99 (2H, ABq, J = 14.8Hz), 6.78 (1 H, s)

Mass spectrometry value (FAB, Pos, m / z): 393 ((M + 1) ⁺ ) Example 22

(1) Using 6-chloro-5-mercaptomethyl-2,3-dihydroimidazo [2,1-b] thiazole, as in (1) of Example 1, (1 R, 5S, 6S) —2 — [[(6-Chloro-2,3-dihydroimidazo [2,1-b] thiabour-5-yl) methyl] thio] 1 6— ((1 R) — 1-hydroxyethyl) 1 1 Monomethylcarbapene-2-em-3-carboxylic acid paranitrobenzyl ester was synthesized.

 Physicochemical properties

Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard) 5: 1.26 (3H, d, J = 7Hz),

 1.36 (3H, d, J = 7Hz),

 3.30 (1H, m), 3.52 (1H, m),

 3.78 (2H, m),

 4.00 (2 H, AB, J = 15 Hz, Δv = 125 Hz),

4.25 (4 H, m),

 5.35 (2H, AB, J = 1 4 Hz, Δ v = lll Hz),

7.65 (2H, d, J = 9Hz),

 8.22 (2H, d, J = 9 Hz),

Mass spec (FAB, Pos, m / z): 55 1 ((M + l) ⁺ )

(2) (1R, 5S, 6S) obtained in (1) —2— [((6—black mouth—2,3-dihydroimidazo [2,1—b] thiazolu-5-y Methyl) thio] — 6— ((1 R) — 1-hydroxyethyl) 1-methylcarbapene 1-2-emu 3-carboxylic acid )) (1R, 5S, 6S) —2-[[(6-Chloro-2,3-dihydro [2,11b] thiazol-5-yl) methyl] thio] -1-6— ( (1 R) — 1-Hydroxyethyl) 1-Methylcarbapene 12-Emmy-3-carboxylic acid was synthesized.

Physicochemical properties

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

 <5: 0.97 (3H, d, J = 7Hz),

 1.13 (3H, d, J = 7Hz),

 3.05 (2H, m), 3.86 (4 H, m),

 4.25 (2 H, m)

Mass spectrometry value (FAB, Pos, m / z): 4 16 ((M + l) ⁺ ) 438 (Cool a) ⁺ ) Example 23

(1R, 5S, 6S) -2 [[((6—chloro-1,2,3-dihydroimidazo [2,11b]) thiazolu-5 obtained in (1) of Example 22) -(Yl) methyl] thio] -1 6- ((1R) -1-hydroxyl-ethyl) -1-methylcarbapene-12-emu-3-carboxylic acid Paranitrobenzyl ester was prepared in the same manner as in Example 2 ( 1 R, 5 S, 6S) —2— ([(6-Cross 1—7-methyl-1,2,3-dihydroimidazo [2,1-b] thiazol-5-io) methyl] thio] 1 6— ( (1 R) — 1-Hydroxyethyl) 1-methylcarbapene 1-2-emu-3-carboxylate was synthesized.

Physicochemical properties

 Nuclear magnetic resonance spectrum (DMSO—d &, TMS internal standard) d: 1.0 1 (3H, d, J = 7Hz),

 1.1 2 (3H, d, J = 6Hz),

 2.98 (1 H, m), 3.1 1 (1 H, m),

 3.6 1 (3H, s), 3.90 (2H, m),

 3.99 (2H, AB, J = 15Hz, Δν = 95Hz), 4.13 (1H, m), 4.28 (1H, m),

 4.55 (1 H, m), 4.67 (1 H, m),

4.99 (1 H, s) Mass spectrometry value (FAB, Pos, m / z) 4 3 0 ((M + l) +) Reference example 1 2

H ₃

(1) To 10.0 g (70.9 mmo 1) of 2-amino-4,6-dihydroxy-15-methylpyrimidine was added 40 ml of phosphorus oxychloride, and the mixture was heated under reflux for 20 minutes. It was poured on ice, and the precipitated salt was collected by filtration and dried to obtain 9.109 g of crude 2-amino-1,4,6-dichloro-5-methylpyrimidine.

