WO2001040228A1

WO2001040228A1 - Carbapenem compounds, use of the same and intermediates thereof

Info

Publication number: WO2001040228A1
Application number: PCT/JP2000/008223
Authority: WO
Inventors: Hiroshi Matsui
Original assignee: Kyoto Pharmaceutical Industries, Ltd.
Priority date: 1999-12-03
Filing date: 2000-11-21
Publication date: 2001-06-07
Also published as: CO5261620A1; AR026682A1; AU1419501A

Abstract

Carbapenem compounds represented by general formula (I), and pharmacologically acceptable salts thereof, [wherein R1 is acyl derived from an α-amino acid whose amino group may be substituted with lower alkyl; R2 is hydrogen or lower alkyl; and R3 is optionally substituted phenyl]. The compounds (I) and the salts exhibit excellent absorbability in the digestive tract when orally administered, and activated substances formed therefrom in vivo exhibit satisfactory antimicrobial activities against a wide variety of microbes. Thus, the compounds (I) and the salts are extremely useful as preventive or therapeutic agents for infectious diseases, particularly microbism.

Description

Specification

Compounds, their uses and their intermediate compounds

Technical field

The present invention relates to a novel potent compound, which is useful as a prophylactic and / or therapeutic agent for bacterial infections, and a pharmaceutically acceptable salt thereof, and more particularly, to a sufficient oral absorbability and activity generated in vivo. Novel potent compound with strong antibacterial activity and its pharmacologically acceptable salt, antibacterial agent for oral use containing the compound as an active ingredient, and intermediate compound for producing the compound and its salt About.

Background art

To date, many compounds having a carbane skeleton have been found as therapeutic agents for infectious diseases, and some of these compounds having excellent antibacterial activity have been commercialized or Development is underway.

For example, Japanese Patent Application Laid-Open No. Hei 4-279958 discloses a formula (A)

Are disclosed. The compound of the present invention has a stronger antibacterial activity than the conventional compound, and shows excellent stability against dehydrobeptidase I.

However, these compounds are poorly absorbed from the gastrointestinal tract and can only be administered clinically as injections. Oral preparations are easier and easier to administer than injections, and their clinical utility is extremely high. For this reason, there is a strong demand for the development of oral administration compounds that have strong antibacterial activity and a broad antibacterial spectrum, and have excellent gastrointestinal absorption. An object of the present invention is to provide a carbamine compound having excellent antibacterial properties and absorbability from the digestive tract. Another object of the present invention is to provide a use of the compound. Still another object of the present invention is to provide an intermediate compound suitable for producing the compound.

Disclosure of the invention

The present inventor has conducted intensive studies to achieve the above object, and as a result, a novel compound of the general formula (I) represented by the following general formula (I) and a pharmacologically acceptable salt thereof have been obtained. It was found to be extremely useful as an antibacterial agent for oral use due to its excellent vascular absorbability, and the ester group being hydrolyzed during the absorption process and being distributed in the body as an active substance having strong antibacterial properties. Furthermore, the present inventors have found a novel intermediate compound used for producing the compound, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (I):

[In the formula, R ¹ is an acyl group of an α-amino acid in which an amino group may be substituted with a lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, and R ³ is a substituted or unsubstituted amino group. And a pharmacologically acceptable salt thereof.

Preferably, in the compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof, R ¹ is an acyl group of a neutral amino acid, an acyl group of a basic amino acid, or an acyl group of a peptide. is there.

More preferably, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is (1 R, 5 S, 6 S) — 6— [(1 R)-1-(L-alanyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine- 1-2-thione- 1-4-thiol — 1- Methylcarno-pent-2-em-3-potassolenoic acid phenyl ester,

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-alanyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine-1-2-thione-1-ylthio] -1-methylcarno Pen 1 2—Emu 3—Norevonic acid 5—Indaninole Estenole,

(1 R, 5 S, 6 S) 1-6-[(1 R) 1-1 1-(L-alanyloxy) ethyl]-2-[(4 R) 1-pyrrolidine _ 2-thione _ 4-ylthio]-1-methylcarboxyl Papene 2-Emu 3 Mono-olevonic acid 3,4-Methylenedioxypheninole ester,

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-(L-valyloxy) ethyl]-2-[(4 R)-Pyrrolidine-1-2-thione-1-4-ylthio]-1-Methylcarba Pen 1-2-1-3-Fe-norenoate

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1— (L-valyloxy) ethyl] 1 2— [(4 R) 1-Pyrrolidine 1-2-Thion-1-4-ylthio] 1 1— Methylcarbapen-2-ene-3—potassolenoic acid 5-indanolenoestenole,

(1 R, 5 S, 6 S)-6-[(1 R) 1 1-(L-valyloxy) ethyl]-2-[(4 R)-pyrrolidine- 1-2-thione-1-4-thiol] 1-1 -methylcarba Pen-2-em-13-carboxylic acid 3,4-methylenedioxyphenyl ester,

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-leucyloxy) ethyl] 1 2— [(4 R) —Pyrrolidine 1 2 —Thion 1 4 1 ^ Perthio] 1 1-Methylcarnopen-2-ene-1 3-force fenobolenate

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1— (L-leucyloxy) ethyl]-2-[(4 R) —pyrrolidine-1- 2-thione-1-ylthio] — 1-methylcal Bappen 1-2-1-3-olenoic acid 5-indani / leestenore,

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1— (L-Isyloxy) ethyl] 1 2— [(4 R) 1-Pyrrolidine 1-2-Thion-1-4-ylthio] 1 1 _ Methylcarpa, pen-I 2-Emu3-N-olevonic acid 3,4-methylenedioxypheninoleestenole, (1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-isoleucyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine-1-2-thione-4 —Irthio] — 1-Methyl canoleno pen 1 2-Mem 3 3-Fe-norebonate

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-(L -isoleucyloxy) ethyl] _ 2-[(4 R)-Pyrrolidine 1-2-Thione 4 1-Methyl canolebapene 2-Emuu 3-Nolevonic acid 5-Indaninoleestenole,

(1 R, 5 S, 6 S) —6— [(1 R) — 1— (L-isoleucyloxy) ethynole]-2-[(4 R) —pyrrolidine-1-2-thione-4 1-methyl-l-rubene-1 2--emu 3-r-rubonic acid 3,4-methylenedioxyphenylester

(1 R, 5 S, 6 S) — 6— [(1 R) 1-1-glycyloxexetil] — 2— [(4 R) 1-pyrrolidine-1- 2-thione-1-ylthio] — 1-methylcarba pen

— 2—1—3—Fenorenoestenole,

(1 R, 5 S, 6 S)-6-[(1 R) 1-1-glycyloxexetil] 1-2-[(4 R)-pyrrolidine-1-2-thione-1-4-thiol-1-1-methyl Carbapen

-2-1-3-olenoic acid 5-indaninoleestenole,

(1 R, 5 S, 6 S)-6-[(1 R) 1-1-glycyloxitytyl] — 2-[(4 R)-pyrrolidine- 1-2-thione-1-4-thiol] 1-1-methyl Carbapen

— 2-Emm-1--3-carboxylic acid 3,4-methylenedioxyphenylester, (1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-lysyloxy) Echil] ―

2 — [(4R) 1-pyrrolidine-1—2-thione-4—inolethiol) 1—1—Methinore Luba Pen 1—2—hem 3—Fe—norrebonate

(1 R, 5 S, 6 S) —6— [(1 R)-1-(L—prolyloxy) ethyl]

-2-[(4 R) —Pyrrolidine-1-2-thione-1-ylthio] _ 1 _Methylcarbapene 2-Em-1-3-Fe-N-olevones

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-phenylalanyloxy) ethyl] 1 2— [(4 R) —pyrrolidine-1- 2-thione-1-ylthio] — 1 —Me Chinolecarbapene 1-2-em-3-potassolenoic acid phenyl ester, and

(1 R, 5 S, 6 S)-6-[(1 R) — 1-Glycylglycyloxoxethyl] — 2— [(4 R) —Pyrrolidine-1-2-thione-1-ylthio] — 1— Methylcarbene 1- 2-em- 3-ferric acid

Selected from the group consisting of

The present invention also provides an antibacterial agent containing, as an active ingredient, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

Preferably, the antibacterial agent is for oral administration.

Further, the present invention provides a compound represented by the general formula (II):

[Wherein R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents a phenyl group which may be substituted] and a salt thereof. Preferably, the compound represented by the general formula (II) is

(1 R, 5 S, 6 S) — 6— [(1 R) — 1-Hydroxityl] — 2— [(4 R) 1-Pyrrolidine-1-2-Thion-1-4-ylthio] — 1-Methylcarbapene 2—Emu 3—Feninole estenole carboxylate,

(1 R, 5 S, 6 S) — 6— [(1 R) 1 1-Hydroxityl] — 2— [(4 R) —Pyrrolidine-1-2-thione-1-ylthio] — 1-Methylcarbapene 1 2 — EM-3—Carboxylic acid 5—Indanolenate, and

(1 R, 5 S, 6 S)-6-[(1 R) — 1-Hydroxitytil] — 2— [(4 R) 1-Pyrrolidine-1 2-Thion-1 4-Inoletio] _ 1—Methinolecanolebapen I 2—Hem I 3—Norevonic acid 3,4—Methylenedioxyphene / Lestenole Selected from the group consisting of

Hereinafter, each definition used in the present specification will be described.

The “acyl group of an α-amino acid in which the amino group may be substituted with a lower alkyl group” for R ¹ has an amino group that is unsubstituted or substituted with one or two lower alkyl groups, and It means an α-amino acid-derived acyl group that forms an ester bond with an adjacent oxygen atom (α-amino acid in which CO Η Η is removed from CO Η). The acyl group of these amino acids may be any of the D-form, L-form and DL-form, and may be one in which two or more amino acids form a peptide.

The “lower alkyl group” capable of substituting the amino group of the α-amino acid acyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methylol, ethylenol, Propinole, isopropynole, butynole, isobutynole, sec-butynole, t-butyl, pentinole, isopentyl, neopentyl, t-pentyl, hexinole, isohexyl, neohexyl, etc., preferably having 1 to 4 carbon atoms Linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl.

Specific examples of the “c_amino acid acyl group” in the “α-amino acid acyl group in which the amino group may be substituted with a lower alkyl group” include the following.

