WO1998034937A1 - Tricyclic heterocyclic compounds - Google Patents

Abstract

Tricyclic heterocyclic compounds represented by general formula (I) or pharmacologically acceptable salts or derivatives thereof having excellent antimicrobial activities: wherein A represents pyrrolidinylalkylthio, phenylalkylthio or aminoalkanoyloxy, each optionally having substitutent(s), or substituted amino.

Description

 Description Tricyclic heterocyclic compound

[Technical field]

 The present invention provides a tricyclic heterocyclic compound having excellent antibacterial activity, a composition for preventing or treating infectious diseases containing them as an active ingredient, and a medicament for preventing or treating infectious diseases. And a method for preventing or treating infectious diseases, which comprises administering a pharmacologically effective amount thereof to a warm-blooded animal, or a method for producing them.

[Background technology]

 Although chenamycin derivatives have excellent antibacterial activity, they are degraded by dehydrobeptidase-I, an enzyme that inactivates the chenamycin derivatives present in the human body, and lose their activity. Agents Chemo the r., 2 262, (1982); S. R. Norrbyeta 1., ibi d., 23, H. Kroppeta 1., Antimi crob. 300 (1983)).

 On the other hand, as tricyclic 13-lactam compounds, some compounds are reported in JP-A-3-167187, JP-A-4-178389, and the like. Compounds belonging to this system are called tribactam or trinem, and among them, Sanfe trinem represented by the following chemical formula is well known (DiMo du gnoetal., Antimi cr ob. Agent s Cemother., 38, 2362 (1994)).

[発明の開示]

[Disclosure of the Invention]

 Chenamycin derivatives generally exhibit excellent antibacterial activity, but have a problem with chemical stability, i.e., dehydrobeptidase I. On the other hand, trinem derivatives represented by sanfetrinem are dehydrobeptidase I. , But has the disadvantage that the antibacterial activity is slightly inferior to the chenamycin derivative. Therefore, the appearance of trinem compounds having good stability against dehydrolipeptidase-I and exhibiting excellent antibacterial activity is desired.

 The present inventors have conducted various studies to solve these drawbacks, and found that the novel tricyclic heterocyclic derivative (I), its pharmacologically acceptable salts and derivatives, have a strong antibacterial activity, and have a dehydrobeptidase activity. The present inventors have found that the present invention is stable with respect to 1I and has a high urinary content, thereby completing the present invention.

(Structure of the invention)

 The tricyclic heterocyclic compound of the present invention has the general formula

Having.

In the formula, A represents any of the following formulas (2), (3), (4) or ₍₅₎

 Expression

[Where k represents 0 or 1, m represents 0, 1 or 2,

R ² is a hydrogen atom, a d-C ₄ alkyl group, a C 7 -d ₄ aralkyl group which may have 1 to 3 substituents (the substituent is a halogen atom, a —C ₄ alkyl group or And a 5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may have 1 to 3 substituents (the substituent is a Haguchigen atom , D to C ₄ alkyl group or carbamoyl group), a group represented by the formula: C (= NH) R ⁴ (wherein R ⁴ is a hydrogen atom, d to (: ₄ alkyl group, amino group or Mono or di-d to (showing ₄ alkylamino groups), 1 to 3 nitrogen atoms, 5 to 6 membered heterocyclyl group containing oxygen or sulfur atom, or 1 to 3 nitrogen atoms, oxygen or sulfur to 5-6 membered containing an atom indicates heteroaryl group, R ³ is a hydrogen atom, Okiso group, sulfamoyl § amino methyl In group (wherein the formula -C0R ^5, R ⁵ is Amino groups, mono- or di-d -C ₄ alkylamino group, the formula

A group represented by the formula (wherein, n represents 1 or 2, R ⁶ is a hydrogen atom, d to (: a ₄ alkyl group, a group represented by the formula C (2NH) R ^4a , R ^4a represents a hydrogen atom, a d-C 4 alkyl group, an amino group or a mono- or di-C ₄ alkylamino group), a 5- to 6-membered group containing 1-3 nitrogen, oxygen or sulfur atoms Represents a heterocyclyl group, or a 5-6 membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms),

Or expression

(s 2)

で表される基 （式中、 sは 0、 1または 2を示し、 pは 0または 1を示し、 R⁷ は水素原子または 〜C₄ アルキル基を示し、 R⁸ は水素原子、 d 〜(： ₄ ァ ルキル基または式一 C ( = N H ) R^4aで表される基 （式中、 R^4aは水素原子、 C

(Wherein s represents 0, 1 or 2, p represents 0 or 1, R ⁷ represents a hydrogen atom or a C ₄ alkyl group, R ⁸ represents a hydrogen atom, d to ( : ₄ alkyl group or a group represented by the formula C (= NH) R ^4a (where R ^4a is a hydrogen atom,

, To (indicating a 4 alkyl group, amino group or mono- or di-C ₄ -C ₄ alkylamino group)). ]

 Expression

[Wherein q represents 0, 1 or 2,

R ⁹ is a phenyl group which may have 1 to 3 substituents (the substituents are d to C ₄ alkyl groups, to C ₄ alkoxy groups, nitro groups, halogen atoms, hydroxyl groups, cyano groups, shows d -C ₄ alkyl force Rubamoiru group, a sulfamoyl group or 1-3 nitrogen, and shows the Teroariru group to 5-6 membered containing oxygen or sulfur atom) - group, mono - or di. ]

 Expression

R10

― C ~ CH ₂ ir "N, ③

 ¾,

[Wherein, r represents 0, 1, 2 or 3;

R ^IQ represents a hydrogen atom or a d-C ₄ alkyl group,

R ¹¹ is a hydrogen atom, a —C ₄ alkyl group or a group represented by the formula —C (= NH) R ⁴ (where R ⁴ is a hydrogen atom, C, to (: ₄ alkyl group, amino group, properly shows the shows the G d -C ₄ alkylamino group).] formula

[Wherein, R ¹² is a hydrogen atom,-(: a _4- alkyl group or a group represented by the formula —C (—NH) R ⁴ , wherein R ⁴ is a hydrogen atom, a d-C ₄ alkyl group, an amino group Or mono- or di-d ~ (: represents ₄ alkylamino group),

R ¹³ is d to (: ₄ alkyl groups having 1 to 3 substituents (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), a C _{3 to} C ₆ cycloalkyl group, and 1 to 3 C _s -C, which may have a substituent, aryl group, C ₇ -C aralkyl group which may have 1 to 3 substituents (the substituent is a nitro group, a halogen atom, a methyl , Amino, sulfamoyl, sulfamoyl, methylcarbamoyl, dimethylcarbamoyl, 5- or 6-membered heteroaryl containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy, difluoromethoxy Group, a methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetylamino group), and 1 to 3 nitrogen atoms which may have 1 to 3 substituents selected from the following substituent group (a): , Oxygen or sulfur atom 5 to 6-membered heteroaryl group or benzene ring-fused 5 to 6-membered heteroaryl group contained, or the following substituent group (a) Force ^ may have 1 to 3 substituents selected 1 A 5- to 6-membered heteroalkyl group containing up to 3 nitrogen, oxygen or sulfur atoms or a 5- to 6-membered benzene-condensed heteroaralkyl group;

Substituent group (a): halogen atom, d to C ₄ alkoxycarbonyl group, carboxy group, amino group which may have a substituent (the substituent is a carbamoyl group, a thiocarbamoyl group, a C, to (: _{A 4-} alkyl group, a 2-hydroxyethyl group, a carbamoylmethyl group or a carboxymethyl group), a sulfamoyl group which may have a substituent (the substituent is d to (: a _4- alkyl group or phenyl) A phenylsulfonyl group, a phenylthio group which may be substituted with a halogen atom, a pyridylthio group A C ₇ -C ₁₄ aralkyl group which may be substituted with a methoxy group, and a c, -c ₄ alkyl group which may have a substituent (the substituent is a carboxy group, a hydroxyl group, a pyrrolidinyl group, a morpholinyl group, Piperidinyl group, imidazolyl group, N-methylimidazolyl group, halogen atom, dimethylamino group, methylamino group, amino group, 4-methoxyphenyl group, carbamoyl group, phenylcarbamoyl group or ethoxycarbyl group), substituent Or a naphthyl group optionally having a halogen atom, a d- (: ₄ alkyl group, a d-C ₄ alkoxy group, a sulfamoyl group, a hydroxyl group, a carboxymethoxy group, a carbamoylmethoxy group , Amino group, methylamino group, dimethylamino group, trimethylammonio group, N-carbamoylmethyl- N, N- dimethyl ammonium Nio group or N- 2-hydroxy-E Chiru N, illustrates a N- dimethyl ammonium Nio group), an optionally substituted d -C ₄ alkyl Chiomoto (said substituent represents a hydroxyl group, A phenyl group or a pyridyl group), a pyridino group having a substituent on the N atom (the substituent represents a methyl group, a rubamoylmethyl group, a 2-hydroxyxethyl group or a carboxymethyl group), a phenoxy group, or a trimethylammonium group. Group, N-hydroxylmethyl-N, N-dimethylammonio group, N-2-hydroxyethyl-N, N-dimethylammonio group, optionally substituted sorbamoyl or thiocarbamoyl group ( The substituent may be: (indicating: ₄ alkyl groups, 2-hydroxyethyl group, carbamoylmethyl group) or 1 to 3 nitrogens, acids which may be substituted with a methyl group 5- or 6-membered heteroaryl group containing an elemental or sulfur atom.]

In the description of equation (I),

R ² , R ⁴ , R ^4a , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹ R ¹² , R ¹³ and the substituent group (a) “C, to (: 4 alkyl Group and the (^ to (: ₄ alkylamino) group and the “^ to (: ₄ alkyl) portion of the“ d to (: ₄ alkylamino group) are linear or branched having 1 to 4 carbon atoms. And represents a branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl group, and is preferably a methyl or ethyl group, more preferably Is a methyl group.

Examples of the "halogen atom" in R ² , R ⁹ , R ¹³ and the substituent group (a) include a fluorine atom, a chlorine atom and a bromine atom, and a fluorine atom or a chlorine atom is preferable. Preferably it is a fluorine atom.

The “C ₇ -C ₁₄ aralkyl group” of R ^{2 represents} the aforementioned re,-(: ₄ alkyl group) substituted with “C ₆ -Ci. Aryl group” such as phenyl, naphthyl, and indul groups. Benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, indenylmethyl, indenylethyl groups and the like can be mentioned, preferably benzyl, 1-naphthylmethyl, 2-naphthylmethyl or phenylethyl group. And more preferably a benzyl or phenethyl group, and even more preferably a benzyl group.

In R ^2, a `` 5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms '' is a 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms. indicating the -C ₄ alkyl group substituted with (5-6 membered aromatic heterocyclic group). Here, as the 5- to 6-membered heteroaryl group, for example, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, triazolyl, thiazolyl, thiaziazolyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, chenyl, etc. And preferably a pyridyl, imidazolyl, thiazolyl or thiadiazolyl group. Further, d -C ₄ alkyl group is defined agree with the, preferably a methyl or Echiru group, more preferably is a methyl group Examples of the above "5- to 6-membered alkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms" include, for example, pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, pyrazinylmethyl, pyrimidylmethyl, pyridazinylmethyl, imidazolylmethyl, Imidazolylethyl, thiazolylmethyl, thiazolylethyl, pyrrolylmethyl, virazolylmethyl, isoxazolylmethyl, isothiazolylmethyl, isoxazolylmethyl, isothiazolylmethyl, chenylmethyl and the like, and preferably pyridylmethyl. And imidazolylmethyl, thiazolylmethyl, thiazolylethyl and thiadiazolylmethyl, more preferably pyridylmethyl.

Of R ² "C ₇ ~ (:" Ararukiru group "and" 1-3 nitrogen, heteroaralkyl group to 5-6 membered containing oxygen or sulfur atom ", 1 to 3 halogen atoms,

It may be substituted with a CC ₄ alkyl or a radical group, with suitable substituents being a fluorine atom, methyl or a radical group.

Examples of the “C ₇ -C ₁₄ aralkyl group which may have a substituent” for R ² include, for example, benzyl, phenethyl, 4-fluorobenzyl, 4-butyrubamoyl pendyl, and 4-methylbenzyl group. Can be.

Examples of the “5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may have a substituent” for R ² include 2-pyridylmethyl, 3-pyridylmethyl, 4 Examples thereof include monopyridylmethyl, 2-imidazolylmethyl, N-methyl-2-imidazolylmethyl, 2-thiadiazolylmethyl, and 2- (4-methyl-5-thiazolyl) ethyl group.

Of R ^4, R ^{4 a} and R ⁵ - as "mono- or di-d -C ₄ alkylamino group" Ki de e.g. Mechiruamino, Echiruamino, Puropiruamino, Puchiruamino, Jimechiruamino, be mentioned Jechiruamino or dipropylamino group, It is preferably a methylamino or dimethylamino group, and more preferably a dimethylamino group. ^{R 2, R s, R 8} , R 11 and R in the "group represented by the formula one C (two NH) R ^4" or "group of the formula one C (= NH) R ^4a 'of R ¹² Examples of ⁴ or R ^4a include a hydrogen atom, methyl, ethyl, propyl, butyl, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, and acetylamino group, preferably a hydrogen atom, methyl or amino group. It is.

R ² , R ^s , R ⁸ , R ^11, and R ^{12 as} the “group represented by the formula C (= NH) R ⁴ ” or the “group represented by the formula C (= NH) R ^4a ” Examples include formimidyl, acetimidoyl, propionimidoyl, amidino, methylamidino, ethylamidino or N, N-dimethylamidino groups, preferably formimidyl, acetimidoyl or amidino groups.

R ^{2 is} a 5- to 6-membered 'acrylic group containing 1 to 3 nitrogen, oxygen or sulfur atoms' is a 5- to 6-membered aliphatic heterocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms And represents, for example, pyrrolidinyl, piberidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, imidazolinyl, thiazolinyl, piperazinyl and the like. A preferred group among these is a 2-imidazolinyl or 2-thiazolinyl group, more preferably a 2-imidazoline-12-yl or 2-thiazoline-2-yl group.

In R ^2, a `` 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms '' is a 5- to 6-membered aromatic complex containing 1 to 3 nitrogen, oxygen or sulfur atoms. Represents a ring group, and has the same meaning as the `` 5- to 6-membered heteroaralkyl group '' in the definition of the `` 5- to 6-membered heteroaralkyl group '', and a preferred group is an imidazolyl, thiazolyl or pyridyl group, more preferably Is a 2-imidazolyl, 2-thiazolyl or 2-pyridyl group. In the group represented by the formula k, k is preferably 0 or 1, and m is 0, 1 or 1. And 2 are both preferred.

Suitable groups for R ² as a whole are a hydrogen atom, a C ₄ alkyl group, benzyl optionally having 1 to 2 substituents, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or thiadiazo. Rirumechiru group (the substituent is a fluorine atom, a methyl group or force Rubamoiru group), the formula - C (= NH) in groups (formula represented by R ^4, R ⁴ is a hydrogen atom, a methyl group or an amino group ), 2-imidazolinyl group, 2-thiazolinyl group, imidazolyl group, thiazolyl group or pyridyl group,

 More preferably, a hydrogen atom, a methyl group, an ethyl group, a benzyl or pyridylmethyl group which may have 1 to 2 substituents (the substituents represent a fluorine atom, a methyl group or a carbamoyl group) A formimidyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or a 2-thiazoline-2-yl group, and more preferably a hydrogen atom, a methyl group, an ethyl group, or a benzyl group. A pyridylmethyl group, a formimidoyl group, an acetimidoyl group, an amidino group, a 2-imidazolin-2-yl group or a 2-thiazoline-2-yl group.

In the group represented by the formula (si) of R ⁵ , n is preferably 1, and in the group represented by the formula (s 2), s is preferably 1, and p is either 0 or 1. Is also preferred.

R ⁶ is (In the formula, R ^4a is a hydrogen atom, a methyl group or an amino group) preferably a hydrogen atom, d -C ₄ alkyl group, a group represented by the formula one C (two NH) R ^4a, A 2-imidazolinyl group or a 2-thiazolinyl group, more preferably a hydrogen atom, methyl, ethyl, formimidoyl, acetimidoyl, 2-imidazoline-1-yl or 2-thiazoline-2-yl group; .

R ⁷ and R ^1Q are preferably a hydrogen atom, a methyl or an ethyl group.

R ⁸ is preferably a hydrogen atom, a C, to C ₄ alkyl group or a group represented by the formula —C (= NH) R ^4a (wherein, R ^4a represents a hydrogen atom, a methyl group or an amino group) And more preferably a hydrogen atom, methyl, ethyl, formimidyl or acetate. It is a midoyl group.

Examples of the “group represented by C 0 R ⁵ ” of R ³ include, for example, carbamoyl, methyl carbamoyl, dimethylcarbamoyl, 1-piperazulcarbonyl, 1-homopiperazinylcarbonyl, 4-methylbiperazine 1-ylcarbonyl, 4-methylhomopyrazine-l-ylcarbonyl, 4-formimidylpyrazine- 1-ylcarbonyl, 4-acetamidoylpyrazine- 1-ylcarbonyl, 4-amidino piperazine 1-ylcarbonyl, 4- (2-imidazoline 1- 2-yl) piperazine- 1-ylcarbonyl, 4- 1- (2-thiazoline-2-yl) piperazine- 1-ylcarbonyl, 3-aminopyrrolidine- 1-ylcarbonyl, 3-aminomethylpyrrolidine- 1-ylcarbonyl, 3 —Methylaminopyrrolidin — 1 —ylcarbonyl, 3 —Methylaminomethylpyrrolidine—1—ylcarbonyl, 3-formimidoylaminopyrrolidine—1-ylcarbonyl, 3-acetimidoylaminopyrrolidine-1-ylcarbonyl, 3-guanidinopyrrolidin-1-ylcarbonyl, aminobiperidine—1 —Ylcarbonyl, aminomethylbiperidine-1-1-ylcarbonyl, methylaminopiperidine-11-ylcarbonyl, methylaminomethylbiperidine-1-ylcarbonyl, formimidylaminopiperidine-1-ylcarbonyl, acetimidoylaminopiperidine-1-1-ylcarbonyl, guanidino Piperidine-1-ylcarbonyl, 2-aminoazetidine-1-ylcarbonyl, 2-aminomethylazetidine-1-ylcarbonyl, 2-methylaminoazetidine-1- 2-ylcarbonyl, 2-methylaminomethylazetidine-1-ylcarbonyl, 2-formimidoylaminoazetidin-1-ylcarbonyl, 2-acetimidoylaminoazetidine-1-ylcarbonyl or 2-guanidinoazetidine-1-ylcarbyl group And preferably a carbamoyl, dimethylcarbamoyl, 1-piperazinylcarbonyl, 3-aminopyrrolidine-11-ylcarbonyl, 3-aminomethylpyrrolidine-1-ylcarbonyl or 2-aminoazetidine-1-ylcarbonyl group. More preferably, it is a group consisting of sorbamoyl, 1-piperazinylcarbonyl, 3-aminopyrrolidine-1-ylcarbonyl or 3-aminomethylpyrrolidine-1-ylcarbonyl. Suitable groups for R ³ as a whole are a hydrogen atom, an oxo group, a sulfamoylaminomethyl group, a sorbamoyl group, a dimethylcarbamoyl group, a 1-piperazinylcarbonyl group, an aminopyrrolidine-1-ylcarbonyl group or an aminomethylpyrrolidine A 1-ylcarbonyl group, more preferably a hydrogen atom, a carbamoyl group, a 1-piperazinylcarbonyl group, a 3-aminopyrrolidine-1-ylcarbonyl group or a 3-aminomethylpyrrolidine-1-ylcarbonyl group. And even more preferably a hydrogen atom. In the group represented by the formula q, q is preferably 0 or 1.

Examples of the “mono- or di-d to C ₄ alkyl rubamoyl group” in the substituent of R ⁹ include, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, getylcarbamoyl or dibuyl pill. Examples include a rubamoyl group, preferably a methylcarbamoyl group or a dimethylcarbamoyl group.

The “5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms” in the substituent of R ⁹ is defined as “5 to 6-membered heteroaralkyl group” in R ² in the definition of A 6-membered heteroaryl group ", preferably an imidazolyl, triazolyl, pyridyl or thiazolyl group, more preferably 1-imidazolyl, 1- (1,2,3-triazolyl), 4 It is a monopyridyl or 2-thiazolyl group.

The d -C ₄ alkoxy substituents R ^9, methoxy, ethoxy, pro epoxy, Isopurobokishi, can be mentioned butoxy group, preferably a was methoxy or ethoxy group, and more preferably a methoxy group It is.

R ⁹ is preferably a phenyl group optionally having 1 to 2 substituents (the substituents may be C 1 to (: ₄ alkyl groups, d to C ₄ alkoxy groups, nitro groups, halogen atoms, water an acid group, Shiano group, forces Rubamoiru group, mono- or di-d ~ C ₄ alkyl force Luba moil group, a sulfamoyl group or 1-3 nitrogen, heteroaryl groups 5-6 membered containing oxygen or sulfur atom, ), And more preferably 1 to 2 A phenyl group which may have a substituent (the substituent is a methyl group, a methoxy group, a nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, a dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, A pyridyl group or a thiazolyl group), and more preferably a phenyl group which may have 1 to 2 substituents (the substituent is a nitro group, a fluorine atom, a carbamoyl group, Dimethylcarbamoyl, imidazolyl, triazolyl, or thiazolyl)

In the group represented by the formula (3), r is preferably 0, 1 or 2.

R ¹¹ and R ¹² are preferably a hydrogen atom, a d-C ₄ alkyl group or a group represented by the formula —C (= NH) R ⁴ (wherein R ⁴ is a hydrogen atom, a methyl group or an amino group) And more preferably a hydrogen atom, methyl, ethyl, formimidoyl or acetimidoyl group.

Examples of the substituent of "d to (: ₄ alkyl group having ^{1 to 3} substituents)" of R ¹³ include a fluorine atom, a chlorine atom, a carbamoyl group and a hydroxyl group. It is a fluorine atom, a sulfamoyl group or a hydroxyl group, and more preferably a fluorine atom.

Examples of the “d to C ₄ alkyl group having ^{1 to 3} substituents” for R 13 include 2-fluoroethyl, 2-chloroethyl, 2-bidroxethyl, 2-carbamoylethyl, dicarbamoylmethyl, difluoromethyl, trifluoromethyl. Methyl, hydroxypropyl, 2,3-dihydroxy-11-propyl group and the like can be mentioned, preferably 2-fluoroethyl, 2-hydroxyethyl or potassium rubamoylmethyl group, more preferably 2 —It is a fluoroethyl group.

As the “C ₃ -C ₆ cycloalkyl group” for R ¹³ , for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like can be mentioned, and a cyclopropyl group is preferable.

As the “C ₆ -d. Aryl group” for R ¹³ , for example, phenyl, naphthyl or An indenyl group can be mentioned, preferably a phenyl or naphthyl group, and more preferably a phenyl group.

The “C ₇ -C ₁₄ aralkyl group” for R ¹³ is d-(: ₄ alkyl group substituted with the aforementioned “C ₆ -d. Aryl group”, for example, benzyl, phenethyl, phenylpropyl, phenyl, phenylphenyl. And naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, indenylmethyl, indenylethyl and the like, preferably benzyl, naphthylmethyl or phenethyl, and more preferably benzyl.

"C ₆ ~ (.:, Ariru group" of the R ^{1 3} and "C ₇ ~ (:" Ararukiru group "" heteroaryl group 5-6 membered "in the substituent is the R ² '5-6 membered It is synonymous with "5- to 6-membered heteroaryl group" in the definition of "heteroaralkyl group", and is preferably imidazolyl, triazolyl or thiazolyl group, more preferably 1-imidazolyl, 1-1 (1, 2 , 4 one Toriazoriru), 4 is an thiazolyl group. as the substituent of the "C s ~ (^. Ariru group" of the R ^{1 3} and "C ₇ -C _{1 4} Ararukiru group", preferably a nitro, halogen It is an atom, carbamoyl, sulfamoyl, imidazolyl, thiazolyl, 1, 2, 4-triazolyl or benzyloxy group.

In R13, a `` 5- to 6-membered heteroaryl group containing ^{1 to 3} nitrogen, oxygen or sulfur atoms or a 5- to 6-membered heteroaryl group condensed with a benzene ring '' Has the same meaning as described above, and “benzene-fused 5- to 6-membered heteroaryl group” represents the above-mentioned “5- to 6-membered heteroaryl group” fused to a benzene ring. Examples of the “benzene-fused 5- to 6-membered heteroaryl group” include, for example, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzophenyl, quinolyl, isoquinolyl, and indolyl groups. It is an imidazolyl, benzothiazolyl or quinolyl group.

Examples of the “5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms or a 5- to 6-membered heteroaryl group condensed with benzene ring” include, for example, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, Imidazolyl, triazolyl, thiazolyl, pyrrolyl, thiadiazolyl, oxazolyl, isothiazolyl, Examples include soxazolyl, furyl, chenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzocenyl, quinolyl, isoquinolyl, and indolyl groups. Or a benzothiazolyl group; more preferably, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2-imidazolyl, 3- (1,2,4-triazolyl), 2-thiazolyl, 2- (1,3,4-thiadiazolyl), 2-benzimidazolyl or 2-benzothiazolyl group.

In R13, a "5- to 6-membered heteroaralkyl group containing ^{1 to 3} nitrogen, oxygen or sulfur atoms or a 5- to 6-membered heteroaralkyl group condensed with a benzene ring" group "are as defined above, is" Teroararukiru group into a benzene-fused 5- to 6-membered "is the" rc substituted with heteroaryl group "to a benzene ring-condensed 5- or 6-membered, -C ₄ alkyl group" .

Examples of the above "5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms or 5- to 6-membered heteroaralkyl group condensed with benzene ring" include, for example, pyridylmethyl, pyridylethyl, pyridylpropyl, Pyridylbutyl, virazinylmethyl, virazylethyl, pyrimidylmethyl, pyrimidylethyl, pyridazinylmethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, thiazolylpropyl, pyrrolylmethyl, vilazolylmethyl, isoxazolylmethyl, isothiazolylmethyl ' Xazolylmethyl, disothiazolylmethyl, chenylmethyl, chenylethyl, benzothiazolylmethyl, benzimidazolylmethyl, quinolylmethyl, isoquinolylmethyl, India And preferably a pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl or quinolylmethyl group, more preferably 2-pyridylmethyl, 3-pyridylmethyl, 4 It is a monopyridylmethyl, 2-benzothiazolylmethyl, 2-benzimidazolylmethyl or 2-quinolylmethyl group. In the above R13, "5- to 6-membered heteroaryl group or 5- to 6-membered heteroaryl group containing ^{1 to 3} nitrogen, oxygen or sulfur atoms" and "1 to 3 nitrogen or oxygen" Alternatively, the 5- to 6-membered heteroaralkyl group or benzene-ring-fused 5- to 6-membered heteroaralkyl group containing a sulfur atom has 1 to 3 substituents selected from the substituent group (a). May be.

Examples of the “〇> to C ₄ alkoxycarbonyl group” of the substituent group (a) include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl group, preferably methoxycarbonyl or ethoxycarbonyl. Group.

 Examples of the “amino group which may have a substituent” in the substituent group (a) include, for example, amino, carbamoylamino (ureido), thiocarbamoylamino (thioureido), methylamino, ethylamino, 2-hydroxyethylamino. Mino, carbamoylmethylamino or carboxymethylamino groups can be mentioned, preferably an amino group.

 The “sulfamoyl group optionally having substituent (s)” in the substituent group (a) includes, for example, sulfamoyl, phenylsulfamoyl, methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl or butylsulfamoyl group. And preferably a sulfamoyl, phenylsulfamoyl or methylsulfamoyl group, more preferably a sulfamoyl group.

 Examples of the “phenylthio group which may be substituted with a halogen atom” in the substituent group (a) include, for example, phenylthio, 4-fluorophenyl'thio, 4-chlorophenylthio, 4-bromophenylthio, and the like. , 2,4-difluorophenylthio and 2,4-dichlorophenylthio groups, preferably phenylthio or 4-chlorophenylthio groups.