Elemental analysis value C ₅ H ₅ N ₃ C 1 ₂

 Calculated value: C, 33.73; H, 2.83; N, 23.60 CI, 39.83; Actual value: C, 33.71; H, 2.77; N, 23.83 C1, 39.54; (2) The obtained 2-amino-4,6- 1,4-dioxane (1.40 ml), 5% palladium-supported carbon (4.0 g), and triethylamine (6.4 ml) (4.5 mmo1) were added to 4.00 g (22.5 mmo1) of dichloride 5-methylpyridine, and hydrogen atmosphere was added. The mixture was stirred at room temperature for 7 hours. Then, after filtration through celite, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1, v / v) to give 1.93 g of 2-amino-15-methylpyrimidine.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 <5: 2.14 (3H, s), 4.95 (2H, broads),

8. 1 3 (2Η, s) Mass spectrometry value (EI, m / z): 109 (M ⁺ )

 (3) To 1.93 g (17.7 mmo 1) of the obtained 2-ryminnow 5-methylpyrimidine was added 200 ml of tetrahydrofuran and 8.90 g (70.8 mmo 1) of 1,3-dichloroacetone, and water was removed. The mixture was heated under reflux for 8 hours. After the precipitated salt was collected by filtration, a 4 N hydrochloric acid / ethyl acetate solution was added to the salt, and the mixture was stirred at room temperature for 20 minutes. Thereafter, the pH was adjusted to 9 with a saturated aqueous potassium carbonate solution, and the mixture was extracted with chloroform. This was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1, v / v). 1.63 g of 2-chloromethyl-6-methylimidazo [1,2-a] pyrimidine was obtained. Obtained.

Physicochemical properties

 Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

 (5: 2.37 (3H, d, J = 1 Hz),

 4.7 8 (2 Η, s), 7.5 2 (1 Η, s),

 8.42 (1 H, d, J = 2 Hz)

Mass spec (EI, m / z): 18 1 (M ⁺ )

(4) p-Methoxybenzylthiol (90%) 2.16 ml (13.5 mmo 1) and sodium hydride (60%) 744 mg (19.9 mmo 1) were added to 20 ml of tetrahydrofuran. The mixture was stirred at 0 for 5 minutes. Dissolve 1.63 g (8.97 mmo 1) of 2-chloromethyl-6-methylimidazo [1,2-a] pyrimidine obtained in 10 ml of tetrahydrofuran and add for 30 minutes at 0 ° C. Stirred. A saturated aqueous sodium chloride solution was added to the reaction mixture for neutralization, and the mixture was extracted with porcine form. This is dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (19: 1, vZv) to give 2- (p-methoxybenzylthiomethyl) imidazo [1,2-a] pyrimidine 2.5 1 g was obtained.

Physicochemical properties

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

 δ: 2. S A (3H, s), 3.78 (7 H, m),

 6.80 (2 H, d, J = 8.4 Hz),

 7.26 (2H, d, J = 8.4 Hz),

 7.37 (1H, s), 8.14 (1H, s),

 8.3 6 (1 H, s)

Mass spectrometry value (FAB, Pos, m / z): 300 ((M + 1) +) (5) Obtained 2- (p-methoxybenzylthiomethyl) imidazo [1,2-a] 10 ml of anisol, 50 ml of trifluoroacetic acid and 1.42 ml of trifluoromethanesulphonic acid were added to 2.40 g (8.0 mmo1) of pyrimidine at 0 at 0 and stirred for 2 hours. _c then 1 5 ° C _c residues of Torifuruoro acetate was distilled off under reduced pressure while cooled below subjected to silica force gel chromatography, black hole Holm one _methanol: eluting with (4 1, Y / Y) , the purpose The fractions were collected, concentrated under reduced pressure, and recrystallized from methanol. The precipitated crystals were collected by filtration and dried to obtain 1.03 g of di (2,6-dimethylimidazo [1,2-a] pyrimidine-12-yl) disulfide.