'Neutral amino acid acyl group: aliphatic amino acid acyl group (glycyl, alanyl, paryl, leucyl, isoleucyl, etc.), hydroxy amino acid acyl group (seryl, threonyl, etc.), sulfur-containing amino acid acyl group (cystinyl, Cistur, methionyl, etc.), amide groups of amino acids (asparaginyl, daltaminyl, etc.), aromatic groups of amino acids (phenyl, tyrosyl, tryptophyl, etc.), and imino acids of acyl group (prolyl, hydroxyprolyl, etc.) ) etc;

• Acyl groups of acidic amino acids: aspartyl, glutamyl, etc.

• Basic amino acid acyl group: histidyl, lysyl, arginyl, etc .; • peptide acyl group: glycylglycyl and the like.

Preferably, an amino group of a neutral amino acid, an acyl group of a basic amino acid and an acyl group of a peptide are exemplified.

Further, specific examples of the “acyl group of an α-amino acid in which an amino group is substituted with a lower alkyl group” include the following.

• Ν—Substituted amino acid acyl group: sarkosyl, Ν, Ν—dimethyldaricyl, etc.

The “lower alkyl group” for R ² has the same meaning as the “lower alkyl group” capable of substituting the amino group of the acyl group of the α-amino acid.

The substituent of the `` optionally substituted phenyl group '' for R ³ includes a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an optionally substituted amino group, and an optionally substituted And a carbamoyl group. The number of the substituents is preferably one or two, and they may be the same or different. Also, two substituents may together form a ring with the carbon atom to which they are attached.

The “lower alkyl group” in the above substituent has the same meaning as the “lower alkyl group” capable of substituting the amino group of the acyl group of the α-amino acid.

The “lower alkoxy group” in the above substituents means an alkoxy group having a linear, branched or cyclic alkyl moiety having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, and isopropoxy. , Butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentinoleoxy, t-pentinoleoxy, hexinoleoxy, isohexynolexy, neohexyloxy, cyclopropoxy, cyclobutoxy, cyclopentyl And hydroxyhexyloxy. Preferably, a linear, branched or cyclic alkoxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopropoxy and the like can be mentioned.

The lower alkoxy part of the “lower alkoxycarbonyl group” in the above substituent has the same meaning as the above “lower alkoxy group”. Preferred lower alkoxycarbonyl group Specific examples thereof include an alkoxycarbonyl group having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and cyclopropoxycarbon.

Examples of the substituent of the “optionally substituted amino group” in the above substituent include a lower alkyl group, a lower alkoxy group, a lower alkylcarbonyl group and a lower alkoxycarbol group. The lower alkyl group and the lower alkyl portion of the lower alkyl carbonyl group are synonymous with the “lower alkyl group” which can substitute the amino group of the acyl group of the α-amino acid. Further, the lower alkoxy group and the lower alkoxycarbonyl group have the same meanings as the “lower alkoxy group” and “lower alkoxycarbonyl group” which can substitute the above-mentioned phenyl group, respectively.

Examples of the substituent of the “optionally substituted carbamoyl group” in the above substituents include the same substituents as those in the above “optionally substituted amino group”.

When the above two substituents together form a ring with the carbon atom to which they are attached, specific examples of R ³ include 4 _ indanyl, 5-indanyl, 3, 4 -methylenedioxy Phenyl, 2,3-methylenedioxyphenyl and the like. Of these, 5-indanyl and 3,4-methylenedioxyphenyl are preferred. Examples of the pharmacologically acceptable salt of the compound of the present invention (I) include an acid addition salt when the compound (I) has a basic group such as an amino group. The acid for forming such an acid addition salt is not particularly limited as long as it is a pharmacologically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid and methanesulfonic acid. When the compound (I) has an acidic group such as a carboxyl group, the pharmacologically acceptable salt of the compound (I) includes a salt in the acidic group. Such salts include, for example, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, Magnesium salts) and organic base salts (eg, triethylamine salt, dicyclohexylamine salt, pyridine salt, etc.).

The salt of the compound of formula (II) of the present invention is not particularly limited, but a pharmaceutically acceptable salt is preferable. Examples of the pharmacologically acceptable salt include those similar to the above-mentioned carbane compound (I).

Preferred specific examples of the compound of the present invention (I) and a pharmaceutically acceptable salt thereof include:

(1 R, 5 S, 6 S) 1 6— [(1 R)-1-(L-alanyloxy) ethyl] —2— [(4 R) 1-pyrrolidine-1-2-thione-1-ylthio] — 1-methylcal Pen-one 2—Emu 3—Power / Pheninoleestenole levonic acid,

(1 R, 5 S, 6 S)-6-[(1 R) 1 1-(L-alanyloxy) ethyl] 1-2-[(4 R) 1 -pyrrolidine-1-2-thione-1-4-ylthio]-1-1-methylcal Bappen 1—2 hem 3—potassolenoic acid 5—indaninoleestenole,

(1 R, 5 S, 6 S) — 6— [(1) — 1— (L-alanyloxy) ethyl] —2— [(4 R) 1-pyrrolidine-1- 2-thione-1-4-thiol) — 1-methylcarbapene 1,2-Em-3,4-Norevonic acid 3,4-methylenedioxypheninoleestenole,

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-valyloxy) ethyl] 1 2— [(4 R) 1-pyrrolidine-12-thione-1-ylthio] — 1-methylcarba Pen 1 2—Emu 3—Power / Feninoleestenole levonic acid,

(1 R, 5 S, 6 S) —6— [(1 R)-1-(L—valyloxy) ethyl] — 2— [(4 R) —pyrrolidine-1-2-thione-1-41 T-thio) — 1-Methylcarbapen-2-ene-1 3-Norevonic acid 5-indaninoleestenole,

(1 R, 5 S, 6 S) —6— [(1 R) 1-1 (L-pariroxy) ethyl] 1-2-[(4 R) 1 -pyrrolidine-1-2-thione-1 -ylthio]-1 -methylcarbapene 1,2-Em-1,3-Denolevonic acid 3,4-Methylenedioxypheninoleestenole,

(1 R, 5 S, 6 S) —6— [(1 R) ー 1- (L-leucyloxy) ethyl] 1 2— [(4 R) —Pyrrolidine 1 —2-Thion-1- 4-ylthio] 1—1 Methylcal Bappen 2-hem 1-fenolenoate

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-Isyloxy) ethyl] — 2— [(4 R) 1-Pyrrolidine-1-2-thione-1-ylthio] -1-1-Methylcal Bappen 1—2 hem 3—potassolenoic acid 5—indaninoleestenole,

(1 R, 5 S, 6 S)-6-[(1 R)-1-(L-leucyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine-1-2-thione-1-ylthio] — 1-methylcal Pappen 2-em-3 3-pot olevonic acid 3, 4-methylenedioxyphenylester

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-(L-isoleucyloxy) ethyl] 1-2-[(4 R)-Pyrrolidine-1-2-thione-4 1-Methyl canolebapene 2- 2-em-3

(1R, 5S, 6S) -6-[(1R) -1- (L-isoleucyloxy) ethyl] —2 — [(4R) —pyrrolidine-1-2-thione-4 -Ylthio] — 1 _methyl canolebapene 2-heme 3-enophorenoic acid 5-indaninoleestenole,

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-Isoleucyloxy) ethyl] — 2— [(4 R) —Pyrrolidine-1-2-Thion-1- 4 1-Methyl canolebapene 2- 2-em-3, 4-Nolevonic acid 3, 4-methylenedioxypheninoles Tenoré,

(1 R, 5 S, 6 S) — 6— [(1 R) — 1-glycyloxexetil] — 2— [(4 R) 1-pyrrolidine-1-2-thione-1-ylthio] — 1-methylcarba pen

— 2—1—3—Fenorenoestenole,

(1 R, 5 S, 6 S) — 6— [(1 R) — 1-glycyloxexetil] _ 2— [(4 R) —pyrrolidine-1-2-thione-1-ylthio] -1-methylcarba Pen 1-2-1-3-Norebonic acid 5-indaninoleestenole,

(1 R, 5 S, 6 S)-6-[(1 R) 1- 1-glycyloxexetil] — 2— [(4 R) — pyrrolidine— 1—2-thione— 1—ylthio] — 1-methyl Carbapene 1- 2-em- 3- 3-Norevonic acid 3,4-methylenedioxypheninoleestenole, (1R, 5S, 6S) -6-[(1R) -1- (L-lysyloxy I) 2 — [(4R) 1-Pyrrolidine-1-2-thione-1-ylthio] —1-methylcarbapene_2—heme-3-carboxylate phenylester

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-(L-prolyloxy) ethyl]-2-[(4 R) 1-pyrrolidine-1-2-thione _ 4-ylthio]-1-1-methylcal z pen-1 2-em _ 3-fenolenoate

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-phenylalanyloxy) ethyl] — 2— [(4 R) —pyrrolidine-1- 2-thione-1-ylthio] ー1-me Chinorecanolebapene 2-em-3 3-force norebonate fuesi, lestenore,

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1—Glycylglycyloxexetil] —2— [(4 R) —Pyrrolidine-1 2-Thion-1-4-inoletio] 1 1— Pen 2 1 3 1 3 力 — ノボンエ二 —

And their hydrochlorides.

Preferred specific examples of the compound of the present invention (II) include:

(1 R, 5 S, 6 S) _ 6— [(1 R) — 1-Hydroxitytil] — 2— [(4 R) —Pyrrolidine-1- 2-thione -4- 4-ylthio] -1-methylcarbapene 2—Em 1 3—Fennolenoestenolate

(1 R, 5 S, 6 S) — 6— [(1) — 1—Hydroxityl] _ 2 — [(4 R) 1-Pyrrolidine-1 2-thione-4-ylthio] _ 1-Methylcarbapene 1 2 _ EM-3-3-Rubonic acid 5-indanyl ester, and

(1 R, 5 S, 6 S) —6— [(1 R) — 1—Hydroxitytil] —2— [(4 R) 1-Pyrrolidine-1 2-Thion-1 4-Inoletio] 1-1-Methinolecanoleva Pen-1 2—Emu 3—Power olevonic acid 3,4—Methylenedioxypheninoleestenole

And the like.

The compound of the present invention (I) can be produced by the following method or the like.