Examples of the “C ₇ -C ₁₄ aralkyl group optionally substituted with a methoxy group” in the substituent group (a) include, for example, benzyl, phenethyl, methoxybenzyl, methoxyphenyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl group And preferably a benzyl, phenethyl or methoxybenzyl group. The “C,-(: ₄ alkyl group optionally having substituent (s)” in the substituent group (a) includes, for example, methyl, ethyl, propyl, butyl, carboxymethyl, carboxyethyl, hydroxymethyl, hydroxyethyl , Hydroxypropyl, pyrrolidinylmethyl, pyrrolidinylethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piberidinylethyl, imidazolylmethyl, imidazolylethyl, N-methylimidazolylmethyl, N-methyl Imidazolylethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, dimethylaminomethyl, dimethylaminoethyl, methylaminomethyl, methylaminoethyl, aminomethyl, Minoethyl, aminobutyral pill, rubamoyl methyl, rubamoylethyl, rubamoylpropyl, phenylcarbamoylmethyl, phenylcarbamoylethyl, ethoxycarbonylmethyl, ethoxycarborethyl group, etc., preferably methyl. , Ethyl, hydroxymethyl, carbamoylmethyl or imidazolylmethyl groups.

 Examples of the “phenyl or naphthyl group optionally having substituent (s)” in the substituent group (a) include, for example, phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methylphenyl. Phenyl, methoxyphenyl, dimethoxyphenyl, sulfamoylphenyl, hydroxyphenyl, dihydroxyphenyl, (carboxymethoxy) phenyl,

(Rubamoylmethoxy) phenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, trimethylammoniophenyl, N-rivamoylmethyl N, N-dimethylammoniophenyl, N-hydroxyethyl-N , N-Dimethylammoniophenyl, (carboxymethoxy) phenyl, naphthyl, fluoronaphthyl, black naphthyl, methoxynaphthyl, sulfamoylnaphthyl, (forcebamoylmethoxy) naphthyl, aminonaphthyl, methylaminonaphthyl, dimethylamino Examples thereof include naphthyl, trimethylammononaphthyl, N-diammonyl naphthyl, N-dimethylammononaphthyl, N-hydroxyethyl-N, and N-dimethylammononaphthyl group, and a phenyl group is preferable. Examples of the “d to (: ₄ alkylthio group) which may have a substituent” in the substituent group (a) include, for example, methylthio, ethylthio, propylthio, butylthio, hydroxyethylthio, dihydroxypropylthio, benzylthio, phenethylthio, and pyridylmethylthio. And a pyridylethylthio group, preferably a methylthio or ethylthio group.

 Examples of the “pyridino group having a substituent at the N atom” in the substituent group (a) include N-methylpyridinio, N-capilluvylmethylpyridinio, N-2-hydroxyshethylpyridinio, N-carboxy A methylpyridino group and the like can be mentioned, and an N-methylpyridino group is preferable.

 Examples of the “optionally substituted rubamoyl or thiolrubamoyl group” in the substituent group (a) include, for example, rubamoyl, thiocarbamoyl, methylcarbamoyl, methylthiolrubamoyl, ethylcarbamoyl, And ethyl thiocarbamoyl group. Group.

Examples of the “5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may be substituted by a methyl group” in the substituent group (a) include, for example, pyridyl, methylpyridyl, pyrimidyl , Methylpyrimidyl, thiazolyl, methylthiazolyl, thiadiazolyl, methylthiadiazolyl, triazolyl, imidazolyl, methylimidazolyl, chenyl, furyl, isoxazolyl, methylisoxazolyl, and oxazolyl groups. Or a methylimidazolyl group. Preferable examples of the substituent group (a) include a halogen atom, an amino group, a carbamoyl group, a sulfamoyl group, a hydroxymethyl group, a carbamoylmethyl group, a phenyl group, an ethylthio group, a pyridyl group, a 1-imidazolylmethyl group, and a trimethyl group. Ammonio group, thiocarbamoyl group or benzyl group. R ¹³ as a whole is preferably a d to C ₄ alkyl group having 1 to 2 substituents (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), a C ₃ to C ₆ cycloalkyl group , 1-2 good C ₆ ~ may have a substituent (:., Ariru group Wakashi Ku is C ₇ ~ (: _{1 4} Ararukiru group (the substituent is a nitro group, a halogen atom, a methyl group , Amino group, sulfamoyl group, carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, 5- to 6-membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy group, difluoromethoxy group , A methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetylamino group), a group of substituents (a) force ^ one to three nitrogens, oxygens which may have one or two substituents selected Or sulfur atom Containing 5- to 6-membered heteroaryl group or benzene ring condensed 5- to 6-membered heteroaryl group, or may have 1 to 2 substituents selected from substituent group (a) 1 to 3 A 5- or 6-membered heteroaralkyl group containing a nitrogen, oxygen or sulfur atom or a 5- or 6-membered heteroaralkyl group condensed with a benzene ring.

R ¹³ is more preferably a d to C ₄ alkyl group having 1 to 2 substituents (the substituent represents a halogen atom, a carbamoyl group or a hydroxyl group), a C _{3 to} C ₆ cycloalkyl group. A phenyl, naphthyl, benzyl, phenethyl or naphthylmethyl group optionally having 1 to 2 substituents (the substituents are a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, a carbamoyl group, Methylcarbamoyl, dimethylcarbamoyl, 5- to 6-membered heteroaryl containing 1 to 3 nitrogen, oxygen or sulfur atoms, methoxy, difluoromethoxy, methylenedioxy, benzyloxy, pyridyl A methoxy group or an acetylamino group) or a group of substituents (a) pyridyl, pyrimidyl which may have one or two substituents selected Le is a Imidazoriru, Toriazoriru, thiazolyl, thiadiazole Lil, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolyl methyl, thiazolylmethyl, benzothiazolyl methyl, benzimidazolyl methylation or quinolylmethyl group.

R ¹³ is more preferably a d to (: ₄ alkyl group having 1 to 2 substituents, wherein the substituent represents a halogen atom, a carbamoyl group or a hydroxyl group), C ₃ to (: ₆ 2-cycloalkyl group, phenyl or benzyl group optionally having 1 to 2 substituents (the substituents may be nitro, halogen atom, carbamoyl, sulfamoyl, imidazolyl, thiazolyl, 1, 2, 4 Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolyl, which may have 1 to 2 substituents. , Benzimidazolylmethyl or quinolylmethyl group (the substituent may be a halogen atom, an amino group, a sulfamoyl group, a sulfamoyl group, a hydroxymethyl group, a sulfamoylmethyl group, a phenyl group, an ethylthio group, a pyridyl group 1 one imidazolylmethyl group, trimethyl ammonium Nio group is an is) Chiokarubamoiru group also Namib Njiru group.

R ¹³ is most preferably 2-fluoroethyl, cyclopropyl, phenyl, 3-pyridyl, 4-pyridyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-pyridylmethyl, 3 —Pyridylmethyl, 4-pyridylmethyl, 4- (1-imidazolyl) benzyl, 4-benzyloxybenzyl, 2-thiazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4- (4-pyridyl) thiazol —2-yl, 4-phenylthiazole—2-yl, 4-benzylthiazol-2-yl, 6-amino-benzothiazol-2-yl, 4 -— (1-imidazolylmethyl) thiazole-2— 1,3,4-thiadiazol—Lu2-yl, 5-phenyl—1,3,4-thiadiazol-2-yl, 5— (4-pyridyl) 1-1,3,4-thiadia -2- (2-) yl, 5-ethylthio-1,3,4-thiadiazol-2-yl, 2-benzothiazolylmethyl, 2-benzimidazolylmethyl or 2-quinolylmethyl . Further, the tricyclic heterocyclic compound (I) of the present invention can be converted into a “pharmacologically acceptable salt or derivative” as necessary.

“Pharmacologically acceptable salts” include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; methanesulfonate, phosphate salt Sulfonic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Salts; organic such as oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate Acid addition salts such as acid salts, glycine salts, lysine salts, arginine salts, amino acids salts such as olnitine salts, glutamates, aspartates, or lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, etc. Inorganic salts or salts with organic bases such as ammonium salts, tritylamine salts, diisopropylamine salts, cyclohexylamine salts, preferably hydrochloride, hydrobromide, phosphate, sulfate, methane. Sulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, gluta Emissions salt, Asuparagin salt, sodium salt, potassium salt, a Anmoniumu salt or Toryechi Ruamin salt, is more preferably Natoriumu salts, hydrochlorides or sulfates. In addition, the compound (I) of the present invention absorbs water by leaving it in the air, freeze-dried from an aqueous solution, or recrystallized to form adsorbed water or a hydrate. In some cases, such salts are also included in the present invention.

A “pharmacologically acceptable derivative” is a group that is cleaved in a human or animal body by a chemical or biological method such as hydrolysis or the like to form the original compound or a salt thereof (which forms a so-called prodrug). A derivative in which the carboxyl group, hydroxyl group, amino group, etc. of the compound (I) is protected by a group). Whether such a derivative is orally or intravenously injected into experimental animals such as rats and mice After the administration, the body fluid of the animal is examined, and the determination can be made by detecting the original compound or its salt. Examples of such a protecting group such as a carboxyl group, a hydroxyl group, and an amino group include groups known in the field of medicinal chemistry, such as an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a phthalidyl group, and 5-methyl-2- Oxo-1,3-dioxolen-1-ylmethyl group, acyl group, alkoxycarbonyl group, aminoacyl group and the like.

Examples of the above-mentioned xyalkyl group include, for example, bivaloyloxymethyl, isoptyryloxymethyl, 11- (isobutyryloxy) ethyl, acetomethoxymethyl, 11- (acetyloxy) ethyl and 1-methylcyclohexylcarbonyloxy. Methyl and 1-methylcyclopentylcarbonyl. Examples of the alkoxycarbonyloxyalkyl group include t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, and 1- (isopropoxycarbonyloxy) ethyl. And 1- (t-butoxycarbonyloxy) ethyl, 11- (cyclohexyloxycarbonyloxy) ethyl and 11- (cyclopentyloxycarbonyloxy) ethyl groups.

 Examples of the acyl group include alkanol groups such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanol, hexadecanyl, octadecanoyl, carbonylpyridyl, carbonylpyridyl, carbonylpyridyl, and carbonyl. Examples include a heteroarylcarbonyl group such as dicarbanol.

 Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, octadecyloxycarbonyl, etc. Is mentioned.

 The aminoacyl group includes, for example, amino acid groups such as glycyl, alanyl, leucyl, isopenyl, fenylalanil, histidyl, asparagyl, prolyl, and lysyl.

Preferred protecting groups among the above are 5-methyl-2-hydroxy-1,4-dioxolen-41-methyl, acetoxymethyl, bivaloyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl, 1- (isopropoxycarbonyl Ethoxy) ethyl is a (cyclohexyloxycarbonyloxy) ethyl group. In the present invention, the following compounds may be mentioned as preferred compounds (I) having a group represented by Formula A.

(①-1) R ² is a hydrogen atom, d to (: ₄ alkyl group, benzyl optionally having 1 to 2 substituents, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or Thiadiazolylmethyl group (wherein the substituent represents a fluorine atom, a methyl group or a carbamoyl group);

(= NH) group represented by R ⁴ (wherein, R ⁴ is a hydrogen atom, a methyl show a group or an amino group), 2-imidazolinyl group, 2-thiazolinyl group, an imidazolyl group, in thia Zoriru group or a pyridyl group Certain compounds.

(①-2) R ² , a hydrogen atom, a methyl group, an ethyl group, a benzyl or pyridylmethyl group optionally having 1 to 2 substituents (the substituent is a fluorine atom, a methyl group or a Which is a formimidoyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or a 2-thiazoline-2-yl group.

(III) R ² is a hydrogen atom, a methyl group, an ethyl group, a benzyl group, a pyridylmethyl group, a formimidyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or 2-thiazoline A compound that is a 2-yl group.

(① -4) R ³ is a hydrogen atom, an oxo group, a sulfamoylaminomethyl group, a sulfamoyl group, a dimethylcarbamoyl group, a 1-pyrazulcarbonyl group, an aminopyrrolidine-1-ylcarbonyl group or an aminomethylpyrrolidine (I) A compound that is a 1-yl carbonyl group.

(①-5) R ³ A compound which is a hydrogen atom, a rubamoyl group, a 1-piperazinylcarbonyl group, a 3-aminopyrrolidine-1-ylcarbonyl group or a 3-aminomethylpyrrolidine-1-ylcarbonyl group.

(①-6) A compound wherein R ^{3 is} a hydrogen atom.

Suitable compounds (I) in which A has a group represented by the general formula (2) include the following compounds.

(②-1) q Compound with 0 or 1 force. (②-2) R ⁹ force A functional group which may have 1 to 2 substituents (the substituents may be C 1, C ₄ alkyl groups, dC ₄ alkoxy groups, nitro groups, halogen atoms, water Acid group, cyano group, carbamoyl group, mono- or di-d ~ (shows a _4- alkylcarbamoyl group, a sulfamoyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms) A compound that is

 (III-3) A phenyl group which may have 1 to 2 substituents (the substituents may be a methyl group, a methoxy group, a nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, A dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a thiazolyl group).

(②-4) R ³ force A phenyl group which may have 1 to 2 substituents (the substituent is a nitro group, a fluorine atom, a carbamoyl group, a dimethylcarbamoyl group, an imidazolyl group, a triazolyl group or a thiazolyl group) Which represents a group).

(②-5) A compound wherein the substitution position is the 4-position when it is a funil group having R ⁹ substituents.

Preferred compounds (I) in which A has a group represented by the general formula (3) include the following compounds.

 (③-1) A compound in which r is 0, 1 or 2.

(③1-2) Compounds in which R ^1D is a hydrogen atom, a methyl group or an ethyl group.

(③１ 3) A compound in which R ^1Q is a hydrogen atom.

(③- 4) R ¹¹ forces a hydrogen atom, d ~ (: indicating group (wherein represented by ₄ alkyl group, or a group of the formula one ^{C (= NH) R 4,} R 4 is a hydrogen atom, a methyl group or an amino group )

(③-5) R ¹¹ force A compound that is a hydrogen atom, a methyl group, an ethyl group, a formimidyl group, an acetimidoyl group, or an amidino group.

(③-6) A compound in which R ¹¹ is a hydrogen atom.

Preferred compounds (I) in which A has a group represented by the general formula (2) include the following compounds. (④- 1) shows R ¹² forces hydrogen atom, C, group (wherein represented by -C ₄ alkyl radical or formula one ^{C (= NH) R 4,} R 4 is a hydrogen atom, a methyl group or an amino group )

(II-2) R ¹² A compound that is a hydrogen atom, a methyl group, an ethyl group, a formimidoyl group, an acetimidoyl group, or an amidino group.

(④-3) R ¹³ force d to (: ₄ alkyl groups having 1 to 2 substituents (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), a C ₃ -C ₆ cycloalkyl group, C _6- (: aryl group or C ₇ -C ₁₄ aralkyl group which may have 1 to 2 substituents (the substituent is a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, Carbamoyl, dimethylcarbamoyl, dimethylcarbamoyl, 5- to 6-membered heteroaryl containing 1 to 3 nitrogen, oxygen or sulfur atoms, methoxy, difluoromethoxy, methylenedioxy, A benzyloxy group, a pyridylmethoxy group or an acetylamino group.)

(a) 5 to 6-membered heteroaryl group or benzene containing 1 to 3 nitrogen, oxygen or sulfur atom which may have 1 to 2 substituents selected from the group consisting of: Ring condensed 5- to 6-membered heteroaryl group, or 1 to 3 substituents selected from substituent group (a), 1 to 3 containing nitrogen, oxygen or sulfur atom 5 to 6-membered heteroaralkyl group or benzene ring-condensed 5- to 6-membered heteroaralkyl group.

(④-4) R ¹³ is a -C ₄ alkyl group having 1 to 2 substituents (the substituent represents a halogen atom, a carbamoyl group or a hydroxyl group), a C ₃ -C ₆ cycloalkyl group, A phenyl, naphthyl, benzyl, phenethyl or naphthylmethyl group which may have 2 to 2 substituents (the substituent is a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, a carbamoyl group, Methylcarbamoyl group, dimethylcarbamoyl group, 5- to 6-membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy group, difluoromethoxy group, methylenedioxy group, benzyloxy group, pyridylmethoxy group or Or an acetylylamino group.) Or pyridyl, pyrimidyl, imimi which may have 1 to 2 substituents selected from the group of substituents (a) Zoriru, triazolyl, thiazolyl, Chiajiazoriru A compound which is a benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl or quinolylmethyl group.

(④-5) R ¹³ is a C ₄ alkyl group having 1 to 2 substituents (the substituent represents an octogen atom, a carbamoyl group or a hydroxyl group), and a C ₃ to (: ₆ cycloalkyl Group, phenyl or benzyl group which may have 1 to 2 substituents (the substituent is nitro, halogen atom, carbamoyl, sulfamoyl, imidazolyl, thiazolyl, 1, 2, 4-triazolyl or benzyloxy) Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, which may have 1 to 2 substituents A benzimidazolylmethyl or quinolylmethyl group (the substituent is a halogen atom , Amino, carbamoyl, sulfamoyl, hydroxymethyl, levamoylmethyl, phenyl, ethylthio, pyridyl, 11-imidazolylmethyl, trimethylammonio, thiocarbamoyl or benzyl.) A compound that is

(④-6) R ¹³ is 2-fluoroethyl, cyclopropyl, phenyl, 3-pyridyl, 4-pyridyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4- (1-imidazolyl) benzyl, 4-benzyloxybenzyl, 2-thiazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4- (4-pyridyl) thiazole— 2-yl, 4-phenylthiazole-2-yl, 4-benzylthiazole-2-yl, 6-amino-benzothiazoyl 2-yl, 4-yl

(1-imidazolylmethyl) thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 5-phenyru1,3,4-thiadiazol-2-yl, 5- ( 4-pyridyl) 1,3,4-thiadiazole-2-yl, 5-ethylthio-1,3,4-thiadiazole-'2-yl, 2-benzothiazolylmethyl, 2-benzyl Compounds having an imidazolylmethyl or 2-quinolylmethyl group. Compounds obtained by appropriately combining the substituents in the above preferable compounds are more preferable, and examples thereof include the following compounds.

(1) A is a group represented by the general formula ①, k is 0 or 1, m is 0, 1 or 2, R ² , a hydrogen atom, a C ₄ alkyl group, A benzyl, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or thiadiazolylmethyl group which may have a substituent (the substituent represents a fluorine atom, a methyl group or a rubamoyl group); C (= NH) group represented by R ⁴ (wherein, R ⁴ represents a hydrogen atom, a methyl group or an amino group), 2-imidazolinyl group, 2-thiazolinyl group, an imidazolyl group, thiazole Lil group or a pyridyl group in and, R ³ is a hydrogen atom, Okiso group, Surufamoirua Minomechiru group, forces Rubamoiru group, dimethylcarbamoyl group, 1-Piperajiniruka Ruponiru group, Aminopirorijin 1 over I nyl group or aminomethyl pyro lysine - 1 compound is Irukaruboniru group.

(2) A is a group represented by the general formula ①, k is 0 or 1, m is 0, 1 or 2, R ² is a hydrogen atom, methyl group, ethyl group, 1-2 substitution A benzyl or pyridylmethyl group which may have a group (the substituent is a fluorine atom, a methyl group or a rubamoyl group), a formimidyl group, an acetimidoyl group, an amidino group, 2-imidazoline-2-y Or a 2-thiazoline-2-yl group, and R ³ is a hydrogen atom.

(3) A is a group represented by the general formula 、, k is 0 or 1, m is 0, 1 or 2, R ² is a hydrogen atom, a methyl group, an ethyl group ', a benzyl group, a pyridylmethyl A compound wherein R ³ is a hydrogen atom, which is a group, formimidyl group, acetimidoyl group, amidino group, 2-imidazoline-1-yl group or 2-thiazoline-2-yl group.

(4) A is a group represented by the general formula 、, q is 0 or 1, and R ⁹ is a phenyl group which may have 1 to 2 substituents (the substituent is a methyl group, a methoxy group , A nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, a dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, a pyridyl group or a thiazolyl group). (5) A is a group represented by the general formula (1), q is 0 or 1, and R ⁹ is a phenyl group which may have 2 substituents (the substituent is a nitro group, a fluorine atom, A carbamoyl group, a dimethylcarbamoyl group, an imidazolyl group, a triazolyl group or a thiazolyl group).

(6) A is represented by the group of general formula (3), r is 0, 1 or 2, and R ¹ . There hydrogen atom, a -C ₄ alkyl group, R ¹¹ is a hydrogen atom, -C ₄ alkyl radical or the radical (wherein the formula one ^{C (= NH) R 4,} R 4 is a hydrogen atom, A methyl group or an amino group).

(7) A is a group represented by the general formula (3), r is 0, 1 or 2, R ^1Q is a hydrogen atom, a methyl group or an ethyl group, and R ¹¹ is a hydrogen atom, a methyl group or an ethyl group A compound which is a formimidyl group, an acetimidoyl group or an amidino group.

(8) A is a group represented by the general formula 、, R ¹² is a hydrogen atom, a d-C ₄ alkyl group or a group represented by the formula —C (= NH) R ⁴ (wherein R ⁴ is A hydrogen atom, a methyl group or an amino group), and only ^ has 丄-substituents ^-(: ₄ alkyl groups (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group) , C ₃ ~ C ₆ cycloalkyl group, one to two may have a substituent Cs~ (:., Ariru group or c ₇ to c ₁₄ Ararukiru group (the substituent is a nitro group, a halogen atom , A methyl group, an amino group, a sulfamoyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, a 5- to 6-membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms, a methoxy group, a difluoro group Romethoxy group, methylenedioxy group, benzyloxy group, pyridylme A substituent group (a) which may have 1 to 2 substituents selected from the group consisting of 1 to 3 nitrogen, oxygen or sulfur atoms; 6-membered heteroaryl group or benzene ring-fused heteroaryl group, or 1 to 3 nitrogen, oxygen or sulfur atoms optionally having 1 to 2 substituents selected from substituent group (a) And a 5- or 6-membered heteroaralkyl group or a benzene ring-fused heteroaralkyl group.

(9) A is a group represented by the general formula 、, and R ¹² is a hydrogen atom, a d-C ₄ alkyl group or a group represented by the formula C (= NH) R ⁴ (wherein R ⁴ is hydrogen atom, a methyl group or an amino group), ^ ^ has丄-substituents, - (- ₄ alkyl Le group (the substituent is a halogen atom, a force Rubamoiru group or a hydroxyl group), C ₃ ~ C s cycloalkyl group, 1-2 may have a substituent phenyl, naphthyl, benzyl, Fuwenechiru or naphthyl Methyl group (The substituent includes a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, and one to three nitrogen, oxygen, or sulfur atoms. Or a 5- or 6-membered heteroaryl group, a methoxy group, a difluoromethoxy group, a methylenedioxy group, a benzyl group, a pyridylmethoxy group or an acetylamino group.) Or a substituent group (a) Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiayl optionally having 1 to 2 substituents Compounds which are diazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl or quinolylmethyl.

(10) A is represented by a group of the general formula 、, and R ¹² is a hydrogen atom, a C 1, -C ₄ alkyl group or a group represented by the formula —C (= H) R ⁴ (wherein R ⁴ Represents a hydrogen atom, a methyl group or an amino group, and R ¹³ is a C ¹ to C ₄ alkyl group having 1 to 2 substituents (the substituent is a halogen atom, a rubamoyl group or A hydroxyl group), a C ₃ -C ₆ cycloalkyl group, a phenyl or benzyl group which may have 1 to 2 substituents (the substituents are nitro, halogen atom, carbamoyl, sulfamoyl, Imidazolyl, thiazolyl, 1, 2, 4-triazolyl or benzyloxy group), or pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl which may have 1 to 2 substituents , Pirizi Methyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl or quinolylmethyl group (the substituents are halogen atom, amino group, carbamoyl group, sulfamoyl group, hydroxymethyl group, carbamoylmethyl group, phenyl group, ethylthio) A pyridyl group, an imidazolylmethyl group, a trimethylammonium group, a livamoyl group or a benzyl group).

(1 1) A is shown under the general formula ④, R ^{1 2} is hydrogen atom, a methyl group, Echiru group, formimidoyl group, an Asetoimidoiru group or amidino group, R ^{1 3} is 2- P

 WO 98/34937

30 Fluoroethyl group, cyclopropyl group, phenyl group, 3-pyridyl group, 4-pyridyl group, benzyl group, 412-trobenzyl group, 4-chlorobenzyl group, 4-fluorobenzyl group , 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4- (1-imidazolyl) benzyl group, 4-benzyloxybenzyl group, 2-thiazolyl group, 2-benzimidazolyl group, 2 —Benzothiazolyl group, 4- (4-pyridyl) thiazo-lu-2-yl group, 4-phenylthiazolu-2-yl group, 4-benzylthiazol-2-yl group, 6-amino-benzo group Thiazolyl-2-yl group, 4- (1-imidazolylmethyl) thiazo-lu-2-yl group, 1, 3, 4-thiadiazol-2-yl group, 5-phenyl-2,3 , 4-thiadiazo-1-2-yl, 5-(4-pyridyl ) — 1,3,4-thiadiazol-2-yl group, 5-ethylthio-1,3,4-thiadiazol-2-yl group, 2-benzothiazolylmethyl group, 2-benzimidazolyl A compound that is a methyl group or a 2-quinolylmethyl group. In the compound represented by the general formula (I) of the present invention, the configuration at the 9-position and the 10-position are (9R, 10S) configuration which is the same configuration as that of chenamycin; The configuration at the α-position having a hydroxyl group is the R configuration, and the 8-position and the 4-position indicate one or a mixture of isomers. Preferable ones of the isomers are compounds in which the 8-position is S-configuration. Specific examples of the compound represented by the general formula (I) of the present invention are shown in the following table.

[table 1]

 (Compound in which A is represented by Formula II) Compound Compound

 A A

 No. No.

① ー 1

① ー 2

①-3

①-4

①— 5

S ~-

Compound Compound No. A

化合物 No. A

化合物 化合物 No. No.

化合物 化合物 No. No.

No. A

Compound No. A

Compound Compound No. No.

Compound Compound No. No.

化合物 化合物 No. No.

Compound Compound No. No.

ほ 2]

Ho 2]

 (A is a compound represented by the formula ②)

 Compound A Compound A N 0.N 0.

 ② ー 1

② ー 2

② ー 3

② ー 4

©-5

② ー 6

② ー 7

② ー 8

3 ]

3]

 (A is a compound represented by formula ③)

 Compound A Compound A

 N 0.

 NH

③— 1 OC〇CH ₂ NH ゥ ③1 8 〇COCH ₂ CH ₂ NH-

NH

@One 2 OCOCH ゥ NHCH ₃ ③ ー 9 OCOCH ₂ CH ₂ NH-

CH ₃

.NH NH

③One 3 OCOCH ₂ NH- ”(3)-l 0 OCOCH ₂ CH ₂ NH-

NH ₂

NH

③ one 4 OCOCH ₂ NH— ③ ー ii OCONH ₂

CH ₃

NH

③One 5 OCOCH ₂ NH- ③—! 2 OCONHCH3

NH ₂

, CH ₃

③— 6 OCOCH ₂ CH ₂ NH ₂ ③ ー 1 3 OCON,

, CH ₃

③ ー 7 OCOCH ₂ CH ₂ NHCH ₃ ③ ー i 4

[表 4]

[Table 4]

 (A is a compound represented by the formula ④)

Compound A Compound A N 0. J 0.

1 ー 1 ④ ー 2 ΝΗ 'Ν

Compound A Compound No. A

 No.

Poo 3 Poo 11

④-1

Poo 5

④-1

Page 7

Page 8

Page 9

H ₂ N

 NH

 ④ ー 10 N '④-18 N- (^

Π ヽ / Compound A Compound No. A

 No.

 1 1 9

Ps 20

2 2 1

Poo 22

化合物 化合物 No. No.

Compound Compound No. No.

 37

OS-®

 • ON "ON

 ^

l € S00 / 86Jf / X3i 6 6 OAV Compound Compound No. No.

化合物 化合物 No. No.

化合物 化合物

Compound Compound No. No.

Compound Compound

 No. No.

Et

化合物 化合物 No. No.

Et

Compound Compound No. No.

Compound Compound No. No.

 H

化合物 化合物 No. No.

Compound Compound No. No.

@ -134 W

Also, in the above table, preferably,

Compound number ①-1, 1, ー 2, ①-3, ①-4, ①-5, ①-18, ①-9, ①-10, ①-11, ①-12, ①-14, ①-17 , ①-22, ①-23, ①-34, ①-35, ①-36, ①-51, ①-53, ①-54, ②--1, ②-2, ②--3, ②--4, ②-5, ②-14, ②-15, ③-1, ③-2, ③-3, ③-4, ③-5, ③-6, ④-3, ④-11, ④-12, ④ -13, ④-14, ④-2

0. ④-28, ④-29, ④-30, ④-41, ④-42, ④47, @ -51, ④-55, @ -60, ④-71, ④-74, ④-86, Compounds of ④-95, ④-100, ④-105, ④-112 can be mentioned, and more preferably, compound No. ①- 1, ①-2, 1--3, 1--4, 1--5 , ①-9, ①-10, ①-11, ①-12, ②-14, ②-15, ①-34, ①-36, ①-51, ①-54, ③--1, ③-6, ④-3, 1-11, ④-12, ④-13, ④-16, ④-29, ④-30, ④-41, ④-47, ④-47, ④-55, ④-60, ④-74, ④ over 86, ④ over 95, ④ one 100, ④ one 105, can be force ^s include compounds of ④-1 12. Particularly preferred compounds include the following compounds.