Physicochemical properties

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

 5: 2.38 (6 H, s), 4.18 (4 H, s),

7.97 (2H, s), 8.69 (2H, d, J = 2Hz),

 8.95 (2H, d, J = 2Hz)

Mass spectrometry value (FAB, Po s, mZz): 357 (CM + 1) ⁺ ) Example 24

(1) (1R, 5 S, 6 S) — p—Nitrobenzyl 2 — (diphenylphosphoryloxy) 1 6— [(1R) —hydroxyethyl] — 1—methyl monolrubapene 2 20 ml of acetonitrile was added to 3,38 g (5.69 mmo 1) of -emu 3-carboxylate, and the mixture was stirred at 0 ° C. There, 1.99 ml (11.3 mmo 1) of diisopropylethylamine and 1.00 g of the obtained di (2,6-dimethylimidazo [1,2-a] pyrimidine-1 2- ^ fru) disulfide (5.58 country ol ) And 3.08 g (11.2 mmo 1) of trityl mercaptan were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into a phosphate buffer of pH 7.00 and extracted with a black hole form. After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with chloroform-methanol (9: I, v / v). Paramethoxybenzyl (1R, 5S, 6S) -6-((1R) -1 -Hydroxyethyl] 11-methyl-12-[(6-methylimidazo [1,2-a] pyridazine-12-ylmethyl) thio] levapene-12-emu-3-carboxylate 785 mg was obtained.

Physicochemical properties Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 (5: 1.30 (3H, d, J = 7.3Hz),

 1.34 (3Η, d, J = 6.4 Hz),

 2.3 7 (3 H, s),

 3.27 (1 H, d d, J i = 6.8 Hz, J = 2.4 H z),

3.86 (1 H, m),

 4.18 (1H, dd, J, = 9.4Hz, J = 2.4Hz), 4.21 (2H, ABq, J = 15.1Hz, Δv = 113.8Hz),

4.25 (1 H, m),

 5.34 (2 H, AB q, J = 14 Hz, Δν = 111.3Ηζ),

7.4 1 (1 H, s),

 7.64 (2H, d, J = 8.8 Hz),

 8.14 (1 H, d, J = 2.0 Hz),

 8.20 (2H, d, J = 8.8 Hz),

 8.4 1 (1 H, d, J = 2.0 Hz),

Mass spectrometry value (FAB, Pos, m / z): 524 ((M + l) ⁺ ) (2) Obtained paramethoxybenzyl (1 R, 5 S, 6 S)-6-((1 R ) — 1-Hydroxyethyl] — 1-methyl-2-C (6-methylimidazo [1,2—a] pyridazine-l-ylmethyl) To 0.3 mmo 1), 5 ml of methylene chloride was added, and the mixture was stirred at 0 ° C. To this, 0.1 ml of methyl trifluoromethanesulfonate (1.0 mmol) was added. After stirring for 3 hours, the solvent was distilled off under reduced pressure, and 4 ml of a potassium phosphate buffer (pH 7), 4 ml of tetrahydrofuran, and 0.50 g of 20% palladium hydroxide on carbon were added to the residue. The mixture was stirred under hydrogen for 2 hours, and the palladium was filtered off. After distilling off the remaining E, the remaining aqueous solution was washed with ethyl acetate, eluted with water adsorbed on Dia HP-20, the target fraction was collected, concentrated under reduced pressure, and lyophilized (1R , 5 S, 6 S) — 6— ((1 R) — 1—hydroquinethyl) — 2— [(1, 6-dimethylimidazo [1, 21 a] pyrimidine-1- 2-) methylthio] 98 mg of 2- 2-am- 3-boxylboxylate was obtained.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

 d: 1.03 (3H, d, J = 6.8 Hz),

 1.12 (3Η, d, J = 5.9Hz),

 2.44 (3H, s), 3.09 (1H, m),

 3.20 (1 H, m), 3.88 (1 H, m),

 3.98 (4H, s),

4.35 (2H, ABq, J = 15.1 H z,

 8.24 (1 H, s), 8.98 (1 H, s),

 9.1 8 (1 H, s)

Quantitative analysis value (FAB, m / z): 403 (M ⁺ )

Reference Example 1 3

(1) 50.8 g (382 mmo 1) of 2-ketopeptic acid sodium salt was dissolved in 500 ml of hexamethylphosphoramide, and 122 ml of ethyl iodide was added thereto, followed by stirring at room temperature for 5 hours. 5% hydrochloric acid aqueous solution 800 ml was added, and extracted three times with 300 ml of ether. The ether solution was washed twice with 200 ml of water and once with 150 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 45.7 g of ethyl 2-ketobutyrate.