Manufacturing method 1

Wherein R ² and R ³ have the same meaning as described above, and R ⁴ has at least one hydrogen atom of the amino group substituted with an amino protecting group and the other hydrogen atom substituted with a lower alkyl group. R ^la represents an acyl group of an α-amino acid in which one hydrogen atom of the amino group may be substituted with a lower alkyl group. ]

Examples of the amino-protecting group for R ⁴ include phthaloyl, formyl, benzyloxycarbinole, p-ditropendinoleoxycaslevonole, trimethinolesilinole, t-toxoxycarbol, trityl, aryl, and arylo. Xycarbonyl and the like. Similarly, when an amino group is contained in the amino protecting group, it is preferable that the amino group is protected by the above amino protecting group.

The lower alkyl group for R ⁴ and R ^1a has the same meaning as the “lower alkyl group” for R ¹ above.

Ashiru group α- amino acids in R ⁴ and R ^{1 a} has the same meaning as "α- amino acid Ashiru group" in the above R ^1.

The compound (1-1) included in the compound (I) of the present invention is obtained by acylating the compound (II) with the compound (III), leading to the compound (IV), and then reacting the amino group at R ⁴ It can be obtained by removing the protecting group by a method known per se.

Compound (IV) is compound (III) in an amount of about 1 to 3 times the amount of compound (II). Or a reactive derivative thereof with a solvent that does not inhibit the reaction (for example, dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethyl acetate, N, N-dimethylformamide, N, N-dimethinoreacetamide, dimethylsulfoxide, etc., and mixtures thereof).

The method for producing the compound (II) will be described later.

In the above reaction, the compound (III) is used as a free carboxylic acid or as a reactive derivative thereof, and any embodiment is included in the present invention. That is, free acid or its acid halide (acid chloride, acid bromide, etc.), alkyl carbonate (monoethyl carbonate, etc.), active amide (amide with imidazole, etc.), ester (cyanomethyl ester, 412 trophenyl ester) , Etc.) to the acylation reaction.

When the compound (III) is used as a free acid in the above reaction, the reaction is preferably carried out in the presence of a condensing agent. Examples of the condensing agent include, for example, N, N′-dicyclohexylcarboxylate Dehydrating agents such as N, N, mono-substituted carbodimids such as diimid and 1-ethyl-3- (3-dimethylaminopropyl) carbodimid are used. Further, in the above reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 130 to 40 ° C, and preferably at 110 to 30 ° C. The reaction time varies mainly depending on the reaction temperature, the type of the reaction reagent, and the like, but is usually 30 minutes to 10 hours.

Can be obtained compound obtained as described above from (IV) compound by divided the Amino protecting group in R ⁴ a (I one 1). The method for removing the protecting group depends on the type of the protecting group, but can be generally removed by a method known in the art.

The above compound (I-1) can also be produced by the following production method 2. You.

Manufacturing method 2

^{^{Wherein, R 2, R 3, R}} 4 and R ^{1 a} are as defined above, R ⁵ represents a carboxyl coercive Mamorumoto. ]

R ⁵ is t-poutinole, neopentynole, benzyl, p-nitrobenzinole, ρ-methoxybenzinole, dipheninolemethinole, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyl Methoxymethyl group, methylthiomethyl group, trityl group, 2,2,2-trichloroethyl group, trimethylsilyl group, diphenylmethoxybenzenesulfonyl group, dimethylaminoethyl group and the like.

Compound (1-1) is obtained by acylating compound (V) with compound (III) to give compound (VI), and then removing R ⁵ by a method known per se to give compound (VII). Then, after the compound (VII) is reacted with the compound (VIII) to obtain the compound (IV), the amino protecting group for R ⁴ is removed by a method known per se. It can also be obtained by removal.

Compound (VI) can be synthesized by acylating compound (V) with compound (III). Reaction conditions for the acylation (solvent, compound

(III) or its reactive derivative, the amount used, the condensing agent, the catalyst, the reaction temperature and the reaction time) are the same as in the acylation of compound (II) by compound (III) in Production Method 1 above. is there.

Compound (V) can be synthesized by the method described in JP-A-4-279588 and the like.

Compound by the removal of R ⁵ in a conventional manner from the compound obtained in the above (VI) (VII) is obtained.

Then, the compound (VII) and the compound (VIII) in an amount of about 1 to 20 times by mole are mixed with a solvent that does not inhibit the reaction (for example, dioxane, acetonitrile, tetrahydrofuran, chlorophonolem, methylene chloride, ethylene chloride, benzene, ethynole acetate). , N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc., and mixtures thereof) using an appropriate condensing agent to give compound (IV). Is obtained.

In the above reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst. Further, the condensing agent used in the above reaction is not particularly limited, but is preferably, for example, N, N, 1-dicyclohexylcarbodiimide or 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide. Dehydrating agents such as N, N, and J-substituted carbodiimides are used.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 130 to 40 ° C, preferably at 0 to 30 ° C. The reaction time depends mainly on the reaction temperature, the type of the reaction reagent, etc., but is usually 30 minutes to 10 hours.

Then, the compound (1-1) is obtained by removing the amino protecting group at R ⁴ from the compound (IV) in the same manner as in the above Production Method 1. Manufacturing method 3

[In the formula, R ² and R ³ have the same meanings as described above, and R ^lb represents an acyl group of an α-amino acid in which an amino group is substituted with two lower alkyl groups. ]

The lower alkyl group for R ^lb has the same meaning as the “lower alkyl group” for R ¹ above.

The acyl group of the α-amino acid in R ^lb is synonymous with “the acyl group of one amino acid” in R ¹ above.

The compound (I-12) included in the compound (I) of the present invention can be synthesized by acylating the compound (II) with the compound (IX).

Compound (I-12) can be prepared by reacting compound (II) with about 1 to 3 moles of compound (IX) or a reactive derivative thereof in a solvent that does not inhibit the reaction (eg, dioxane, acetonitrile, tetrahydrofuran). In drofuran, chloroform, methylene chloride, ethylene chloride, benzene, ethynole acetate, Ν, ジ -dimethylinolenolemamide, Ν, Ν-dimethylacetamide, dimethyl sulfoxide, and mixtures thereof. It can be obtained by doing this.

In the above reaction, compound (IX) is used as a free carboxylic acid or as a reactive derivative thereof, and any embodiment is included in the present invention. That is, a free acid or its acid halide (acid chloride, acid bromide, etc.), alkyl carbonate (monoethyl carbonate, etc.), active amide (amide with imidazole, etc.), ester (cyanomethyl ester, 4-methyl , Etc.) to the acylation reaction as a reactive derivative such as nitrophenyl ester. When the compound (IX) is used as a free acid in the above reaction, the reaction is preferably carried out in the presence of a condensing agent. Examples of the condensing agent include N, N'-dicyclohexylcarboxy Dehydrating agents such as N, N, and mono-substituted carbodiimids such as imide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid are used. Further, in the above reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst.

The reaction temperature is not particularly limited, but it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, usually at 130 to 40 ° C, preferably at 110 to 30 ° C. The reaction time varies depending mainly on the reaction temperature, the type of reaction reagent, etc., but is usually 30 minutes to several hours.

The above compound (I-12) can also be produced by the following production method 4.

Manufacturing method 4

Wherein R ² , R ³ , R ⁵ and R ^lb are as defined above. ] Compound (I one 2), the compound (V) is Ashiru by compound (IX), after that led to the compound (X), leading to remove the R ⁵ in a manner known per se a compound (XI), Subsequently, it can be obtained by reacting compound (XI) with compound (VIII).

Compound (X) can be synthesized by acylating compound (V) with compound (IX). The reaction conditions (solvent, compound (IX) or its reactive derivative, its amount used, condensing agent, catalyst, reaction temperature, reaction time, etc.) in the acylation are the same as the compound (IX) of compound (II) in the above-mentioned production method 3. )).

More compounds to removing R ⁵ compound obtained as described above from (X) according to a conventional method (XI) is obtained.

Then, the compound (XI) is reacted with the compound (VIII) to obtain a compound (1-2). The reaction conditions (solvent, amount of compound (VIII) used, condensing agent, catalyst, reaction temperature, reaction time, etc.) are the same as in the reaction between compound (VII) and compound (VIII) in Production Method 2 above. .

The compound of the present invention (II) can be produced by the following method and the like.

Manufacturing method 5

Wherein R ² and R ³ are as defined above. ]

Compound (II) can be synthesized by reacting compound (XII) with compound (VIII). Conditions for the reaction (solvent, compound (VIII) The amount used, the condensing agent, the catalyst, the reaction temperature and the reaction time, etc.) are the same as in the reaction between compound (VII) and compound (VIII) in production method 2 described above.

The compound (XII) can be synthesized by liberating the carbonate described in JP-A-4-1279588 by a method known per se.

The thus-obtained carbanem compounds (I) and (II) of the present invention can be used, if necessary, in a conventional manner, for example, by recrystallization, preparative thin-layer chromatography, or column chromatography. Can be purified by In addition, it can be purified as its salt if necessary.

The compounds (I) and (II) can be converted into pharmaceutically acceptable salts thereof by a method known per se.

Preferred steric configurations of the carbane compounds (I) and (II) of the present invention are the following compounds (la) and (IIa), respectively.

[Wherein, RR ² and R ³ are each as defined above. ]

Wherein R ² and R ³ are as defined above. ]

The compound of the present invention (I) and a pharmaceutically acceptable salt thereof are orally administered. When administered, it is rapidly absorbed into the blood and its metabolite has the general formula

In (I), R ¹ and R ³ are hydrogen atoms, and they are hydrogenated compounds and their pharmacologically acceptable salts, and show high blood concentrations.

Further, the compound (I) has a pharmacologically acceptable salt, whereby the solubility in the digestion tube is remarkably increased, the absorption effect is further improved, and the absorption is further enhanced.

Therefore, the prophylactic / therapeutic agent for infectious diseases comprising the above compound (I) or a pharmaceutically acceptable salt thereof has an excellent action as described above by oral administration, and is usually administered as an oral agent. You.

The infectious disease preventive / therapeutic agent can be produced by diluting with a pharmaceutical excipient according to a method known per se. As the excipient, for example, starch, lactose, sugar, calcium carbonate, calcium phosphate and the like are used.

Further, it is preferable to further add an organic acid to the agent for preventing and treating infectious diseases. Thus, the solubility of the compound (I) and a pharmaceutically acceptable salt thereof in the gastrointestinal tract is increased, and thus absorption into the blood becomes easier. The organic acid is not particularly limited as long as it is pharmacologically acceptable. For example, maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid, benzoic acid Organic carboxylic acids such as acids are preferred. The amount of the organic acid is usually 0.01 to 20 mol, preferably 0.02 to 2 mol, per 1 mol of the compound (I) or a pharmaceutically acceptable salt thereof.