1. (4 R, 8 S, 9 R, 1 OS)-10- [(R) — 1-hydroxyethyl] 1-4 [(S) 1-3-pyrrolidinyl] thiomethyl-11-oxo-1 -azatri Cyclo [7. 2.0.0. ³ ' ⁸ ] pendant-2-ene-2-butyric acid [(4R) isomer of exemplified compound ①-1]

2. (4R, 8S, 9R, 10S) -10-[(R) -11-hydroxyethyl] 111-oxo-4--4-[(S) -12-pyrrolidinyl] methylthiomethyl-1-aza Bok Rishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2 En 2 force carboxylic acid [example shows compounds of ① over 5 (4 R) isomer]

 3. (4 S, 8 S, 9 R, 10 S) 1-4-N-benzylaminomethyl-10- [(R) — 1-hydroxyethyl] 1 1 1-oxo-1 1-azat Licyclo [7.2

. 0 ³ ' ⁸ ] Pendeca-2-ene-2-carboxylic acid [(4S) isomer of exemplified compound III-3] 4. (4 R, 8 S, 9 R, 1 OS) 1 4 1 N-benzylaminomethyl 1 10— [(R) — 1-hydroxyethyl] 1 1 1 oxo— 1 1azatricyclo [7. Two

^3. 0 ³ · ⁸ ] pendecar 2-ene-2-carboxylic acid [(4R) isomer of exemplified compound ④-3]

5. (4 R, 8 S, 9 R, 1 OS) 1-4-[(S)-1-amidinopyrrolidine-1-3-yl] thiomethyl-10-[(R)-1-hydroxyethyl] 1-1 1 1-year-old oxo- 1-azatricyclo [7. 2. 0. ³ · ⁸ ] pendant force 2-en-2-carboxylic acid [(4R) isomer of exemplified compound ①-4]

6. (4 R, 8 S, 9 R, 1 OS) 1 10— [(R) — 1-hydroxyethyl] -4- [(S)-1-(2-imidazoline-1- 2-yl) pyrrolidine — 3-yl] Thiomethyl-11-oxo-11-azatricyclo [7. 2.0.0 ³ · ⁸ ] (4R) isomer]

7. (4R, 8 S, 9R, 1 OS) 1 10— [(R) — 1-hydroxyethyl] 1 4 1 [(S) 1 1 1 (2-thiazoline-2-yl) pyrrolidine 1 3 - I le] Ji Omechiru one 1 1 one Okiso one 1- § the Bok Rishikuro [7.2.3 .0 ^3.8] Unde force one 2- En 2- force carboxylic acid [example compound ①- 34 of (4R ) Isomer]

8. (4 R, 8 S, 9 R, 10S) — 10— [(R) — 1-hydroxyethyl] 1-41 [1- (2-thiazoline-2-yl) azetidine— 2-yl] thiomethyl one 1 1 Okiso one 1- Azatorishikuro [7.2.3 0.0 ^{3 '8]} Unde force one 2- E Hmm 2- carboxylic acid [example compound ①- 38 of (4R) isomer]

9. (4 R, 8 S, 9 R, 10S) 1-4-[1-amidinoazetidine-2-yl] thiomethyl-10-[(R)-1-hydroxyethyl]-1 1 1 one Azatorishikuro [7.2.3 0.0 ^{3 '8]} Unde force one 2- En 2- force carboxylic acid [example compound ① over 12 (4R) isomer]

10. (4 R, 8 S, 9 R, 10S) — 10— [(R) — 1-hydroxyethyl] -4- [N— (4- (11-imidazolyl) benzyl) aminomethyl] 1 1 1 — Oxo-1 1-azatricyclo [7. 2.0.0. ³ · ⁸ ] pendant force 2-ene-1-carboxylic acid [(4R) isomer of Exemplified Compound II-29]

1 1. (4 S, 8 S, 9 R, 10S) 1 10— [(R) — 1-hydroxyethyl ] 4- 1- [N- (2-thiazolyl) aminomethyl] 1- 1-oxo- 1- 1-azatricyclo [7. 2. 0. ³ · ⁸ ] Illustrative compound (29) (4S) isomer]

12. (4 R, 8 S, 9 R, 1 OS) -10-[(R) -1-hydroxyethyl] -4- [N— (2-thiazolyl) aminomethyl] 1-11-oxo-1 - Azato Rishikuro [7.2.3 .0 ^3.8] Undeka 2 E emissions - 2-carboxylic acid [illustrative of compounds ④ over 29 (4R) isomer]

13. (4 S, 8 S, 9 R, 1 OS) 1 4— [N- (2-benzothiazolyl) aminomethyl] 1 10— [(R) — 1-hydroxyethyl] — 1 1 1- Azatorishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2 E down one 2-force carboxylic acid [example compound ④- 47 of (4R) isomer]

14. (4 R, 8 S, 9 R, 10 S) i 4— [N— (2-benzothiazolyl) aminomethyl] — 10— [(R) — 1-hydroxyethyl] — 11 1-oxo— 1 1-azatricyclo [7. 2. 0. ³ · ⁸ ] pendecar 2-ene-2-carboxylic acid [(4R) isomer of Exemplified Compound II-47]

15. (4 S, 8 S, 9 R, 1 OS) 1 10— [(R) 1 1-hydroxyethyl) 1 4 1 [N— (2- (4-phenyl) thiazolyl) aminomethyl] — 1 1 one year old Kiso 1 one Azatorishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2 En 2 force carboxylic acid [example compound of ④ over 60 (4S) isomer]

16. (4R, 8 S, 9R, 1 OS) 1 10— [(R) 1 1-hydroxyethyl) —4 1 [N- (2— (4-phenyl) thiazolyl) aminomethyl] —1 1 1才 キ ソ 一 一 一 一 一 7 [7. 2. 0. ³ ' ⁸ ] カ ー カ ー 2 — ル 力 ル 例 示 [Exemplified compound 60-60 (4R) isomer]

17. (4 S, 8 S, 9 R, 10 S) 1-41 [N- (2- (4-benzyl) thiazolyl) aminomethyl] 1 10— [(R) — 1-hydroxyethyl] — 1 1 1 year old Kiso 1 1-azatricyclo [7. 2. 0. ³ ' ⁸ ] pendecar 2-ene 2-force rubonic acid [(4S) isomer of exemplified compound II-71]

18. (4 R, 8 S, 9 R, 1 OS) —4- [N— (2- (4-benzyl) thiazolyl) aminomethyl] —10— [(R) — 1-hydroxyethyl] 1 1 One year old Kiso 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ] pentadecane 2-ene-2-force rubonic acid [(4R) isomer of exemplary compound II-71]

19. (4S, 8S, 9R, 10 S) -10-[(R) -1-Hydroxyethyl] -4-[N— (5-phenyl-1,3,4-thiadiazoyl-2-yl) Aminomethyl] — 1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ] pendant force 2- 2-en-2-carboxylic acid [(4S) isomer of exemplified compound 100-100 ]

20. (4R, 8S, 9R, 10S) — 10— [(R) — 1-hydroxyethyl] —4— [N— (5—Feneru 1, 3,4—Thiadiazo 2—2 Le) amino Nomechiru] one 1 1- Okiso one 1 one Azatorishikuro [7.2.3 .0 ^3.8] Unde car 2 E emissions - 2-carboxylic acid [example compound ④ -100 of (4R) isomer]

21. (4 S, 8 S, 9 R, 10 S) — 10— [(R) — 1-hydroxyethyl] —4— [N— (1, 3, 4-thiadiazol-2-yl) Aminomethyl] — 1

1-oxo 1 1-azatricyclo [7. 2. 0. ³ ' ⁸ ]

2-Rubronic acid [(4S) isomer of Exemplified Compound II-30]

22. (4 R, 8 S, 9 R, 1 OS) — 10— [(R) — 1-hydroxyethyl] 1-4 — [N— (1, 3, 4-thiadiazol-2-yl) amino Methyl] 1 1 1 1-oxo-1 1-azatricyclo [7. 2.0.0. ³ · ⁸ ] pendecar 2-en-2-carboxylic acid [(4R) isomer of exemplary compound II-30]

23. (4R, 8 S, 9 R, 10 S) — 10— [(R) — 1-hydroxyethyl] 1 4— [1— (2-thiazoline-2-yl) Le] Chiomechi Roux 1 1 one Okiso one 1 one Azatorishikuro [7.2: 0. 0 ^{3 '8]} Unde force one 2-E emissions - 2 - force carboxylic acid [example compound ①- 40 of (4R) isomer]

24. (4R, 8 S, 9 R, 1 OS) 14- (1-Amidinopiperidine-14-yl) thiomethyl-10-[(R) —1-hydroxyethyl] 1-11-oxo-1— § The Bok Rishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2-E down one 2-force carboxylic acid

[(4R) isomer of Exemplified Compound II-12] The tricyclic heterocyclic compound having the general formula (I) can be produced by the following methods (Method A, Method B and Method C).

(Method A)

No. A 2

A4

 (VI) (I)

In the above formula, A has the same meaning as described above, R ¹⁴ represents a protecting group for a hydroxyl group, R ¹⁵ represents an alkyl group or an aryl group, R ¹⁶ represents a protecting group for a carboxy group, and Ap represents When A contains a hydroxyl group, an amino group and / or an imino group, these A which may be force-protected are shown. When A is a group having a quaternary ammonium group or a pyridino group, Ap includes a group having a corresponding tertiary amino or pyridyl group.

The "protecting group for the hydroxyl group" of R "is, for example, a trialkylsilyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl; An aralkyloxycarbonyl group such as oxycarbonyl and benzyloxycarbonyl; chlorine or 2-aryloxycarbonyl such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl; A diaryloxycarbonyl group which may be substituted by methyl; 2-position such as trimethylsilylethyloxycarbonyl or 2,2,2-trichloroethyloxycarbonyl is substituted by trialkylsilyl or chlorine; And an ethyl carbonyl group, preferably a t-butyldimethylsilyl group or an aryloxycarbonyl group, and particularly preferably a t-butyldimethylsilyl group.

The `` alkyl group '' of R ¹⁵ represents a C ₄ alkyl group which may be substituted with 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, isopropyl, trifluoromethyl and butyl. The “aryl group” is C ₆ which may be substituted with a methyl group such as phenyl, tolyl, and naphthyl. Represents an aryl group. R ^{1 S} is preferably a methyl group or a fuunyl group, particularly preferably a methyl group.

The “carboxyl-protecting group” of R ¹⁶ is a protecting group commonly used in the field of synthetic organic chemistry. For example, the 2-position such as aryl, 2-chloroallyl, and 2-methylaryl is substituted with chlorine or methyl. Aralkyl groups such as benzyl and 412-trobenzyl; and benzhydryl groups, which are preferably aryl groups and 412-nitrobenzyl groups, and particularly preferably Is an aryl group.

 The “protecting group for hydroxyl group, imino group and amino group” contained in A is a protecting group usually used in the field of organic synthetic chemistry, such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, — An aryloxycarbonyl group which may be substituted at the 2-position with chlorine or methyl, such as methylaryloxycarbonyl; an arylalkyloxy group such as benzyloxycarbonyl, 412-trobenzylyloxycarbonyl An xyloxycarbonyl group is preferred, and an aryloxycarbonyl group or a 412-hydroxybenzyloxycarbonyl group is preferred, and an aryloxycarbonyl group is particularly preferred.

In the method A, a compound having the formula (III) is reacted with a compound having the formula (II) in the presence of a base to produce a compound having the formula (III) (Step A1), and the obtained compound (II The I) in the presence of a base with a compound having the formula HA p to produce a compound of formula (IV) (the A2 step), followed by C 1 C0C00R ¹⁶ and is reaction in the presence of a base, wherein (V) (Step A3), followed by a closure reaction to produce a compound having the formula (VI) (Step A4), and finally removing the protecting group, if necessary. And converting the compound into a pharmacologically acceptable salt or an ester that undergoes hydrolysis in vivo (Step A5) to produce a compound having the general formula (I). Hereinafter, each step will be described in detail.

 (Step A1) Sulfonylation

 The A1 step is a step of producing a compound having the formula (III) by reacting a compound having the formula (III) with a sulfonylating agent in an inert solvent in the presence of a base. The compound having the formula (II) as a starting material was synthesized according to Reference Example 1.

 Sulfonylation agents include, for example, alkanesulfonyl chlorides such as methanesulfonyl chloride and ethanesulfonyl chloride; arylsulfonyl chlorides such as benzenesulfonyl chloride and p-toluenesulfonyl chloride; methanesulfonic anhydride Sulfonic anhydrides such as trifluoromethanesulfonic anhydride and ethanesulfonic anhydride; and arylsulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride. Sulfoyluryl chloride and P-toluenesulfonyl chloride.

 The solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, N, N— Examples thereof include amides such as dimethylformamide or N, N-dimethylacetamide or sulfoxides such as dimethylsulfoxide, and are preferably tetrahydrofuran or acetate nitrile.

The base used is not particularly limited as long as it does not affect other parts of the compound, especially | 3-lactam ring. Preferably, triethylamine, diisopropylethylamine or 4-dimethylamino is used. Examples include organic bases such as pyridine, preferably triethylamine or diisopropylethylamine. P

 WO 98/34937

The reaction temperature is not particularly limited, but is usually from -20 ° C to room temperature (preferably 0 ° C to room temperature), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 10 hours). ).

 After completion of the reaction, the target compound (III) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent from the reaction mixture, washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or mouth chromatography.

 (Step A 2) Substitution (Ap conversion) reaction

 Step A2 is a step of reacting compound (III) with a compound represented by the formula HAp in the presence of a base to obtain compound (IV).

 Solvents used are, for example, amides such as N, N-dimethylformamide or N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, tetrahydrofuran, dioxane or 1 And ethers such as 2,2-dimethoxyethane, and preferably N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide.

 The base used is, for example, an organic base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, or an inorganic base such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate. Triethylamine or disopropylethylamine.

 The reaction temperature is not particularly limited, but the reaction is usually carried out at -20 ° C to 100 ° C (preferably at room temperature to 60 ° C), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 10 hours). Time).

After completion of the reaction, the target compound (IV) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A3) Oxalylation reaction

The A 3 is a step for preparing a compound (IV) is reacted with the formula C ¹ COCOOR 1 compound represented by ⁶ in the presence of a basic compound (V).

 Solvents used are, for example, methylene chloride, chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, nitriles such as acetonitrile, tetrahydrofuran, dioxane or 1,2-dimethyloxetane Ethers such as the following are preferred, and methylene chloride or chloroform is preferred.

 The base used is, for example, an organic base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, preferably triethylamine or diisopropylpropylethylamine.

 Although the reaction temperature is not particularly limited, it is usually carried out at −20 ° C. to 60 ° C. (preferably 0 ° C. to room temperature), and the reaction time is 30 minutes to 24 hours (preferably 3 hours). 0 minutes to 12 hours).

 After completion of the reaction, the target compound (V) of the reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reaction, chromatography or the like.

 (Step A4) Ring closure reaction

 Step A4 is a step of subjecting compound (V) to a ring closure reaction in a molecule using a trivalent phosphorus compound to produce compound (V I). '

 Trivalent phosphorus compounds used include, for example, triethyl phosphites such as triethyl phosphite, trimethyl phosphite, tripropyl phosphite, tributyl phosphite, getyl methylphosphonite, Dialkylalkylphosphonites such as chillethylphosphonite are preferred, and triethyl phosphite and lithite are preferred.

Solvents used are, for example, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, aliphatic hydrocarbons such as cyclohexane and decalin, Ethers such as oxane, tetrahydrofuran, and 1,2-dietoxetane; and toluene, xylene or mesitylene is preferred.

 The reaction temperature is not particularly limited, but the reaction is usually performed at 40 ° C to 200 ° C (preferably 40 ° C to 160 ° C), and the reaction time is 30 minutes to 24 hours (preferably 30 minutes to 24 hours). (Between).

 After completion of the reaction, the target compound (VI) of the reaction can be further purified by a conventional method, if necessary, for example, recrystallization, reprecipitation or chromatography, if necessary, by removing the solvent from the reaction solution. .

 When A is a group having a quaternary ammonio group or a pyridino group, the compound (VI) is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI) according to a conventional method. be able to.

 (Step A5) Deprotection reaction

In the step ^A5 , when the protecting group R ^I4 of the hydroxyl group of the compound (VI), the protecting group R ¹⁶ of the carboxy group, and the protecting group s are contained in Ap, the protecting group is removed and the desired compound (I) is removed. ).

The removal of the protecting groups contained in the protecting groups R ¹⁴ , R ¹⁶ and Ap depends on the type of the protecting group, but it is generally known by methods known in the art (“Protective Groups in Organic Synthesis, 2nd Edition” Ed. By TWGreene and PGMWuts, 1991, John Wiley Sons, Inc.).

When the protecting group R ^{14 is} a trialkylsilyl group such as trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl, the deprotecting agent may be an organic fluorine such as ammonium hydrogen fluoride or tetrabutylammonium fluoride. Examples thereof include a compound and an inorganic fluorine compound such as potassium fluoride, and preferred is ammonium hydrogen fluoride or tetrabutylammonium fluoride.

The solvent used depends on the type of the deprotecting agent. S, ethers such as tetrahydrofuran, dioxane or 1,2-dimethyloxetane, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, a Nitriles such as cetonitrile; hydrogen halides such as methylene chloride, chloroform and 1,2-dichloroethane; Furan or dimethylformamide.

 Although the reaction temperature is not particularly limited, it is generally carried out at −20 ° C. to 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours.

After completion of the reaction, the deprotected compound is collected from the reaction mixture according to a conventional method, and then subjected to a reaction for removing a protecting group and removing a protecting group R ¹⁶ when Ap contains a protecting group. it can.

Protecting group R ^{1 4} is, for example trimethylsilyl E chill O alkoxycarbonyl, 2, 2, 2-position, such as 2-Bok Li chloro E chill O alkoxycarbonyl group Bok trialkyl silyl Wakashi Ku is substituted by chlorine Echiruo When the compound is an oxycarbonyl group, examples of the deprotecting agent include Lewis acids such as boron trifluoride etherate and metal-organic acids such as zinc monoacetic acid. Zinc monoacetic acid. The solvent used depends on the type of the deprotecting agent, but includes hydrogen halides such as chloroform and 1,2-dichloroethane, esters such as ethyl acetate, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Ethers, nitriles such as acetonitrile, and alcohols such as methanol, ethanol or propanol, preferably methylene chloride, ethyl acetate or tetrahydrofuran.

 Although the reaction temperature is not particularly limited, it is generally carried out at a temperature of from 20 ° C to 100 ° C (preferably from 0 ° C to 60 ° C), and the reaction time is usually from 30 minutes to 48 hours ( (30 minutes to 12 hours).

After completion of the reaction, the deprotected compound is collected from the reaction mixture according to a conventional method, and then subjected to a reaction for removing a protecting group and removing a protecting group R ¹⁶ when Ap contains a protecting group. it can.

An aryloxycarbonyl group which may be substituted at the 2-position with chlorine or methyl, such as an aryloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylallyloxycarbonyl in which R ¹⁴ is a protective group; Where the protecting group R ¹⁶ is substituted with chlorine or methyl at the 2-position such as aryl, 2-chloroallyl, 2-methylaryl. And the protecting group contained in Ap is substituted with chlorine or methyl at the 2-position such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylaryloxycarbonyl. In the case of an aryloxy carbonyl group which may be optionally used, deprotecting agents include palladiums such as bis (triphenylphosphine) palladium chloride tributyltin hydride and tetrakis (triphenylphosphine) palladium tributyltin hydride — Trialkyltin hydrides or tetrakis (triphenylphosphine) palladium—Palladiums such as 2-ethylhexanoic acid or sodium 2-ethylhexanoate—metals of organic carboxylic acids Salts, preferably bis ( Riff enyl) palladium black Li dough tributyltin Hyde Lai de tetrakis (triflate Nini Le phosphine) palladium - a hexanoic acid force Li to 2 Echiru.

 The solvent to be used is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, and esters such as ethyl acetate. And ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof. Is methylene chloride, ethyl acetate or a mixed solvent thereof.

 Although the reaction temperature is not particularly limited, it is generally −20 ° C. to 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 4.8 hours ( (30 minutes to 12 hours).

 After completion of the reaction, the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent.

When the protecting group R ¹⁴ is an aralkyloxycarbonyl group such as benzyloxycarbonyl and 412 trobenzyloxycarbonyl, the protecting group R ¹⁶ is benzyl and 412 trobenzylyl And the protecting group contained in Ap is benzyloxycarbonyl, 412-trobenzylo, etc. If it is an aralkyloxycarbonyl group such as xycarponyl, the deprotecting agent may be hydrogen and a catalytic reduction catalyst such as palladium on carbon or an alkali metal sulfide such as sodium sulfide or lithium sulfide. And preferably hydrogen and palladium-carbon.

 The solvent to be used is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, and esters such as ethyl acetate. And ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof. Is a mixed solvent of tetrahydrofuran or tetrahydrafuran-water.

 The reaction temperature is not particularly limited, but it is usually from room temperature to 100 ° C (preferably from room temperature to 60 ° C), and the reaction time is usually from 30 minutes to 48 hours (preferably from 30 minutes to 48 hours). 20 hours).

 After completion of the reaction, compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the catalyst used for the reaction and the precipitated insoluble matter from the reaction mixture, and then distilling off the solvent.

In the case where R ¹⁴ , R ¹⁶ or Ap uses a protecting group which is removed by the same deprotecting agent, those protecting groups can be removed at the same time.

The compound (I) thus obtained can be purified, if necessary, by a conventional method such as a recrystallization method, column chromatography, or preparative liquid chromatography. If necessary, it can be converted into an ester or other derivative that undergoes hydrolysis in vivo by a conventional method (Japanese Patent Laid-Open No. 5-502404), and is pharmacologically acceptable by a conventional method. Can be purified as a salt. On the other hand, the tricyclic heterocyclic compound having the general formula (I) of the present invention can also be produced by the following method B (method B).

(Method B)

上記式中、 R¹⁴、 R^1S、 Aおよび Apは、 A法において前述したものと同意義 である。 以下、 各工程について説明する。

In the above formula, R ¹⁴ , R ^1S , A and Ap have the same meanings as described above in Method A. Hereinafter, each step will be described.

 (Step B 1) Ap condensation reaction

 Step B1 is a step of reacting a compound having the formula HAp with a compound having the general formula (VII) to produce a compound having the formula (VI). Incidentally, the compound (V I I) as a starting material is produced according to Reference Example 2.

 When Ap corresponds to a group represented by general formula II, II or III as A, this step is achieved in an inert solvent by a reaction known as the Mitsunobu reaction.

 The solvent to be used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, and nitriles such as acetonitrile. Is tetrahydrofuran.

The condensing agent to be used is a combination of phosphines such as triphenylphosphine-getylazodicarboxylate and azodicarboxylates. The reaction temperature is not particularly limited, but is preferably triphenylphosphine-getylazodicarboxylate. The reaction is preferably carried out at a relatively low temperature in order to suppress a side reaction. The reaction time performed at a temperature of from room temperature to room temperature (preferably from −40 ° C. to room temperature) depends mainly on the reaction temperature and the type of the reaction reagent, but is usually from 15 minutes to 75 hours (preferably from 30 minutes to 6 hours).

 After completion of the reaction, the target compound (VI) of the reaction can be collected from the reaction mixture according to a conventional method.

 When A p corresponds to the group represented by the general formula (3) as A, this reaction is achieved by a condensation reaction between the compound (V I I) and the carboxylic acid component (H A p) in an inert solvent.

 The solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxyethane Ethers such as tan, nitriles such as acetonitrile, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, water or a mixed solvent thereof, and preferably methylene chloride. Or tetrahydrofuran.

 Examples of the condensing agent to be used include carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 4-dimethylaminopyridine. And 1-hydroxybenzotriazole may be used together. Preferably, 1,3-dicyclohexylcarbodiimide is used as a condensing agent, and 4-dimethylaminopyridine is also used.

 The reaction temperature is not particularly limited, but the reaction is preferably carried out at a relatively low temperature to suppress the lj reaction, preferably at a temperature of 120 ° C to 4 CTC (preferably 120 ° C to room temperature). Will be The reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually 15 minutes to 75 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method. Can be taken. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 When A is a group having a quaternary ammonium group or a pyridino group, the compound (VI) can be reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI) according to a conventional method. it can.

 (Step B2) Deprotection reaction Step B2 is a step of producing a compound (I) by removing the protecting group contained in the compound (VI), and is accomplished according to the method of the aforementioned step A5. .

Further, the tricyclic heterocyclic compound having the general formula (I) of the present invention can also be produced by the following method (Method C).

(Method C)

 () (W)

.S5C 2 processes

上記式中、 R¹⁴、 R¹⁶、 Aおよび Apは、 A法において前述したものと同意義 である。 P

In the above formula, R ¹⁴ , R ¹⁶ , A and Ap have the same meanings as described above in Method A. P

 WO 98/34937

66 In this synthesis method, a compound having the general formula (VII) is subjected to an oxidation reaction to produce a compound having the formula (VIII) (Step C1). This is a method in which a compound having the formula (VI) is produced by condensation under the following conditions (Step C2), and finally, a protecting group is removed to produce a compound having the general formula (I) (Step C3). This synthesis method is used for a group represented by the general formula (A). Hereinafter, each step will be described.

 (Step C1) Oxidation reaction

 Step C1 is a step of reacting the compound (VII) with an oxidizing agent to produce a compound having the formula (VIII).

 The oxidizing agent is, for example, an oxidizing agent using a dimethylsulfoxide-based reagent such as dimethylsulfoxide doxalyl chloride or dimethylsulfoxide anhydrous trifluoroacetic anhydride in the presence of an organic base, or a chromic acid-based oxidizing agent such as pyridinamide or lorochromate. And preferably dimethylsulfoxide-oxalyl chloride.

 The organic base used is not particularly limited as long as it does not affect the other parts of the compound, and examples thereof include organic bases such as triethylamine, diisopropylamine, and Ν-methylbiperidine. Is triethylamine. The solvent used is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxy Ethers such as ethane, ketones such as acetone or methyl ether ketone, nitriles such as acetonitrile, amides such as dimethylformamide or dimethylacetamide, and sulfoxides such as dimethyl sulfoxide or these And preferably a mixed solvent of methylene chloride and tetrahydrofuran.

The reaction temperature is not particularly limited, but is usually from -75 ° C to room temperature (preferably from -60 ° C to room temperature) in order to suppress a side reaction. The reaction time varies depending on the reaction temperature and the type of reaction reagent, and is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours). After completion of the reaction, compound (VIII) obtained by this reaction is collected according to a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, and the solvent is distilled off after washing with water.

. The obtained compound (VIII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 (Step C2) Ap condensation reaction

 Step C2 is a step of subjecting compound (VIII) to a condensation reaction in the presence of a compound represented by the formula HAp and a reducing agent to produce compound (VI).

 The reducing agent used is, for example, sodium cyanoborohydride, hydrogen-palladium carbon catalyst or platinum platinum monohydrogen, and is preferably sodium cyanoborohydride.

 The solvent used is not particularly limited as long as it does not participate in the reaction. For example, alcohols such as methanol, ethanol or propanol, ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane are used. And nitriles such as acetate nitrile, water or a mixed solvent thereof, and preferably methanol or ethanol.

 The reaction temperature is not particularly limited, but is usually -20 ° C to 40 ° C (preferably o ° C to room temperature) in order to suppress a side reaction. The reaction time varies depending on the reaction temperature and the type of the reaction reagent. The reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

 After completion of the reaction, the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

 When A is a group having a quaternary ammonio group or a pyridino group, the compound (VI) is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI) according to a conventional method. Can be.

(Step C3) Deprotection reaction Step C3 is a step of producing compound (I) by removing the protecting group contained in compound (VI), and is accomplished according to the method of step A5 described above. The compound having the general formula (I) thus produced by Method A, Method B or Method C may be used, if necessary, in medicinal chemistry, especially in the field of (3-lactam antibiotics). It can be converted to a derivative such as an ester that undergoes hydrolysis in vivo according to a known method or technique, and can be purified as a pharmacologically acceptable salt.