Physicochemical properties

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

 <5: 1.13 (3H, t, J = 7.3Hz),

 1.37 (3 H, t, J = 7.1 Hz),

 2.87 (3H, q, J = 7.3Hz),

 4.32 (2 H, q, J = 7.1 Hz)

Mass spectrometry (EI, m / z): 1 30 (M ⁺ )

 (2) 45.6 g (35 Ommo 1) of ethyl 2-ketobutyrate obtained in (1) was dissolved in 200 ml of ethanol, 0.5 ml of hydrobromic acid was added under ice cooling, and 45 ml of bromine was added dropwise. . The mixture was stirred at room temperature for 4 hours and poured into 400 ml of saturated sodium hydrogen carbonate under ice-cooling. After the precipitated salt was removed by filtration, ethanol was distilled off under reduced pressure. The remaining aqueous solution was extracted three times with 150 ml of black-mouthed form, washed with 100 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate (9: 1). The solvent was distilled off under reduced pressure to obtain 54.8 g of ethyl 3-bromo-2-ketobutyrate.

Physicochemical properties

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 (5: 1.39 (3H, t, J = 7.3 Hz),

 1.82 (3 H, d, J = 6.8 Hz),

4.39 (2H, q, J = 7.3Hz), 5.1 7 (1 H, q, J = 6.8 Hz)

Mass spec (EI, mXz): 209 (M ⁺ )

 30 1 ((M + 2) +)

 (3) Dissolve 54.8 g of ethyl 3-promo 2-ketobutyrate obtained in (2) in 30 Om1 of ethanol and add 2-aminovirimidine

24.9 g and 44.0 g of sodium hydrogen carbonate were added, and the mixture was stirred under reflux for 6 hours. After filtering off the insoluble matter, the solvent was distilled off, and the residue was dissolved by adding 400 ml of chloroform and 30 Oml of water. The organic layer was separated and the aqueous layer was extracted twice with 100 ml of chloroform. The organic layer was collected, washed with 150 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated solid was collected by filtration. After washing with ether, the solvent was distilled off under reduced pressure to obtain 9.38 g of 2-ethoxycarbonyl 3-methylimidazo [1,2-a] pyrimidine. Physicochemical properties

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

 (5: 1.46 (3H, t, J = 7.3Hz),

 2.8 1 (3 H, s),

 4.48 (2H, q, J = 7.3 Hz),

6.97 (1 H, dd, J, = 4.1 Hz, J ₂ = 7.1 Hz), 8.28 (1 H, dd, J, = 2.0 Hz, J ₂ = 7.1 Hz),

8.65 (1 H, dd, J, = 2.0 Hz, J ₂ = 4.1 Hz),

(4) Dissolve 5.46 g (26.6 mmo 1) of 2-ethoxyethoxycarbonyl 3-methylimidazo [1,2-a] pyrimidine obtained in (3) in 100 ml of methylene chloride and at -20 ° C. A hexane solution of 1 N-diisobutylaluminum hydride was dropped by 80 ml. The mixture was stirred for 30 minutes, and 5 ml of a 1N aqueous solution of sodium hydroxide was added dropwise. For 1 hour. The precipitated solid was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and eluted with chloroform-methanol (9: 1) to give 727 mg of 2-hydroxymethyl-13-methylimidazo [1,2-a] pyrimidine.

Physicochemical properties

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

 5: 2.38 (3 H, s), 3.35 (2 H, s),

6.8 9 (1 H, dd, J, = 4.1 Hz, J ₂ = 7.1 Hz), 8.17 (1 H, dd, Ji = 2.0 Hz, J ₂ = 7.1 Hz), 8.4 8 (1 H, dd, J, = 2.0 Hz, J ₂ = 4.1 Hz), mass spectrometry (EI, m / z): 16 3 ( ⁺ )

 (5) Ethyl 2-hydroxymethyl-3-methylimidazo [1,2-a] pyrimidine obtained in (4) 727 mg (4.4 6 mm 01) was dissolved in thionyl chloride 2 Oml, and dissolved in 50 ml. Stirred at ° C for 30 minutes. The thionyl chloride was distilled off under reduced pressure to obtain 0.85 g of crude 2-chloromethyl-3-methylimidazo [1,2-a] pyrimidine hydrochloride.