The infectious disease preventive / therapeutic agent may further contain other additives, if desired. For example, a binder (eg, polyvinylpyrrolidone, starch, gum arabic, carboxymethinoresenolerose, hydroxypropiate) Preferred additives include, for example, noresenorelose and crystalline senorelose, a lubricant (eg, magnesium stearate, talc, etc.), and a disintegrant (eg, calcium carboxymethylcellulose, talc, etc.). After mixing the various components, the mixture is formulated into a dosage form suitable for oral administration such as capsules, tablets, fine granules, granules, dry syrup, etc. according to a means known per se. Thus, a prophylactic / therapeutic agent for infectious diseases for oral administration is manufactured.

The dose of the compound of the present invention (I) and a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms, and the like.For example, when administered for adult purulent disease, Oral administration of a dose of about 1-4 Omg / kg body weight about 1-4 times a day.

In addition, the compound (I) and a pharmaceutically acceptable salt thereof may be used in combination with other antibacterial active substances such as antibacterial agents (penicillins, aminoglycosides, cephalosporins, etc.) or systemic symptoms caused by bacterial infection. It may be used in combination with therapeutic drugs (antipyretic, analgesic, anti-inflammatory, etc.).

Next, the physical properties and production method of the compound of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Example 1

(1 R, 5 S, 6 S) — 6— [(1 R) — 1—Hydroxitytil] — 2—

[(4 R) 1-pyrrolidine-1 -2-thione-1 -ylthio] _ 1-methylcarbapene-2-em-1 3 -force

(1 R, 5 S, 6 S) —6— [(1 R) — 1—Hydroxyshetil] _ 2—

[(4R) 1-pyrrolidine-l- 2-thione-l-ylthio]-1-methylcarbapene-2-em-13-capillonic acid (900 mg) was added to water (1.92 ml) and aceto nitrile (1 Dissolve the mixture in 9.2 ml), add phenol (4.96 g), 41-dimethylaminopyridine (161 mg) and N, N'-dicyclohexylcarbodiimide (598 mg), and allow to stand at room temperature. And stirred for 1 hour. Ethyl acetate was added, and the mixture was washed with a 10% aqueous solution of citric acid, a 5% aqueous solution of sodium bicarbonate and a saturated saline solution, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (37 Omg).

IRV (Nujo 1, cm- ¹ ): 3340, 1765, 1720.

] H-NMR (CDC 13, 5 ppm): 1.25 (3H, d, J = 7.3 Hz), 1.34 (3H, d, J = 6.4 Hz), 2.96 (1 H, dd, J24.6, 18.2 Hz), 3.20 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 7.10 to 7.60 (5H, m), 8.36 (1 H, br).

Example 2

(1 R, 5 S, 6 S)-6-[(1 R) — 1—Hydroxitytil] 1 2—

[(4R) -Pyrrolidine-l- 2-thione-l-ylthio] -l-Methylcarbapene-2-l-emu- 3--Norevonic acid 5-indaninoleestenole

The title compound (26 Omg) was obtained by treating in the same manner as in Example 1 except that 5-indanol (7.07 g) was used instead of phenol.

'H-NMR (CDC 13, δ ppm): 1.24 (3H, d, J = 7.1 Hz), 1.33 (3H, d, J = 6.5 Hz), 1.90 to 2 40 (2H, m), 2.70 to 3.10 (5H, m), 3.10 to 3.70 (4H, m), 3.80 to 4.50 (4H, m) , 6.70-7.40 (3H, m), 8.34 (1H, br).

(1 R, 5 S, 6 S) —6— [(1 R) — 1-hydroxyl) — 2—

[(4 R) 1-pyrrolidine- 1- 2-thione 4- 4-inolethio] — 1-methylcanolebapene 1- 2-em- 1- 3-carboxylic acid 3,4-methylenedioxyphenolenoestenole

The title compound (330 mg) was obtained by treating in the same manner as in Example 1 except that sesamol (7.28 g) was used instead of phenol.

_{Ή-NMR (CDC 1 3,} δ ppm): 1. 26 (3H, d, J = 7. 3 H z), 1. 3 5 (3 H, d, J = 6. 3 H z), 2. 98 (1H, dd, J = 4.4, 18.4Hz), 3.10 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 6. 03 (2H, m), 6.50 to 7.20 (3H, m), 8.30 (1H, br).

Example 4

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-alanyloxy) ethyl] 1 2 — [(4 R) 1-pyrrolidine 1-2-thione 1-4-thiol — 1-Methyl sorbapene- 2-heme-3-carboxylic acid phenol ester hydrochloride (1) N-aryloxycarbonyl L-alanine (339 mg) was dissolved in methylene chloride (13 ml), and N, N, dicyclohexylcarbodiimid (404 mg) was dissolved under ice-cooling. ) And stirred at the same temperature for 15 minutes. The compound of Example 1 (630 mg) and 4-dimethylaminopyridine (55 mg) were added, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate was added, washed with 10% aqueous citric acid, 5% aqueous sodium bicarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and (1 R, 5 S, 6 S) 1-6 — [(1 R) —1

(N-aryloxycarbonyl-l-aralanyloxy) ethyl] -1-[(4R) -pyrrolidine-l-2-thione-l-ylthio] -l-methylcarbapene-l-l-em-l-capronic acid The phenyl ester (64 Omg) was obtained.

I R V (N ujo 1, cm—)): 1 7 7 5, 1 7 1 5.

— NMR (CDC 13, δ ppm): 1.29 (3 H, d, J = 7.3 Hz), 1.42 (3 H, d, J = 7.2 Hz), 1. 4 5 (3 H, d, J = 6.1 Hz), 2.99 (1 H, dd, J = 4.2, 18.4 Hz), 3.20 to 3.7

0 (4H, m), 3.80 to 4.40 (4H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.60 (4H, m m), 5.70-6.20 (1H, m), 7.10-7.60 (5H, m), 8.34 (1H, br).

(2) The compound (64 Omg) obtained in (1) is dissolved in methylene chloride (6.4 ml), and water (51 mg), tetrakis (triphenylphosphine) norradium (0) is dissolved under ice-cooling. (16 mg) and n-butyltin hydride (0.39 ml) were added, and the mixture was stirred at the same temperature for 20 minutes. After adding cold 0.1 N hydrochloric acid (28 ml) and washing with ethyl acetate, the aqueous layer was concentrated under reduced pressure, applied to a column of Diaion HP-21 (manufactured by Mitsubishi Chemical Corporation), and added to an aqueous solution of acetonitrile. The target fraction was concentrated under reduced pressure and lyophilized to give the title compound (28 Omg).

1 R (N ujo 1, c nT ¹ ): 3 3 6 5, 1 7 4 5.

'H-NMR (DMS O-d ₆ , 6 ppm): 1.25 (3 H, d, J = 7.5 Hz), 1.35 (3 H, d, J = 6.8 H) z), 1.45 (3 H, d, J = 7. 2 Hz), 2.60 to 3.00 (1 H, m), 3.10 to 3.80 (4H, m), 3.90 to 4.30 (3H, m), 4.30 to 4.40 (1H, m), 5, 10 to 5.40 (1H, m), 7.00 to 7.60 (5H, m), 10.34 (1H, br).

Example 5

(1 R, 5 S, 6 S) 1 6— [(1 R) 1 1 1 1 (L-ara-Roxy) ethyl] — 2— [(4 R) —Pyrrolidine-1 2--Thion-1 4-Inoletchio] — 1-Methinole Power Bap 1-2-3-Carboxylic acid 5-Indanyl ester hydrochloride

(1) By treating the compound of Example 2 and N-aryloxycarbonyl-L-alanine in the same manner as in Example 4 (1), (1R, 5S, 6S) 16 —

[(1R) -1-1 (N-aryloxycarboxyl-L-alanyloxy) ethyl] -1-2-[(4R) -Pyrrolidine-1-2-thione-1-ylthio] 1-1-methinole —Emm-1 3-carboxyl 5-indanyl ester was obtained.

'H-NMR (CDC 13, δ p pm): 1.28 (3H, d, J = 7.4 Hz), 1.43 (3H, d, J = 7.2 Hz), 1. 46 (3H, d, J = 6.3 Hz), 1.90 to 2.40 (2 H, m), 2.70 to 3.10 (5 H, ra), 3.10 0 to 3. 70 (4 H, m), 3.80 to 4.40 (4 H, m), 4.50 to 4.80 (2 H, m), 5.10 to 5.50 (4 H, m) , 5.70-6.10 (1 H, m), 6.70-7.50 (3H, m), 8.38 (1 H, br).

(2) The title compound was obtained by treating the compound obtained in (1) in the same manner as in Example 4 (2).

^{! H-NMR (DMS 0- d} 6, δ ppm): 1. 26 (3 H, d, J = 7. 2 H z), 1. 3 5 (3 H, d, J = 6. 6 H z ), 1.47 (3 H, d, J = 7.2 Hz), 1.70 to 2.40 (2H, m), 2.70 to 3.10 (5 H, m), 3. 20 to 3.80 (4H, m), 3.80 to 4.50 (4H, m), 5.10 to 5.40 (1H, m), 6.70 to 7.40 (3H, m ), 10.34 (1 H, br). Example 6

(1 R, 5 S, 6 S) — 6— [(1 R)-1-(L-alanyloxy) ethyl] 1 2 — [(4 R) 1-pyrrolidine 1-2-thione-1 4 T-Luthio] _ 1-Methyl canolebapene 2-Emu3 3-force / levonic acid 3,4-Methylenedioxypheninolester hydrochloride

(1) By treating the compound of Example 3 and N-aryloxycarbonyl-L-alanine in the same manner as in Example 4 (1), (1R, 5S, 6S)- 6-

[(1 R) — 1— (N-aryloxycarboxyl-L-alanyloxy) ethyl] 1 2— [(4 R) 1-pyrrolidine-1 2-thione-1-ylthio] 1 1 _methyl 2,3-methylenedioxyphenylester 2-olem-levonic acid was obtained.