(The invention's effect)

 The tricyclic heterocyclic compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt or derivative thereof has excellent antibacterial activity and has an activity of inhibiting 3-lactamase. That is, the compound (I) of the present invention is a gram-positive bacterium such as Staphylococcus aureus and enterococcus, a gram-negative bacterium such as Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacterium, Serratia, Enterobacter, and Pseudomonas aeruginosa. It exhibits antibacterial activity against a wide range of pathogens including anaerobic bacteria such as Teloides fragilis, and especially strong against methicillin-resistant Staphylococcus aureus (MRSA), which has recently become a problem. In addition, although chenamycin compounds are susceptible to metabolism by mammals, the compound (I) of the present invention has excellent stability against dehydrobeptidase-I, which is known as an enzyme that catalyzes the inactivation of chenamycin. The urine recovery rate is high. Furthermore, compound (I) has low toxicity. Therefore, the tricyclic heterocyclic compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt or derivative thereof is useful as a medicament, and particularly for treating or preventing (preferably treating) bacterial infections. Useful as an antibacterial agent.

[Industrial applicability]

When the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used as an antibacterial agent, the compound (I) itself or an appropriate pharmacologically acceptable excipient, diluent or the like may be used. They can be mixed and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by intravenous or intramuscular injection.

These preparations may contain excipients (eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbite; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch). Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light silicic anhydride Silicate derivatives such as synthetic aluminum silicate, magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; calcium sulfate , A binder (eg, the above-mentioned excipient; gelatin; polyvinylpyrrolidone, magrogol, etc.); a disintegrant (eg, the above-mentioned excipient; croscarmellose sodium, carboxy) Chemically modified starch such as sodium methyl starch, crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stearic acid; calcium stearate, metal stearate such as magnesium stearate; colloidal silica) Luxes such as bigum, gay mouth; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfuric acid such as sodium sulfate. Salts; leucine; sodium lauryl sulfate, lauryl sulfate Lauryl sulfates such as gnesium; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, paraoxybenzoic acid esters such as methylparaben and propylparaben) Alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzolconidum chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid and the like; Commonly used sweeteners, acidulants, flavors, etc., suspending agents (eg, polysorbate 80, sodium carboxymethylcellulose, etc.), diluents, formulation solvents (eg, water, ethanol, glycerin) And the like, and is manufactured by a known method using additives such as The dosage varies depending on symptoms, age, etc.In the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 1000 mg) per dose. In this case, the lower limit of 1 Omg (preferably 50 mg) and the upper limit of 300 Omg (preferably 200 Omg) per dose may be administered to an adult 1 to 6 times daily according to symptoms. desirable.

[Best mode for carrying out the invention]

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples. The scope of the present invention is not limited thereto. Incidentally, sodium trimethylsilyl propionate unless otherwise specified for the measurement of heavy water for nuclear magnetic resonance Supekubokuru in Examples and Reference Examples - using d ₄ as the internal standard, tetramethyl for other Solvent The measurement was performed using silane as an internal standard.

 (Example 1)

(4 S, 8 S, 9R, 10 S) — 10— “(R) — 1-hydroxyethyl” — 4— [(S) -3-pyrrolidinyl] thiomethyl-1 1-oxo-1 1-azatricyclo [7 . 2 - 0.0 ^3.8 1 one Undeka 2- En 2- carboxylic acid

 [(4 S) isomer of Exemplified Compound II]

(1) (3 S, 4 R) 1-4 [(2 R, 6 S)-6-[(S)-(1 -aryloxycarbonyl) pyrrolidine-1 -yl] thiomethylcyclohexanone-2 — Yl] 1 3— [(R) — 1- (t-butyldimethylsilyloxy) ethyl] azetidine— 2-one (6S form) and (3S, 4 R) —4— [(2 R , 6 R) —6-[(S)-(1 -aryloxycarbonyl) pyrrolidine- 1 -yl] thiomethylcyclohexanone-2 -yl] —3-[(R) 1-1 (t —Butyldimethylsilyloxy) ethyl] azetidin-1-one (6R)

Reference Example 11 The compound (1.26 g) obtained in (8) was dissolved in tetrahydrofuran (15 ml), and triethylamine (430 mg) and methanesulfonyl chloride (447 mg) were added under ice-cooling, followed by stirring for 2 hours. . The precipitate was filtered, and the filtrate was concentrated to obtain a methanesulfonic acid ester intermediate. The methanesulfonate intermediate was dissolved in dimethylformamide (15 ml), and a solution of (S) —1-allyloxycarboxy-2-3-mercaptopyrrolidine in dimethylformamide (5 ml) and triethylamine was added. Ethylamine (592 mg) was added, and the mixture was stirred at room temperature for 2 hours and at 40 ° C for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 100 g, hexane: ethyl acetate = 2: 5-1: 3) to obtain the title compound as a diastereomer mixture.

The Jiasutereoma mixture is purified using reverse phase column prep (Cosmosil _{5 C 18 AR 28 X 25 Omm} ) by high performance liquid chromatography, (6S) body (0. 72 g), (6 R) body (1.03 g) as a colorless oil

(6 S) body

Infrared absorption spectrum _{(CHC 1 3) v max cm-} 1: 3417, 2953, 2860, 1698, 1413.

Nuclear magnetic resonance spectrum _{(400MHz, CDC l 3) 5} ppm: 0. 06 (3 H, s), 0. 07 (3H, s), 0. 87 (9 H, s), 1. 78 (3 H, d, J = 6.3Hz), 1.58-2.26 (8Η, m), 2.61 -2.73 (3Η, m), 2.85-2.92 (2Η, m) , 3.24-3.80 (5 Η, m), 4.04 (1 Η, dd, J = 5.7 and 1.7 ζ ζ), 4.19 (1 Η, qd, J = 6. 3 and 5.1 Hz), 4.59 (2 H, d, J = 5.5 Hz), δ. 21 (1 H, dd, J = 10.3 and 1.3 Hz), 5.31 (l H, dd, J = 17.5 and 1.3 Hz), 5.85 (1H, brd, J = 6.0Hz), 5.89-5.99 (1H, m).

 (6R) body

Infrared absorption spectrum ^{_{(CHC 1 3) max cm- 1}} : 3418, 2953, 2860, 1758, 1702, 1412.

Nuclear magnetic resonance spectrum (400 MHz, CDC 13) δ p pm: 0.06 (3H, s), 0.07 (3H, s), 0.87 (9H, s), 1.23 (3H, d) , J = 6.3 Hz), 1.33 -2.62 (1 H, m), 2.86 (1 H, dd, J = 4.8 and 2.4 Hz), 2.98 (1 H, dd, J = 13.9 and 5.8 Hz, 3.26-3.81 (5H, m), 4.09-4.12 (1H, m), 4.20 (1H, qd) , J = 6.3 and 4.8Hz ), 4.59 (2 H, d, J = 5.9 Hz), 5.21 (1 H, d, J = 10.3 Hz), 5.31 (1 H, d, J = 19.〇 Hz), 5.72 (1H, brs), 5.89-5.99 (1H, m).

(2) (4 S, 8 S, 9 R, 1 OS) 1 4 1 [(S)-(1 -aryloxyl-propionyl) pyrrolidine-1 3-yl] thiomethyl- 10— [(R) — 1— (t— Bed chill dimethylsilyl O carboxymethyl) Echiru] one 1 1 one Okiso one 1 one Azatorishikuro [7. 2. 0.0 ^{3 '8]} Undeka 2 E down one 2-force carboxylic acid Ariru

 Example 11 The 6S form (720 mg) obtained in (1) was dissolved in dichloromethane (10 m 1), and triethylamine (277 mg) and aryloxalyl chloride (305 mg) were added under ice-cooling, followed by stirring for about 1 hour. Then, 2-propanol (41 mg) was added to the reaction solution, and after stirring for 15 minutes, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 20 g, hexane: ethyl acetate = 1: 1) to obtain an intermediate (959 mg). The intermediate was dissolved in 2 ml of toluene, dimethylethylphosphonite (617 mg) was added, and the mixture was stirred at 60 ° C for 1.5 hours. Toluene was distilled off once, mesitylene (50 ml) was added, and 140 was added for 1 hour. 120. Heated for 1.5 hours. The mesitylene was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (silica gel 100 g, hexane: ethyl acetate = 3: 2 → 1: 1) to obtain the title compound as an oil (672 mg). .

Infrared absorption spectrum ^{_{(CHC 1 3) max cm- 1}} : 2933, 2860, 1773, 1693, 1413.

Nuclear magnetic resonance spectrum (400MHz, CD'C 13) δ ppm: 0.07 (3H, s), 〇.08 (3H, s), 0.88 (9H, s), 1.23 (3H, s) , D, J = 6.4 Hz), 1.20-2.33 (8 H, m), 2.68-2.80 (2H, m), 2.94 (1 H, m), 3.17 (1H, dd, J = 6.4 and 3.1Hz), 3.24-3.62 (4H, m), 3.75-3.80 (1H, m), 3.88 (1H, br), 4.11 (1H, dd, J = 10.3 and 3.1 Hz), 4.20 (1H, quint, J = 6.4Hz) , 4.59 (2H, d, J = 5.6 Hz), 4.65-4.80 (2H, m), 5.21 (1H, d, J = 13.2 Hz), 5.24 ( 1 H, d, J = 1 1.1 Hz ), 5.31 (1H, d, J = 17.5Hz), 5.44 (1H, d, J = 17 • 5Hz), 5.89-6.00 (2H, m ).

(3) (4 S, 8 S, 9 R, 1 OS) —4— [(S) 1- (1-aryloxyl-ponyl) pyrrolidine-1-3-yl] thiomethyl- 10— [(R) —1-hydroxystil] — 1 1-oxo-1 1-azatricyclo [7. 2. 0. ³ · ⁸ ]

 Example 11 The compound (670 mg) obtained in (2) was dissolved in dimethylformamide (10 ml), ammonium hydrogen fluoride (316 mg) was added, and the mixture was stirred at room temperature for 2 days. Neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate (100m 1 X 3). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 1: 5) to give the title compound (253 mg) as a colorless oil.

Infrared absorption spectrum _{(CHC 1 3) v max cm-} 1: 3610, 2940, 1 771, 1693, 1413.

 Nuclear magnetic resonance spectrum (400MHz, CDC13) δ ppm: 1.33 (3H, d, J = 6.2Hz), 1.57-2.23 (9H, m), 2.69-2. 81 (2 H, m), 2.96—3.06 (1 H, m), 3.22 (1 H, dd, J = 6.6 and 3.1 Hz), 3.20-3. 62 (4 H, m), 3.77 (1 H, dd, J = 10.6 and 6.0 Hz), 3.90 (1 H, m), 4.17 (1 H, dd, J = 10 3 and 3.1 Hz), 4.2 1 — 4.28 (1H, m), 4.56 (2H, d, J = 5.7Hz), 4.66—4.84 (2H, m), 5.2 1 (1 H, d, J = 10.1 Hz), 5.26 (1 H, d, J = 10.1 Hz), 5.31 (1 H, d, J = 17.4 Hz), 5.44 ί 1 H, d, J = 17.4 Hz), 5.89-6.02 (1 H, m).

(4) (4 S, 8S, 9R, 1 OS)-10- [(R) — 1-hydroxyethyl] — 4-([S) 13-pyrrolidinyl] thiomethyl — 11-oxo — 1-azatricyclo [7 . 2.0. 0 ³ ' ⁸ ] Pendecar 2-ene-2-carboxylic acid

The compound (250 mg) obtained in Example 1- (3) was dissolved in dichloromethane. Under ice-cooling, water (51 mg), bis (triphenylphosphine) palladium (II) chloride (18 mg) and tri-n-butyltin hydride (1.05 g) were added, and the mixture was stirred for 5 minutes, and further stirred at room temperature. For 30 minutes. Dichloromethane (30 ml) was added, extracted with water (30 ml X 3), and the aqueous layer was collected and water was distilled off under reduced pressure. Concentrate the solution to about 2 ml, reverse column silica gel column chromatography (Cosmoseal 75C 18-P REP (12 g), and gradually increase the acetate nitrile concentration from 0% to 16% using an aqueous solution of acetonitrile. The residue was purified by lyophilization, and lyophilized to give the desired compound (127 mg) as a powder.

Infrared absorption spectrum (KB r) v _max cm ' ¹ : 3408, 2929, 1758, 1586, 1392, 1252.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) <} 5 ppm: 1. 27 (3 H, d, J = 6. 2 H z), 1. 26- 1. 38 (1 H, m), 1. 60 -1.71 (3H, m), 1.82-2.00 (3H, m), 2.34-2.44 (1H, m), 2.88 (1H, d, J = 13.5 and 6.1 Hz), 2.9

4 (1H, d, J = 13.5 and 10.3Hz), 2.97-3.06 (1H, m), 3.24 (1H, q, J = 6.8Hz), 3. 34--3.41 (2 H, m), 3.49 (1 H, dt, J = 11.8 and 7.5Hz), 3.

59-3.71 (3H, m), 4.15 (1H, dd, J = 10.7 and 3.0Hz), 4.23 (1H, quint, J = 6. 2 Hz).

(Example 2)

(4R, 8 S, 9 R, 1 OS)-10- [(R) -1-hydroxyethyl]-4-[(S) — 3-pyrrolidinyl] thiomethyl-11-oxo-1-1-azatricyclo [ 7. 2.0.0 ³ ' ⁸ ] pentadecane 2-en-2-carboxylic acid

 [(4R) isomer of Exemplified Compound II]

( 1 ) (4 R, 8 S, 9 R, 1 OS) 一 4— [ (S) ― ( 1—ァリルォキシ力 ルポニル） ピロリジニル— 3—ィル] チオメチルー 10— [ (R) ― (t—プチ ルジメチルシリルォキシ） ェチル] — 1 1一ォキソ一 1一ァザトリシクロ [7.

(1) (4 R, 8 S, 9 R, 1 OS) 1 4— [(S) ― (1-aryloxyl-propionyl) pyrrolidinyl-3-yl] thiomethyl- 10— [(R) ― (t-petit Dimethylsilyloxy) ethyl] — 1 1-oxo-1 1-azatricyclo [7.

2. 0.0 ³ ' ⁸ ] Pendeker 2-ene 2- 2-aryl ribonate

 Example 1—The compound (6R) (1.02 g) obtained in (1) was dissolved in dichloromethane (10 ml), and triethylamine (393 mg) and aryloxalyl chloride (432 mg) were dissolved under ice-cooling. ) Was added and stirred for 1.5 hours. 2-Propanol (58 mg) was added to the reaction solution, and the mixture was stirred for 10 minutes, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 25 g, hexane: ethyl acetate = 1: 1) to obtain an intermediate (1.24 g). The intermediate was dissolved in toluene (lml), dimethylethylphosphonite (874mg) was added, and the mixture was stirred at 60 ° C for 1.5 hours, then toluene was distilled off once, and mesitylene (50ml) was added. The mixture was stirred at 130 ° C for 2.5 hours, and further heated to reflux for 2 hours. Mesitylene was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (silica gel 100 g, hexane: ethyl acetate 3: 1-1: 1) to obtain the title compound (142 mg) as an oil. Was.

Infrared absorption spectrum _{(CHC 1 3) v max cm-} 1: 2933, 1769, 1691, 1413.

Nuclear magnetic resonance spectrum _{(400MHz, CDC 1 3) δ} ppm: 0. 07 (6 H, s), 0. 88 (9 H, s), 1. 22 (3H, d, J = 6. 2 H z) , 1.17-1.61 (3H, m), 1.79-2.32 (5H, m), 2.5

3—2.82 (3H, m), 3.13-3.79 (7H, m), 4.09-4.22 (2H, m), 4.59 (2H, d, J = 5. 4 Hz), 4.62-4.80 (2 H, m), 5.21 (1 H, d, J = 11.3 Hz), 5.25 (1 H, d, J = 11.3 Hz) ), 5.30 (1 H, d, J = 17.0 Hz), 5.42

(1H, d, J = 17.0Hz), 5.89-6.01 (2H, m).

(2) (4R, 8 S, 9R, 1 OS) 1 4— [(S)-(1-aryloxy-propionyl) pyrrolidinyl-3-yl] thiomethyl- 10— [(R) — 1-hydroxyxethyl] 1 1 1 One-year-old Kiso 1—azatricyclo [7. 2. 0. 〇 ³ ' ⁸ ] Pin Deca-2-ene-2-Aryl arbonate

 The same reaction and isolation procedure as in Example 1- (3) were carried out using the compound (140 mg) obtained in Example 2- (1) to give the title compound (65 mg) as a colorless oil.

 Nuclear magnetic resonance spectrum (400MHz, CDC 13) ό ppm: 1.33 (3H, d, J = 6.3Hz), 3.15-3.78 (7H, m), 4.1 1—4.24 (2H, m), 4.59 (2H, d, J = 5.4 Hz), 4.67-4.81 (2H, m), 5.19-5.49 (4H, m), 5. 87—6.06 (2H, m).

(3) (4R, 8S, 9R, 10S) 1-10 — [(R) 1-1-Hydroxethyl) —4 — [(S) —3-Pyrrolidinyl] thiomethyl-11-oxo-1-1-azatricyclo [7. 2. 0. 0 ³ · ⁸ ] pentadecane-2-ene-2-carboxylic acid The compound obtained in Example 2_ (2) (60 mg) was used as an example: The same reaction as [I (4)] After purification and lyophilization, the target compound (18 mg) was obtained as a powder.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) 5} ppm: 1. 08 (3 H, d, J = 6. 4Hz), 0. 97- 1. 39 (3H, m), 1. 65- 1. 88 (4H, m), 2.15-2.24 (1H, m), 2.32-2.40 (1H, m), 2.58 (1H, dd, J = 12.7 and 7 .3Hz), 2.62-2.68 (1H, m), 3.00 (1H, dd, J = 12.7 and 7.8Hz), 3.05 (1H, dd, J = 1'3.7 and 4.4Hz), 3.14-3.22 (2H, m), 3.32 (1H, td, J = l l.7 and 7.8Hz), 3. 38-3.48 (2H, m), 3.96 (1H, dd, J = 9.8 and 2.9Hz), 4.03 (1H, quint, J = 6.4 Hz ).

(Example 3)

(4 S, 8 S, 9R, 1 OS) —4- (4-N, N-dimethylaminocarbamoylphenyl) thiomethyl— 10— [_ (R) — 1-hydroxyethyl] — 1 1— Oxo-1 1-azatricyclo [7. 2. 0. 0 ³ ' ⁸ ] pendecar 2-ene-2 carboxylate

 [(4 S) isomer of Exemplified Compound II-15]

(1) (3 S, 4R) -3- [(R)-1-(t-butyldimethylsilyloxy) ethyl] 4-1 [(2 R, 6 S) —6— (4 -N, N-dimethylcarbamoylphenyl) thiomethylcyclohexane-1-yl] azetidin-12-one (6S form) and (3S, 4R) -3-[(R) — 1— (t-butyl Dimethylsilyloxy) ethyl] —4-([2 R, 6 R) — 6— (4-N, N-dimethylcarbamoylphenyl) thiomethylcyclohexane-1-yl] azetidine-1-one (6 R Body)

 Reference Example 11 The same reaction and isolation procedure as in Example 1- (1) using the compound (1.45 g) obtained in (8) and N, N-dimethylcarbamoylthiophenol (986 mg). To give the title compound as a diastereomer mixture. The diastereomer mixture was purified by column chromatography (silica gel (Cosmosil 75 C18—PREP), 30 g, water: acetonitrile = 1: 1), and the (6S) form (883 mg) (6R) form (1 .25 g) as a colorless amorphous powder.

 (6 S) body

Infrared absorption spectrum (KB r) v _max cm " ¹ : 3230, 2930, 1 761, 1 707, 1623, 1394, 1097, 835.

Nuclear magnetic resonance spectrum (400MHz, CDC 1a) δ ppm: 0.07 (6H, s), 0.86 (9H, s), 1.16 (3H, d, J = 6.3Hz), 1.69—1.92 (3 H, m), 2.03—2.10 (2 H, m), 2.63—2.72 (2H, m), 2.91 (1 H, dd) , J = 4.5 and 2. 2Hz), 2.95-3.20 (7H, m), 3.30 (1H, dd, J = 13.2nd 7.1Hz), 4.05 (1H, dd, J = 6 0 and 2.2 Hz), 4.20 (1 H, qd, J = 6.3 and 5.0 Hz), 7.32—7.37 (4H, m).

^{Polarimetry: [a] D 25 = +} 34. 8 ° (C = 0. 750, CHC 1 3).

 (6 R) body

Infrared absorption spectrum (KB r) v _max cm ": 3251, 2931, 2856, 1759, 1709, 1631, 1394, 1097, 835.

 Nuclear magnetic resonance spectrum (40 OMH z, CDC 1 a) ό p pm: 0.06

(3H, s), 0.07 (3H, s), 0.87 (9H, s), 1.22 (3H, d, J = 6.1 Hz), 1.34-1.45 (1H, m), 1.58-1.83 (2H, m), 1.98-2.05 (1H, m), 2.14-2.20 (1H, m), 2.42-2.48 (1H, m), 2.55-2.64 (2H, m), 2.76 (1H, dd, J = 13.6 and 7.6Hz), 2. 87 (1H, dd, J = 4.9 and 2.6Hz), 3.00 (3H, brs), 3.10 (3H, brs), 3.44 (1H, dd, J = 13.6 and 5.2 Hz), 4.10-4.15 (1H, m), 4.21 (1H, qd, J = 6.1 and 4.9Hz), 5.74 (1H, brs), 7.29—7.36 (4H, m).

Light intensity: [α]. ²⁵ = + 42. 1 ° (C = 〇. 625, CHC 1 ₃ ).

(2) (4 S, 8 S, 9 R, 10 S) 1-10-[(R)-1-(t-butyldimethylsilyloxy) ethyl]-4-(4 -N, N-dimethylcarbamoylphen) Nil) Thiomethyl-1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ]

 Using the (6S) form (800 mg) obtained in Example 3-f 1), the same reaction and isolation procedure as in Example 1- (2) were carried out to give the title compound (715 mg) as a colorless oil. As obtained.

Infrared absorption spectrum 1β _{(CHC 1 3) v max cm} ": 2933, 2859, 1 774, 171 6, 1 625, 1400, 1 284. Nuclear magnetic resonance spectrum _{(400MHz, CDC l 3) 5} ppm: 0. 07 (3 H, s), 0. 08 (3 H, s), 0. 88 (9 H, s), 1. 28 (3 H , d, J = 6.1 Hz), 1.36-2.05 (6H, m), 3.00 (3H, brs), 3.09 (3H, brs), 2.93-3. 2 1 (4 H, m), 3.93-3.99 (1 H, m), 4.09 (1 H, dd, J = 10.4 and 3.3 Hz), 4.19 (1 H, quint, J = 6.1 Hz, 4.62-4.71 (2 H, m), 5.23 (1 H, d, J = 9.7 Hz), 5.40 (1 H, d, J = 17.6 Hz), 5.86-5.96 (1H, m), 7.3 1—7.36 (4H, m).

^{_{Polarimetry:. [A] D 25 =}} + 74 4 ° (C = 0. 905, CHC 1 3).

(3) (4 S, 8 S, 9 R, 10 S) —4 (4-, N-dimethylcarbamoylphenyl) thiomethyl — 10— [(R) — 1-hydroxyethyl) 1 1 1 1 Oxo-1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ] INDECAR 2-ENE-1 2-carboxylate

Example 3—The compound (650 mg) obtained in (2) was dissolved in tetrahydrofuran (5 ml), and acetic acid (655 mg) and a 1.0 M tetrahydrofuran solution of tetrabutylammonium fluoride (7.60 ml) were added. The mixture was stirred at room temperature for 16 hours, added with a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2-18 ml), and stirred for 4 hours. The mixture was extracted with ethyl acetate (50 ml X 3), and the organic layer was washed with aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel (30 g), ethyl acetate: methanol = 99: 1-20: 1) to obtain the title compound (344 mg) as a colorless amorphous powder, infrared absorption spectrum (KBr) v _max cm— ¹ : 3397, 2932, 1 774, 1 71 7, 1624, 1285.

Nuclear magnetic resonance spectrum (40 OMHz, CDC 13) δ ppm: 1.29 (3H, d, J = 6.2 Hz), 1.56-1.96 (6H, m), 3.00 (3H, brs) ), 3.00-3.10 (2H, m). 3.10 (3H, brs), 3.28 (1H, dd, J = 13.4 and 9.7Hz), 3.63 ( 1 H, dd, J = 10.1 and 2.9 Hz), 3.98-4.02 (1H, m), 4.10-4.17 (1H, m), 4.68 (1 H, dd, J = 13.7 and 5.3 Hz), 4.76 (1 H, dd, J = 13.7 and 5.7 Hz), 5.26 (1 H, d, J = 10.3 H z), 5.44 (1 H, d, J = 17.8 Hz), 5.91 -6.01 (1 H, m), 7.33 (2 H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4Hz).

(4) (4 S, 8 S, 9 R, 1 OS) 1-4- (4-N, N-dimethylcarbamoylphenyl) thiomethyl-10-[(R) -1-hydroxyethyl] 1-11-oxo 1-11 Hazatricyclo [7. 2. 0. ³ ' ⁸ ] pentadecane 2-carboxylic acid

The compound (200 mg) obtained in Example 3- (3) was dissolved in a mixed solvent of dichloromethane: ethyl acetate = 1: 1 (6 ml), and potassium 2-hexylhexanoate (75 mg) was added at room temperature. Further, tetrakistriphenylphosphine palladium (0) was added, and the mixture was stirred for 2.5 hours. A mixed solvent of hexane-isopropyl ether was added to the reaction solution, and the mixture was extracted with water. The aqueous layer was concentrated under reduced pressure to 2 ml and purified by high performance liquid chromatography (column: Cosmoseal 5C18-AR28X250 mm) to obtain the title compound (123 mg) as a lyophilized powder. Was. Infrared absorption spectrum _{(KB r) v m ax cm} "1: 3400, 2928, 1 754, 1629, 1596, 1393, 1097.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) 5} ppm: 1. 24 (3 H, d, J = 6. 4Hz), 1. 21 - 1. 30 (l H, m), 1. 56- 1. 69 (3 H, m), 1.81-1.92 (2 H, m), 2.84-2.92 (1 H, m), 3.04 (3H, s), 3.10 (3H , S), 3.18 (1 H, dd, J = 13.3 and 5.6 Hz), 3.29 (1 H, dd, J = 6.1 and 2.9 Hz), 3.43 ( 1 H, dd, J = 13.3 and 10.6 Hz), 3.74-3.79 (1H, m), 3.77 (1H, dd, J = 10.1 and 2. 9 Hz), 4.16 (1 H, quint, J = 6.4 Hz), 7.39 (2 H, d, J = 8.4 Hz), 7.51 (2 H, d, J = 8.4 Hz). : Example 4)

 _ (4 R, 8 S, 9 R, 10 S) 1 4 1 (4-N, N

Enyl) thiomethyl-10-[(R) -1-hydroxyethyl) 1 1 1oxo- 1-azatricyclo [7. 2.0.0 ³ · ⁸ ] pendecar 2-en-2-carbonate

 [(4R) isomer of exemplified compound V-15]

(1) (4 R, 8 S, 9 R, 1 OS) 1 10— [(R) 1-11 (t-butyldimethylsilyloxy) ethyl] —4— (4-N, N-lucarbamoylphenyl) Thiomethyl 1 1-oxo 1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ]

 Example 3-Using the compound (6R) form (1.15 g) obtained in (1), the same reaction and isolation procedure as in Example 2-(1) were carried out to give the title compound (937 mg) Was obtained as a colorless oil.

Infrared absorption spectrum ^{_{(CHC 1 3) max cm- 1}} : 2933, 2859, 1771, 1724, 1624, 1278, 1097.

Nuclear magnetic resonance spectrum (40 OMH z, CDC 1 a) δ ρ pm: 0.07 (6Η, s), 0.87 (9Η, s), 1.22 (3Η, d, J = 6.2 Hz) ), 1.36-1.57 (3H, m), 1.82-2.32 (3H, m), 3.0 〇 (3H, brs), 3.08-3.17 (2 H, m ), 3.10 (3 H, brs), 3.59 (1 H dd, J = 13.3 and 7.0 Hz), 4.14 (1 H, dd, J = 71 and 3.1) Hz), 4.19 (1H, quint, J = 6.2Hz) 4.76-4.65 (2H, m), 5.24 (1H, d, J = 10.2Hz) 5.41 (1H, d, J = 17.5 Hz), 5.90- 6.00 (1H, m) 7.29 (2H, d, J = 8.4Hz), 7.34 ( Two H, d, J = 8.4 Hz).

^{_{Polarimetry: [a] D 25 = +}} 1 14 ° (. C = 0 80, CHC 1 3).

(2) (4 R, 8 S, 9 R, 1 OS) 1-4- (4-N, N-dimethylcarbamoylphenyl) thiomethyl—10 — [(R) —1-hydroxyshetyl] 1 1 1 oxo I 1-azatricyclo [r.2.0.0.0 ³ · ⁸ ] pendecar 2-ene-1-carboxylate

 Example 4- Using the compound (800 mg) obtained in (1), the same reaction and isolation procedure as in Example 3- (3) were carried out to give the title compound (559rag) as a colorless amorphous powder. .

Infrared absorption spectrum (KBr) v _max cm ": 3397, 2934, 1770, 1724, 1622, 1399, 1277, 1098.

 Nuclear magnetic resonance spectrum (400 MHz, CDC 13) δ ppm: 1.32

(3 H, d, J = 6.2 Hz), 1.28-1.65 (3 H, m), 1.87-2.16 (3 H, m), 2.57- 2.65 ( 1 H, m), 2.75-2.86

(1H, m), 3.00 (3H, brs), 3.03-3.14 (1H, m), 3.11 (3H, brs), 3.19 (1H, dd) , J = 7.1 and 3.0Hz), 3.59 (1H, dd, J = 13.2 and 7.2Hz), 4.13-4.24 (2H, m), 4. 60-4.77 (2H, m), 5.25 (1H, d, J = 9.8Hz), 5.41 (1H, d, J = 16.9Hz), 5.91-6 0 1 (1H, m), 7.29 (2H, d, J = 8.5Hz), 7.34

(2 H, d, J = 8.5 Hz).

(3) (4R, 8 S, 9 R, 1 OS) —4- (4-N, N-dimethylcarbamoylphenyl) thiomethyl—10— [(R) — 1-hydroxyloxetyl] 1 1 1 1-Azatricyclo [7. 2. 0. ³ ' ⁸ ] Palladium 2--1-ene 2-carboxylate

 Example 4 The same reaction and purification as in Example 3- (4) were carried out using the compound (350 mg) obtained in (2) to give the desired compound (227 mg) as the title dry powder.

Infrared absorption spectrum (KB r) v _max cm— ¹ : 3412, 2928, 1 751, 626, 1596, 1393, 1097.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) δ} ppm:. 1. 21 - 1 53 (3 H, m), 1. 27 (3 H, d, J = 6. 2 H z), 1. 83- 2.10 (3 H, m), 2.53 -2.60 (1 H, m), 2.73 -2.79 (1 H, m), 3.03 (3 H, s), 3. 10 (3H, s), 3.16 (1H, dd, J = 13.3 and 7.4Hz), 3.38 (1H, dd, J = 6.2 and 2.9Hz), 3. 60 (lH, dd, J = 13.5 and 7.4Hz), 4.14 (1H, dd, J = 9.7 and 2.9Hz), 4.22 (1H, qu int, J = 6.2 Hz), 7.38 (2H, d, J = 8.4Hz), 7.44 (2H, d, J = 8.4Hz).

(Example 5)

(4S, 8 S, 9 R, 1 OS) — 10— “(R) — 1-Hydroxyethyl] —11-oxo-1 4-1 [(S) 1-2-Pyrrolidinyl] methylthiomethyl-1-azatricyclo [ 7. 2. 0 ³ · ⁸ ]

 [(4S) isomer of Exemplified Compound II-5]

(1) (3S, 4R) 1-41 [(2R, 6S) 16-[(S)-(1-arinoleoxycarbonyl) pyrrolidine-1 2-yl] methylthiomethylcyclohexanone 2-yl] —3— [(R) -1-(t-butyldimethylsilyloxy) ethyl] azetidin-1-one (6S form) and (3 S, 4R) —4— [(2R, 6 R) 1-6-[(S) 1-(1 -aryloxycarbonyl) pyrrolidine-1-2-yl] methylthiomethylcyclohexanone-2 -yl]-3-[(R)-1- (t-butyldimethylsilyloxy) ethyl] azetidin-2-one (6R form)

Reference Example 11 The compound (980 mg) obtained in (8) and (S) -1 The same reaction and isolation procedure as in Example 1- (1) were carried out using cycarbonyl 2-mercaptomethylpyrrolidine (111 mg) to obtain the title compound as a diastereomer mixture. The Jiasutereoma mixture, high-performance liquid chromatograph I by chromatography (Column: Cosmosil 75 C 18- AR 28 x 25 Omm , Asetonito Lil: water = _80: 20) to purified using reverse phase column prep, (6S ) (383 mg) and (6R) -isomer (543 mg) were obtained as colorless oils.

 (S S) body

Infrared absorption spectrum (ne at) v _max cm " ¹ : 3276, 2932, 2858, 176 1, 1705, 1406, 837.

 Nuclear magnetic resonance spectrum (270MHz, CDC13) δ ppm: 1.20 (3H, d, J = 6.2Hz), 1.64-2.16 (10H, m), 2.40-1.44 (7H, m), 3.38-3.44 (2H, m), 3.88-3.97 (1H, m), 4.02 (1H, m), 4.14-4 .24 (1H, m), 4.57-4.62 (2H, m), 5.22 (2H, d, J = 10.5Hz), 5.31 (2H, d, J = 17.2 Hz), 5.87-6.02 (1 H, m), 6.23 (1 H, brs).

^{_{Polarimetry: [a] D 25 = +}} 13. 4 ° (. C = 0 70, CHC 1 3).

 (6 R) body

Infrared absorption spectrum (ne at) v _max cm " ¹ : 3277, 293 1, 2858, 1760, 1705, 1405, 1105, 837.

Nuclear magnetic resonance spectrum (27 OMH z, CDC 1a) δ ppm: 0.06 (3H, s), 0.07 (3H, s), 0.87 (9H, s), 1.10-2 20 (10H, m), 1.23 (3H, d, J = 6.0Hz), 2.38-2.66 (4H, m), 2.82-3.04 (2H, m ), 2.87 (1H, dd, J = 4.8 and 2.4Hz), 3.40-3.47 (2H, m), 3.92-3.98 (1H, m) , 4.08-4.22 (2 H, m), 4.59 (2 H, m), 5.21 (1 H, d, J = 8.8 Hz), 5.31 (1 H, m d, J = 17.2 Hz), 5.75 (1H, brs), 5.87—6.01 (1H, m). Polarimetry: [α ²⁵ = one 4. 4 ° (C = 0. 853 , CHC 1 3:

 (2) (4 S, 8 S, 9 R, 1 OS) -4- [(S) ― (1

Ruponyl) pyrrolidine-1-yl] methylthiomethyl-10-[(R) -1- (t-butyldimethylsilyloxy) ethyl] 1-11 1-year-old oxo-1-1-azatrisic mouth [7. 2. 0. 0 ³ ' ⁸ ] Pendecar 2-ene-2-aryl carboxylate

 The same reaction and isolation procedure as in Example 1- (2) was carried out using the compound (6S) form (330 mg) obtained in Example 5- (1) to give the title compound (200 mg) as a colorless oil. Obtained.

Infrared absorption spectrum (neat) v _max cm— ¹ : 2931, 2858, 1779, 1702, 1404, 1285, 1 136, 836.

 Nuclear magnetic resonance spectrum (270 MHz, CDC 1 a) δ ppm: 0.08 (6 H, s), 0.88 (9 H, s), 1.1 1 -2.5.5 (10 H, m), 1 23 (3 H, d, J = 6.3 Hz), 2.37—2.54 (1 H, m), 2.72-2.98 (4 H, m), 3.16 (1 H, dd, J = 6.4 and 3.1 Hz), 3.42-3.45 (2H, m), 3.84-4.00 (2H, m), 4.10 (1H, dd, J = 10.4 and 3.1 Hz), 4.20 (1H, quick, J = 6.3Hz), 4.57-4.81 (4H, m), 5.18- 5.46 (4H, m), 5.88-6.01 (1H, m).

. ^{_{Polarimetry: [a] D 25 = +}} 37 2 ° (C = 0. 790, CHC 1 3) -

(3) (4 S, 8 S, 9R, 1 OS) -4 [(S)-(1-aryloxyl-propionyl) pyrrolidine-2-yl] methylthiomethyl-10- [(R) — 1-h Droxityl] — 1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ] pentadecane 2-ene 2-arylaryl

 The same reaction and isolation procedure as in Example 3- (3) were carried out using the compound (190 mg) obtained in Example 5- (2) to give the title compound (120 mg) as a colorless oil.

Nuclear magnetic resonance spectrum _{(270MHz, CDC 1 3) 5} ppm: 1. 25 one 2. 04 (10 H, m) , 1. 32 (3H, d, J = 5. 9 H z), 2. 33 one 2 56 (2 H, m), 2.69-3.13 (4H, m), 3.21 (1 H, m W

87 dd, J = 6.6 and 2.6 Hz), 3.36-3.49 (2H, m), 3.86-3.97 (2H, m), 4.16 (1H, dd, J = 10.6 an d 2.6 Hz), 4.18-2.29 (1H, m), 4.59 (2H, brm), 4.68 (1H, dd, J = 13 2 and 5.3 Hz), 4.80 (1H, dd, J = 13.2 and 5.9Hz), 5.18-5.46 (4H, m), 5.87-6 .02 (2 H, m).

(4) (4 S, 8 S, 9R, 10 S) -10- [(R) — 1-hydroxyethyl] 1 1 1 1oxo 1 4 1 [(S) 2 -pyrrolidinyl] methylthiomethyl 1 1 Azato Rishikuro same manner as in [7.2.3 0.0 ^{3 '8]} Undeka 2 E down one 2-force carboxylic acid example 5- (3) the compound obtained in (120 mg) of example 1 i (4) The desired compound (71 mg) was obtained as a lyophilized powder. Infrared absorption spectrum (KB r) v _max cm— ¹ : 3372, 2928, 1758, 1582, 1390, 1250.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) δ} p pm: 1. 27 (3 H, d, J = 6. 4Hz), 1. 28- 1. 38 (1 H, m), 1. 58- 1 93 (6H, m), 1.99—2.16 (2 H, m), 2.13—2.32 (1 H, m), 2.78-2.85 (2 H, m), 2.94-3.01 (2 H, m), 3.03-3.1 1 (1 H, m), 3.29-3.38 (2 H, m), 3.40 (1 H , Dd, J = 6.1 and 3. I Hz), 3.66 -3.72 (1H, m), 3.74—3.83 (1H, m), 4.15 (1H, dd, J = 10.2 and 3.I Hz), 4.23 (1 H; quint, J = 6.4 Hz)

(Example 6)

 (4 R, 8 S, 9 R, I P S) 1 10 — “(R) — 1-hydro

1 1-oxo-1 4-[[S] —2-pyrrolidinyl] methylthiomethyl-1-azatricyclo [7. 2.0.0 ³ · ⁸ 1

 [(4R) isomer of Exemplified Compound II-5]

(1) (4R, 8 S, 9 R, 1 OS) 1-4-[(S) 1-(1-aryloxyl-propionyl) pyrrolidine-1-2-yl] methylthiomethyl- 10-[(R) — (t- butyldimethylsilyl O carboxymethyl) Echiru] one 1 1 Okiso - 1 § The Bok Rishikuro [7.2.3 0.0 ^{3 '8]} Unde force one 2- En 2- carboxylic acid Ariru

 Using the compound (6R) form (500 mg) obtained in Example 5- (1), the same reaction and isolation procedure as in Example 2- (1) were carried out to give the title compound (265 mg) in an unoccupied oil. Obtained as material.

Infrared absorption spectrum (ne at) v _max cm " ¹ : 2930, 2856, 1775, 1701, 1405, 1279, 1148, 837.

 Nuclear magnetic resonance spectrum (270MHz, CDC13) δ ppm: 0.07 (6H, s), 0.88 (9H, s), 1.11-2.96 (1OH, m), 1.22 ( 3H, d, J = 6.2 Hz), 3.07—3.14 (2H, m), 3.42-3.43 (2H, m), 3.89-3.98 (1H, m), 4.08-4.21 (2H, m), 4.57-4.81 (4H, m), 5.19—5.44 (4H, m), 5.87-6 .04 (2H, m).

^{Polarimetry: [a] D 25 = +} 54. 5 ° (C = 0. 820, CHC 1 3).

(2) (4 R, 8 S, 9 R, 1 OS) -4- [(S)-(1-aryloxy-rubonyl) pyrrolidine- 1-2-] methylthiomethyl- 1 10-[(R)-hydroxyxetil ] — 1 1-oxo-1 1-azatricyclo [7. 2. 0. 0 ³ · ⁸ ] pin Deca _2 2-en-2-alyl arbonate

 Using the compound (250 mg) obtained in Example 6- (1), the same reaction and isolation procedure as in Example 3- (3) were carried out to obtain the title compound (127 mg) as a colorless oil. .

 Nuclear magnetic resonance spectrum (27 OMHz, CDC13) δ ppm: 1.33 (3 H, d, J = 6.3 Hz), 1. 24-2.18 (9 H, m), 2. 30-2.95 (5H, m), 3.07-3.25 (m, 2H), 3.30—3.49 (2H, m), 3.94 (1H, m), 4 17 (1H, dd, J = 9.9 and 2.8Hz), 4.13—4.28 (1H, m), 4.53-4.89 (4H, m), 5.18- 5.50 (4H, m), 5.88-6.1 1 (2H, m

) o

(3) (4R, 8 S, 9R, 1 OS) — 10— [(R) — 1-hydroxyethyl] — 1 1-oxo-14 — [(S) 1-2-pyrrolidinyl] methylthiomethyl-1-azato Rishikuro similar to [7.2.3 0.0 ^{3 '8]} Undeka 2 En 2 force carboxylic acid example 6- (2) the compound obtained in (120 mg) with example 1 i (4) The reaction and purification were performed to give the desired compound (59 mg) as a lyophilized powder.

Infrared absorption spectrum (KB r) v _max cm— ¹ : 3363, 2927, 1

758, 1583, 1390.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) δ} p pm:. 1. 23- 1 37 (l H, m), 1. 27 (3 H, d, J = 6. 2Hz), 1. 49- 1 63 (1H, m), 1.68-1.78 (1H, m), 1.84—1.98 (3H, m), 2.04-2.15 (2H, m), 2.22-2.30 (1H, m), 2.69 (1H, dd, J = ll. 8 and 5.7Hz), 2.79-2.87 (1H, m), 2. 76 (1H, dd, J = 14.6 and 10.0Hz), 3.01 (1H, dd, J = 14.6 and 4.5Hz), 3.2

8 (1H, dd, J = 11.8 and 9.5Hz), 3.34-3.42 (3H, m), 3.79-3.87 (1H, m), 4.1 5 (1H, dd, J = 9-7 and 2.9Hz), 4.22 (1H, quint, J = 6.2Hz) (Example 7)

(4 S, 8 S, 9 R, 1 OS) —4-Glycyloxymethyl-10— [(R) 11-hydroxyethyl 1 — 11 1-oxo-1 1-azatricyclo “7.2.0.0” ³ · ⁸ ]

 [Exemplary compound ③-1 (4S) isomer]

(1) (4 S, 8 S, 9 R, 1 OS) — 4-Aryloxycarbonylglycyloxymethyl— 10— [(R) — 1- (t-butyldimethylsilyloxy) ethyl] 1 1 1-oxo 1 1-azatricyclo [7. 2. 0. ³ · ⁸ ]

 Reference Example 2—The compound (400 mg) obtained in (1) was dissolved in dichloromethane, and aryloxycarbonylglycine (161 mg), 1,3-dicyclohexyl carbodiimide (284 mg), 4-dimethylaminopyridine ( 34 mg) and reacted at room temperature for 3 hours and at 4 ° C for 15 hours. The insoluble material was filtered, the filtrate was collected, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 40 g, hexane: ethyl acetate = 3: 2-1: 1) to give the title compound (358 mg) as a colorless oil.

Infrared absorption spectrum (ne at) v _max cm " ¹ : 3381, 2932, 2859, 1780, 1723, 1522, 1283, 1187.

Nuclear magnetic resonance spectrum (270MHz, CDC13) δ ppm: 0.08 (6H, s), 0.89 (9H, s), 1.23 (3H, d, J = 6.0Hz), 1. 3 1-1.94 (6 H, m), 2.95-3.09 (1 H, m), 3.20 (1 H, dd, J = 6.2 and 3.3 Hz), 3. 93 (2H, d, J = 5.7 Hz), 3.97-4.05 (1H, m), 4.07-4.38 (4H, m), 4.58 (2H, d, J = 5.7H z), 4.68 (1 H, dd, J = 13.6 and 5.3 Hz), 4.77 (1 H, dd, J = 13.6 an d 5.3 Hz), 5.19 ( 1H, brm), 5.20-5.52 (4H, m), 5.83-6.03 (2H, m).

(2) (4S, 8S, 9R, 10S) 1-4-aryloxycarbonylglycyloxymethyl-10-[(R) -1-hydroxyethyl] 1-11-oxo-1-11azatricyclo [ 7. 2.0.0 ³ · ⁸ ]

 Using the compound (340 mg) obtained in Reference Example 2- (1), the same reaction and isolation procedure as in Example 1- (3) were performed to give the title compound (80 mg) as a colorless oil.

Nuclear magnetic resonance spectrum _{(270MHz, CDC 1 3) δ} ppm:. 1. 32 (3 H, d, J = 6. 5Hz), 1. 24-2 19 (7H, m), 3. 05- 3. 19 (1H, m), 3.24 (1H, dd, J = 6.5 and 3.2Hz), 3.92 (2H, d, J = 5.6Hz), 3.95-4. 04 (1H, m), 4.11-4.40 (4H, m), 4.59 (2H, d, J = 5.5Hz), 4.68 (1H, dd, J = 13.3 and 5.9 Hz), 4.80 (1H, dd, J = 13.3 and 5.3Hz), 5.21 -5.49 (5H, m), 6.83-6. 07 (2H, m).

(3) (4 S, 8S, 9R, 10 S) — 4-Glycyloxymethyl— 10— [(R) — 1-hydroxyethyl] —11 1-oxo-1 1-azatricyclo [7.2.0 . 0 ³ · ⁸ ] Pendeker 2-ene-2-carboxylic acid

Using the compound (80 mg) obtained in Example 7- (2), the same reaction and purification as in Example 1- (4) were carried out to obtain the target compound (19 mg) as a lyophilized powder. KB r) v _max cm ' ¹ : 3409, 2933, 1 751, 1591, 1396, 1223.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) 5} ppm: 1. 08 (3 H, d, J = 6.4Hz), 1.05-1.77 (6H, m), 2.96-3.03 (1H, m), 3.27 (1H, dd, J = 5 9 nd 3.2Hz), 3.57-3.62 (1H, m), 3.68 (2H, s), 3.98 (1H, dd, J = 10.3 and 3.2Hz ), 4.04 (1 H, quent, J = 6.4 Hz), 4.16 (1 H, dd, J = 10.8 nd 5.4 Hz), 4.40 (1 H, t, J = 10.8 Hz).

(Example 8)

 (4 S, 8 S, 9 R 10 S) -4- β arani-10-[(

R) — 1-Hydroxyethyl] — 1 1-oxo-1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ]

 [Exemplary compound ③— (4S) isomer of 6]

(1) (4 S, 8 S, 9 R, 1 OS) — 4-Aryloxycarbonyl—] 3-aralanoxymethyl-10— [(R) — 1- (t-butyldimethylsilyloxy) 1) 1-oxo-1 1-azatricyclo [7. 2. 0. ³ · ⁸ ] pendyl 2--1-ene 2-carboxylate

 Using the compound (600 mg) obtained in Reference Example 2- (2) and aryloxycarbonyl-1-13-alanine, the same reaction and isolation procedure as in Example 7- (1) were carried out to give the title compound ( 532 mg) as a colorless oil.

Infrared absorption spectrum (ne at) v _max cm " ¹ : 3385, 2932, 2858, 1780, 1 724, 1 521, 1 284.

Nuclear magnetic resonance spectrum (27 OMH z, CDC 1a) δp pm: 0.08 (6H, s), 0.88 (9H, s), 1.24 (3H, d, J = 6.2 Hz), 1.2 1—1.92 (6H, m), 2.5 1 (2H, t, J = 6.1 Hz), 2.98-3.10 (1H, m), 3.19 (1H, dd, J = 6.3 and 3.3Hz), 3.42 (2H, dt, J = 6.3 and 6. 1 Hz),

3.93-4.05 (1H, m), 4.07-4.32 (4H, m), 4.55 (2H, d, J = 5.3Hz), 4.68 (1 H, dd, J = 13.4 and

5.7 Hz), 4.77 (1 H, dd, J = 13.4 and 5.3 Hz), 5.18-5.48 (5 H, m), 5.87-6.03 (2 H, m).

(2) (4 S, 8 S, 9 R, 1 OS) 1-4-aryloxycarbonyl j3-alanyloxymethyl-10-[(R)-1-hydroxyethyl]-1 1- Oxo — 1-azatricyclo [7. 2. 0. ³ · ⁸ ] pentadecane 2-ene-2-aryl carboxylate

 The same reaction and isolation procedure as in Example 1- (3) were carried out using the compound (510 mg) obtained in Example 8- (1) to give the title compound (137 mg) as a colorless oil. .

Infrared absorption spectrum _{(CHC 1 3) v max cm-} 1: 3453, 2940, 1774, 1720, 1763, 1514.

Nuclear magnetic resonance spectrum _{(270MHz, CDC 1 3) δ} ppm:. 1. 32 (3 H, d, J = 6. 1 Hz), 1. 24-2 19 (7H, m), 2. 50 (2 H , t, J = 6.0Hz), 3.03-3.18 (1H, m), 3.24 (1H, dd, J = 6.5 and 3.2Hz), 3.42 ( 2H, dt, J = 6.1 and 6.〇Hz), 3.95-4.09 (1H, m), 4.12—4.35 (4H, m), 4.56 (2H, d, J = 5.6Hz), 4.68 (1H, dd, J = 13.7 and 5.4Hz), 4.80 (1H, dd, J = 13.7 and 8.3H z), 5.17—5.48 (5H, m), 5.82-6.06 (2H, m).

(3) (4 S, 8 S, 9 R, 1 OS) — 4— / 3—Aranyloxymethyl-10 1 [(R) — 1-hydroxyethyl] 1 1 1 1-year-old oxo 1 1 1-azatricyclo [7. 2. 0. ³ · ⁸ ]

Example 8 Using the compound (130 mg) obtained in (2), the same reaction and purification as in Example 11 (4) were carried out to obtain the desired compound (46 mg) as a lyophilized powder. Was.

Infrared absorption spectrum (KB r) _max cm— ¹ : 3385, 2932, 1737, 1578, 1396, 1207.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) δ} ppm: 1. 27 (3 H, d, J = 6. 4Hz), 1. 36- 1. 95 (6H, m), 2. 76 (2 H, t, J = 6.9 Hz), 3.12—3.23 (1 H, m), 3.25 (2H, t, J = 6.9 Hz), 3.45 (1 H, dd, J = 5.8 and 3.3 Hz), 3.74—3.83 (1 H, m), 4.16 (1 H, dd, J = 10.4 and 3.3 Hz), 4. 19-4. 29 (2H, m), 4.50 (1H, t, J = 10.7Hz).

: Example 9)

 _ (4 S, _8 S, 9 R, 1 OS) — 4— N—benzylaminomethyl— 10— [(

R) —— 1—H — 1 1—oxo-1 1—azatricyclo [7.2.

0. 0 ³ · ⁸ ]

 [(4S) isomer of Exemplified Compound II-15]

(1) (4S, 8S, 9 R, 1 OS)-10- [(R) 1- (t-butyldimethylsilyloxy) ethyl] — 4-formyl-1 1-oxo- 1-azatricyclo [ 7. 2.0.0 ³ · ⁸ ] Pendecar 2-ene-2-carboxylate allyoxalyl chloride (873 mg) is dissolved in dichloromethane (30 ml) and — Dimethyl sulfoxide (1.8 g) at 75 ° C. Was added dropwise and the mixture was stirred for 30 minutes. Next, the compound (1.20 g) obtained in Reference Example 2- (2) was dissolved in dichloromethane (5 ml), added dropwise at 75 ° C, stirred for 1 hour, and then diisopropyle at 60 ° C. Add tilamine (2.84 g) and add 1.5 hours The temperature was raised to 30 ° C. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (5 Om13). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 60 g, hexane: ethyl acetate = 4: 1—3: 1) to give the title compound (960 mg) as a colorless oil.

Infrared absorption spectrum (neat) v _max cm " ¹ : 2932, 2858, 1781, 1 720, 1285, 1 143.

 Nuclear magnetic resonance spectrum (27 OMHz, CDC 13) δ ppm: 0.08 (6 H, s), 0.88 (9 H, s), 1.25 (3H, d, J = 6.2 Hz) ), 1.20-1.91 (6H, m), 2.40 (1H, brd, J = 13.3Hz), 2.89-3.08 (1H, m), 3. 20 (1H, dd, J = 6.3 and 3.4Hz), 4.17-4.29 (2H, m), 4.62 (1H, d, J = 4.5Hz), 4.69 (1 H, dd, J = 13.7 and 5.8 Hz), 4.78 (1 H, dd, J = 13.7 and 5.3 Hz), 5.27 (1 H, d , J = l〇. 5 Hz), 5.44 (1 H, d, J = 17.2 Hz), 5.88-6.04 (1 H, m).

^{_{Polarimetry: [a] D 25 = +}} 1 65. 6 ° (C = 0. 765, CHC 1 3).

(2) (4 S, 8 S, 9R, 1 OS) -4-1 (N-aryloxycarbonyl-N-benzyl) aminomethyl-10-[(R) -1-(t-butyldimethylsilyloxy) Ethyl] — 1 1-oxo-1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ] pendecar 2-ene-2-aryl carboxylate

Example 9 The compound (600 mg) obtained in (1) was dissolved in methanol (10 ml), benzylamine (163 mg) and anhydrous magnesium sulfate were added, and the mixture was stirred for 1 hour. Under ice-cooling, sodium cyanoborohydride (96 mg) was added, and the mixture was further stirred for 1 hour. DMF (10 ml) was added to the reaction solution, methanol was distilled off under reduced pressure, and acryloyl formate (333 mg) and triethylamine (279 mg) were added under ice cooling, followed by stirring for 30 minutes. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate (50 ml × 3), the organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. I left. The obtained residue is subjected to column chromatography. The residue was purified by silica gel (silica gel 40 g, hexane: ethyl acetate = 3: 1) to give a mixture (530 mg) of the title compound and N-aryloxycarbonyl-N-benzylamine.

(3) (4 S, 8 S, 9 R, 1 OS) -4- (N-aryloxycarboxy-N-benzyl) aminomethyl- 10— [(R) — 1—Hydroxityl] — 1 1 — Oxor 1-azatricyclo [7. 2. 0. ³ · ⁸ ]

 Example 9 The same reaction and isolation procedure as in Example 3- (3) were carried out using the mixture (530 mg) obtained in (2) to give the title compound (98 mg) as a colorless oil.

 Nuclear magnetic resonance spectrum (270MHz, CDC13) δ ppm: 1.31 (3H, d, J = 6.1Hz), 1.21-2.05 (6H, m), 3.02 — 3.18 (1H, m), 3.21 (1H, dd, J = 6.5nd3.2Hz), 3.81-4.32 (6H, m), 4.48- 4.87 (4H, m), 5.14-5.34 (2H, m), 5.23 (1H, d, J = 11.8 Hz), 5.46 (1H, d, J = 17.2 Hz, 5.75-6.09 (2 H, m), 7.17-7.39 (5H, m).

(4) (4 S, 8 S, 9 R, 1 OS) 1 4 1 N-benzylaminomethyl 1 10 ― [(R) 1 1-hydroxyxethyl]-1 1-year-old oxo — 1-azatricyclo [7 . 2.0.0 ³ · ⁸ ]

Example 9 The compound (90 mg) obtained in (3) was subjected to the same reaction and purification as in Example 1- (4) to obtain the desired compound (24 mg) as a lyophilized powder. KB r) v _maK cm " ¹ : 3455, 2933, 1 762, 1 574, 1393.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) δ} ppm:. 1. 07 (3 H, d, J = 6. 4Hz), 1. 01 - 1. 71 (6H, m), 2. 73-2 81 (1 H, m), 3.04 (1 H, dd, J = 13.2 and 4.9 Hz), 3.1 8-3.24 (2 H, m), 3.69—3.76 ( 1 H, m), 3. 99 (lH, dd, J = 10.8 and 2.9Hz), 4.〇0 (lH, d, J = 13.2Hz), 4.03 (1H, quint, J = 6. 4Hz), 4.10 (1H, d, J = 13.2Hz), 7.24-7.38 (5H, m).

(Example 10)

(4 S, 8 S, 9R, IPS) -10-[(R) -11-hydroxyethyl] -14- [N- (4-picolyl) aminomethyl] —11-oxo-1-1-azatrisic mouth [ 7. 2. 0. 0 ³ · ^s 1 Undeka 2-E down one 2-force carboxylic acid

 [Example Compound II-2

(1) (4 S, 8 S, 9 R, 1 OS) 1-41 [N-aryloxycarbonyl N- (4-picolyl) aminomethyl] 1 10— [(R)-1-( t one Puchirujime Chirushiriruokishi) Echiru] one 1 1 one year old Kiso one 1 one Azatorishikuro [7. 2.0. 0 ^{3 '8]} Unde force one 2- En 2- carboxylic acid Ariru

 Example 9 The same reaction and isolation procedure as in Example 9- (2) was carried out using the compound (300 mg) obtained in Example 1 (1) and 41-picolylamine (94 mg) to obtain the title compound (131). mg) as a colorless oil. '

 Nuclear magnetic resonance spectrum (270MHz, CDC13) 6 ppm: 0.08 (6H, s), 0.89 (9H, s), 1.22 (3H, d, J = 7.2Hz), 1.30—1.94 (6 H, m), 3.01—3.38 (2 H, m), 3.8 9-4.28 (3H, m), 4.42-4.88 ( 5H, m), 5.13-5.45 (3H, m), 5.47 (1H, d, J = 17.2Hz), 5.71-6.06 (2H, m), 7. 52 (2 H, dd, J = 15.9 Hz, J = 6.〇Hz), 8.53 (2 H, brm).

(2) (4S, 8 S, 9 R, 1 OS) —4— [N-aryloxycarbonyl— N- (4-picolyl) aminomethyl] 1 10— [(R) — 1-hydroxyethyl] — 11 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ · ⁸ ] — ENE-2—Aryl rubrate

 Using the compound (160 mg) obtained in Example 10- (1), the same reaction and isolation procedure as in Example 3- (3) were carried out to give the title compound (95 mg) as a colorless oil. Obtained.

 Nuclear magnetic resonance spectrum (27 OMHz, CDC 13) δ p pm: 1.38 (3 H, d, J = 6.0 Hz), 1.58- 1.89 (6 H, m), 3.34 (1 H, d, J = 7.2 Hz), 3.25-3.42 (1H, m), 3.6 1—3.98 (3H, m), 4.30-4.47 ( 2H, m), 4.56 (1H, d, J = 5.6Hz), 4.91-5.05 (1H, m), 5.22-5.38 (4H, m ), 5.62-5.78 (1H, m), 5.81-6.01 (1H, m), 7.32-7.39 (1H, m), 7.52-7. 61 (1H, m), 8.40-8.5.1 (2H, m).

(3) (4 S, 8 S, 9 R, 1 OS) 1 10— [(R) — 1-hydroxyethyl] 1 4— [N- (4-picolyl) aminomethyl] — 11 1—oxo 1 —Azatricyclo [7. 2.0.0. ³ · ⁸ ] pendecar 2-ene-1-carboxylic acid

 Using the compound (90 mg) obtained in Example 10- (2), the same reaction and purification as in Example 11- (4) were performed. The crystals precipitated from the aqueous solution were filtered to obtain a crystalline target compound (22 mg).

Infrared absorption spectrum (KB r) v _max cm ' ¹ : 3430, 2934, 2415, 1752, 1636, 1446, 1388, 1297, 1108.

Nuclear magnetic resonance spectra _{(40 OMHz, D 2 0)} δ p pm:. 0. 81 -0 94 (1 H, m), 1. 19 (3 H, d, J = 6. 6 Hz), 1. 14 -1.72 (5H, mi, 2.29-2.38 (1H, m), 2.88—2.98 (2H, m), 3.11 (2H, dd, J = 10. 3 and 9.5 Hz), 3.22 (2H, t, J = 8.8 Hz), 3.97-4.09 (1H, m), 4.17 (1H, d, J = 2.9 Hz), 4.99 (1 H, d, J = 5.1 Hz), 7.76 (2 H, d, J = 6.1 Hz), 8.44 (2 H, d, J = 6.1 Hz) (Example 11)

 (4 R, 8 S, 9 R, 1 OS)-10- [(R) 1-1-hydroxyethyl] 1-4- [N-cyclopropylaminomethyl] 1 1 1-oxo-1 1-azatricyclo

[7. 2. 0. 0 ³ · ⁸ ]

 [(4R) isomer of Exemplified Compound II-131]

(1) (3 S, 4R) — 4 I [(2R, 6 S) — 6— (N—

Bonyl-N-cyclopropylaminomethyl) cyclohexanone-1-yl] —31-((R) —11- (t-butyldimethylsilyloxy) ethyl) azetidine-1-one

 Reference Example 11 The compound (1.00 g) obtained in (8) was dissolved in tetrahydrofuran (15 ml), and triethylamine (364 mg) and methanesulfonyl chloride (378 mg) were added under ice-cooling, followed by stirring for 10 minutes. did. After the reaction solution was filtered to remove insolubles, the filtrate was concentrated to obtain a methanesulfonic acid ester intermediate. The obtained methanesulfonic acid ester intermediate was dissolved in dimethylformamide (20 ml), and cyclopropylamine (514 mg) and triethylamine (364 mg) were added, followed by stirring at 60 ° C. for 2.5 hours. The reaction solution was cooled to 0 C, acrylyl chloroformate (1.08 g) and triethylamine (91 Omg) were added, and after stirring for a while, pH 7 phosphate buffer was added. After extraction with ethyl acetate (10 Om 1 X 4), the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 100 g, hexane: ethyl acetate = 1: 4 → 1: 1) to give the title compound (427 mg) as an oil.

Infrared absorption spectrum (neat) _max cm " ¹ : 3275, 2933, 2858, 1757, 1707, 1408, 125 3,1145,836,776. Ί ί £ 6 OAV

2 inch o 〇 〇

IX

2

Two

) (Dimension S〇 6 S * ^ ί ^ Λ-. Ί ΐρΗb 'II

1 〇 2

(Example 12)

(4 S, 8 S, 9 R, 1 O) —4- [N- (2-fluoroethyl) aminomethyl] -1 10— “(R) — 1-hydroxyethyl] — 11—oxo-1 Zatricyclo [7. 2.0.0. ³ · ⁸ ]

 Illustrative compound II— (4S) isomer of 35

(1) (3 S, 4 R) —4— [(2R, 6 R) —6— (N-aryloxycarbonyl-N— (2-fluoroethyl) aminomethyl) cyclohexanone-2-yl] 1 3 — [(R)-1-(t-butyldimethylsilyloxy) ethyl] azetidin-2-one, (6R) form, and (3S, 4 R) —4-[(2 R, 6 S)- 6— (N-aryloxycarbonyl—N— (2-fluoroethyl) aminomethyl) cyclohexanone-1-yl] —3 — [(R) -1- (t-butyldimethylsilyloxy) ethyl] Azetidine 1-one, (6S) form

The compound (1.07 g) obtained in Reference Example 1- (8) was dissolved in tetrahydrofuran (15 ml), and tritylamine (364 mg) and methanesulfonyl chloride (378 mg) were added under cooling with water, followed by stirring for 30 minutes. The insolubles were removed by filtration, and the filtrate was concentrated to obtain a methanesulfonic acid intermediate. This was dissolved in tetrahydrofuran (15 ml) without purification, and a solution of fluoroethylamine (343 mg) in dimethylformamide (1 ml) was added under ice cooling. Triethylamine (334 mg) was further added, and the mixture was stirred at room temperature for 20 hours. Then, acryloyl formate (398 mg) and triethylamine (343 mg) were added to the reaction solution, and the mixture was stirred for 30 minutes. A PH 7 phosphate buffer was added to the reaction solution, extracted with ethyl acetate (50 ml X3), and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel 65 g, hexane: ethyl acetate = 4: 1-1: 1) to give the title compound (6R) form (256 mg) and (6S) -isomer (442 mg), respectively.

 (6 R) body

Infrared absorption spectrum (neat) _max cm— ¹ : 3274, 2932, 2858, 1757, 1706, 1253, 1144, 836.

Nuclear magnetic resonance scan Bae spectrum _{(270MHz, CDC1 3) δ ppm} : 0.05, 0.07, 0.09 (6H, sx3), 0.87, 0.88, 0.89 (9H, sx3), 2.25~1.06 (9H, m), 2.52~3.89 ( 7H, m), 3.87 to 4.29 (3H, m), 4.39 to 69 (3H, m), 5.18 to 5.36 (2H, m), 5.75 to 5.95 (lH, m).

 (6 S) body

Infrared absorption scan Bae spectrum ^{_{(neat) v max cnT 1:}} . 3280, 2933, 1757,1707,1253, 1145,836 NMR scan Bae spectrum _{(270MHz, CDC1 3) δ ppm} : 0.06 (3H, s), 0.07 (3H, s), 0.87 (9 H, s), 1.12 to 2.23 (6H, m), 1.23 (3H, d, J = 6.3Hz), 2.56 to 2.65 (lH, m), 2.67 -2.98 (1

H, m), 2.86 (1H, dd, J = 4.8, 2.4Hz), 3.31-3.81 (4H, m), 4.06 to 4.09 (lH, m), 4.20 (1H, td, J = 6.3, 4.8Hz) , 4.39 to 4.50 (lH, m), 4.52 to 4.68 (2H, m), 5.13 to 5.36 (2H, m), 5 • 71 (lH, brs), 5.84 to 6.01 (lH, m).

(2) (4 S, 8 S, 9 R, 1 OS) —4— [N-aryloxycarbonyl N— (2-fluoroethyl) aminomethyl] 1 1 0— [(R)-1- (t-butyldimethylsilyloxy) ethyl] 1 1 1 1-oxo 1 1-azatricyclo [7. 2. 0. ³ · ⁸ ]

 The (6R) form (250 mg) obtained in Example 12- (1) was subjected to the same reaction and isolation procedures as in Example 1-2 (2) to give the title compound (30 mg).

Infrared absorption spectrum (neat) v _max cm— ¹ : 2932, 1780, 1713, 1284, 1146, 835.

Nuclear magnetic resonance scan Bae spectrum _{(270MHz, CDC1 3) δ ppm} : 0.07 (6H, s), 0.89 (9H, s), 1 · 21~

I.95 (9H, m), 3.12 ~ 3.24 (lH, m), 3.25 ~ 3.75 (4H, m), 3.92 ~ 4.28 (4H, m), 4.34 ~ 4.85 (6H, m), 5.14 ~ 5.53 (4H , M), 5.79 to 6.04 (2H, m).

(3) (4 S, 8 S, 9 R, 1 OS) 1-41 [N-aryloxycarbonyl N- (2-fluoroethyl) aminomethyl] 1 10— [(R) — 1— Hydroxyethyl] — 1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ · ⁸ ]

The compound (29 mg) obtained in Example 1 2— (2) was used as Example 11 (3). The same reaction and isolation procedure were performed to give the title compound (14 mg) as an oil.

(4) (4 S, 8 S, 9 R, 1 OS) —4— [-(2-Fluoroethyl) aminomethyl] 1 10— [(R) — 1-hydroxyethyl) 1 1 1 similar to (3) the compound obtained in the (14 mg) example 1 i (4) - a Azatorishikuro [7.2.3 .0 ^3.8] Undeka 2 En 2 force carboxylic acid example 1 2 the reaction was carried out and isolation procedure, the title compound (5. 6 mg) ultraviolet absorption scan Bae was obtained as a freeze-dried product of the _{vector; ax (H 2 0) nm} : 269.2

: Example 13)

_ (4 R, 8 S, 9 R, 10 S 4-[N-(2-fluoroethyl) aminomethyl] — 10 0 [[(R) — 1-hydroxyethyl] — 11 1-oxo-1 1-azato Licyclo [_7. 2. 0.0 ³ ' ⁸ ] —Pendecar 2—

 [(4R) isomer of Exemplified Compound II-35]

(1) (4R, 8 S, 9R, 1 OS) — 4- [N-aryloxycarbonyl-N- (2-fluoroethyl) aminomethyl] — 10 — [(R)-1-(t Butyldimethylsilyloxy) ethyl] 1 1 1-oxo 1 1-azatricyclo [7. 2.0.0 ³ · ⁸ ] pentadecane 2-ene-2-aryl arbonate

 The (6S) form (682 mg) obtained in Example 12- (1) was subjected to the same reaction and isolation procedure as in Example 11- (2) to give the title compound (271 mg).

Infrared blotter scan Bae spectrum ^{_{(neat) v max cnT 1:}} 2932, 1775, 1704, 1259, 1145, 989, 836. Nuclear Magnetic Resonance scan Bae spectrum _{(270MHz, CDC1 3) δ ppm} : 0.07 (3H, s), 0.09 (3H, s), 0.88,0-89 (9H, sx2), 1.22 (3H, d, J = 6.3Hz), 2.54-2.94 (2H, m), 3.16 (1H, dd, J = 6.2,3.2 Hz) , 3.30 to 4.02 (4H'm), 4.03 to 4.82 (8H, m), 5.00 to 5.49 (4H, m), 5.84 to 6.03 (2H, m)

(2) (4 R, 8 S, 9 R, 1 OS) 1-41 [N-aryloxycarbonyl-N- (2-fluoroethyl) aminomethyl] 1 10— [(R) — 1-hydroxy [Ethyl] — 1 1-oxo-1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ]

The compound (265 mg) obtained in Example 13-) was subjected to the same reaction and isolation procedure as in Example 11- (3) to give the title compound (52 mg) as an oil. vector ^{_{(neat) v max cm- 1:}} 3446,2938,1771,1699, 1276, 1151. nuclear magnetic resonance scan Bae spectrum _{(270MHz, CDC1 3) δ ppm} : 1.08~2.12 (6H, m), 1.32 (3H, d, J = 6.2 Hz), 2.69 to 3.05 (2H, m), 3.22 (1H, dd, J = 3.0 Hz), 3.32 to 4.02 (4H, m), 4.12 to 4.31 (2H, m), 4.38 ~ 4.88 (6H, m), 5.28 to 5.49 (4H, m), 5.85 to 6.07 (2H, m).

(3) (4 R, 8 S, 9 R, 10 S)-4-[N-(2-fluoroethyl) aminomethyl] — 10 — [(R) — 1-hydroxyethyl) — 1 1 1 Example 1 1-azatricyclo [7. 2.0.0. ³ · ⁸ ] pendane 2--1-ene-2-carboxylic acid Example 13 The compound (50 mg) obtained in 3-(2) was used in Example 1 The target compound (23 mg) was obtained as a lyophilized powder by performing the same reaction and isolation procedure as in (4).

Infrared absorption spectrum (KBr) v _max cm ' ¹ : 3368, 2932, 1754, 1612, 1395.

Nuclear magnetic resonance spectrum _{(400MHz, D 2 0) δ} ppm: 1.09 (3H, d, J = 6.3Hz), 1.03 -1.22 (2H, m), 1.34~1.48 (lH, m), 1 · 67 ~ 1.83 ( 3H, m), 2.64 — 2.73 (2H, m), 3.06 (1H, dd, J = 12.1,5.3Hz), 3.15-3.32 (4H, m), 3.94 (1H, dd, J = 9.6,2.6Hz) , 4.03 (1H, quint, 6.3Hz), 4.52 to 4.68 (2H, m).

(Example 14)

(4 R, 8 S, 9 R, 1 OS) -4- “(S) — 1-Amidinopyrrolidine- 1-3-yl] Thiomethyl- 1 10 — [(R) — 1 — Hydroxyethyl]-1 1 —Oxo 1 1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ] Acid [(4R) isomer of Exemplified Compound IV-4]

参考例 1一 （8) で得られた化合物を （S) — 1— （ 1 , 2—ビスァリルォキ i

Reference Example 11 The compound obtained in (8) was treated with (S) — 1— (1,2—bisaryloki i

Example 11 using (3-carbonylamidino) -1-mercapo-topyrrolidine

 6

, 2- (1), 2- (2), and 11- (4) were performed sequentially to obtain the target compound as a lyophilized powder.

UV absorption scan Bae click Torun _{max (H 2 0) nm:} 269.

(Example 15)

 (4 R, 8 S, 9 R, _1 OS)-10- [(R) 1 _ hydroxyethyl 1

4 one [(S) - 1 - ( 2- imidazolin one 2-I le) pyrrolidine one 3-I le] Ji Omechiru one 1 1 one Okiso one 1- Azatorishikuro "7.2.3 0.0 ^3.8] Unde Power — 2-ene — 2-Rubonic acid [Exemplified compound II— (4R) isomer of 35]

参考例 1一 （8) で得られた化合物を （S) — 1一 （2—イミダゾリン一 2— ィル） —3—メルカプトピロリジンを用いて実施例 1— ( 1 ) ， 2— （ 1) ， 2 - (2) ， 1 - （4) と同様の反応及び単離操作を順次行い、 目的化合物を凍結 乾燥粉末として得た。

Reference Example 11 Using the compound obtained in (8) and (S) -1-1 (2-imidazoline-1-yl) -3-mercaptopyrrolidine, Examples 1- (1) and 2- (1) , 2- (2) and 1- (4) were performed sequentially to obtain the target compound as a lyophilized powder.

UV absorption scan Bae click Torun _{max (H 2 0) nm:} 268.7 (Example 16)

(4R, 8S, 9R, 1 OS) -10-[(R) -1-Hydroxyethyl] -14-[(S) —1- (2-Thiazoline-2-yl) pyrrolidine-1-3-y Thiomethyl-1-11-oxo-11-azatricyclo [7. 2.0.0. ³ · ⁸ ] pendecar 2-eso-2-carboxylic acid [(4R) isomer of exemplary compound III-34]

参考例 1— (8) で得られた化合物を （S) - 1 - (2—チアゾリン— 2—ィ ル） —3—メルカプトピロリジンを用いて実施例 1一 （ 1 ) ， 2— ( 1 ) , 2— (2) ， 1— (4) と同様の反応及び単離操作を順次行い、 目的化合物を凍結乾 燥粉末として得た。

Using the compound obtained in Reference Example 1- (8) and (S) -1- (2-thiazoline-2-yl) -3-mercaptopyrrolidine, Example 11 (1), 2- (1) , 2- (2) and 1- (4) were carried out in the same reaction and isolation procedure to obtain the target compound as a freeze-dried powder.

N UV absorption spectrum _{max (H 2 0) nm:} 269

(Example 17)

(4 R, 8 S, 9 R 1 0 S) - 4. [(S) - 1 one base Njirupirorijin one three to I le] Chiomechiru 1 1 one Okiso one 1 one Azatorishikuro ί7 2. 0. 0 ³ ' ⁸ ] Pendeca-2-ene-2-carboxylic acid [(4R) isomer of Exemplified Compound II-51]

参考例 1一 （8) で得られた化合物を （S) — 1—ベンジル— 3—メルカプト ピロリジンを用いて実施例 1— ( 1 ) ， 2— ( 1 ) , 2— （2) , 1— （4) と 同様の反応及び単離操作を順次行い、 目的化合物を凍結乾燥粉末として得た。 紫外線吸取スぺク トルん _max (H₂0) nm: 268.4

Reference Example 11 The compound obtained in (8) was prepared using (S) -1-benzyl-3-mercaptopyrrolidine in Examples 1- (1), 2- (1), 2- (2), 1- The same reaction and isolation procedure as in (4) were performed sequentially, and the desired compound was obtained as a lyophilized powder. UV blotter scan Bae click Torun _{max (H 2 0) nm:} 268.4

(Example 18)

(4 R, 8 S, 9 R, 10 S) —4- [N-benzylaminomethyl] — 10— [(R) -1-hydroxyethyl] —11-oxo-1 1-azatricyclo [7 . 2.0.0 ³ · ⁸ ] pentadecane-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound III-3]

 i

 o

参考例 1一 （8) で得られた化合物をベンジルァミンを用いて実施例 1 1— ( 1 ) 〜 （4) と同様の反応及び単離操作を行い、 目的化合物を凍結乾燥粉末とし て得た。 8

Reference Example 11 The compound obtained in (8) was subjected to the same reaction and isolation procedures as in Examples 11- (1) to (4) using benzylamine to give the desired compound as a lyophilized powder. .

UV absorption scan Bae click _{ax (H 2 0) nm:} 268.2

(Example 19)

 (4 R, 8 S, 9 R, _1 O S) ——10— [(R) — 1—H

4 1 [N—— (4—— (1—zolyl) beaminomethyl 1 1 1 1-oxo 1 1-azatricyclo [7. 2.0.0 ³ ′ ⁸ ] —Carbonic acid [Exemplified compound II— (4R) isomer of 41]

Reference Example 11 The compound obtained in (8) was subjected to the same reaction and isolation procedure as in Example 11 (1 (4)) using 4- (1-imidazolyl) benzylamine. Thus, the target compound can be obtained as a lyophilized powder.

(Example 2〇)

(4R, 8 S, 9 R, 10 S) 1-41 [N- (4-benzyloxybenzyl) aminomethyl] — 10— [(R) — 1-hydroxyethyl] 1 1 1 1-oxo-1 —Azatricyclo [7. —2. 0.0 ³ · ⁸ J

[Example

 1

 o

9

 The compound obtained in Reference Example 1- (8) was subjected to the same reaction and isolation procedures as in Examples 11- (1) to (4) using 4-benzyloxybenzylamine to give the compound. The target compound can be obtained as a lyophilized powder.

(Example 21)

 (4 S, 8 S, _9 R, 1 OS)-10-_ [(R) 1

4-[N- (2-thiazolyl) aminomethyl] — 11-oxo-11-azatricyclo [7. 2. 0. ³ ' ⁸ ] [Exemplified compound II— (4S) isomer of 29]

(1) (4 S, 8 S, 9 R, 1 OS) —4— [N-aryloxycarbonyl—N— (2-thiazolyl) aminomethyl] — 10— [(R)-1-(t 1-Phtyldimethylsilyloxy) ethyl] 1 1 1-oxo-1 1-azatricyclo [7.2. 0. 0 ³ · ⁸ ] Aryl 2-aryl-1-aryl

 Reference Example 2—The compound (250 mg) obtained in (2) was dissolved in toluene (10 ml), and 2-aryloxycarbonylaminothiazole (21 mg) and triphenylphosphine (753 mg) were dissolved. And acetyldicarboxylate (500 mg) were sequentially added, followed by stirring at room temperature for 3 hours. A small amount of water was added to the reaction solution, and the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 30 g, hexane: ethyl acetate = 4: 1—2: 1) to give the title compound. (229 mg) as an oil.

Infrared absorption spectrum (neat) v _max cm " ¹ : 2931, 2858, 1780, 1716, 1207.

 Nuclear magnetic resonance spectrum (270MHz, CDCls) δ ppm: 0.07 (6H, s), 0.89 (9H, s), 1.23 (3H, d, J = 6.0Hz), 1.47-1.91 (5H, m) , 3.11 (lH, dd, J-7.0, 3.2Hz), 3.32-3.34 (lH, m), 3.91 (IH, dd, J = 10.D, 3.2Hz), 4.08-4.26 (3H, m), 4.48 -4.64 (2H, m), 4.65-4.81 (1H, m), 4.79 (2H, d, J = 6.0Hz), D.14-5.47 (4H, m), 5.73-5.91 (ΙΗ, πι), 5.96 -6.12 (lH, m), 6.93 (1H, d, J = 3.5Hz), 7.37 (lH, d, J = 3.5Hz).

(2) (4 S, 8 S, 9 R, 1 OS) 1-41 [N-aryloxycarbonyl N- (2-thiazolyl) aminomethyl] — 10 — [(R) — 1— Hydroxyethyl] 1 1 1-year-old oxo 1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ]

 Example 21 The compound obtained in 1- (1) was subjected to the same reaction and separation procedure as in Example 11- (3) to give the title compound (144 mg) as an oil.

 Nuclear magnetic resonance spectrum (270MHz, CDCI3) δ ppm: i.29 (3H, d, J = 6.1Hz), 1.15-1.41 (1H, m), 1.41-2.08 (5H, m), 3.19 (1H , Dd, J = 6.5, 3.2Hz), 3.38-3.52 (lH, m), 4.00 (1H, dd, J = 10.5, 3.1Hz), 4.05-4.25 (3H, m), 4.45-4 , m), 4.65-4.82 (lH, m), 4.79 (2H, d, J = 5.6Hz), 0.12-5.45 (4H, m), 5.95-6.13 ilH, m), 6.94 (lH, d, J = 3.9Hz), 7.39 (lH, d, J = 3.9Hz).

(3) (4 S, 8 S, 9 R, 10 S) 1 10 — [(R) — 1-hydroxyethyl] — 4 — [-(2-thiazolyl) aminomethyl] — 11 1-oxo — 1 —Aza tricyclo [7. 2.0.0. ³ · ⁸ ] pendant force — 2-ene-1-carboxylic acid

Example 21 The compound obtained in 1- (2) was subjected to the same reaction and

• (^ = Γ 'Ρ' Ηΐ) 96 · 9 '(ΖΗ -f = P' Ρ 'Ηΐ) 29 · 9' [· 9 = Γ '^ inb Ήΐ) SO' ¹ (· ε '5 · 0ΐ = Γ'ΡΡ'Ηΐ) 96 · ε '(' Ηΐ) ΑΈ-Α9 · '' ( ^ζ Η3 · 0Γ8 · εΐ-Γ'ΡΡΈΤ) 0 '( ^ζ Η6ζζ88εΐ

-Γ'ΡΡ'ΗΪ) LZ · ε 'z · ε'6'9 = Γ' ρρ 'ΗΪ) η · ε' () so · ε-86 'ζ' (ω'Ηζ) o6'i-er (

'Ηΐ) 7-90

6ει'8 ΐ'εζ9Γ 9Π '^ 6Γ £ ^ ε'ε / ^ ε: ^ χ _{(m (} ^ w ^ M \ ^

 ° Tsu (S tug g) 呦 ^: ^^ eyes ヽ ¾ if cormorant ΐ I ΐ

T £ S00 / 86 «ir / XDd 6W / 860A (Example 22)

(4 S, 8 S, 9 R, _l 0 S) _ 41- [N- (2-benzothiazolyl) amimethyl] — 1 0— [(R) — 1-hydroxyethyl] 1 1 1—oxo 1 -Aza tricyclo [7. 2.0.0. ³ · ⁸ ] pentadecane 2-ene-2-carboxylic acid

 [(4S) isomer of Exemplified Compound IV-47]

参考例 2— （2) で得られた化合物を 2— （ァリルォキシカルボニルァミノ） ベンゾチアゾールを用いて実施例 2 1— （ 1 ) 〜 （3) と同様の反応及び単離操 作を行うことにより、 目的化合物を得ることができる。

Reference Example 2—The compound obtained in (2) was subjected to the same reaction and isolation procedures as in Examples 21- (1) to (3) using 2- (aryloxycarbonylamino) benzothiazole. By performing the above, the target compound can be obtained.

(Example 23)

 (4 S, 8 S, 9 R, 10 S) 11 10— [(R) — 1

4 one [N-(2- (4-phenyl) thiazolyl) aminomethyl] - 1 1 one Okiso one 1 one Azatorishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2 En 2-carbomethoxy down醆Exemplified Compound ④— (4S) isomer of 60]

参考例 2— （2) で得られた化合物を 2—ァリルォキシカルボニルアミノー 4 一フエ二ルチアゾールを用いて実施例 2 1— （ 1 ) 〜 （3) と同様の反応及び単 離操作を行うことにより、 目的化合物を得ることができる。 〔実施例 24)

Reference Example 2—The compound obtained in (2) was subjected to the same reaction and isolation procedure as in Examples 21- (1) to (3) using 2-aryloxycarbonylamino-4'-phenylthiazole. By performing the above, the target compound can be obtained. (Example 24)

— (4 S, 1 8S, 9 R, 10 S) 4- [N 2-(4-benzyl) thiazolyl) aminomethyl 1 10— “(R) —1-hydroxyethyl” 1 1 1 1 Oxo — 1-azatricyclo [7. 2. 0. ³ · ⁸ ] pendecar 2-ene-12-carboxylic acid [(4S) isomer of example compound II-71]

参考例 2— (2) で得られた化合物を 2—ァリルォキシカルボニルアミノー 4 一べンジルチアゾールを用いて実施例 21— （ 1 ) ~ (3) と同様の反応及び単 離操作を行うことにより、 目的化合物を得ることができる。

Reference Example 2 The same reaction and separation procedure as in Example 21 (1) to (3) were carried out by using the compound obtained in (2) with 2-aryloxycarbonylamino-4 monobenzylthiazole. By performing the above, the target compound can be obtained.

(Example 25)

 (4 S, 8S, 9 R, 1 OS) — 10— [(R) — 1-hydroxyethyl] 1 4— [N- (5-phenyl—1, 3, 4-thiadiazoyl 2-yl) )

Chill] 1 1 1-oxo 1 1-azatricyclo [7. 2.— 0.0 ³ ' ⁸ ]

 2-en-2-carboxylic acid [(4S) isomer of Exemplified Compound II-100]

参考例 2— （2) で得られた化合物を 2—ァリルォキシカルボニルァミノ— 6 —フエ二ルー 1， 3, 4—チアジアゾールを用いて実施例 2 1— ( 1) 〜 （3) と同様の反応及び単離操作を行うことにより、 目的化合物を得ることができる。 〔実施例 26 )

Reference Example 2—Using the compound obtained in (2) using 2-aryloxycarbonylamino-6-phenyl-1,3,4-thiadiazole, Example 21— (1) to (3) The target compound can be obtained by carrying out the same reaction and isolation procedure as described above. (Example 26)

 — (4 S, — 8 S, 9 R, J OS) 10— f (R) 1 1—H

4-[N-(1, _3, 4-amino 2-aminomethyl) 1 _1 1-oxo 1 1 azatricyclo [7. 2.0. 0 ³ ' ⁸ ] Acid [(4S) isomer of Exemplified Compound III-30]

参考例 2— (2) で得られた化合物を 2—ァリルォキシカルボニルァミノ— 1 ， 3, 4ーチアジアゾールを用いて実施例 2 1— ） 〜 （3) と同様の反応及 び単離操作を行うことにより、 目的化合物を得ることができる。

The compound obtained in Reference Example 2- (2) was reacted with 2-aryloxycarbonylamino-1,3,4-thiadiazole in the same manner as in Examples 21-) to (3), and the reaction was carried out simply. By performing the separation operation, the target compound can be obtained.

(Example 27)

 (4 R, 8 S, 9 R, 1 OS) -10-IR) — 1-hydroxyethyl)

4-I-[-(2-thiazolyl) aminomethyl] 1-oxo-1-azatricyclo [7. 2.0.0 ³ · ⁸ ] pendeca 2-ene-2-carboxylic acid

 [(4R) isomer of Exemplified Compound II-29]

実施例 1— (8) で得られた化合物を 2 -ァミノチアゾールを用いて実施例 1 1— ( 1 ) 〜 （4) と同様の反応及び単離操作を行うことにより、 目的化合物を 得ることができる。 (実施例 28)

The target compound is obtained by subjecting the compound obtained in Example 1- (8) to the same reaction and isolation procedure as in Examples 11- (1) to (4) using 2-aminothiazole. be able to. (Example 28)

(4 R, 8 S, 9 R, 1 OS) — 4— [N (2-benzothiazolyl) amimethyl] 1 10— [(R) — 1-hydroxyethyl] 1 1 1-oxo-1 1-azatricyclo [7.2.3 0.0 ³ - ^8] Undeka 2 E down one 2-force carboxylic acid

 [(4R) isomer of Exemplified Compound IV-47]

実施例 1一 （8) で得られた化合物を 2—ァミノ—ベンゾチアゾ一ルを用いて 実施例 1 1一 （ 1 ) 〜 （4) と同様な反応及び単離操作を行うことにより、 目的 化合物を得ることができる。

The compound obtained in Example 11 (8) was subjected to the same reaction and isolation procedures as in Examples 11-1 (1) to (4) using 2-amino-benzothiazole to obtain the desired compound. Can be obtained.

(Example 29)

(4 R, 8 S, 9 R, 1 OS)-10- “(R) — 1-Hydroxyethyl” -1- 4- [N- (2- (4-phenyl) thiazolyl) aminomethyl] — 1 1 1 Oxo — 1-azatricyclo [7. 2. 0. ³ ' ⁸ ] ndene-2-ene-2-carboxylic acid [(4R) isomer of Exemplified Compound -60]

実施例 1一 （8) で得られた化合物を 2—アミノー 4—フヱニルチアゾ一ルを 用いて実施例 1 1一 （ 1) 〜 （4) と同様の反応及び単離操作を行うことにより 、 目的化合物を得ることができる。 (実施例 30)

The compound obtained in Example 11 (8) was subjected to the same reaction and isolation procedures as in Examples 11-1 (1) to (4) using 2-amino-4-phenylthiazol to obtain the desired compound. A compound can be obtained. (Example 30)

(4 R, 8 S, 9 R 10 S) 4 -— [N— (2-—benzylthiazolyl) aminomethyl] —10— [(R) —1-hydroxyethyl] —11— 1 over § The Bok Rishikuro [7.2.3 0.0 ^{3 '8]} Unde force one 2- En 2- force carboxylic acid

 [(4R) isomer of Exemplified Compound II-71]

実施例 1一 （8) で得られた化合物を 2—ァミノ— 4—ベンジルチアゾールを 用いて実施例 1 1— ( 1 ) （4) と同様の反応及び単離操作を行うことにより 、 目的化合物を得ることができる。

Example 11 By subjecting the compound obtained in (8) to the same reaction and isolation procedure as in Example 11- (1) (4) using 2-amino-4-benzylthiazole, the title compound was obtained. Can be obtained.

(Example 31)

 (4 R, 8 S, 9 R, 1 0 S)-10- [(R) —1-1H

4 one IN- (5-phenylene Lou 1, 3 4-thiadiazole - 2- I le) ami chill] one 1 1 one year old Kiso one 1 Azatorishikuro [7.2.3 0.0 ^{3 '8]} Unde force 2- 2-carboxylic acid [(4R) isomer of Exemplified Compound II-100]

実施例 1一 （8) で得られた化合物を 2—アミノー 5—フヱニル— 1 3, 4 ーチアジアゾールを用いて実施例 1 1一 （ 1 ) （4) と同様の反応及び単離操 作を行うことにより、 目的化合物を得ることができる。 (参考例 1 )

Example 11 The compound obtained in (8) was subjected to the same reaction and isolation procedures as in Example 11 (1) (4) using 2-amino-5-phenyl-13,4-thiadiazole. By doing so, the target compound can be obtained. (Reference example 1)

 (3 S, _4R) — 3—— [(R)-1 -ethyl] —4-1 ((2 R, 6 R) —6— (Hydroxymethyl) cyclohexanone 1-yl] azetidine 2—on

 (1) Ethyl 2-hydroxycyclohexanecarboxylate

 Ethyl 2-cyclohexanone carboxylate (10.2 g) was dissolved in 200 ml of methanol, cooled to 140 ° C, sodium borohydride (2.72 g) was added, and the mixture was heated at the same temperature for 3 hours. After stirring, the temperature was raised to room temperature. After treating with an appropriate amount of acetic acid, the reaction solution was diluted with water, extracted with ethyl acetate (200 ml × 4), the organic layer was washed with aqueous sodium hydrogen carbonate and saturated saline, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel 400 g, hexane: ethyl acetate = 3: 1—1: 2) to give the title compound (cis-form 5.47 g trans-form 1.59 g) colorless Obtained as an oil.

 Cis body

Infrared absorption spectrum (ne at) v _max cm " ¹ : 3513, 2937, 1713, 1185, 1040, 976.

 Nuclear magnetic resonance spectrum (27 OMHz, CDC 1a) δ ppm: 1.28 (3H, d, J = 7. OHz), 1.24 to 1.98 (8H, m), 2.48 (

1 H, ddd, J = 1 1.3, 3.5 and 2.8 Hz), 3.20 (1

H, b r d, J = 2.6 Hz) 4.1 1 -4. 18 (1 H, m), 4. 17 (2 H, q, J = 7. OHz;).

 Transformer body

Infrared absorption spectrum (ne at) v _max cm 3448, 2936, 1733, 1 180.

Nuclear magnetic resonance spectra _{(27 OMH z, CDC 1 3} ) δ ppm: 1. 28 (3H, t, J = 7. 2Hz), 1. 14- 1. 45 (4H, m), 1. 68 -

I. 94 (2 H, m), 1.95-2.09 (2 H, m), 2.25 (1 H, d dd, J = 3. 7, 9.8 and 12.1 H z) , 2.83 (1H, brs), 3.79-3.84 (1H, m), 4.18 (2H, q, J = 7.2Hz) ) o

 (2) Ethyl (IS, 2R) — 2-Acetoxycyclohexanecarboxylate

 Reference Example 11 The cis form (1.72 g) obtained in (1) was dissolved in a mixed solvent of 75 ml of tetrahydrofuran and 175 ml of vinyl acetate, and 10 g of immobilized lipase (LIP-3 31, manufactured by Toyobo) Was added, and the mixture was stirred at 37 ° C. for 9 hours. The reaction solution was filtered through celite, the filtrate was collected, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel 100 g, hexane: ethyl acetate = 5: 1—3: 1) to obtain the title compound (71 Omg) as a colorless oily substance. 86 lmg) were recovered.

Infrared absorption spectrum (ne at) _max cm— ¹ : 1238, 1250,

1 740, 2940.

Nuclear magnetic resonance spectra _{(27 OMHz, CDC 1 3)} δ ppm: 1. 19 - 1. 38 (1 H, m), 1. 23 (3 H, t, J = 7. 2 Hz), 1. 41- 1.65 (3H, m), 1.72-1.88 (3H, m), 1.92-2.11 (1 H, m), 2.03 (3 H, s), 2.43 -2.59 (1H, m), 4.02 -4.21 (2H, m), 5.35-5.42 (1H, m).

Light intensity: [α]. ^{25 = - 10. 7 ° (C} = 0. 605, CHC 1 3).

 (3) (1 R, 2 R) 1-hydroxymethylcyclohexanol

 Lithium aluminum hydride (122 mg) was dissolved in tetrahydrofuran (5 ml), and a tetrahydrofuran solution (5 ml) of the compound (690 mg) obtained in Reference Example 1- (2) was added dropwise at 170 ° C. . The temperature was raised to 0 ° C, and lithium aluminum hydride (36 mg) was added, followed by stirring for 40 minutes. Sodium sulfate decahydrate (1.56 g) was added, the resulting precipitate was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 25 g, hexane: ethyl acetate = 1: 2) to give the title compound (395 mg) as a colorless oil.

Infrared absorption spectrum (ne at) v _max cm " ¹ : 3356, 2931,

2857, 1450. Nuclear magnetic resonance spectrum (27 OMHz, CDC 13) δp pm: 1.18-1.85 (9H, m), 2.24 (2H, brm), 3.76 (2H, d, J = 4.1 Hz), 4.1 3-4. 19 (1 H, m).

^{Polarimetry: [a] D 25 = -} 32. 6 ° (C = 0. 725, CHC 1 3).

 (4) (1 R, 2 R) — 2-t —butyldimethylsilyloxymethylcyclohexanol

 Reference Example 11 The compound (380 mg) obtained in (3) was dissolved in dichloromethane, and t-butyldimethylsilyl chloride (506 mg), triethylamine (369 mg) and 4-dimethylaminopyridine (20 mg) were added. In addition, the mixture was stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 15: 1—9: 1) to give the title compound (61 Omg) as a colorless oil.

 Nuclear magnetic resonance spectrum (27 OMHz, CDC 1 a) δ ppm: 0.07 (6 H, s), 0.90 (9H, s), 1.17-1.84 (9 H, m), 3 35 (1 H, br s), 3.72 (3H, dd, J = 10.0 and 4.8 Hz), 3.81 (1 H, dd, J = 10.0 and 3.7 Hz ), 4.09-4. 15 (1H, m).

^{Polarimetry: [a] D 25 = -} 12. 7 ° (C = 0. 755, CHC 1 3).

 (5) (R) —2— t —butyldimethyloxy I Reference Example 11 The compound (550 mg) obtained in (4) was dissolved in dichloromethane (5 ml), and molecular sieves 4 A, dichromic acid was added. Pyridinium (93 mg) was added, and the mixture was stirred for 4.5 hours. The insolubles were removed by celite filtration, the filtrate was collected, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (480 mg) as a colorless oil.

Infrared absorption spectrum (ne at) v _max cm " ¹ : 2931, 2859, 17010, 1254, 1087, 835. Nuclear magnetic resonance spectrum (27 OMHz, CDC 1a) δ ppm: 0.05 (6H, s), 0.88 (9H, s), 1.30—1.48 (1H, m), 1. 54—1.76 (1H, m), 1.84—1.97 (1H, m), 1.96—2.13 (1H, m), 2.24—2.42 (2H , m), 2.42 -2.56 (1H, m), 3.56 (1H, dd, J = 10.3 and 8.0Hz), 3.98 (1H, dd, J = 4.7 and 10.4 Hz;).

^{_{Polarimetry: [a] D 2S = +}} 39. 0 ° (C = 0. 580, CHC 1 3).

 (6) (R) 11-trimethylsilyloxy-2-tert-butyldimethylsilyl The compound (400 mg) obtained in Reference Example 1- (5) was dissolved in tetrahydrofuran (2 ml), and lithium pistrimethylsilylamide 1 The solution was added dropwise to a 0.1 M tetrahydrofuran solution (1.8 ml) at 178 ° C. One hour later, trimethylsilyl chloride (269 mg) was added to the reaction solution, and the temperature was raised to room temperature over one hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 10 g, hexane: ethyl acetate = 40: 1) to obtain the title compound (653 mg) as a colorless oil.

 (7) (3 S, 4R) -3- [(R)-1-(t-butyldimethylsilyloxy) ethyl]-4- [(2 R, 6 R) -6- (t-butyldimethyl Silyloxymethyl) cyclohexanone-1-yl] azetidin-2-one

(3 S, 4 R) —4—acetoxy 3_ [(R) — 1- (t-butyldimethylsilyloxy) ethyl] — 1-trimethylsilylazetidine-2-one (653 mg) dissolved in dichloromethane Then, 4 ml of a dichloromethane solution of the compound obtained in Reference Example 7- (6) was added, and 450 mg of zinc chloride was further added, followed by stirring at room temperature for 3 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the insolubles generated were removed through celite. The mixture was extracted with ethyl acetate (50 ml x 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. The obtained residue was dissolved in 1 Oml of ethyl acetate, 5 g of silica gel was added, and the mixture was stirred for 2 hours. After filtration, the solvent was distilled off and the residue was subjected to column chromatography (silica gel 50 g, hexane: ethyl acetate). = 3: 1- → 2: 1) to give the title compound as white crystals (485 _mg ) in a stereoselective manner. Infrared absorption spectrum (KB r) v _max cm " ¹ : 3080, 2930, 1761, 1716, 1257, 836.

 Nuclear magnetic resonance spectrum (400 MHz, CDC 1 a) δ p pm: 0.04 (6 H, s), 0.06 (3H, s), 0.07 (3 H, s), 〇. 88 (18 H) , s), 1.17 (3H, d, J = 6.1 Hz), 1.66- 2.09 (6H, m), 2.57-2.62 (1H, m), 2.63 -2.75 (1H, m), 2.87 (1H, dd, J = 4.3 and 2.4Hz), 3.74 (1H, dd, J = 10.2nd 7.0Hz) , 3.90 (1H, dd, J = 10.2 and 7.0Hz), 4.09 (1H, dd, J = 5.4 and 2.4Hz), 4.21 (1H, dq , J = 6.1 and 4.3 Hz), 5.79 (1H, brs).

^{_{Polarimetry:. [A] D 25 =}} + 65 4 ° (C = 0. 895, CHC 1 3).

 (8) (3 S, 4 R) —3— [(R) — 1- (t-butyldimethylsilyloxy) ethyl] 1-41 [(2 R, 6 R) -6- (hydroxymethyl) Cyclohexanone-2-yl] azetidine-1-2-one

Reference Example 11 The compound (10 Og) obtained in (7) was dissolved in dimethylformamide (100 ml), ammonium hydrogen fluoride (1.34 g) was added, and the mixture was stirred for about 2 days. Aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate (250 ml × 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography '(silica gel 350 g, hexane: ethyl acetate = 1: 1 → 1: 4) to give the title compound (5.61 g). Infrared absorption spectrum (KBr) _max cm- ¹ : 3154, 3073, 2935, 1762, 171 5.

Nuclear magnetic resonance spectrum (27 OMHz, CDC13) 5 ppm: 0.07 (6H, s), 0.88 (9H, s), 1.1 1 (3H, d, J = 6.2 Hz) ), 2.05- 1.64 (6H, m), 2.42 (1H, brs), 2.56-2.66 (2H, m), 2.93 (1H, dd, J = 3.5 and 2.1 Hz ), 3.69 (lH, dd, J = 11.2 and 4.6Hz), 3.82 (1H, dd, J = 11.2 and 7.8Hz), 4.08 (1H , dd, J = 7.9 and 2.1 Hz), 4.21 (1H, qd, J = 6.1 and 3.5Hz), 6.28 (1H, brs).

^{Polarimetry: [a] D 25 = +} 48. 9 ° (C = 0. 845, CHC 1 3).

 (9) (IS, 2R) — 2-t-butyldimethylsilyloxymethylcyclohexanol

 Catalytic asymmetric hydrogenation of ethyl 2-cyclohexanone carboxylate using BI NAP—Ru (M. Kit am ura et al., Tet rhedron As ymme try, Vol. 1, p. 1, 1990) (1S, 2R) —2-acetoxycyclohexanecarboxylate (20 g, 87.5% ee) obtained by dissolving in dichloromethane (200 ml), acetic anhydride (13.0 g) under ice cooling, 4 —Dimethylaminopyridine (15.6 g) was added, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (700 ml × 3). The organic layer was washed successively with 1N hydrochloric acid and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude acetyl derivative (26.9 g) was subjected to the same reaction and isolation procedure as in Reference Example 11- (3) without isolation and purification, thereby obtaining (1S, 2R) A crude product of 1-hydroxymethylcyclohexanol was obtained. This was subjected to the same reaction and isolation procedure as in Reference Example 11 (4) without isolation and purification to give the title compound (24.3 g) as a colorless oil.

 Nuclear magnetic resonance spectrum (270MHz, CDCls) δ ppm: 0.09 (3H, s), 0.10 (3H, s), 0.74-1.79 (8H, m), 0.91 (9H, s), 1.92-2.02 (lH , M), 3.42-3.57 (lH, m), 3.58 (lH, dd, J = 9.9, 9.4Hz), 3.72 (1H, dd, J = 9.4, 4.0Hz), 4.33 (1H, brs).

(10) The compound (7.14 g) obtained in Reference Example 1- (9) was dissolved in 6 Oml of dichloromethane, and molecular sieve 4A (14.6 g) and tetrapropylammonium perruthenate (513 mg) were dissolved. ) And N-methylmorpholine-N-oxide (5.13 g) were added, and the mixture was stirred for 3 days. After removing insolubles by celite filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 4〇0 g, hexane: ethyl acetate = 9: 1—5: 1), and the target compound (3 44 g, 86, 1% ee). This was in agreement with the compound obtained in Reference Example 1- (5) in both infrared absorption spectrum and nuclear magnetic resonance spectrum. Optical rotation: [α]. ^{25 = 33. 6 ° (C} = 1. 23. CHC 1 3)

(Reference example 2)

(4 S, 8 S, 9 R, 1 OS) 1 10— [(R)-1-(t-butyldimethylsilyloxy) ethyl] —4-hydroxymethyl-1- 1-oxo— 1-azatricyclo [7. 2.0.0 ³ · ⁸ 1 Pendecar 2-ene _ 2 —Aryl arbonate

(1) (4 S, 8 S, 9 R, 1 OS) — 10— [(R) — 1— (t-butyldimethylsilyloxyxethyl) —4— t-butyldimethylsilyloxymethyl-1 1-oxo-1 1-azatricyclo [7. 2. 0. 0 ³ · ⁸ ]

 Reference Example 11 The compound (1.68 g) obtained in (7) was dissolved in dichloromethane (30 ml), and triethylamine (725 mg) and aryloxalyl chloride (796 mg) were added under ice-cooling, followed by stirring for 3 hours. . 2-Propanol (84 mg) was added to the reaction solution, and the mixture was stirred for 15 minutes, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 30 g, hexane: ethyl acetate = 3: 1) to obtain an oil. This was dissolved in toluene (30 ml), dimethylethylphosphonite (1.60 s) was added, and the mixture was stirred at 50 ° C for 2 hours. Then, the solvent was replaced with xylene and refluxed at 160 ° C for 3 hours. . Xylene was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (silica gel 12'0 g, hexane: ethyl acetate = 5: 1) to give the title compound (1.72 g) as a colorless oil. As obtained.

Infrared absorption spectrum ^{_{(CHC 1 3) max cm- 1}} : 2932, 2859, 1771, 1715, 1259, 1 102.

Nuclear magnetic resonance spectrum _{(270MHz, CDC 1 3) δ} ppm: 0. 04 (3H, s), 0. 07 (3H, s), 0. 87 (9H, s), 1. 24 (3 H, d, J = 6.2Hz), 1.21-2.04 (6H, m), 2.94-3.08 (1H, m), 3.17 (1H, dd, J = 6.7 and 3.2 Hz), 3.67-3.85 (3 H, m), 4.08 (1 H, dd, J = 10.5 an d 3.2 Hz), 4.19 (1 H, quint, J = 6.2 Hz), 4.67 (lH, dd, J = 13.7 and 5.5 Hz), 4. 78 (1 H, dd, J = 10.4 and 5.5 Hz), 5.24 (1 H, d, J = 9.0 Hz), 5.42 (1 H, d, J = 17.2 Hz) ), 5. 89-6 06 (1 H , m) optical ^{rotation:. [a] D 2S =} + 96. 0. (C = l. 32, CHC 1 ₃ )-(2) (4 S, 8 S, 9 R, 1 OS)-10- [(R) — 1— (t-butyldimethylsilyloxy) ethyl] one 4-hydroxymethyl-1 1-Okiso - 1 § The Bok Rishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2 En 2 force carboxylic acid § Li Le

 Reference Example 2—The compound (5.90 g) obtained in (1) was dissolved in DMF (60 ml), and ammonium hydrogen fluoride (641 mg) was added, followed by stirring at room temperature for 3 days. The reaction solution was neutralized by adding aqueous sodium bicarbonate, and extracted with ethyl acetate (250 ml X4). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 300 g, hexane: ethyl acetate = 3: 2-1: 1) to give the title compound (2.22 g) as a colorless oil.

Infrared absorption spectrum _{(CHC 1 3) v max cm-} 1: 2933, 2859, 1771, 1720.

Nuclear magnetic resonance spectrum (27ΟΜΗζ, CDC 13) δ ppm: 0.08 (6H, s), 0.88 (9H, s), 1.16-1.92 (6H, m), 1.23 (3H , D, J = 6.2 Hz), 2.97-3.10 (1H, m), 3.20 (1H, dd, J = 6.3 and 3.4Hz), 3.71 -3 88 (3H, m), 4.16 (1H, dd, J = 10.6 and 3.4Hz), 4.21 (1H, quint, J = 6.2Hz), 4 69 (1 H, dd, J = 13.6 and 5.5 Hz), 4.77 (1 H, dd, J = 13.6 and 5.2 Hz), 5.26 (1 H, dd, J = 10.6 and 1.2 Hz, 5.46 (1 H, dd, J = 17.2 and 1.2 Hz), 5.88-6, 04 (1 H, m). Light intensity: [a] _D ²⁶ = + 133.3 ° (C = 0.780, CHC 1

(Test Example 1)

 The antibacterial activity of the compound (I) of the present invention against various bacteria was measured by an agar plate dilution method. Table 5 shows the minimum inhibitory concentration (M I C / m 1) against Staphylococcus aureus containing methicillin-resistant Staphylococcus aureus (MRSA).

 Five]

M I C (u g / m 1)

 Compound

 A B C Compound of Example 2 ≤0.01 0.05 1.5

 Compound of Example 9 ≤0.01 0.02 3.1

 Example 21 1 Compound 0.02 0.05.

 S an f e t r i nem 0.02 0.05 12.5

A: Staphylococcus aureus 209P

 B: Staphylococcus aureus 56R

 C: Staphylococcus aureus 535 (MRSA) The compound represented by the general formula (I) of the present invention exhibited good antibacterial activity against various pathogenic bacteria. In particular, it exhibited excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

The compounds of the present invention exhibited superior antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), which is considered a clinical problem, as compared with Sanfetrin em known as Trinem. (Test Example 2)

 The compound represented by the general formula (I) obtained in the Examples was recovered in urine at a high rate when administered subcutaneously to mice.

(Formulation Example 1)

 Injection

 500 mg of the compound of Example 1 is dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and then lyophilized to give a lyophilized preparation for injection.

(Formulation Example 2)

 Capsule

 50 mg of the compound of Example 1

 Lactose 128 mg

 70mg corn starch

 Magnesium stearate 2mg

 25 Om g

 After mixing the powder of the above formulation and passing through a 60 mesh sieve, the powder is placed in a 25 Omg No. 3 gelatin capsule to form a capsule.

(Formulation Example 3)

 Tablets

 50 mg of the compound of Example 1

 Lactose 126 mg

 Corn starch 23mg

 Magnesium stearate 1 mg

 20 Om g

 The powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give 20 Omg tablets per tablet. These tablets can be sugar-coated if necessary.

Claims

 Claims General formula

{In the formula, A represents one of the following formulas (2), (3), (3) or (4). formula

[Where k represents 0 or 1,  m represents 0, 1 or 2, and R ² represents a hydrogen atom, a C, to (: ₄ alkyl group, a C to (: an aralkyl group which may have 1 to 3 substituents (the substituent is a halogen atom, a C, to (: alkyl group Or a 1- to 3-membered hetero-T aralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms, which may have 1 to 3 substituents. represents a halogen atom, d -C ₄ alkyl group or force Rubamoiru group), the formula - C (= NH) group (wherein represented by R ^4, R ⁴ is a hydrogen atom, d -C ₄ alkyl group, amino or mono - or di indicates a C -C ₄ alkylamino group), 1-3 nitrogen, heterocyclyl groups 5-6 membered containing oxygen or sulfur atom or 1-3 nitrogen, A 5- or 6-membered heteroaryl group containing an oxygen or sulfur atom, R ³ is a hydrogen atom, an oxo group, a sulfamoylaminomethyl group, a group represented by the formula —C0R ⁵ (wherein, R ⁵ is an amino group, a mono- or di- to (: _4- alkylamino group,

A group represented by the formula (wherein n represents 1 or 2, R ⁶ is a hydrogen atom, d to ( ₄ alkyl group, a group represented by the formula C (= NH) R ^4a , wherein R ^4a is a hydrogen atom, C, ~ C 4 alkyl group, amino group or mono- or di-d ~ (indicating 4 alkylamino groups), 5 to 6 membered heterocyclyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms, or 1 to 3 Represents a 5- to 6-membered heteroaryl group containing one nitrogen, oxygen or sulfur atom), Or expression

(Wherein, s represents 0, 1 or 2, p represents 0 or 1, R ⁷ represents a hydrogen atom or d to C ₄ alkyl group, R ⁸ represents a hydrogen atom, d to A C ₄ alkyl group or a group represented by the formula C (= NH) R ^4a (where R ^4a is a hydrogen atom, ! -C ₄ alkyl group, a an amino group or a mono- or di-one d -C showing a ₄ Arukirua amino group))) shows a. ],  Expression ② — ^{S R9} [Wherein q represents 0, 1 or 2, R ⁹ is a phenyl group which may have 1 to 3 substituents (the substituents are a C ₄ alkyl group, a dC ₄ alkoxy group, a nitro group, a halogen atom, a hydroxyl group, a cyano group, a carbamoyl group) Group, mono or ji ~ (: 4 alkyl group rubamoyl group, A sulfamoyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms). ],  Equation 10  -OC dimension CHrfr "N, ③  Π ヽ [Wherein, r represents 0, 1, 2 or 3; R ^1. Represents a hydrogen atom or a C, to C ₄ alkyl group, R ¹¹ is a hydrogen atom, d -C ₄ alkyl radical or formula one C (= NH) represented Ru group R ⁴ (wherein, R ⁴ is a hydrogen atom, d ~ (: ₄ alkyl group, amino group or mono- youth Or di-d ~ (: indicating ₄ alkylamino groups). formula

④ [Wherein, R ¹² is a hydrogen atom, a d-C ₄ alkyl group or a group represented by the formula —C (= NH) R ⁴ (where R ⁴ is a hydrogen atom, a d-C ₄ alkyl group, an amino group Or mono or di-C! To (: indicating ₄ alkylamino groups), R ¹³ has 1 to 3 substituents; a C ₄ ′ alkyl group (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), C ₃ to (: ₆ cycloalkyl groups, and 1 to 3 C ₆ -d which may have a substituent, aryl group, C ₇ -C ₁₄ aralkyl group which may have 1 to 3 substituents (the substituent is a nitro group, a halogen atom, a methyl Group, amino group, sulfamoyl group, carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, 5- or 6-membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy group, difluoromethoxy group A methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetylamino group), the following substituent group (a) 1 to 3 substituents which may be selected from the group consisting of 5 to 6 membered heteroaryl group or benzene ring condensed 5 to 6 membered heteroaryl group containing a nitrogen, oxygen or sulfur atom, or the following substituent group (a): Represents a 5- to 6-membered heteroaralkyl group or a 5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may have one or more substituents. Substituent Group (a): halogen atoms, d -C ₄ alkoxycarbonyl group, carboxy group, an optionally substituted amino group (the substituent is force Rubamoiru group, Chiokaru Bamoiru group, d ~ (: ₄ alkyl group, 2-hydroxy E methyl group, indicating the force Rubamoirume methyl group or carboxymethyl group), the substituents may Surufamoi Le group (the substituent group which may have a can a d ~ C ₄ alkyl group or a phenylene le radical Phenylsulfonyl group, a phenylthio group optionally substituted with a halogen atom, a pyridylthio group, a C ₇ -C ₁₄ aralkyl group optionally substituted with a methoxy group, and a substituent. d to C ₄ alkyl groups (the substituents are carboxy, hydroxyl, pyrrolidinyl, morpholinyl, piperidinyl, imidazolyl, N-methylimidazolyl, halogen, A methylamino group, a methylamino group, an amino group, a 4-methoxyphenyl group, a carbamoyl group, a phenylcarbamoyl group or an ethoxycarbonyl group), a phenyl or naphthyl group which may have a substituent (the substituent is halogen atom, d -C ₄ alkyl group, d -C ₄ alkoxy group, Surufamoi group, a hydroxyl group, carboxymethoxy group, a force Luba moil methoxy group, an amino group, main Chiruamino group, Jimechiruamino group, Bok trimethyl ammonium Nio group, N- force Rubamoiru methyl-N, N- dimethyl ammonium Nio group or N- 2 - hydroxy E chill -N, N- show dimethyl ammonium Nio group), an optionally substituted d ~ C ₄ alkyl Chiomoto ( The substituent is a hydroxyl group, a phenyl group or a pyridyl group), a pyridino group having a substituent on the N atom (the substituent is methyl , A carbamoylmethyl group, a 2-hydroxyxethyl group or a carboxymethyl group), a phenoxy group, a trimethylammonio group, an N-potumbamoylmethyl-N, an N-dimethylammonio group, an N-2-hydroxyethyl-N, N —Dimethylammonio group, optionally substituted carbamoyl or thiocarbamoyl group (the substituent represents a C> to C ₄ alkyl group, 2-hydroxyethyl group, or sorbamoylmethyl group), or methyl Based on An optionally substituted 5-6 membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms. ] Or a pharmacologically acceptable salt or derivative thereof. 2. In claim 1, in which A is represented by a group of the formula ^II , R ^{2 is a} hydrogen atom, a C 1, -C ₄ alkyl group, benzyl optionally having 1-2 substituents, phenethyl , Naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or thiadiazolylmethyl group (wherein the substituent represents a fluorine atom, a methyl group or a carbamoyl group), a formula —C (2NH) R ⁴ Wherein R ⁴ represents a hydrogen atom, a methyl group or an amino group, a 2-imidazolinyl group, a 2-thiazolinyl group, an imidazolyl group, a thiazolyl group or a pyridyl group or a tricyclic heterocyclic compound or a pharmacology thereof. Or a salt or derivative that is acceptable. 3. In claim 1, in which A is a group of the formula I, and R ² is a hydrogen atom, a methyl group, an ethyl group, a benzyl or pyridyl group which may have 1 to 2 substituents. A methyl group (the substituents represent a fluorine atom, a methyl group or a rubamoyl group), a formimidoyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or a 2-thiazoline-2-yl group. Certain trivalent heterocyclic compounds or pharmacologically acceptable salts or derivatives thereof. 4. In claim 1, A is a group represented by the general formula (I), and R ² , a hydrogen atom, a methyl group, an ethyl group, a benzyl group, a pyridylmethyl group, a formimidyl group, an acetimidoyl group, an amidino group A heteroheterocyclic compound, which is a 2-imidazoline-2-yl group or a 2-thiazoline-2-yl group, or a pharmaceutically acceptable salt or derivative thereof. 5. In claim 1, 2, 3, or 4, A represents a group of the formula II, and R ³ represents a hydrogen atom, an oxo group, a sulfamoylaminomethyl group, a carbamoyl group, a dimethylcarbamoyl. Group, 1-piperazinylcarbonyl group, aminopyrrolidine A heterocyclic heterocyclic compound having a 1-ylcarbonyl group or an aminomethylpyrrolidine-1-ylcarbonyl group, or a pharmaceutically acceptable salt or derivative thereof. 6. In claim 1, 2, 3, or 4, wherein A is represented by a group of formula II, R ³ , hydrogen, hydrogen, carbamoyl, 1-piperazinylcarbonyl, 3-aminopyrrolidine. A heterogeneous heterocyclic compound having a 1-ylcarbonyl group or a 3-aminomethylpyrrolidine-1-ylcarbonyl group, or a pharmacologically acceptable salt or derivative thereof. 7. In Claims 1, 2, 3, or 4, A is a group of the formula 、, and R ³ is a hydrogen atom, or a pharmaceutically acceptable salt or a tricyclic heterocyclic compound thereof. Is a derivative. 8. The tricyclic heterocyclic compound or a pharmacologically acceptable salt or derivative thereof according to claim 1, wherein A is represented by a group of the formula (I) and q is 0 or 1. 9. In claim 1 or 8, in which A is represented by a group of the formula (II), R ^{9 s is} a phenyl group which may have 1 to 2 substituents (the substituents being d to C ₄ alkyl group, C, ~ C ₄ alkoxy group, a nitro group, a halogen atom, a hydroxyl group, Shiano group, force Luba moil group, mono- or di-d to c ₄ alkyl force Rubamoiru group, Surufamo I group or 1-3 A 5- or 6-membered heterocyclic group containing a nitrogen, oxygen or sulfur atom) or a pharmacologically acceptable salt or derivative thereof. 10. In Claim 1 or 8, in which A is represented by a group of the formula 、, R ^g force ^ a phenyl group which may have 1 to 2 substituents (the substituent is a methyl group, A methoxy group, a nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, a dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a thiazolyl group. Compound or its pharmacologically acceptable Salts or derivatives. 1 1. In claim 1 or 8, in which A is represented by a group of the formula ②, R ⁹ is a fuunyl group which may have 1 to 2 substituents (the substituent is a nitro group, A fluorine atom, a carbamoyl group, a dimethylcarbamoyl group, an imidazolyl group, a triazolyl group or a thiazolyl group), or a pharmaceutically acceptable salt or derivative thereof. 12. In claim 1, a trivalent heterocyclic compound or a pharmacologically acceptable salt or derivative thereof, wherein A is represented by the group of the formula ③ and r force is 0, 1 or 2. 13. A tricyclic heterocyclic compound or a pharmacologically acceptable salt thereof, wherein A is a group of formula ③ and R ^1Q is a hydrogen atom, a methyl group or an ethyl group in claims 1 or 12. Or derivatives. 14. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or derivative thereof according to claim 1 or 12, wherein A is represented by a group of formula ③, and R ¹¹³ is a hydrogen atom. 15. In Claims 1, 12, 13, or 14, A is represented by a group of formula ③, and R ^{11 is a} hydrogen atom, a d-C ₄ alkyl group or a formula —C (= NH) R ⁴ . (Wherein R ⁴ represents a hydrogen atom, a methyl group or an amino group) or a pharmacologically acceptable salt or derivative thereof. 16. In claim 1, 12, 13, or 14, A is represented by a group of formula ③, and R ^{11 is} a hydrogen atom, a hydrogen atom, a methyl group, an ethyl group, a formimidyl group, an acetimidyl group or an amidino group. A certain tricyclic heterocyclic compound or a pharmaceutically acceptable salt or derivative thereof. 17. In Claims 1, 12, 13, or 14, a tricyclic heterocyclic compound or a pharmacologically acceptable salt or derivative thereof, wherein A is a group of the formula ③ and R ¹¹ is a hydrogen atom. . 18. In claim 1, in which A is represented by a group of formula (II), R ¹² hydrogen atom, C> to (: ₄ alkyl group or a group represented by formula —C (= NH) R ⁴ ( Wherein R ⁴ represents a hydrogen atom, a methyl group or an amino group) or a pharmacologically acceptable salt or derivative thereof. 19. In claim 1, wherein A is a group represented by the formula (I), and R ^{12 is} s', a hydrogen atom, a methyl group, an ethyl group, a formimidoyl group, an acetimidoyl group or an amidino group. Or a pharmacologically acceptable salt or derivative thereof. 20. In Claims 1, 18 or 19, A is a group of the formula 、, and R ¹³ is a d-C ₄ alkyl group having 1-2 substituents (the substituent is a halogen atom force Rubamoiru a group or a hydroxyl _{group), C 3 ~ (:.} 6 cycloalkyl group, 21 to one of which may have a substituent Cs~d Ariru group or C ₇ -C ₁₄ Araru kill group (the Substituents are nitro, halogen, methyl, amino, sulfamoyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 5- to 6-members containing 1-3 nitrogen, oxygen or sulfur atoms A heteroaryl group, a methoxy group, a difluoromethyoxy group, a methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetylamino group), and one or two substituents selected from the substituent group (a). Good 5- to 6-membered heteroaryl group or benzene-condensed 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms, or substituent group (a) Force Tricyclic that is a 5- to 6-membered heteroaralkyl group or a 5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may have 1 to 2 substituents Or a pharmacologically acceptable salt or derivative thereof. 21. In Claims 1, 18 or 19, wherein A is a group of the formula 、, and R ^{13 has 1 to} 2 substituents (^ to C ₄ alkyl group (the substituted group is a halogen atom, a force Rubamoiru group or a hydroxyl group), C ₃ -C ₆ cycloalkyl group, 21 to one of the good phenyl may have a substituent, naphthyl, benzyl, phenethyl Wakashi Ku is naphthylmethyl (The substituent may be a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, a 5- to 5-nitrogen-containing oxygen or sulfur atom, A 6-membered aryl group, a methoxy group, a difluoromethoxy group, a methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetylamino group), or a group of substitution groups (a) Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolyl, benzimidazolylmethyl, which may have 1 to 2 substituents A tricyclic heterocyclic compound which is a quinolylmethyl group, or a pharmaceutically acceptable salt or derivative thereof. 22. In Claims 1, 18, or 19, wherein A is a group of the formula 、, and R ¹³ is a d-C ₄ alkyl group having 1-2 substituents (the substituent halogen atom represents a force Rubamoiru group or a hydroxyl group), C ₃ -C ₆ cycloalkyl group, 21 to substituent good phenyl or benzyl group (the substituent group which may have a can nits port, a halogen atom Or pyruvamoyl, sulfamol, imidazolyl, thiazolyl, 1, 2, 4-triazolyl or benzyloxy group.) Or pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, which may have 1 to 2 substituents. Thiadiazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl Or a quinolylmethyl group (the substituents are halogen atom, amino group, carbamoyl group, sulfamoyl group, hydroxymethyl group, carbamoylmethyl group, phenyl group, ethylthio group, pyridyl group, 1-imidazolylmethyl group, trimethylammonio group) Group, thiocarbamoyl group or benzyl group Or a pharmacologically acceptable salt or derivative thereof. 2 3. In the first, 1-8 or 1-9 wherein the claims, A is represented by the group of the formula ④, R ^{1 3} power 2 Furuoroechiru, cyclopropyl, phenyl, 3-pyridyl, 4-pyridyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4- (1-imidazolyl) benzyl, 4-benzyloxybenzyl, 2-thiazoli 2-benzimidazolyl, 2-benzothiazolyl, 4- (4-pyridyl) thiazol-2-yl, 4-phenylthiazole-2-yl, 4-benzylthiazolu-2-yl, 6-a Minnow benzothiazole-2-yl, 4- (1-imidazolylmethyl) thiazole-2-yl, 1,3,4-thiadiazol-2-yl, 5-phenyl-1,3,4-thiadiazo 2-yl, 5- (4-pyridyl) 1,3,4-thiadiazole-2-yl, 5-ethylethyl-1,3,4-thiadiazole 2-yl, 2-b A tricyclic heterocyclic compound represented by nzthiazolylmethyl, 2-benzimidazolylmethyl or 2-quinolylmethyl group, or a pharmaceutically acceptable salt or derivative thereof. 24. In claim 1, A is represented by the group of formula 、, k is 0 or 1, m is 0, 1 or 2, R ² , a hydrogen atom, d to C ₄ alkyl Group, benzyl, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolyltyl, thiazolylethyl or thiadiazolylmethyl group which may have 1 to 2 substituents (the substituent is a fluorine atom, a methyl group or indicating a force Rubamoi Le group), group (wherein the formula one ^{C (= NH) R 4,} R 4 represents a hydrogen atom, methylation group or an amino group), 2-imidazolinyl, 2- thiazolinyl group, an imidazolyl group, a thiazolyl group or a pyridyl group, R ³ is a hydrogen atom, O Kiso group, sulfamoyl § amino methyl force Rubamoiru group, dimethylcarbamoyl group, 1 over piperazinylcarbonyl , Aminopirorijin one 1- Irukaruboniru group or aminomethyl pyrrolidine - 1 three 璟性 complex 璟 compound or a pharmacologically acceptable salt or derivative thereof is Irukaruboniru group. 25. In claim 1, A is represented by the group of formula II, k is 0 or 1, m is 0, 1 or 2, and R ² is a hydrogen atom, a methyl group or an ethyl group. A benzyl or pyridylmethyl group which may have 1 to 2 substituents (the substituents represent a fluorine atom, a methyl group or a carbamoyl group), a formimidyl group, an acetimidoyl group, An amidino group, 2-imidazoline-1-yl group or 2-thiazoline-12-yl group, wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt or derivative thereof; . 26. In Claim 1, A is represented by a group of formula II, k is 0 or 1, m is 0, 1 or 2, and R ² is a hydrogen atom, a methyl group or an ethyl group. A benzyl group, a pyridylmethyl group, a formimidoyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-12-yl group or a 2-thiazoline-2-yl group, and R ³ is a hydrogen atom. A cyclic heterocyclic compound or a pharmacologically acceptable salt or derivative thereof. 27. In claim 1, in which A is represented by a group of the formula (1), q is 0 or 1, and R ⁹ is a phenyl group which may have 2 substituents (the substituent Represents a methyl group, a methoxy group, a nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, a dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, a pyridyl group or a thiazolyl group. Or a pharmaceutically acceptable salt or derivative thereof. 28. In claim 1, in which A is a group represented by the formula (1), q is 0 or 1, and R ⁹ is a phenyl group which may have 2 substituents (the substituent Represents a nitro group, a fluorine atom, a carbamoyl group, a dimethylcarbamoyl group, an imidazolyl group, a triazolyl group or a thiazolyl group) or a pharmacologically acceptable salt or derivative thereof. 29. In claim 1, A is represented by the group of formula ③, and r is 0, 1 or R ^{1 (5} is a hydrogen atom, a C ₄ alkyl group; R ¹¹ is a hydrogen atom, a C! To C ₄ alkyl group or a group represented by the formula C (= NH) R ⁴ (formula Wherein R ⁴ represents a hydrogen atom, a methyl group or an amino group), or a pharmaceutically acceptable salt or derivative thereof. 30. In claim 1, A is a group of formula ③, r is 0, 1 or 2, R ^1Q is a hydrogen atom, a methyl group or an ethyl group, R ¹¹ is a hydrogen atom, A tricyclic heterocyclic compound which is a methyl group, an ethyl group, a formimidyl group, an acetimidoyl group or an amidino group, or a pharmaceutically acceptable salt or derivative thereof. 31. In claim 1, A is a group represented by the formula 、, R ¹² is a hydrogen atom, C, ~ (: ₄ alkyl group or a group represented by the formula C (2NH) R ⁴ ( In the formula, R ⁴ represents a hydrogen atom, a methyl group or an amino group, and R ¹³ is a d-(: ₄ alkyl group having one or two substituents (the substituent is a halogen atom, a carbamoyl group) or a hydroxyl group), C ₃ -C ₆ cycloalkyl group, one to two but it may also have a substituent C ₆ to d. Ariru group or C ₇ -C ₁₄ Ararukiru group (the substituent Nitro group, halogen atom, methyl group, amino group, sulfamoyl group, carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, 1-3 nitrogen, 5- or 6-membered heteroaryl group containing oxygen or sulfur atom , Methoxy, difluoromethoxy, methylenedioxy, benzene Containing 1 to 3 nitrogen, oxygen or sulfur atoms which may have 1 to 2 substituents selected from the group of substituents (a), which represents a oxy group, a pyridylmethoxy group or an acetylamino group. 5 to 6-membered heteroaryl group or benzene ring condensed 5 to 6-membered heteroaryl group or substituent group (a) force ^ may have one or two selected substituents 1-3 Heteroalkyl group containing 5 to 6 membered heteroalkyl group or benzene ring-condensed 5 to 6 membered heteroalkyl group containing nitrogen, oxygen or sulfur atom, or a pharmaceutically acceptable compound thereof Salts or derivatives. 32. In Claim 1, A is represented by a group of the formula 、, R ¹² is a hydrogen atom, C: -C ₄ (wherein, R ⁴ is a hydrogen atom, a methyl group or an amino group) alkyl group, or a group of the formula -C (= NH) group represented by R ⁴ is, R ¹³ is 1 to 2 of d -C ₄ alkyl group having a substituent (said substituent is a halogen atom, a force Rubamoiru group or a hydroxyl group), C ₃ -C _S cycloalkyl group, which may have 1 to 2 substituents Phenyl, naphthyl, benzyl, phenethyl, or naphthylmethyl groups (the replacement groups are a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, 5- to 6-membered heteroaryl group containing three nitrogen, oxygen or sulfur atoms, methoxy group, difluoromethoxy group, methylenedioxy group, benzyloxy group, pyridylmethoxy group or acetylami Or pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, which may have 1 to 2 substituents selected from substituent group (a). A tricyclic heterocyclic compound which is an imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl or quinolylmethyl group, or a pharmaceutically acceptable salt or derivative thereof. 33. In Claim 1, A is a group represented by the formula 、, and R ¹² is a hydrogen atom, a C i -C ₄ alkyl group or a group represented by the formula —C (= NH) R ⁴ (the formula Wherein R ⁴ represents a hydrogen atom, a methyl group or an amino group, and R ¹³ is a d-C ₄ alkyl group having 1 to 2 substituents (the substituent is a halogen atom, a carbamoyl group or a hydroxyl group) the illustrated), C ₃ -C _S cycloalkyl group, '1-2 substituted but it may also phenyl or benzyl group (the substituent is nitro, halogen atom, Karubamo I Le, sulfamoyl, imidazolyl , Thiazolyl, 1, 2, 4-triazolyl or benzyloxy) or pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, which may have 1 to 2 substituents. Benzothi Azolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, benzimidazolylmethyl or quinolylmethyl group (the substituents are halogen atom, amino group, carbamoyl group, sulfamoyl group, hydroxymethyl group, carbamoylmethyl Group, phenyl Or a pharmacologically acceptable salt or derivative thereof, which is a group, ethylthio group, pyridyl group, 11-imidazolylmethyl group, trimethylammonio group, thiocarbamoyl group or benzyl group). 34. In claim 1, A is represented by a group of formula II, R ¹² is a hydrogen atom, a methyl group, an ethyl group, a formimidoyl group, an acetimidoyl group or an amidino group, and R ¹³ is 2-fluoroethyl, cyclopropyl, phenyl, 3-pyridyl, 4-pyridyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl Pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4- (1-imidazolyl) benzyl group, 4-benzyloxybenzyl group, 2-thiazolyl group, 2-benzimidazolyl group, 2-benzothiazolyl group , 4- (4-pyridyl) thiazole-2-yl group, 4-phenylthiazole-2-yl group, 4-benzylthiazo-l-2-yl group, 6-aminobenzothiazo-l-yl group , 4- (1-imidazolylmethyl) thiazol-2-yl group, 1,3,4-thiadiazole-2-yl group, 5-phenyl-1,3,4-thiadiazol-2-yl group, 5- (4-Pyridyl) 1-1,3,4-thiadiazole-2-yl group, 5-ethylthio-1,3,4-thiadiazole-2-yl group, 2-benzothiazolylmethyl group, 2-benz A tricyclic heterocyclic compound which is an imidazolylmethyl group or a 2-quinolylmethyl group, or a pharmacologically acceptable salt or derivative thereof. 35. In claim 1, a trivalent heterocyclic compound selected from the following compounds, or a pharmaceutically acceptable salt or derivative thereof. (1) (4 R, 8 S, 9 R, 10 S) 1-10— [(R) —1-hydroxyethyl] 1-41 [(S) -13-pyrrolidinyl] thiomethyl-11-oxoxo 1-aza Tricyclo [7. 2. 0. 0 ³ · ⁸ ] pentadecane 2-ene-2-carboxylic acid (2) (4R, 8S, 9R, 10S) -10-[(R) -11-hydroxyethyl] 1-111oxo-14-1 [(S) 1-2-pyrrolidinyl] methylthiomethyl-1 —Azatricyclo [7. 2.0.0. ³ ' ⁸ ] (3) (4 S, 8 S, 9 R, 10 S) 1 4-N-benzylaminomethyl-10 1 [(R) — 1-hydroxyethyl] 1 1 1-oxo 1-azatricyclo [ 7. 2. 0.0 ^{3 '8]} Undeka 2- En 2- carboxylic acid (4) (4 R, 8 S, 9 R, 1 OS) 1 4-N-benzylaminomethyl 1 10 1 [(R) 1 1-hydroxyethyl] 1 1 1-oxo-1 1-azatricyclo [ 7. 2. 0. ³ · ⁸ ] Pendoca 2-ene-2-carboxylic acid (5) (4 R, 8 S, 9 R, 10 S) 1-4-[(S)-1-amidinopyrrolidin-3 -yl] Thiomethyl-10-[(R)-1-hydroxyethyl] 1 1 1 1-oxo 1 1-azatricyclo [7. 2. 0. 0 ³ · ⁸ ] carboxylic acid 2-ene-2-carboxylic acid (6) (4R, 8 S, 9 R, 1 OS) — 10— [(R) — 1-hydroxyethyl] — 4— [(S) — 1— (2-imidazoline-1-yl) Pyrrolidine-1 3 —Yl] Thiomethyl-1 1-oxoxo 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ] デ decan 2-ene-1-2-carboxylic acid (7) (4 R, 8 S, 9 R, 1 OS) — 10— [(R) 1-hydroxyethyl] — 4— [(S)-1-(2-thiazoline— 2-yl) pyrrolidine — 3—yl] Thiomethyl-1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ] (8) (4 R, 8 S, 9 R, 1 OS) — 10— [(R) 1-1-hydroxyethyl] 1-41 [1- (2-thiazoline-2-yl) azetidine-2-yl] Chiome Chiru 1 1- Okiso one 1 one Azatorishikuro [7. '2. 0.0 ^3.8] Unde force one 2 one En 2- force carboxylic acid (9) (4 R, 8 S, 9 R, 10 S) —4— [1-Amidinoazetidine-1- 2-yl] thiomethyl- 10— [(R) — 1-hydroxyethyl) — 1 1 year old Kiso one 1 one Azatorishikuro [7.2.3 0.0 ^{3 '8]} Undeka 2 E down one 2- carboxylic acid (10) (4R, 8S, 9R, 1 OS)-10- [(R) 1- 1-hydroxyethyl] 1-41 [N- (4- (1-imidazolyl) benzyl) aminomethyl] 1 1 1 1-year-old 1-azatricyclo [7. 2. 0. ³ · ⁸ ] One-stroke rubonic acid (1 1) (4 S, 8 S, 9 R, 1 OS) 1 10 — [(R) 1 1-hydroxyethyl] —4— [N- (2-thiazolyl) aminomethyl] —1 1-oxo 1 1-azatricyclo [7. 2. 0. ³ ' ⁸ ] pentadecane 2-ene-2-carboxylic acid (12) (4 R, 8 S, 9 R, 1 OS) 1 10— [(R) 1-hydroxyethyl) —4— 1 [N- (2-thiazolyl) aminomethyl] 1 1 1-oxo-1 1 § The Bok Rishikuro [7.2.3 0.0 ^3.8] Unde force one 2-En 2-force carboxylic acid (13) (4S, 8S, 9R, 10S) 1-41 [N— (2-benzothiazolyl) aminomethyl] —10 — [(R) —1-hydroxyethyl) 1-111 One oxo 1-Azatricyclo [7. 2.0.0. ³ · ⁸ ] pentadecane 2-ene-2-carboxylic acid (14) (4R, 8S, 9R, 10S) 1-41 [N- (2-benzothiazolyl) aminomethyl] 1 10-[(R)-1-hydroxyethyl] 1 1 1 -oxo 11-Azatricyclo [7. 2.0.0. ³ · ⁸ ] (15) (4 S, 8 S, 9 R, 1 OS)-10— [(R) — 1-hydroxyethyl] 4-1 [N— (2- (4-phenyl) thiazolyl) aminomethyl] 1 1 —Oxo-1 1-azatricyclo [7. 2.0.0. ³ ' ⁸ ] (16) (4R, 8 S, 9 R, 1 OS) 1 10— [(R) — 1-hydroxyethyl] 1 4 1 [N— (2- (4-phenyl) thiazolyl) aminomethyl] — 1 1 1-year-old 1-azatricyclo [7. 2. 0. ³ · ⁸ ] (1 7) (4 S, 8 S, 9 R, 10 S) —4— [N— (2- (4-benzyl) thiazolyl) aminomethyl] 1 10— [(R) — 1-hydroxyethyl] 1 1 1 —Oxo 1 1-azatricyclo [7. 2. 0. 0 ³ · ⁸ ] (18) (4 R, 8 S, 9 R, 10 S) —4— [N- (2- (4-benzyl) thiazolyl) aminomethyl] — 10— [(R) — 1-hydroxyethyl] 1 1 1 43 1-oxo-1 1-azatricyclo [7. 2. 0. 0 ³ · ⁸ ] (19) (4 S, 8 S, 9 R, 1 OS) 1 10— [(R) 1-hydroxyethyl) —4— [— (5—Feneru 1, 3, 4—Thiadiazol— 2 —Yl) Aminomethyl] 1 1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ] ゥ deca-2-ene-2-carboxylic acid (20) (4 R, 8 S, 9 R, 10 S)-10- [(R) — 1-hydroxyethyl] — 4-— [-(5-phenyl-1, 3, 4, 4-thiadiazole— 2-yl ) Aminomethyl] 1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ · ⁸ ] ゥ -deca-2-ene-2-carboxylic acid (21) (4 S, 8 S, 9 R, 1 OS) 1-10 — [(R) 1—1-hydroxyethyl) —4—1—N- (1,3,4-thiadiazole—2-yl) Aminomethyl] 1 1 1 oxo 1 1 1 azatricyclo [7. 2. 0. ³ ' ⁸ ] (22) (4 R, 8 S, 9 R, 1 OS) 1 10— [(R) — 1-hydroxyethyl] —4— [N— (1, 3, 4-thiadiazole— 2-yl) Aminomethyl] 1 1 1-oxo-1 1-azatricyclo [7. 2.0.0 ³ ' ⁸ ] (23) (4 R, 8 S, 9 R, 10 S) — 10— [(R) -1-hydroxyethyl] 1-41 [1- (2-thiazoline-2-yl) piperidine 4 one I le] Chio methyl-1 1 one Okiso one 1- § The Bok Rishikuro [7: 2 0.0 ^{3 '8]} Undeka 2 En 2 force carboxylic acid (24) (4 R, 8 S, 9 R, 10 S) -4- (1 -amidinopiperidine- 1 -yl) Thiomethyl- 10-[(R)-1-hydroxyethyl]-11 11-Azatricyclo [7. 2.0.0. ³ · ⁸ ] pentadecane 2-ene-2-carboxylic acid 36. A composition for preventing or treating infectious diseases, comprising the tricyclic heterocyclic compound according to any one of claims 1 to 35 as an active ingredient.