Physicochemical properties

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

 5: 2.62 (3H, s), 5.14 (2H, s),

7.64-7.7 3 (1H, m), 9 · 0—9.27 (2H, m) Mass spectrometry (EI, m / z): 18 1 (M ⁺ )

(6) Dissolve 37 Omg of crude 2-chloromethyl-3-methylimidazo [1,2-a] pyrimidine hydrochloride obtained in (5) in 5 ml of dimethylformamide and add 4-methoxy-1-α-toluene. 0.38 ml of thiol, 0.32 ml of triethylamine and 0.48 g of potassium carbonate were sequentially added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was Gel chromatography was performed, and elution was carried out with chloroform-methanol (20: 1). 2-[(4-Methoxybenzyl) thiomethyl] -13-methylimidazo [1,2-a] pyrimidine 32 Omg I got Physicochemical properties ''

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 5: 2.38 (s), 3.76 (5 H, s),

 3.8 1 (2H, s),

6.80, 7.1 1 (4 H, AB q, J = 8.6 Hz), 6 · 84 (1 H, dd, J, = 4.1 Hz, J ₂ = 7.1 Hz), 8.1 2 (1 H, dd, J , = 2.0 Hz, J ₂ = 7.1 Hz), 8.50 (1 H, dd, J, = 2.0 Hz, J ₂ = 4.1 Hz) Mass spec (FAB, Pos, m / s): 300 CCM + 1) +) Example 25

(1) Reference Example 13 2-[(4-Methoxybenzyl) thiomethyl] -13-methylimidazo [1,2-a] pyrimidine obtained in Reference Example 6 (6) Same as Reference Example 7 (4) To give 2-mercaptomethyl-3-methylimidazo [1,2-a] pyrimidine.

(2) 2-Mercaptomethyl-3-methylimidazo [1,2-a] pyrimidine was treated in the same manner as in Example 3 (1) to give paranitrobenzyl (1R, 5S, 6S). 6— ((1 R) — 1-hydroxy Ethil) One 2—! : (3-Methylimidazo [1,2-a] pyrimidine-2-yl) methylthio] 1-1-methylcarbapene-2-em to obtain ruboxylate.

 (3) The compound of (2) was treated in the same manner as in Example 3 (2) to give (1R, 5S, 6S—6 -— ((1R) —1-hydroxyethyl) 1-2—

[(3-Methylimidazo [1,2-a] pyrimidine-12-yl) methylthio] —1-methylcarbapene-12-em-carboxylic acid is obtained <Example 26

Example 25 Paranitrobenzyl (1R, 5S, 6S) of (2) —6 — ((1R) —1-hydroxyethyl) —2-C (3-methylimidazo [1,2-a] Pyrimidine-12-yl) methylthio] -11-methylcarbapene-12-em-carboxylate was treated in the same manner as in Example 4 to give (1R, 5S, 6S) -6- ((1 R)-1-hydroxyethyl) 1-2-[(1, 3-dimethylimidazo [1, 2-a] pyrimidine-1-io) methylthio] 1-1-methylcarbabene 2-hem- Obtain the carboxylate.

Prescription example (tablet)

 Compound of the present invention 25 Omg Lactose 52 mg Crystalline cellulose 35 mg Hydroxypropyl cellulose 1 Omg Magnesium stearate 3 mg

 1 tablet: 35 Omg 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 give sugar-coated or film-coated tablets.

 (Capsule)

 Compound of the present invention 250 mg corn starch 3 3 mg magnesium stearate 2 mg

 1 capsule: 285 mg The above ingredients are mixed, and the mixture is filled into an ordinary hard gelatin capsule to form a capsule.

 (Dry syrup)

 Compound of the present invention 20 Omg White sugar 790 mg Hydroxypropylcellulose 5 mg Perfume 5 mg Total: 100 Omg The above components are mixed to prepare a dry mouthwash.

 (freeze drying)

An appropriate amount of water for injection was added to 10 g of the compound of the present invention to give a dose of 100 m1, Filtrate the membrane at night.