'H-NMR (CD C 13, δ ppm): 1.28 (3H, d, J = 7.4Hz), 1.42 (3H, d, J = 7.2Hz) , 1.45 (3H, d, J = 6.3Hz), 2.96 (1H, dd, J = 4.2, 18.2Hz), 3.20-3 7 0 (4 H, m), 3.8 0 to 4.40 (4 H, m), 4.5 0 to 4.7 0 (2 H, m), 5.10 to 5.6 0 (4 H, m), 5.70 to 6.20 (1 H, m), 6.00 (2 H, s), 6.50 to 7.30 (3 H, m) , 8.30 (1 H, br).

'Η— NMR (DMS O— d ₆ , δ ppm): 1.26 (3 H, d, J = 7.3 Hz), 1.33 (3 H, d, J = 6.5 H) z), 1.44 (3H, d, J = 7.4Hz), 2.70 to 3.00 (1H, m), 3.10 to 3.70 (4H , M), 3.80 to 4.40 (4H, m), 5.10 to 5.40 (1H, m), 6.05 (2H, s), 6.5 0 to 7.20 (3H, m), 10.38 (1H, br). Example 7

(1 R, 5 S, 6 S) — 6— [(1 R) _ 1- (L-valyloxy) ethyl] 1 2— [(4 R) 1-pyrrolidine-12-thione-1-ylthio] — 1 —methylcal PAPEN-2-EME-3-PHENYL CARBOXYLIC ACID

(1) The compound of Example 1 and N-aryloxycarbonyl-L-parin were treated in the same manner as in Example 4 (1) to give (1R, 5S, 6S) — 6—

[(1 R)-1-(N-aryloxycarbonyl) L-paryloxy) ethyl] — 2— [(4 R) 1-pyrrolidine-1 2-thione-1-ylthio] 1 1 _methylcarnopentene 2-Emuu 3-carboxylic acid phenyl ester was obtained.

_{Ή-NMR (CDC 1 3,} δ p pm): 0. 87 (6 H, d, J = 5. 2H z), 1. 28 (3H, d, J = 7. 1 H z), 1. 43 (3H, d, J = 6.5Hz), 1.70 to 2.20 (1H, m), 2.93 (1H, dd, J = 4.4, 18.2H z), 3.10 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 4.50 to 4.70 (2H, m), 5.10 to 5. 60 (4 H, m), 5.70 to 6.10 (1 H, m), 7.10 to 7.60 (5 H, m), 8.30 (1

H, b r).

— NMR (DMS O-d ₆ , S p pm): 0.80 to: 1.20 (6H, m),

I. 26 (3H, d, J = 7.3Hz), 1.36 (3H, d, J = 6.6Hz), 1.80 to 2.50 (1H, m), 2 60-3.00 (1H, m), 3.10-3.80 (4H, m), 3.80-4.40 (4H, m), 5.10-5.30 ( 1H, m), 7.00 to 7.60 (5H, m), 10.30 (1H, br).

Example 8

(1 R, 5 S, 6 S) —6— [(1 R) — 1- (L-valyloxy) ethyl] —2— [(4 R) —Pyrrolidine-1-2-thione-1-ylthio] -11-Methylcal PAPEN-2-EME-3-carboxylic acid 5-indanyl ester hydrochloride

(1) By treating the compound of Example 2 and N-aryloxycarbonyl-L-valine in the same manner as in Example 4 (1), (1R, 5S, 6S) 6— [(1 R) — 1— (N-aryloxycarbonyl L-valyloxy) ethyl]-2-[(4 R) —pyrrolidine-1 2-thione-1-ylthio] 1 1-methylcarpapene 1 2 —Emu 3—Norevonic acid 5-Indanil estenole was obtained.

'H-NMR (CD C 13, δ p p m): 0.86 (6 H, d, J = 5.0 Hz),

1.27 (3H, d, J = 7.3Hz), 1.43 (3H, d, J = 6.6Hz), 1.70 to 2.50 (3H , M), 2.70 to 3.10 (5 H, m), 3.10 to 3.70 (4 H, m), 3.80 to 4.4 0 (4 H, m ), 4.50 to 4.80 (2H, m), 5.10 to 5.60 (4H, m), 5.70 to 6.20 (1H, m), 6.70 to 7.50 (3H, m), 8.30 (1H, br).

Ή-NMR (DMS O— d ₆ , 6 ppm): 0.80 to: L. 20 (6 H, m),

1.28 (3H, d, J = 7.4Hz), 1.35 (3H, d, J = 6.4Hz), 1.70 to 2.50 (3H , m), 2.70 to 3.10 (5 H, m), 3.10 to 3.70 (4 H, m), 3.80 to 4.50 (4 H, m ), 5.10 to 5.30 (1H, m), 6.70 to 7.40 (3H, m), 10.25 (1H, br)

Example 9

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1— (L-Valyloxy) ethyl] 1 2— [(4 R) —Pyrrolidine— 1—2-Thion—14 Perthio) — 1 Methylcarno-pent-2-em-3-potassolenoic acid 3,4-methylenedioxypheninoleestenolate

(1) The compound of Example 3 and N-aryloxycarbonyl-L-parin were treated in the same manner as in Example 4 (1) to give (1R, 5S, 6S)- 6— [(1 R) — 1— (N-aryloxycarbonyl—L-valyloxy) ethyl]-2-[(4 R) —pyrrolidine — 2-thione — 4-ylthio] — 1 — methylcal 1,2,3,4, -methylenedioxypheninoleestenole I got

^! H-NMR (CDC 13, 0 ppm): 0.88 (6H, d, J = 5.0Hz), 1.27 (3H, d, J = 7.3Hz), 1.45 (3H, d, J = 6.3 Hz), 1.70 to 2.20 (1 H, m), 2.90 (1 H, dd, J = 4.2, 18.4 Hz), 3.10 to 3.70 (4H, m), 3.70 to 4.40 (4H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.50 (4H , m), 5.70 to 6.10 (1 H, m), 6.05 (2 H, s), 6.50 to 7.30 (3

H, m), 8.35 (1H, br).

'H-NMR (DMS 0- d ₆ , δ ppm): 0.80-: 1.20 (6H, m),

I. 25 (3H, d, J = 7.1 Hz), 1.35 (3H, d, J = 6.4 Hz), 1.80 to 2.50 (1H, m), 2. 70-3.00 (1H, m), 3.20 to 3.80 (4H, m), 3.80 to 4.40 (4H, m), 5.10 to 5.40 (1H, m ), 6.03 (2 H, s), 6.50-7.20 (3 H, m), 10.35 (1 H, br).

Example 10

(1 R, 5 S, 6 S) —6— [(1 R) — 1— (L-leucyloxy) ethyl] —2— [(4 R) —Pyrrolidine-1-2-thione-1-ylthio] — 1 —Methyl Rubapen-1 2-Em-1-3-Rubonic acid phenyl ester hydrochloride

(1) Using the compound of Example 1 and N-aryloxycarporinul L-one-isine, the same treatment as in Example 4 (1) yielded (1R, 5S, 6S)- 6-

[(1 R)-1-(N-aryloxycarbonyl) L 1-bit (isyloxy) ethyl] 1-2-[(4 R)-Pyrrolidine-1-2-thione-1-4-thiol-1-1-methyl One-two-three-potassium phenylester was obtained.

Ή-NMR (CD C 13, δ ppm): 0.88 (6H, d, J-6.0 Hz), 1.26 (3H, d, J = 7.4 Hz), 1.44 (3H, d, J = 6.4 H

28

Corrected form (Rule 91) z), 1.50 to 1.90 (3 H, m), 2.90 (1 H, dd, J = 4.2, 18.0 Hz), 3.00 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.60 (4H, m), 5.60 to 6.1 0 (1 H, m), 7.1 0 to 7.60 (5 H, m), 8.34 (1

H, br).

Ή-NMR (DMSO—d ₆ , S p pm): 0.80 to 1.10 (6H, m),

1.27 (3H, d, J = 7.3Hz), 1.35 (3H, d, J = 6.2Hz), 1.50 ~: I.90 (3H, m) , 2.60-3.00 (1 H, m), 3.10-3.70 (4 H, m), 3.80-4.40 (4 H, m), 5.10 0-5 30 (1H, m), 7.00 to 7.60 (5H, m), 10.35 (1H, br).

Example 1 1

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-leucyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine- 1-2-thione- 1-4-inolecho] _ 1-methyl-l-rapapene 2-l-emu 3- 3-rhulbonic acid 5-indanil ester hydrochloride

(1) The same procedure as in Example 4 (1) was carried out except that the compound of Example 2 and N-aryloxycarbonyl-2-L-isocyanate were used to obtain (1R, 5S, 6S) 6—

[(1 R)-1-(N-aryloxycarbonyl-1-L-leucyloxy) ethyl] 1-2-[(4 R)-pyrrolidine _ 2-thione-1-4-thiol]-1-methylcanolebapene 2-Emu 3-3-Rubonic acid 5-Indanil estenole was obtained.

Ή-NMR (CD C 13, δ p p m): 0.88 (6H, d, J = 6.0 Hz),

1.28 (3 H, d, J = 7.5 Hz), 1.43 (3 H, d, J = 6.2 Hz), 1.50 to 2.40 (5 H, m), 2.70 to 3.10 (5H, m), 3.10 to 3.70 (4H, m), 3.80 to 4.30 (4H, m), 4.50 to 4.70 ( 2 H, m), 5.10 to 5.60 (4 H, m), 5.70 to 6.20 (1 H, m), 6.70-7.40 (3H, m), 8.35 (1H, br).

'H-NMR (DM SO— d ₆ , δ ppm): 0.80 to: 1.10 (6H, m),

I. 26 (3H, d, J = 7.2Hz), 1.36 (3H, d, J = 6.4Hz), 1.50 to 2.40 (5H, m), 2. 60 to 3.10 (5H, m), 3.10 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 5.10 to 5.30 (1H , m), 6.60 to 7.50 (3H, m), 10.30 (1H, br).

Example 1 2

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-leucyloxy) ethyl] _ 2_ [(4) —pyrrolidine- 1 2-thione _ 4-ylthio] _ 1 _methyl Carpapene 2- 2-em-3-Potassium olevonic acid 3,4-Methylenedioxypheninoles Tenore hydrochloride

(1) The compound of Example 3 and N-aryloxycarbonyl-L-leucine were used and treated in the same manner as in Example 4 (1) to give (1R, 5S, 6S)- 6-

[(1 R)-1-(N-aryloxycarbonyl-leucyloxy) ethyl] 1-2-[(4 R) 1-pyrrolidine-1-2-thione-1-4-thiol-1-1-methyl-canolebapene 1- 3,4-Methylenedioxyphenolenoester was obtained.