 One vial is filled with 2.5 ml of an aqueous solution (containing 25 Omg of the compound of the present invention), and frozen and dried. At the time of use, add about 2 to 4 ml of water for injection to make an injection.

 (Powder filling)

 One vial is filled with 25 Omg of the compound of the present invention aseptically as powder. At the time of use, add about 2 to 4 ml of water for injection to make an injection.

Claims

The scope of the claims

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,

Contains 1 to 3 nitrogen atoms, plus oxygen atoms

Or a substituted or unsubstituted substituted or unsubstituted di-heterocyclic group X, Y condensed with a saturated or unsaturated 5- or 6-membered heterocycle (ring A) optionally containing one sulfur atom: Nitrogen atom or group represented by the formula: CH = Broken line: One of the broken lines represents a single bond, and the other represents a double bond.

 R: hydrogen atom, negative charge or ester residue)

2. The bicyclic heterocyclic group represented by the formula is unsubstituted or

Is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an acyl lower alkyl group, a lower alkyl group, a halogen atom, a nitro group, a cyano group, a lower alkoxy group, a lower alkoxy group, a lower alkyl group, or A group substituted with a trihalogenomethyl group A compound _{c according to} claim 1

3. The bicyclic heterocyclic group represented by the formula is substituted or

The compound _{c according to} claim 1, which is an unsubstituted group represented by the following formula:

, N,

R ²

(Wherein, R ² is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an acyl lower alkyl group, a carbamoyl lower alkyl group, a carbamoyl group, or a lower alkyl carbamoyl group; R ³ is absent or One or more of the same or different lower alkyl groups, lower alkenyl groups, lower alkynyl groups, hydroxyl groups, acyl lower alkyl groups, rubamoyl lower alkyl groups, halogen atoms, nitro groups, cyano groups, lower alkoxy groups, A lower alkyl group, a lower alkyl group, or a trihalogenomethyl group.

4. The bicyclic heterocyclic group represented by the formula is

4. The compound according to claim 3, which is a group represented by /

 I

CH _S

5. When the group represented by the formula R ³ is 1-methylimidazo

 , N,, N

 I

R ²

 [1,2-a] The compound according to claim 4, which is a pyrimidine-12-yl group.

 6. (1R, 5S, 6S) — 6— ((1R) — 1-hydroxyethyl) 1-2— [(1-methylimidab [1, 2-a] pyrimidine 12-yl) methylthio] 1 2. The compound according to claim 1, which is 1-methylcarbapene-2-emcarboxylate. -

7. 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, Ring: contains 1 to 3 nitrogen atoms, and oxygen atoms

Or a substituted or unsubstituted bicyclic heterocyclic group X and Y condensed with a saturated or unsaturated 5- or 6-membered heterocyclic ring (ring A) optionally containing one sulfur atom Nitrogen atom or group represented by the formula: CH = Broken line: One of the broken lines means a single bond, and the other means a double bond.

 R: a hydrogen atom, a negative charge or an ester residue)

a) —General formula (II)

Wherein R ⁴ is a carboxyl-protecting group, and R ⁵ is

 0

 †

-OPO (OPh) ₂ or a group represented by 1 S Ph. Hereinafter the same)

In the compound represented by

—General formula (III)

(In the formula, M represents a hydrogen atom or an alkali metal. The same applies hereinafter.) After the protecting group is removed, if necessary, the compound is further esterified by a conventional method, subjected to a salt-forming reaction, or b) a compound represented by the general formula (I). In the expression

(In the formula, R ² represents a lower alkynyl group, a lower alkenyl group, a lower alkynyl group, an acyl lower alkyl group, a carbyl lower alkyl group, a carbamoyl group, or a lower alkyl carbamoyl group. The same applies), the general formula (IV)

The compound represented by the general formula (V)

R ₂ one Z (V)

 (Wherein, Z represents a halogen atom; the same applies hereinafter), and the protective group is removed. If desired, the compound is further esterified by a conventional method or subjected to a salt-forming reaction. The method that consists of doing.

 8. An antibacterial agent comprising the compound according to claim 1, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable hydrate thereof as an active ingredient. .

 9. 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. A pharmaceutical composition comprising a carrier.