Ή-NMR (CD C 13, δ ppm): 0.88 (6H, d, J = 6.0 Hz), 1-26 (3H, d, J = 7.4 Hz), 1.43 (3 H, d, J = 6.5 Hz), 1.50 to: 1.90 (3 H, m), 2.95 (1 H, dd, J = 4.4, 18.2 Hz) , 3.10 to 3.70 (4H, m), 3.70 to 4.40 (4H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.50 (4H, m) H, m), 5.70 to 6.10 (1H, m), 6.02 (2H, s), 6.50 to 7.40 (3H, m), 8.35 (1 H, br). (2) The title compound was obtained by treating the compound obtained in (1) in the same manner as in Example 4 (2).

'H-NMR (DMS O-d ₆ , δ ppm): 0.80 to: 1.10 (6H, m), 1.25 (3 H, d, J = 7.0 Hz), 1. 36 (3H, d, J = 6.2 Hz), 1.50 to: L. 90 (3H, m), 2.70 to 3.00 (1H, m), 3.10 to 3. 80 (4 H, m), 3.80 to 4.40 (4H, m), 5.10 to 5.40 (1H, m), 6.05 (2H, s), 6.50 to 7. 30 (3 H, m), 10.35 (1 H, br).

Example 13

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-isoleucyloxy) ethyl] _ 2— [(4 R) —Pyrrolidine-1-2-Thion-1- 4— Ylthio] 1-methylcarbapene 1-2 meth-3 phenyl phenyl carboxylate hydrochloride

(1) By treating the compound of Example 1 and N-aryloxycarbonyl-L-isoleucine in the same manner as in Example 4 (1), (1R, 5S, 6S) 6— [(1 R)-1-(N-aryloxycarbonyl) L-iso-isocyanoxy) ethyl] _2 _ [(4 R) 1-pyrrolidine- 1-2-thione 1-4-thiol — 1- Methinorecanolebapen 1- 2-emu 3- 3-force Norebonate feninoleestenore was obtained.

'H—NMR (CDC 13, δ ppm): 0.70 to: 1.00 (6H, m), 1.00 to 2.00 (9H, m), 2.96 (1H, dd, J = 4.2, 18.4 Hz), 3.10 to 3.70 (4H, m), 3.70 to 4.40 (4H, m), 4.50 to 4, 70 (2H, m ), 5.10 to 5.60 (4 H, m), 5.60 to 6.10 (1 H, m), 7.10 to 7.60 (5 H, m), 8.35 ( 1 H, br).

'HNR (DMSO— d ₆ , δ ppm): 0.70 ~: L. 10 (6H, m), 1.26 (3H, d, J = 7.4 Hz), 1.35 (3 H, d, J = 6.7 Hz), 1.40 to 2.30 (3H, m), 2.70 to 3.00 (1H, m), 3. 10 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 5.10 to 5.40 (1H, m), 7.00 to 7.60 (5H, m) m), 10.35 (1H, br).

Example 14

(1 R, 5 S, 6 S) —6— [(1 R) — 1— (L-isoleucyloxy) ethyl] —2— [(4 R) —Pyrrolidine-1-2-Thion-1- 4— Inolethio] 1-methylcarbapene 1-2-em-3-carboxylic acid 5-indanyl ester hydrochloride

(1) The same treatment as in Example 4 (1) was carried out using the compound of Example 2 and N-aryloxycarbonyl L-isoloisine to give (1R, 5S, 6S)- 6-[(1 R) — 1— (N-aryloxycarbonyl) L-iso-isocyanoxy) ethyl] — 2— [(4 R) 1-pyrrolidine- 1- 2-thione- 1- 4-thiol] 1-Methinorecanolebapen 1-2-em-1 3-force nolevonic acid 5-Indani / leestenole was obtained. Ή-NMR (CD C 13, δ ppm): 0.70 to 1.10 (6H, m), 1.10 to 2.40 (11H, m), 2.70 to 3.10 (5 H, m), 3.10 to 3.70 (4 H, m), 3.80 to 4.40 (4 H, m), 4.50 to 4.70

(2H, m), 5.10 to 5.60 (4H, m), 5.70 to 6.10 (1H, m), 6.70 to 7.50 (3H, m), 8 3 5 (1 H, br).

! H—NMR (DMSO—d ₆ , δ ppm): 0.70 to 1.10 (6H, m), 1.26 (3 H, d, J = 7.5 Hz), 1.35 ( 3 H, d, J = 6.2 Hz), 1.40 to 2.50 (5H, m), 2.70 to 3.10 (5H, m), 3.10 to 3.70 (4H , m), 3.80 to 4.40 (4 H, m), 5.10 to 5.40 (1 H, m), 6.70 to 7.50 (3H, m), 10.35 ( 1 H, br).

Example 15

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-isoleucyloxy) Tyl] — 2— [(4 R) 1-Pyrrolidine-1-2-thione-1-4-thiolthio] — 1-Methinolecanolevapene 2-Em-1- 3-force / levonic acid 3,4-methylenedioxypheninolester salt

(1) The compound of Example 3 and N-aryloxycarbonyl L-isoloisine were used and treated in the same manner as in Example 4 (1) to give (1 R, 5 S, 6 S) − 6 — [(1R) 1-1-1— (N-aryloxycarboxyl-L-iso-isocyanoxy) ethyl] -1-2 — [(4R) —Pyrrolidine-1-2-thione-1-ylthio] -1— 3,4-Methylenedioxyphenonole ester of methinolecarpapene-2-heme-3-force / levonic acid was obtained.

^J H-NMR (CDC 13, δ ppm): 0.70 to 1.10 (6H, m), 1.10 to 2.00 (9H, m), 2.93 (1H, dd, J = 4.4, 18.2 Hz), 3.10 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 4.50 to 4.70 (2H, m ), 5.10 to 5.60 (4 H, m), 5.70 to 6.10 (1 H, m), 6.07 (2H, s), 6.50 to 7.40 (3 H, m), 8.30 (1H, br).

Ή-NMR (DMS O-d ₆ , δ ppm): 0.70 to: 1.10 (6H, m), 1.27 (3H, d, 1 = 7.6 Hz), 1.34 (3H, d, J = 6.4Hz), 1.40 to 2.30 (3H, m), 2.70 to 3.00 (1H, m), 3.10 to 3.70 (4H, m), 3.80 to 4.40 (4H, m), 5.10 to 5.40 (1H, m), 6.05 (2H, s), 6.50 to 7. 30 (3H, m), 10.35 (1H, br).

Example 16

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-glycyloxexetyl] 1-2-[(4 R) 1-pyrrolidine-1-2-thione-1-4-thiol] 1-1-methyl Carbapen-2-ene-1-carboxylic acid phenyl ester hydrochloride (1) By treating the compound of Example 1 and N-aryloxycarbonyldaricin in the same manner as in Example 4 (1), (1R, 5S, 6S) -6- [(1 R)-1-(N-aryloxycarbonyldaricyloxy) ethyl] — 2—

[(4R) 1-Pyrrolidine-l- 2-thione-l-ylthio] -l-methylcarbapene-12-em-13-force

'H-NMR (CDC 13, δ ppm): 1.26 (3H, d, J = 7.2Hz), 1.44 (3H, d, J = 6.4Hz), 2. 94 (1H, dd, 1 = 4.4, 18.2Hz), 3.10 to 3.70 (4H, m), 3.80 to 4.40 (5H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.40 (4H, m), 5.70 to 6.10 (1H, m), 7.10 to 7.60 (5H, m), 8.36 (1H, br).

'H-NMR (DMS 0- d ₆ , 6 ppm): 1.28 (3H, d, J = 7.4 Hz), 1.35 (3H, d, J = 6.2 Hz), 2 70-3.00 (1H, m), 3.10-3.70 (4H, m), 3.70-4.40 (5H, m), 5.10-0-5.40 ( 1H, m), 7.00 to 7.50 (5H, m), 10.38 (1H, br).

Example 17

(1 R, 5 S, 6 S) 1 6— [(1 R) _ 1-glycyloxoxetyl] —2— [(4 R) —pyrrolidine-1-2-thione-1-ylthio] — 1-methylcarba Pen 1 -2 emu 3 -Rubonic acid 5 -Indanil ester hydrochloride

(1) The compound of Example 2 and N-aryloxycarbonyldaricin were treated in the same manner as in Example 4 (1) to give (1R, 5S, 6S) -6- [(1 R)-1-(N-aryloxycarbonyldaricyloxy) ethyl] — 2—

[(4R) 1-Pyrrolidine-l- 2-thione-4-ylthio]-1-methylcarbapene 12-emu 3- 3-Rubonic acid 5-indanyl ester was obtained. _{'Η- NMR (CDC 1 3,} δ ppm): 1. 26 (3 H, d, J = 7. 2 H z), 1. 45 (3 H, d, J = 6. 6 H z), 1 90 to 2.40 (2H, m), 2, 70 to 3.10 (5H, m), 3.10 to 3.70 (4H, m), 3.70 to 4.40 (5H, m m), 4.50 to 4.70 (2H, m), 5.10 to 5.40 (4

H, m), 5.70 to 6.10 (1H, m), 6.70 to 7.50 (3H, m), 8.38 (1H, br).

! H—NMR (DMS O-d ₆ , δ ppm): 1.25 (3 H, d, J = 7.2 Hz), 1.35 (3H, d, J = 6.4 Hz), 1.70 to 2.40 (2H, m), 2.70 to 3.00 (5H, m), 3.10 to 3.70 (4H, m), 3.70 to 4.40 (5H, m m), 5.10 to 5.40 (1H, m), 6.60 to 7.40 (3H, m), 10.35 (1H, br).

Example 18

(1 R, 5 S, 6 S) —6— [(1 R) — 1-glycyloxexetil] —2— [(4 R) 1-pyrrolidine — 2—thion-1 4-inoletio] — 1-methinolelate 3,2-Methylenedioxyphenylester hydrochloride hydrochloride (1) Example 4 using the compound of Example 3 and N-aryloxycarbonyldaricin By treating in the same manner as in (1), (1 R, 5 S, 6 S) 1-6-[(1 R)-1-(N-aryloxycarbonyldaricyloxy) ethyl]-2-

[(4R) -Pyrrolidine-1-2-thione-4-ylthio] -11-methylcarbapene-12-em-13-tetracarboxylic acid 3,4-methylenedioxyphenyl ester was obtained. _{Ή-NMR (CDC 1 3,} δ ppm): 0. 88 (6 H, d, J = 5. 0 H z),

I. 27 (3H, d, 1 = 7.3 Hz), 1.45 (3H, d, J = 6.3 Hz), 1.70 to 2.20 (1 H, m), 2. 90 (1H, dd, J = 4.2, 18.4Hz), 3.10 to 3.70 (4H, m), 3.70 to 4.40 (4H, m), 4 50 to 4.70 (2H, m), 5.10 to 5.50 (4H, m), 5. 70 to 6.10 (1H, m), 6.05 (2H, s), 6.50 to 7.30 (3H, m), 8.35 (1H, br).

^J H-NMR (DMS 0-d ₆ , δ ppm): 1.26 (3H, d, J = 7.4 Hz), 1.33 (3H, d, J = 6.2 Hz), 2.70-3.00 (1H, m), 3.10-3.70 (4H, m), 3.70-4.40 (5H, m), 5.10-5.40 (1 H, m), 6.03 (2H, s), 6.50 to 7.30 (3

H, m), 1 0.30 (1 H, b r).

Example 19

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-lysyloxy) ethyl] 1 2— [(4 R) —pyrrolidine-12-thione-1-ylthio] — 1-methylcal 1-Bapene 2-Em-3-Phenyl rubrate dihydrochloride

(1) By treating the compound of Example 1 with N, N, diaryloxycarbonyl-L-lysine in the same manner as in Example 4 (1), (1 R, 5 S, 6 S) 1 6— [(1) — 1— (N, Ν '—diaryloxycarbonyl _L-lysyloxy) ethyl] 1 2— [(4 R) 1-pyrrolidine-1 2--thione-1-ylthio ] 1-Methylcarbapene-12-emu-3-phenylphenol was obtained. ^] H-NMR (CDC 13, δ ppm): 1.27 (3H, d, J = 7.4 Hz),

I. 45 (3H, d, J = 6.6Hz), 1.40 to 2.20 (6H, m), 2.70 to 3.70 (7H, m), 3.80 to 4.40 (4H, m), 4.40 to 4.70 (4H, m), 5.10 to 5.50 (5H, m), 5.70 to 6.20 (2H, m) , 7.10 to 7.60 (5H, m), 8.32 (1H, br).

Ή-NMR (DMSO— d ₆ , δ ppm): 1.28 (3H, d, J = 7.5 Hz), 1 · 35 (3H, d, J = 6.7 Hz), 1.40 ~ 2.10 (6H,

36

Corrected form (Rule 91) m), 2.60 to 3.10 (3H, m), 3.10 to 3.70 (4H, m), 3.70 to 4.40 (4H, m), 5.10 to 5.40 (1H, m), 7.00 to 7.60 (5H, m), 10.30 (1H, br).

Example 20

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-(L-prolyloxy) ethyl] 1-2-[(4 R) 1-pyrrolidine-1-2-thione-1-4-ylthio] _ 1 1-methyl-r-bapene 2-hem-l- 3-r-rubonic acid phenyl ester hydrochloride

(1) The compound of Example 1 and N-aryloxycarbonyl-L-proline were used and treated in the same manner as in Example 4 (1) to give (1R, 5S, 6S) — 6—

C (1 R)-1-(N-aryloxycarbonyl L-prolyloxy) ethyl] 1-2-[(4 R)-pyrrolidine-1-2-thion-1-4-thiol]-1-methyl canolebapene One-two-one-three-force phenolic olevones were obtained.

— NMR (CDC 1 J, δ ppm): 1.28 (3 H, d, J = 7.4 Hz), 1.44 (3H, d, J = 6.3 Hz), 1.70- 2.40 (4H, m), 2.90 (1H, dd, J = 4.0, 18.2Hz), 3.00 to 3.70 (6H, m), 3.80 to 4 70 (6 H, m), 5.10 to 5.40 (3 H, m), 5.70 to 6.10 (1 H, m), 7.1 0 to 7.60 (5 H , m), 8.25 (1 H, br).

^{! H-NMR (DMS O- d} 6, 5 ppm): 1. 26 (3H, d, J = 7. 5 H z), 1. 35 (3 H, d, J = 6. 6 H z), 1.70 ~ 2.40 (4 H, m), 2.70 ~ 3.00 (1 H, m), 3.00 ~ 3.70 (6 H, m), 3.80 ~ 4.60 ( 4H, m), 5.10 to 5.40 (1H, m), 7.00 to 7.60 (5H, m), 10.28 (1H, br).

Example 2 1

(1 R, 5 S, 6 S) 1 6— [(1 R) 1 1 1 (L 1 S) ethyl]-2-[(4 R) 1-pyrrolidine- 1- 2-thione 4- 1 ^ T-lthio]-1-methylcarbapene 12-em- 1- 3-carboxylic acid phenyl ester hydrochloride

(1) The compound of Example 1 and N-aryloxycarbonyl-L-phenylalanine were treated in the same manner as in Example 4 (1) to give (1R, 5S, 6S) —6— [(1 R) — 1— (N-aryloxycarbonyl-1 L-phenylalyloxy) ethyl] 1 2_ [(4 R) 1-pyrrolidine-1 2-thione 1-4 1-ylthio] 1 1 —Methylcarbapene-12-em-13-carboxylic acid phenyl ester was obtained.

_{Ή-NMR (CD C 1 3} , δ ppm): 1. 29 (3 H, d, J = 7. 6 H z), 1. 46 (3H, d, J = 6. 6 H z), 2. 86 (1H, dd, J = 4.2, 18.4Hz), 3.10 to 3.70 (6H, m), 3.80 to 4.40 (4H, m), 4. 50 to 4.70 (2 H, m), 5.10 to 5.40 (4 H, m), 5.70 to 6.10 (1 H, m), 7.00 to 7.60 ( 10 H, m), 8.28 (1 H, br).

^{_{! H-NMR (DMSO- d 6}} , δ ppm): 1. 26 (3 H, d, J = 7. 4 H z), 1. 36 (3H, d, J = 6. 2 H z), 2 70-3.00 (1H, m), 3.10-3.70 (6H, m), 3.80-4.40 (4H, m), 5.10-5.40 (1H , m), 7.00 to 7.60 (10H, m), 10.30 (1H, br).

Example 22

(1 R, 5 S, 6 S) —6— [(1 R) 1-1-glycinoleglycyloxixethyl] 1 2— [(4 R) 1-pyrrolidine 1-2-thione-1 4-ylthio] 1 1-Methyl l-lappaene 2-heme 3-carboxylate phenyl ester hydrochloride

(1) By treating the compound of Example 1 and N-aryloxycarbonyldaricylglycine in the same manner as in Example 4 (1), (1R, 5S, 6S) -6 1 [(1 R) — 1— (N-aryloxycarbonyl-1-glycylglycyroxy) ethyl] —2— [(4 R) 1-pyrrolidine-1-2-thione-1-ylthio] -1- Methylenolecanolebapene-2-em-13-force fenolenoic acid feninole ester was obtained.

^ -NMR (CDC 13, δ p pm): 1.26 (3H, d, J = 7.2 Hz), 1.45 (3H, d, J = 6.2 Hz), 2.95 ( 1 H, dd, J = 4.0, 18.4 Hz), 3.10 to 3.80 (6H, m), 3.80 to 4.40 (5 H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.40 (4H, m), 5, 70 to 6.10 (1H, m), 7.10 to 7.60 (5H, m) , 8.40 (1 H, br).

Ή-NMR (DMSO—d ₆ , δ ppm): 1.28 (3H, d, J = 7.4 Hz), 1.36 (3H, d, J = 6.4 Hz), 2 70-3.00 (1H, m), 3.10-3.80 (6H, ra), 3.80-4.40 (5H, m), 5.10-5.40 ( 1 H, m), 7.00 to 7.60 (5H, m).

Example 23

(1 R, 5 S, 6 S) —6— [(1 R) — 1— (L-alanyloxy) ethyl]-2-[(4 R) 1-pyrrolidine-1 -2-thione-1 -4-ylthio] 1 1 1-Methyl carpapene 2-Emuu 3-Carboxylic acid phenyl ester hydrochloride

(1) Dissolve N-aryloxycarbonyl L-alanine (218 mg) in methylene chloride (6 ml), and cool with ice to cool N, N, 1-dicyclohexylcarbodiimide.

(26 Omg) and stirred at the same temperature for 15 minutes. (1 R, 5 S, 6 S) 1 6— [(1 R) 1—1 hydrodoxetyl] —2 — [(4 R) —pyrrolidine 1—2—thione 1—4—inolethio] 1—Methinolecanoleva Pen 1- 2-emu 3- 3-Rubonic acid 4 12-Trobenzyl ester (30 Omg) and 4-dimethylaminopyridine

(26 mg) and stirred at the same temperature for 30 minutes. Ethyl acetate was added, washed with 10% aqueous citric acid, 5% aqueous sodium bicarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. WO 01/40228 ― PCT / JPO0 / O8223

I left. The residue was purified by silica gel column chromatography, and (1R, 5S, 6S) -6-[(1R) -1- (N-aryloxycarboxyl-L-alanyloxy) ethyl] 2-[(4R) -Pyrrolidine-l- 2-thione-l-^^-l-thiol-l-l-methylcanolebapene-l-emu-u- 3-mole-nolevonic acid 4-l-trobenzyl ester (324 mg) was obtained. .

IRV (Nujo 1, cm— ¹ ): 1750, 1710, 1645.

'H-NM (CDC 13, δ ppm): 1.27 (3H, d, J = 7.2Hz), 1.40 (3H, d, J = 7.3Hz), 1.44 (3H, d, J = 6.1 Hz), 2.98 (1H, dd, J = 4.4, 18.2Hz), 3.20 to 3.70 (4H, m) , 3.90 to 4.40 (4H, m), 4.50 to 4.70 (2H, m), 5.10 to 5.60 (6H, m), 5.70 to 6.20 (1H, m), 7.64 (2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6Hz), 8.52 (1H, br) ).

(2) Compound (324 mg) obtained in (1) was treated with tetrahydrofuran (12 ml), ethanol (4 ml), IM acid buffer (pH 7.0) (12 ml) And hydrogenated at room temperature for 2 hours in the presence of 5% palladium on carbon catalyst (230 mg). After filtering off insolubles, the residue was washed with ethyl acetate. The aqueous layer was acidified with formic acid, extracted with methylene chloride, washed with brine, and concentrated under reduced pressure to 8.0 g. Phenol (72 mg), 4-dimethylaminoviridine (31 mg) and N, N'-dicyclohexylcarpoimide (116 mg) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed with a 10% aqueous solution of citric acid, a 5% aqueous solution of sodium bicarbonate and a saturated saline solution, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and (1 R, 5 S, 6 S) —6— [(1 R) — 1— (N-aryloxycarbonyl-1-L-aralanyloxy) ethyl] — 2— [(4R) -Pyrrolidine-l- 2-thione-l-ylthio] -l-methylcarbapene- 2-em-13-potassic acid phenyl phenyl ester (90 mg) was obtained. IR and NMR were identical to those of the compound of Example 4 (1). (3) The compound (90 mg) obtained in (2) was treated in the same manner as in Example 4 (2) to give the title compound (30 mg). IR and NMR were identical to those of the compound of Example 4.

Next, in order to clarify the excellent properties of the compound of the present invention, the following oral absorption experiment was performed.

Experimental example 1 (oral absorption experiment)

The compound of the present invention (the compound of Example 4) was orally administered at a dose of 20 mg / kg to mice (three in a group), and 0.125 of the hydrolyzed potavane compound (compound of the above formula (A)) was added. The plasma concentrations at 0.25, 0.5, 1.0, 1.5 and 2.0 hours were determined using the test bacterium Baci 11 ussubtilis ATCC 6633, a medium with the following composition (sodi um citrateagar) It was measured by the paper disk method using a. The results are shown in Table 1.

(Medium composition)

Peptone 5.0 g

b e e f e t r a c t 3.0 g

Sodium citrate 10.0 g

15.0 g

Distilled water 1 000ml

Formulation example 1

A tablet having the following composition was produced by a usual method.

Compound 1 of Example 4 25 mg Polyvinyl pyrrolidone 20mg

20mg starch

Magnesium stearate 20mg

Formulation example 2

The compound of Example 4 and tartaric acid were added and mixed to produce a capsule according to a usual capsule filling method.

Compound 1 of Example 4 25 mg

Tartaric acid 25 mg

Lmg magnesium stearate

Starch was added to a total volume of 30 Omg.

Formulation example 3

A dry syrup was prepared according to the following composition.

62.5 mg of the compound of Example 4

Cuenoic acid 25 mg

Sugar 70 mg

Power Noreboxime / Resenolerose Sodium 20mg

The compound of the present invention (I) and a pharmaceutically acceptable salt thereof are excellent in gastrointestinal absorption by oral administration, and the active substance produced in living organisms is sufficient for a wide variety of bacterial species. It is highly useful as a prophylactic and therapeutic agent for infectious diseases (especially bacterial infections). The infectious disease preventive and therapeutic agents include diseases caused by bacteria in warm-blooded animals including humans (dogs, cats, cows, horses, rats, mice, etc.) (eg, purulent diseases, respiratory infections, biliary tract infections). Disease, urinary tract infection, etc.). Further, the carbane compound (II) of the present invention is useful as an intermediate compound of the above compound (I).

This application is based on a patent application No. 345535/1999 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

General formula (I)

[Wherein, R ¹ represents an acyl group of an α-amino acid in which an amino group may be substituted with a lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents a phenyl group which may be substituted. Or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1, wherein R ¹ is an acyl group of a neutral amino acid, an acyl group of a basic amino acid or an acyl group of a peptide, or a pharmaceutically acceptable salt thereof.

3. (1R, 5S, 6S) -6-[(1R) _1- (L-alanyloxy) ethyl] — 2 — [(4R) 1-pyrrolidine-1-2-thione-1-4-ylthio ] 1- 1-methyl canolebapene 2- 2-em-3

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-alanyloxy) ethyl]-2-[(4 R) —pyrrolidine-1-2-thione-1-4-inorethio] — 1— Methinole Pore 1 2-Pem 1 3-Emolenoic acid 5 1 ^ i

(1 R, 5 S, 6 S) _ 6— [(1 R) — 1— (L-alanyloxy) ethyl]-2-[(4 R) —pyrrolidine-1-2-thione-1-4-thiol) — 1-methylcal Bappen-I 2-Emu3-Potassium olevonic acid 3, 4-Methylenedioxyphene / Lestenolle,

(1 R, 5 S, 6 S) — 6 _ [(1 R) — 1— (L—valyloxy) ethyl] — 2-[(4 R) —Pyrrolidine-1-2-thione-1-ylthio] — 1-methylcarbapen-2-ene _ 3—Fe-norebolic acid / Liestenol,

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1— (L—valyloxy) ethyl] 1 2 — [(4 R) 1 pyrrolidine— 1—2-thione—1—4-ylthio] — 1—methylcarba Pen-1 2-em-3 3-pot olevonic acid 5-indaninoleester,

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L—valyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine- 1- 2-thione- 1-ylthio] 1- 1-methylcarba Pen 2-em-1 3-potassolenoic acid 3, 4-methylenedioxypheninoleestenole,

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-leucyloxy) ethyl] — 2— [(4 R) —Pyrrolidine — 2—Thion-1-4-thiol) 1 1 _ Methylcarnopen-2-ene-3-force fenobolenate

(1 R, 5 S, 6 S) 1-6-[(1 R)-1-(L-leucyloxy) ethyl]-2-[(4 R) 1-pyrrolidine-1-2-thione-1-4-thiol]-1-1-methylcal Pen 1 2-Em 3 3-Norevonic acid 5-Indaninoleestenole,

(1 R, 5 S, 6 S)-6-[(1 R) — 1— (L-Isyloxy) ethyl]-2-[(4 R) 1-Pyrrolidine _2-Thion _ 4-ylthio] Bapene 2-em-3-carboxylic acid 3,4-methylenedioxyphenyl ester,

(1 R, 5 S, 6 S) — 6— [(1 R)-1-(L-isoleucyloxy) ethyl] — 2— [(4 R) 1-pyrrolidine-1-2-thione-1 4 —Ylthio] 1-methyl-1-canolebapene 2-em-3-carboxylic acid phenyl ester

(1 R, 5 S, 6 S)-6-[(1 R)-1-(L-isoleucyloxy) ethyl] — 2 — [(4 R) 1-pyrrolidine-1 2--thione-1 4 1 ^ T-Luthio] — 1-Methyl carpapene 2-Em 3-E-Norevonic acid 5-Indani / Leestenole,

(1 R, 5 S, 6 S) — 6— [(1 R) 1-11 (L-isoleucyloxy) ethyl] _ 2— [(4 R) 1-Pyrrolidine 1-2-Thion 1 4 1-methyl-canolebapene 2-em-l- 3-nonolevonic acid 3,4-methylenedioxypheninolenes (1 R, 5 S, 6 S) — 6— [(1 R) 1 1—Glycyloxicetil] — 2—

C (4R) —Pyrrolidine-1-2-thione-1-ylthio] —1-Methylcarbapene 1-2-Emu 3-Fe-N-olevones

(1 R, 5 S, 6 S) 1 6— [(1 R) 1 1-Glysiloxyxetil] — 2—

[(4R) 1-pyrrolidine-l- 2-thione-l-ylthio] l-l-methylcarbapene- 2-em-l- 3- olenoleic acid 5- indani / leester,

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1-Glysiloxekitil] _ 2—

[(4R) 1-pyrrolidine-l- 2-thione-l-ylthio] l-l-methylcarbapene-l- 2-em-l- 3- phenolic acid 3,4-methylenedioxypheninoleestenole,

(1 R, 5 S, 6 S) _ 6— [(1 R) _ 1— (L-lysyloxy) ethyl] 1-2-[(4 R)-pyrrolidine- 1-2-thione-1 4 T-Luthio] 1-1-methylcarba Pen 1—2—3—Phenolenoestinole

(1 R, 5 S, 6 S) — 6— [(1 R) ー 1-(L-prolyloxy) ethyl] — 2— [(4 R) 1-Pyrrolidine 1-2-Thion 1-4-ylthio] 1 1 1 Methyl carpentene pen 2-hem 1-3-force

(1 R, 5 S, 6 S) — 6— [(1 R) — 1— (L-Fenylaralanyloxy) ethyl] 1 2— [(4 R) —Pyrrolidine 1 2-thione— 4-ylthio] _ 1 -Metinolecarpapene 2-em-3 3-Fe-norrebonate

(1 R, 5 S, 6 S)-6-[(1 R) _ 1 -glycylglycyloxoxethyl]-2-[(4 R) 1-pyrrolidine-1 2-thione _ 4-ylthio] — 1 —Methylcarnox pen 1—2—1—3—force

2. The compound of claim 1, which is selected from the group consisting of: or a pharmacologically acceptable salt thereof.

4. An antibacterial agent comprising, as an active ingredient, the compound represented by the general formula (I) according to claim 1 or a pharmacologically acceptable salt thereof.

5. The antibacterial agent _{c according to} claim 4, which is for oral administration.

6. General formula (II)

[Wherein, R ² represents a hydrogen atom or a lower alkyl group, and R ³ represents an optionally substituted phenyl group] or a salt thereof.

7. (1R, 5S, 6S) — 6 — [(1R) 1-1—Hydroxyshetyl] 1-2 — [(4R) -1-Pyrrolidine-1-2-thione-1-ylthio] -1-methylcarba Pen 1—2—1—3—Fenorenoestenolate

(1 R, 5 S, 6 S) — 6— [(1 R) — 1—Hydroxyshetyl] 1 2— [(4

R) -pyrrolidine-1-thione-1-ylthio] -1-methylcarbapene-2-emu 3-carboxylic acid 5-indanyl ester, and

(1 R, 5 S, 6 S) 1 6— [(1 R) — 1—Hydroxyshetyl] 1 2— [(4

R) —Pyrrolidine-1-2-thione-1-ylthio] —1-Methylcarbapene-1-Emuu 3-force / Revonic acid 3,4-methylenedioxypheninolenestenol

7. The compound of claim 6, wherein the compound is selected from the group consisting of: