WO1991009860A1 - New carbapenem derivative - Google Patents

Abstract

A compound of general formula (I), pharmaceutically acceptable salts and esters thereof, process for the production thereof, and antibacterial agents containing the same as the active ingredient, wherein R represents hydrogen or methyl; R1 represents hydrogen, lower alkyl, lower alkanoyl, formyl, formimidoyl, acetimidoyl, diamidino, prolyl or any of the groups (i), (ii), (iii), (iv); R2 represents hydrogen, hydroxy-(lower alkyl), or any of the groups (v), (vi), (vii); A represents methylene or carbonyl; and B represents oxygen or NR3, wherein R3 represents hydrogen, lower alkyl, lower alkanoyl, formyl, formimidoyl, acetimidoyl, amidino, prolyl or any of the groups (i), (ii), (iii), (iv), provided that the case wherein all of R?1, R2 and R3¿ are hydrogen atoms and A is methylene is excluded.

Description

Detail

Novel rivanem derivative technology

 The present invention relates to a novel compound (7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid) compound, a method for producing the compound and an active ingredient comprising the compound. As an antimicrobial agent.

Background technology

 In recent years, new / 3-lactam antibiotics having the same /?-Lactam ring as penicillins and cephalosporins, but having different basic skeletons have been discovered one after another in nature.

 For example, fermentation of Streptomyces cattle isolated thienamycin [J. Am. Chem. Soc., Vol. 100, 6491 (1978)]. Chenamisin has excellent antibacterial spectrum and strong antibacterial activity over a wide range of Gram-positive and Gram-negative bacteria, and is expected to be developed as a highly useful / 3-lactam agent. However, chenamycin itself is unstable in terms of histology, and is degraded by certain in vivo enzymes such as renal dehydrobeptidase I (hereinafter abbreviated as DHP-I), and its antibacterial activity is It has been reported that urinary recovery is low [Antimicrobial Agents Chemoter, (Vol. 22, p. 62 (1982); Vol. 23, 300). Page (1983)].

 Merck has synthesized a number of analogs of chenamycin with the aim of maintaining the superior antibacterial activity of chenamycin and ensuring its chemical stability. As a result, imipenem in which the amino group of chenamycin was formimidylated (J. Med. Chem., 22: 1435 (1979)) was a pharmaceutical product. As a result.

Imidenem has antibacterial activity against various bacterial species at least as high as that of cenamycin. It retains sex and S-lactamase resistance, and its antibacterial activity is 2-4 times better, especially against Pseudomonas aeruginosa. In addition, the stability of imidenem as an aqueous solution and solid was significantly improved as compared to that of cenamycin.

 However, imidenem, like chenamycin, is degraded by DHP-I in the human kidney and cannot be used for urinary tract infections, but also exhibits nephrotoxicity due to degradation products. Therefore, imidenem cannot be administered alone and must be used in combination with DHP_IP and harmful agents such as cilastatin [Antimicrob. Agents Chemoter.]. 12 (Suppl D), 1 page (1983)]. In recent years, imidenem has been frequently used in the treatment and prevention of infectious diseases. . Imidenem has not shown a sufficient therapeutic effect on these resistant bacteria.

 Prior art of the present invention includes JP-A-59-89,683, JP-A-61-63,678, and JP-A-83,183. However, both publications only broadly and generically refer to compounds of an aromatic heterocyclic alkylthio group or an aromatic heterocyclic thio group at the 2-position of the venom skeleton.

 That is, the compound of the present invention having an isooxazolidinylthio group or a birazolidinylthio group at the 2-position of the compound, which is a feature of the present invention, is a novel compound not described in the literature, And in patent specifications, etc., are not disclosed at all and are not even suggested.

 ^ -Lactam antibiotics have selective toxicity to bacteria only and have no effect on animal cells, so they are widely used as antibiotics with few side effects for the treatment of bacterial infectious diseases and have high utility. It is.

 However, in recent years, highly resistant methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa have often been isolated from patients with reduced immunity as pathogens of intractable infections, and are becoming a major clinical problem. Therefore, the development of antibacterial agents having improved antibacterial activity against these resistant bacteria, especially in the case of rubanem compounds, improved antibacterial activity, improved stability against DHP-I, reduced nephrotoxicity, Reduction of side effects on the central nervous system is strongly desired.

 Disclosure of the invention

The present inventors have developed a novel drug Lubabe which has excellent antibacterial activity and is resistant to DHP-I. With the aim of providing nem compounds, intensive research was conducted. As a result, a new compound having a isoxazolidinylthio group or a birazolidinylthio group at the 2-position of the kerbaenem skeleton contains gram-positive bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. The present inventors have found that they have strong antibacterial activity against Gram-negative bacteria and also show excellent stability against DHP-I, and thus completed the present invention.

 The present invention has the general formula

Wherein R is a hydrogen atom or a methyl group, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanoinole group, a forminole group, a formimidoyl group, an acetimidoyl group, a imidino group, a prolyl group, or a compound represented by the following formula:

/ (CH ₂ ) _n R ⁷ R ⁸ iii) — COCH iv) — C0 (CH ₂ ) _n CH ヽ

NH ₂ NH ₂

(Wherein, R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom form an aziridinyl group, an azetidinyl group, a pyrrolidinole group or a piperazinyl group, R ⁶ may be substituted by a hydroxyl group, a lower alkyl group or an aryl group, R ⁷ is a carboquinol group, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group, a lower alkylthio group or a guanidino group, R ⁸ Is a carboxyl group, lower alkoxycarbonyl group or aminocarboninole group, m is an integer of 0 to 3, n is an integer of 1 to 3, R ² is a hydrogen atom, a hydroxy lower alkyl group Or the following formula

V)-CON vi)-(CH ₂ ) nC0N vii)-(CH ₂ ) _n 0C0N (Wherein R ⁹ and R ¹ represent a hydrogen atom or a lower alkyl group, or R ⁹ and R ^w together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperidyl group, and n A has a methylene group or a carbonyl group, B is an oxygen atom or a formula> NR ³ (where R ³ is a hydrogen atom, a lower alkyl group, a lower alkanol group, a formizole group) , Holm imino Doyle group, Asetoimi Doyle group, amidino group, prolyl group or the following formula _{i) - CO (CH 2)} m N / R4 z R s

 ii)-COCH

ヽ R ⁵ NH ₂ iii) COCH

_Two

(Wherein, R ⁴ , R ⁵ , R ⁶ , RR m and n have the same meanings as described above) wherein R, R ² and R ³ are both hydrogen Or a pharmaceutically acceptable salt or ester thereof, a method for producing them, and an antibacterial agent containing them as an active ingredient.

 Among the compounds of the general formula [I],

[Wherein, R ¹⁰⁰ is a hydrogen atom, a lower alkyl group, a formimidoyl group, an acetate dinole group, an amidino group, a prolinole group, or the following formula:

R ⁶

ii)-COCH z (CH ₂ ) _n R ⁷

 iii) — COCH

NH ₂ NH ₂

R ⁸

iv) — C0 (CH ₂ ) _n CH viii) — C0 (CH ₂ ) _n N

NH ₂

(Wherein, R ⁴ ° and R ⁵ ° represent a hydrogen atom or a lower alkyl group, R ⁶ , R and n has the above-mentioned meaning), and R and R ² have the above-mentioned meanings].

[Wherein, R, II ¹ , R ³ and A have the above-mentioned meanings (excluding the case where R ¹ and R ³ are both hydrogen atoms)]. You.

 The symbols and terms described in this specification will be described.

 The compound of the present invention has a basic structure

Systematically called 7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-forcerbonic acid. In the present specification, the canoleno penem commonly used widely for simplicity

Numbered based on the basic structure; -Canolebapene-2-em-3-carboxylic acid.

The present invention encompasses optical isomers and stereoisomers based on the asymmetric carbon atoms at positions 1, 5, 6, and 8 of the carbane skeleton, and preferred compounds among these isomers include: (5i?, 6S) configuration (5,6- (5R.6S.8R), or a compound with a methyl group at position 1 (1R, 5S, 6S, 8R) Compounds can be mentioned.

 That is, among the compounds of the general formula [I], a group of compounds having a preferred configuration is represented by

[Wherein, R, R ^1, R ² , A and B have the above-mentioned meanings].

 The compounds of the present invention have stereoisomers based on the asymmetric carbon atom of the isoxazolidinylthio group or the vilazolidinylthio group, which is the 2-position side chain of the carbane skeleton. Included within the scope of the invention.

 The lower alkyl group means an anoalkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a ri-butyl group, and a methyl group, an ethyl group, and a propyl group are preferable. is there.

 The lower alkanosole group means an acetyl group, a propionyl group, an acryloniole group, a propioloyl group, and the like.

 The aryl group means a phenyl group, a naphthyl group or the like.

 The lower alkoxycarbonyl group refers to an oxycarbonyl group substituted by the above-mentioned lower alkyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, ieri_butoxycarbonyl group. And a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group. '

The lower anoalkylthio group refers to a thio group substituted by the above lower alkyl group, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a teri-butylthio group, and the like, and particularly, a methylthio group, an ethylthio group, Butylthio groups are preferred. The hydroxy lower alkyl group refers to the above-mentioned lower alkyl group substituted by a hydroxy group, such as a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, an I-hydroquinpropyl group, and a 3-hydroxy group. And a propyl group. A hydroxymethyl group and a 2-hydroxyethyl group are preferred.

 The substituent of the compound of the present invention will be described.

 R represents a hydrogen atom or a methyl group.

R ¹ and R ³ is a hydrogen atom, a lower alkyl group, a lower Arukanoiru group, a formyl group, Horumuimi Doyle group, Asetoimi Doyle group, amidino group, the following formula was or prolyl group Roh R ⁶

i) — CO (CH ₂ ) _m N)) COCH

NH ₂

/ (CH ₂ ) _n R ⁷ R ⁸ iii)-COCH iv)-CO (CH ₂ ) n CH

NH ₂

Wherein either R ⁴ and R ⁵ is a hydrogen atom or a lower alkyl group, R ⁴ and R ⁵ together with the adjacent nitrogen atom, form an aziridinyl group, Azechijiniru group, pyrrolidin Le group or piperazinyl group, R ⁶ is but it may also be substituted by hydroxyl, a lower alkyl group or Ariru group, R ⁷ is a carboxyl group, a lower an alkoxy carbonyl group, § amino carbonyl group, an amino group, a lower alkylthio group or Guanijino group, R ⁸ is carboxyl A lower alkoxycarbonyl group or an aminocarbonyl group, m represents an integer of 0 to 3, and n represents an integer of 1 to 3]. R ¹ and R ³ may be the same or different.

Preferred examples of R ¹ or R ³ include a hydrogen atom, a lower alkyl group, a lower alkyl group,

CO (CH ₂ ) _m N (wherein, R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom represent an aziridinyl group, an azetidinyl group, and a piperidinyl group. A m or a piperazinyl group, and m represents an integer of 0 to 3). R ⁴⁰

Preferred examples of R ¹⁰⁰ include a hydrogen atom or one CO (CH ₂ ) _n N (wherein

, R ⁵⁰

R ⁴⁰ and R ^{5Q each} represent a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 3.).

Specific examples of R ¹ , R ³ or R ¹⁰⁰ include a hydrogen atom, a methyl group, an ethyl group, an rt-butynole group, an aminocarbonyl group, an N-methylaminocarbonyl group, an N, N-dimethylaminocarbonyl group , 1-aziridinylcarbonyl group, 1-azetidinylcarbonyl group, 1-pyrrolidinylcarbonyl group, piperazinylcarboninole group, formimidoyl group, acetimidinole group, amidino group, prolyl group, glycyl group, 3 -Aranyl group, 4-aminobutyrinole group, sarkosyl group, N-dimethyldaricyl group, N, N-dimethyl-3-aralanyl group, N-methyl- -aralanyl group, 4- (aminomethyl) butyrinole group, aranyl group, 2 -Aminobutyryl group, 2-aminopainylyl group, seryl group, homoseryl group, 5-hydroxynorleucyl group, 2-phenylglycyl group, 2- (3-hydroxyphenyl Glycyl group, 2- (3,4-dihydroxyphenyl) glycinol group, na-aspartyl group, 4-methoxyspartoyl group, 4-ethoxyaspartoyl group, 4-propoxyspartoyl group, arginyl group , Na-glutamyl group, 5-methoxyglutamoyl group, glutamyl group, methionyl group, lysyl group, yS-aspartyl group, 1-methoxyaspaltoyl group, 1-ethoxyquinaspaltoyl group, 1- Examples include an aminoaspartinole group, an a-glutamyl group, a 1-methoxyglutamoinole group, and a 1-aminoglutamoinole group, and preferred are a hydrogen atom, a methyl group, an acetimidoyl group, and an amidino group. In addition, a substituent derived from a natural amino acid is particularly preferable, and a glycyl group, a ^ -aralanyl group, a sarcosyl group, an N, N-dimethylglycyl group, an alanyl group, a seryl group, (3,4-dihydroxyphenyl) A glycinole group, a -aspartinole group, a 4-methoxyaspaltoyl group, a methionyl group, an arginyl group and the like are preferable.

R ² is a hydrogen atom, a hydroxy lower alkyl group or the following formula

Wherein R ⁹ and R ^1Q represent a hydrogen atom or a lower alkyl group, or R ⁹ and together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperidyl group, and n is 1 to Represents an integer of 3] Means a group. _R9

Preferred examples of R ² include a hydrogen atom or one of CON ′, ¾ιο [wherein R ^g and

R ^1Q has the above-mentioned meaning].

Specific examples of R ² include a hydrogen atom, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, an aminocarbonyl group, an N-methylaminocarboninole group, an N-dimethylaminocarbonyl group, and a 1-azine Lysinylcarbonyl group,

1-azetidinylcarbonyl group, 1-pyrrolidinylcarbonyl group, piperidino carbonyl group, aminocarbonylmethyl group, N-methylaminocarbonylmethyl group, Nv-dimethylaminocarbonylmethyl group, 1 -Aziridinylcarbonylmethyl group, 1-azetidinylcarbonylmethyl group, 1-pyrrolidinylcarbonylmethyl group, piperidinocarbonylmethyl group, 2-aminoaminocarbonylethyl group, 2--( N-methylaminocarbonyl) ethynole group, 2- (N-dimethylaminocarbonyl) ethynole group, 2- (aziridinylcarbonyl) ethyl group, 2- (1-azetidinylcarbonyl) ethyl group, 2- (1- Pyrrolidinylcarbinole) ethynole, 2-piberidinocarbonylethyl, 3-aminocarbonylpropyl, 3- (N-methylaminocarbonyl) propyl, 3- (N, N-dimethyl (Minocarbonyl) propyl group, aminocarbonylcarbonylmethyl group, N-methylaminocarbonyloxymethyl group, N-dimethylaminocarbonyloxymethyl group, 1-aziridinylcarboxyloxymethyl group, 1- Azetidinylcarponinoleoxymethyl group, 1-pyrrolidinylcarbonyloxymethyl group, piperidino-carbonyloxymethyl group,

2-aminoaminocarbonyloxyethyl, 2- (N-methylaminocarbonyl) ethyl, 2- (NN-dimethylaminopropyl) ethyl, 2- (1-aziridinylcarbonyloxy) ethyl Group, 2- (1-azetidinylcarbonyldioxy) ethyl group, 2- (topyrrolidinylcarbonyloxy) ethyl group, 2-piperidinocarbonyloxyshethyl group, 3-amino Carbonyloxypropyl group, 3-

(N-methylaminocarbonyloxy) propyl group, 3- (N, N-dimethylaminopropylonyloxy) propyl group and the like are preferable, and preferable ones are a hydrogen atom, a hydroxymethyl group, an aminocarbonyl group, an I-α Diridinylcarbonyl group, 1-azetidininolecarbonyl group, 1-pyrrolidinylcarbonyl group, piperidinocarbonyl group, aminocarbonylmethyl group, N-methylaminocarbonylmethyl group, N, N- Dimethylaminocarbonylmethyl group, 1-aziridinylcarbonylmethyl group, 1-azetidinylcarbonylmethyl group, 1-pyrrolidinylcarbonylmethyl Group, piperidinocarbonylmethyl group, 2-aminocarbonylethylesole group, 2- (N-methylaminocarbonyl) ethyl group, 2- (N, N-dimethylaminocarbodizole) ethyl group , 2- (1-aziridinylcarbonyl) ethyl group, 2-U-azetidinylcarbonyl) ethyl group, 2- (topyrrolidinylcarbonyl) ethynole group, 2-piperidinocarbonylethyl group, aminoaminocarbonyloxymethyl group, N -Methylamino force A roponyoxymethyl group, a 2-aminocarbonyloxyxethyl group and the like are mentioned, and A means a methylene group or a carbonyl group.

However, among the compounds represented by the general formula [I], compounds in which both RR ² and R ³ are hydrogen atoms and A is a methylene group are not included in the scope of the present invention.

R ¹¹ represents a hydrogen atom or a protecting group for a carboxy group. Examples of the protecting group for the carboxyl group include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and ri-butyl group; for example, 2,2,2-trichloroethyl group, 2,2, Halo-substituted lower alkyl groups such as 2-trifluoroethyl group; lower groups such as acetoxmethyl group, propioninoleoxymethyl group, pivaloneoleoxymethyl group, 1-acetoxethyl group and 1-propionyloxethyl group; Alkyloxyalkyl groups: lower alkoxycarbonyl groups such as 1- (methoxycarbonyloxy) ethyl group, tri (ethoxycarbonyloxy) ethyl group, 1- (isopropoxycarbonyloxy) ethyl group and the like. Xyalkyl group; for example, 2-propenyl group, 2-chloro-2-propenyl group, 3-methoxycarbonyl-2-propininole group, 2-methyl-2-pro- Lower alkenyl groups such as ぺ ninole group, 2-butenyl group and cinnamyl group; for example, benzyl group, P-methoxybenzyl group, 3,4-dimethoxybenzinole group, 0-nitrobenzinole group, -nitrobenzinole group An aralkyl group such as a benzhydrinole group or a bis (/)-methoxyphenyl) methyl group; for example, a (5-) group such as a (5-methylino-2-oxo-1,3-dioxo-1-yl) methyl group; Substituted-2-oxo-1,3-dioxo-1-yl) methinole group; lower alkylsilyl group such as trimethylsilinole group and tert-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxy Examples include a methyl group and the like, and particularly preferred are a 2-propenyl group, a -nitrobenzyl group, a -methoxybenzyl group, a benzhydrinole group, and an iert-butyldimethylsilyl group.

R ¹² represents a hydrogen atom or a protecting group for a hydroxyl group. Examples of the protecting group for the hydroxyl group include lower alkyl groups such as trimethylsilyl group and ieri-butyldimethylsilyl group. A lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydroviranyl group; a benzyl group, a ^ -methoxybenzyl group, a 2,4-dimethoxybenzyl group; An aralkyl group such as a -nitrobenzyl group, a p-nitrobenzyl group or a trityl group; an acyl group such as a formyl group or an acetyl group; an ri-butoxycarbonyl group or a 2--3-ethyloxycarbonyl group; Lower alkoxycarbinole groups such as 2,2,2-trichloroethyloxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, Methoxycarbonyl-2-propenyloxycarbonyl group, 2-methinole-2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnami Alkenyloxycarbonyl groups such as oxycarbonyl group; for example, benzyloxycarbonyl group, P-methoxybenzyloxycarbonyl group, 0-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. And particularly preferred are a 2-propenyloxycarbonyl group, a nitrobenzyloxycarbonyl group, and a tert-butyldimethylsilyl group.

—In the compound represented by the general formula [m], R ¹³ , R ²¹ , R ³¹ , R ⁴¹ , R ⁵¹ , R ⁷¹ , R ^81, and R ″ ° are the aforementioned R ′, R ² , R ³ , RVR ⁵ , Included in the definitions of R ⁷ and R ⁸ respectively are the amino, imino and hydroxyl groups and isoxazozo in R ¹³ , R ²¹ , R ³¹ , R ⁴¹ , R ⁵ⁱ , R ⁷¹ , R ⁸¹ and R ^110. The nitrogen atom on the lysine ring must be protected by reaction conditions and the like.

Examples of the protecting group for the amino or imino group include benzylidene, /)-chlorobenzylidene, -nitrobenzylidene, salicylidene, na-naphthylidene, and 3-naphthylidene; For example, benzyl group,) -methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, nitrobenzyl group, benzhydrisole group, bis (^-methoxyphenolene) methinole group, etc. An aralkyl group; for example, a lower alkanoinole group such as a forminole group, an acetyl group, a propionyl group, a butyrinole group, an oxalyl group, a succinyl group, a bivaloyl group; Halo-substituted lower alkanoyl groups such as o-acetyl group; for example, phenylacetinole group, phenol § Li one Ruarukanoinore groups such Asechinore group; e.g. main preparative alkoxycarbonyl group, E butoxycarbonyl group, a propoxycarbonyl group, Ieri - lower alkoxycarbonyl group such as a blanking butoxycarbonyl group; for example 2- Yodoechi Halo-substituted lower alkoxycarbinole groups such as oxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propeninoleoxy Carbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butenyloxycarbinole group, cinnamyloxycarbonyl group, etc. Alkenyloxycarbonyl group; for example, benzyloxycarbonyl group, 0-nitrobenzyloxycarbonyl group, -nitrobenzyloxycarbonyl group, phenylalkyloxycarbonyl group such as phenyloxycarbonyl group; for example, trimethylsilyl And lower alkylsilyl groups such as tert-butyldimethylsilyl group, and particularly, 2-propenyloxycarbonyl. Group, Iert- butoxycarbonyl group, p - two preparative port base Nji Ruo butoxycarbonyl group and the like.

 —Specific compounds having the general formula [I] include, for example, the following compounds.

 The meanings of the abbreviations in the table are shown below.

 Me: Methinole group

 Bt: ethyl group

 Ac: acetinol group

(Hereinafter the margin)

Compound

RR ² number

1 Me XI XI

ώ Me ri Ό 一 Ux ₂ Url

3 Me H 5—one CH ₂ CH ₂ OH

4 Me H 5— CONH?

 rr

 0 Me XI O J XliV 6 β υ n. <J

 7 VXti R ΓΠ ^ Ι β-CON '

9 Me H 5-CON. 1

10 Me H 5-CON '〉

11 Me H 5— C CONH ₂

12 Me H 5-C¾CONHMe

13 Me H 5- CH ₂ CONMe ₂

14 Me H 5-CH ₂ CON

15 Me H 5-C¾CON '>

Compound

RR ²

34 Me CH = NH H

35 Me CH = NH 5--CH ₂ OH

36 Me CH = NH 5--CONH ₂

37 Me CH = NH 5- -CONHMe

38 Me CH = NH 5--CONMe ₂

39 Me C (= NH) Me H

40 Me C (= NH) Me 5--CH ₂ OH

41 Me C (= NH) Me 5-CONH ₂

42 Me C (= NH) Me 5--CONHMe

43 Me C (= NH) Me 5--CONMe ₂

44 Me C (= NH) Me 5- CH ₂ CONH ₂

45 Me C (= NH) Me 5- CH ₂ CONMe ₂

46 Me C (= NH) Me 5- CH ₂ OCONH ₂

47 Me C (= NH) Me 5- CH ₂ OCO marauder e ₂

48 Me C (= NH) NH ₂ H

49 Me C (= NH) NH 2 5- CH 2 OH

50 Me C (= NH) NH ₂ 5- CONH ₂

51 Me C (= NH) NH 2 5 - CONHMe

52 Me C (= NH) NH ₂ 5-CO painting e ₂

53 Me C (= NH) NH ₂ 5— CH ₂ CONH ₂

54 Me C (= NH) NH 2 5 - CH 2 CONMe 2

55 Me C (= NH) NH ₂ 5- CH ₂ OCONH ₂

56 Me C (= NH) NH 2 5 - C¾_rei_CONMe ₂

57 Me COCH ₂ NH ₂ H

_{58 Me COCH 2 NH 2 5 -} CH 2 OH

Compound

RR ¹ R ² "

84 Me COCH (NH ₂ ) Me H

85 Me C0CH (NH ₂ ) Me 5-C OH

86 Me COCH Master ₂ ) Me 5-CONH ₂

87 Me COCH (NH ₂ ) Me 5-CONHMe

88 Me COCH (NH ₂ ) Me 5 CONCON ₂

89 Me COCH (NH ₂ ) Me 5-CH ₂ CONH ₂

90 Me COCH (skin) Me 5-CH ₂ CONMe ₂

91 Me COCH (NH ₂ ) Me 5-CH ₂ OCON¾

92 Me COCH (NH ₂ ) Me 5-CH ₂ OCONMe ₂

93 Me COCH (NH ₂ ) CH ₂ OH H

94 Me COCH (NH ₂ ) CH ₂ OH 5-C¾OH

95 Me COCH (NH ₂ ) CH ₂ OH 5 CO H ₂

96 Me COCH (NH ₂ ) CH ₂ OH 5 CONHMe

97 Me COCH (NH ₂ ) C¾OH 5-CONMe ₂

98 Me COCH (wind) CH ₂ OH 5 CH ₂ CONH ₂

99 Me COCH (NH ₂ ) CH ₂ OH 5-CH _z CO image e ₂

100 Me COCH (NH ₂ ) CH ₂ OH 5-1 C¾OCONH ₂

101 Me COCH (NH ₂ ) CH ₂ OH 5-C¾OCO bandits e ₂

102 Me COCH (H ₂ ) CH ₂ COOH H

103 Me eOCH (NH ₂ ) CH ₂ COOH 5-1 C¾OH

104 Me COCH (NIL) CH'COOH 5-CONHo

105 Me COCH (NH ₂ ) CH ₂ COOH 5-CONHMe

106 Me COCH (NH ₂ ) CH ₂ COOH 5-C0NMe ₂

107 Me COCH (NH ₂ ) CH ₂ COOH 5 CH ₂ CONH ₂

108 Me COCH (NH ₂ ) CH ₂ COOH 5-CH ₂ CONMe ₂

Compound

RR ¹ R ²

145 H CH = NH 5- CH ₂ 0H

146 H CH = NH 5— CONH ₂

147 H CH = NH 5-CONHMe

148 H CH = NH 5-CO painting e ₂

149 H C (= NH) Me H

'' 150 HC (= NH) Me 5-CH ₂ OH

151 HC (= NH) Me 5-CONH ₂

152 H C (= NH) Me 5-CONHMe

153 HC (= NH) Me 5-CONMe ₂

154 HC (= NH) Me 5-CH ₂ CONH ₂

155 HC (= NH) Me 5-CH ₂ CONMe ₂

156 HC (= NH) Me 5— C¾0C0NH ₂

157 HC (= NH) Me 5-CH ₂ OCONMe ₂

158 HC (= H) NH ₂ H

_{159 HC (= NH) NH 2} 5- CH 2 0H

160 HC (= NH) NH ₂ 5-CONH ₂

_{161 HC (= NH) NH 2} 5- CONHMe

162 HC (= NH) NH ₂ 5-CONMe ₂

163 HC (= NH) H ₂ 5- CH ₂ C0NH ₂

164 HC (= NH) H ₂ 5- CH ₂ CONMe ₂

165 HC (= NH) NH ₂ 5- CH ₂ OCONH ₂

166 HC (= NH) NH ₂ 5-C¾0C0NMe ₂

167 H COCH skin H

168 HC〇CH skin 5-CH ₂ OH

169 H COCH ₂ N¾ 5- CONH ₂

i

Compound RR ¹ R ² number

195 H COCH (NH ₂ ) Me 5 CH ₂ OH

196 H COCH (NH ₂ ) Me 5-CONH ₂

197 H COCH (NH ₂ ) Me 5 CONHMe

198 H COCH (NH ₂ ) Me 5 CONCON ₂

199 H COCH (NH ₂ ) Me 5 CH ₂ CONH ₂

200 H COCH (NH ₂ ) Me 5― C¾C0NMe ₂

201 H COCH (NH ₂ ) Me 5 CH ₂ OCONH ₂

202 H COCH (NH ₂ ) Me 5-CH ₂ 0C0 belly e ₂

203 H C0CH (NH ₂ ) CH ₂ 0H H

204 H COCH (NH ₂ ) CH ₂ OH 5 CH ₂ OH

205 H COCH (NH ₂ ) CH ₂ OH 5-CONH ₂

206 H COCH (wind) C¾OH 5 CONHMe

207 H COCH (NH ₂ ) CH ₂ 0H 5 CONME ₂

208 H COCH (NH ₂ ) CH ₂ OH 5 CH ₂ CONH ₂

209 H COCH (NH ₂ ) C¾OH 5 CH ₂ C0 NMe ₂

210 H COCH (NH ₂ ) C¾OH 5-CH ₂ OCONH ₂

211 H COCH (NH ₂ ) CH _z OH 5 CH ₂ OCONMe ₂

212 H COCH (Country CH ₂ C00H H

_{213 H COCH (NH 2) CH} 2 COOH 5- CH 2 0H

214 H COCH (Country CH ₂ COOH 5-CONH ₂

215 H COCH (NH ₂ ) CH ₂ COOH 5 CONHMe

216 H COCH (NH ₂ ) CH'COOH 5 CONME,

217 H COCH (Country CH ₂ COOH 5-CH ₂ CONH ₂

218 H C0CH (NH ₂ ) CH ₂ C00H 5-CH ₂ CONMe ₂

219 H COCH (NH ₂ ) C¾COOH 5-CH ₂ OCONH ₂

220 H COCH (NH ₂ ) CH ₂ COOH 5-CH ₂ 0C0NMe _z

匕

RR 'R ³ A number

Me then H = JNii then l2J llMe then H ₂

291 Me CH = ΝΉ to 0 teeth Me2 Mr. H ₂ 92 Me and H = J Xl and U and Y ₂ teeth Jtl2iNli2 Mr. Y ₂

293 Me then H = NH then U then JizJN JtlMe then ₂

Z9 Me H H = NH リ₂ i i ^ WMez ez

295 Me CH = NH H H CNH ₂ Q Qti ¾

296 Me CH = NH COCH (NH ₂ ) CH ₂ C〇〇H CH ₂

297 Me and H = NH CUCH CNxi2 teeth JI2 Mr. ϋ · Νϋ ₂ Mr H ₂

Me one UUtitJNJn J one * JI Me ₂ Lrl ₂ zyy Me one iNrl θ Xl one ₁₂ oUU Μβ one ΓΪ) Μβ M6 then J¾ Γ \ 1

oUl Me し (一 Nri) Me JCt ϋ ₂

Me 一 J Me し し ± 1― Ull2 o o U Me Λ = J xl Me ϋ ₂し = L H H ₂

304 Me C (= NH) Me CH〇 CH ₂

305 Me C (= NH) Me Ac CH ₂

306 Me C (= NH) Me CONH ₂ CH ₂

307 Me C (= NH) Me CONHMe CH ₂

Compound

RR ³ A number

344 Me Ac COCH ₂ C¾NH ₂ CH ₂

345 Me Ac COCH ₂ CH2 HMe CH ₂

346 Me Ac COCH ₂ CH ₂ NMe ₂ C¾

347 Me Ac COCH (NH ₂ ) CH ₂ OH CH ₂

348 Me Ac COCH (NH ₂ ) CH2COOH C

349 Me Ac COCH (NH ₂ ) CH ₂ CONH ₂ C¾

350 Me Ac COCH (NH ₂ ) C¾CONMe ₂ CH ₂

351 Me COCHzNHs H CH ₂

352 Me COCH ₂ NH ₂ Me CH ₂

353 Me COCH ₂ NH ₂ Et CH ₂

354 Me C0C¾ H ₂ CH2CH-CH2 CH ₂

355 Me COCH wind CH ₂ OCH CH ₂

356 Me COCH ₂ NH ₂ CHO CH ₂

357 Me COC¾NH ₂ Ac CH ₂

358 Me COCH ₂ NH ₂ CONH ₂ CH ₂

359 Me C0C¾NH ₂ CONHMe CH ₂

360 Me COCH skin CONMe ₂ CH ₂

361 Me COCH ^ z CON ^] CH ₂ Compound

so.a R FT R ³ A number

 Μ6 リ Jrl2iNI 2 CON rig 丄 VL6 U U ¾ J¾i, i2

And ^N J then XI2

Ot> 4 Μβ Γ * Ϊ \ Τ, V

 \ _ iNTll then il2 οοο Μβ then ± 1— iNxl then H2

ODD Μβ then u H2i i 2 then 1 一 1V16 then JTl2 CT Μβ then U ils! J U UU xl2i ll2 LXI2 Ό β then U then ϋ2

Me

Ϋ ϋ ₂

 -> ^ ττ τττ O Λ »ττ · τττ (Ό Me U U H2iNil2 リ し 2 ϋ2ΐ ■ ¾

 121 Μβ リ ± 121 \ \ U il2 _tl2i JrlMe ■ ¾ Ι Δ me リ 2 丄 丄 i2 ■ t zi iYlSs JJTl2

373 Me COCH skin COCH (NH ₂ ) C¾OH CH ₂

374 Me COC¾NH ₂ COCH (NH ₂ ) CH ₂ COOH CH ₂

375 Me GOCH ₂ NH ₂ COCH (NH ₂ ) CH ₂ CONH ₂ C¾

376 Me COCH wind COCH (NH ₂ ) CH ₂ CONMe ₂ CH ₂ Compound

RR 'R ³ A number

377 HHH CH ₂

378 HH Me CH ₂

379 H H Ac C¾

380 HH CONHz CH ₂

381 HH CO Me ₂ CH ₂

382 HH CON ^ NH CH ₂

383 HH CH = NH CH ₂

384 HHC (= NH) Me CH ₂

385 HH COCKtNHz CH ₂

386 HH COCHz Mez CH ₂

387 HH COCH ₂ CH ₂ NHMe CH ₂

388 HH COCH ₂ CH ₂ NMe ₂ CH ₂

389 HH COCH (NH ₂ ) CH ₂ OH CH ₂

390 HH C0CH (NH ₂ ) CH ₂ C00H CH ₂

391 HH COCH (NH ₂ ) CH ₂ CONH ₂ CH ₂

392 HH COCH (NH ₂ ) CH ₂ CONMe ₂ CH ₂ Compound

RR 'R ³ A

* S "one

 393 H Me H C¾

394 H Me Me CH ₂

395 H Me Ac CH ₂

396 H Me CONH ₂ CH ₂

397 H Me CONMe ₂ CH ₂

398 H Me CON ^ NH CH ₂

399 H Me CH = NH CH ₂

400 H Me C (= NH) Me CH ₂

401 H Me COC¾NH ₂ CH ₂

402 H Me COC¾NMe ₂ CH ₂

403 H Me COCHzCHz HMe CH ₂

404 H Me COCH ₂ GH ₂ NMe ₂ CH ₂

405 H Me COCH (NH ₂ ) CH ₂ OH CH ₂

406 H Me COCH (NH ₂ ) CH ₂ COOH CH ₂

407 H Me COCH (NH ₂ ) CH ₂ CONH ₂ CH ₂

408 H Me COCH (NH ₂ ) CH ₂ CONMe ₂ CH ₂

Compound

RR ¹ R ³ A number

441 Me H H CO

442 Me H Me CO

443 Me H Ac CO

444 Me H CONH ₂ CO

445 Me H CONMe ₂ CO

446 Me H CON ^ NH CO

 II

 447 Me H CO

448 Me H C (= NH) Me CO

449 Me H COCHzNHa CO

450 Me H C0C¾NMe ₂ CO

451 Me H COCH ₂ CH ₂ NHMe CO

452 Me H COCH ₂ C¾NMe ₂ CO

453 Me H COCH (NH ₂ ) C¾OH CO

454 Me H C0CH (NH ₂ ) CH ₂ C00H CO

455 Me H COCH (NH ₂ ) C CO jump CO

456 Me H COCH (NH ₂ ) CH ₂ CO painting e ₂ CO

Compound

RR 'R ³ A

473 Me Ac H CO

474 Me Ac Me CO

475 Me Ac Ac CO

476 Me Ac CONH ₂ CO

477 Me Ac CONMe ₂ CO

478 Me Ac CON. NH CO

479 Me Ac CH = NH CO

480 Me Ac C (= NH) Me CO

481 Me Ac COCHJSTHz CO

482 Me Ac COCHzNMea CO

483 Me Ac COCH ₂ CH ₂ NHMe CO

484 Me Ac COCH ₂ C picture e ₂ CO

485 Me Ac COCH (NH ₂ ) C¾OH CO

486 Me Ac COCH (NH ₂ ) CH _z COOH CO

487 Me Ac COCH (NH ₂ ) CH ₂ C0NH ₂ CO

488 Me Ac COCH (NH ₂ ) CH ₂ CONMe _z CO

Compound

¾ & RR 'R ³ A

521 H Me H CO

522 H Me Me CO

523 H Me Ac CO

52 H Me CONH, CO

525 H Me CONMe, CO

526 H Me. CO

527 H Me CH = NH CO

528 H Me C (= NH) Me CO

529 H MeCOCH, NH ₂ CO

530 H Me COCH NMe CO

531 H Me COCH ₂ CH ₂ NHMe CO

532 H Me COCH ₂ C¾Hidden e ₂ CO

533 H Me COCH (NH ₂ ) CH ₂ OH CO

534 H Me COCH (NH ₂ ) CH ₂ COOH CO

535 H Me COCH (NH ₂ ) CH ₂ CONH ₂ CO

536 H Me COCH (NH ₂ ) C¾CONMe ₂ CO

Compound

RR, R ³ A number

 553 H COCH tool H CO

554 H COCH ₂ NH ₂ Me CO

555 H COC¾NH ₂ Ac CO

556 H COCH 2'NH, 2 CONH ₂ CO

557 H COCH2NH2 CO painting e ₂ CO

558 H COCHzNHz CON '^ H CO

559 H COCHzNHz CH = NH CO

560 H COCH ₂ NH ₂ C (= NH) Me CO

561 H COCH2NH2 COCH2NH2 CO

562 H COCH _z NH ₂ COCH ₂ NMe ₂ CO

563 H COCH ₂ NH ₂ COCHaCHzNHMe CO

564 H COCH ₂ NH ₂ COCH ₂ C¾NMe ₂ CO

565 H COCH ₂ NH ₂ COCH (NH ₂ ) CH ₂ OH CO

566 H COCH ₂ NH ₂ COCH (NH ₂ ) CH ₂ COOH CO

567 H COCH tool COCH (NH ₂ ) CH ₂ CONH ₂ CO

568 H COCH ₂ jump COCH (NH ₂ ) CH ₂ CONMe ₂ CO ― S 4――

The compound of the general formula [I] can be converted into a pharmaceutically acceptable non-toxic salt or ester by a conventional method.

— The non-toxic salt of the compound of the general formula [I] means a conventional pharmaceutically acceptable salt, and means a carboxyl group at the 3-position of the carbenem skeleton or an isoxoxazolidine ring or virazolidine at the 2-position side chain. salts can be mentioned at the carboxyl group or Amino group substituted on salifiable nitrogen atom or R \ R ² or R ³ on the ring.

 Examples of the basic addition salt at the carboxyl group include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as potassium salt and magnesium salt; ammonium salt; trimethylamine salt Aliphatic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, genoleamine salt, triethanolamine salt and procaine salt; for example, NV * -dibenzylethylenediamine and the like. Aralkylamine salts; for example, aromatic heterocyclic amide salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammoniumゥ salt, benzyltributylammonium salt Methyl trioctyl ammonium Niu arm salts, quaternary Anmoniumu salts such as tetramethylammonium Petit Ruan monitor © unsalted; e.g. arginine salt, basic amino acid salts such as lysine salts.

Examples of the acid addition salt at the nitrogen atom capable of forming a salt on the isoxazolidine ring or villazolidine ring or at the amino group substituted with R ² or R ³ include, for example, hydrochloride, sulfate, nitrate, phosphate, Inorganic acid salts such as carbonates, bicarbonates and perchlorates; for example, acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbic acid Organic salts such as salts; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; acidic amino acids such as aspartate and glutamate And the like.

The non-toxic ester of the general formula CI] includes a carboxyl group at the 3-position of the carbane skeleton or a drug at the carboxyl group substituted for RR ² or R ³ on the isoxazolidine ring or villazolidine ring at the 2-position. Means the conventional ones permitted above. For example, an ester with an alkanoyloxymethyl group such as an acetooxymethyl group or a bivaloyloxymethyl group, 1- (ethoxycarbonyloxy) C) an ester with an alkoxycarbonyloxyalkyl group such as an ethyl group, an ester with a phthalidyl group, or a .5- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group; -Substituted-2-oxo-1,3-dioxomono-4-ynole) Ester with methyl group.

 Next, a method for producing the compound represented by the general formula [I] of the present invention will be described. The compound of the general formula [I] of the present invention has the general formula

[Wherein, R represents a hydrogen atom or a methyl group, R ¹¹ represents a hydrogen atom or a carboxyl group protecting group, and R ¹² represents a hydrogen atom or a hydroxyl group protecting group] or a reactive derivative thereof. formula

[Wherein, R ²¹ is a hydrogen atom, an optionally protected hydroxy lower alkyl group, or a compound represented by the following formula 9:

vii) — (CH ₂ ) _n 0C0N

(In the formula, R ⁹ and R ¹ represent a hydrogen atom or a lower alkyl group, or R ⁹ and R ′ ° together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinyl group, or pyridyl group. And η represents an integer of 1 to 3), and R "° represents a hydrogen atom, a protecting group for an imino group, a lower alkyl group, a lower alkanoyl group, a formyl group, or a formyl group which may be protected. Doyl group, acetimidinole group, amidino group or prolinole group or the following formula

R ⁴ 'R ⁶ ' i ') — C0 (CH ₂ ) _m N ii,) one COCH

R ⁵ 'NHR' (CH ₂ ) _n R ⁷ 'R 81

1 ') — COCH z iv') — CO (CH ₂ ) _n CH

NHR ' ³ヽ NHR Ϊ3

(Wherein, R ¹³ is a hydrogen atom or a protecting group for an amino or imino group, R ⁴¹ and R ⁵¹ are a hydrogen atom, a lower alkyl group or a protecting group for an amino group or an imino group, or R ⁴¹ and R ⁵¹ are Together with an adjacent nitrogen atom, forms an aziridinyl, azetidinyl, pyrrolidinyl or optionally protected piperazinyl group, and R ⁶¹ is a lower alkyl group optionally substituted by an optionally protected hydroxyl group; Or an aryl group, R ⁷¹ is a carboxyl group which may be protected, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group which may be protected, a lower alkylthio group or a guanidino group which may be protected , R ⁸¹ is a protected or unprotected carboxyl group, a lower Arukokishikarupo Nirumotoma other aminocarbonyl group, m is 0 to 3 The number, n represents a group represented by a) defined above, A is a methylene group or a carbonyl group, B is an oxygen atom or the formula> NR ³ '{wherein, R ³¹ is a hydrogen atom, a protecting group for Imino group, A lower alkyl group, a lower alkanoyl group, a formyl group or an optionally protected formimidoyl group, acetimidoyl group, amidino group or prolyl group or a group represented by the following formula:

R ⁴ no R ⁶ i ') — CO (CH ₂ ) _m N ii') — COCH

R ⁵ , NHR ¹³

(Wherein, R ⁶ , R ¹³ , R ⁴¹ , R ⁵¹ , R ⁵¹ , R ⁷¹ , R ⁸¹ , m and n have the same meanings as described above)}. , R ^11D and R ³¹ are each a hydrogen atom or a protecting group for an imino group, and R ²¹ is a hydrogen atom, and A is a methylene group.) formula

[Wherein R, ⁿ . R ¹² , R ²¹ , R ^u A and B have the above-mentioned meanings]. If necessary, the protecting group of the compound of the general formula [IV] is removed. It can be manufactured in some cases.

 — In the reaction of the compound of the general formula [Π] with the compound of the general formula [m], it is preferable to use the reactive derivative thereof as the compound of the general formula [H]. That is, a compound of the general formula [Π] is reacted with an activating reagent in the presence of a base in an inert organic solvent to obtain a compound of the general formula

[Wherein, R, R ¹¹ and R ¹² have the above-mentioned meanings, and Y represents a leaving group].

 Examples of the inert organic solvent used in the reaction include getyl ether, tetrahydrofuran, dioxane, benzene, tonoleene, chlorobenzene, dimethylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, and acetone. Ethethyl acetate, acetonitrile, N-dimethylformamide, hexamethylphosphoric triamide, and the like, or a mixture of the above solvents, and particularly preferred is acetonitrile and benzene.

 Examples of the base used in the reaction include trimethylamine, triethylamine, -diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, Ν, Ν-dimethylazine, 1,8 Tertiary aliphatic amines such as -diazavicik mouth [5.4.0] pendant-7-ene (DBU), 1,5-diazabicyclo [43.0] non-5-ene (DBN); for example, pyridine, 4- Examples thereof include aromatic amines such as dimethylaminopyridine, purine, lutidine, quinoline, and isoquinoline, and N-diisopropinoleethylamine and triethylamine are particularly preferable.

Examples of the activating reagent used in the reaction include trifluoroacetic anhydride, methanesulfonic anhydride, trifluorosulfonic methanesulfonic anhydride, and P-toluene. Acid anhydrides such as sulfonic anhydride; and acid chlorides such as methanesulfonyl chloride, P-toluenesulfonyl chloride, diphenyl chloride and the like, and diphenylchlorophosphate is particularly preferred.

 —The group 般 in the general formula [Π '] represents a leaving group, for example, trifluoroacetoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, diphenyl And a nonoxyphosphoryloxy group. A diphenyloxyphosphoryloxy group is particularly preferable.

 In the reaction, 1 to 3 bases, preferably 1 to: 0.5 mol of the base and 1 to 1.2 mol of the activating reagent are used per 1 mol of the compound of the general formula [[].

 The reaction is carried out at a temperature of 40 to 50 ° C, preferably at a temperature of 120 to 2 (TC

Complete quantitatively in 3 hours.

 After the completion of the reaction, the reaction is carried out according to a conventional method to quantitatively obtain the reactive derivative [Π ′] of the general formula [I].

 The compound of the general formula [Π ′] can be isolated or reacted without isolation with the compound of the general formula [m]. The reaction is carried out using the above-mentioned inert organic solvent and a base, and 1 to 2 mol of a base, preferably 1 to 1.5 mol, and 1 to 1.5 mol of a compound represented by the general formula [m 1 to 1.2 mol is used in a temperature range of -40 to 50 ° C, preferably -20 to 20 ° C, and is usually quantitatively completed in 0.5 to 3 hours.

 The compound of the general formula [IV] can also be produced in one step from the compound of the general formula [H]. That is, without isolating the reactive derivative of the general formula [Π '] derived from the compound of the general formula [H], the compound of the general formula [m] is reacted in the same reaction system to obtain the compound of the general formula [IV] ] Can be efficiently produced. When the reaction is carried out in one step, 2 to 4 moles, preferably 2.5 to 3.5 moles of a base are used per 1 mole of the conjugate of the general formula [Π].

 After the completion of the reaction, the crude product represented by the general formula [IV] can be subjected to deprotection reaction without purification by performing a usual treatment, but the crude product [IV] is crystallized or purified. Purification by column chromatography using silica gel or the like is preferred.

The compound of the general formula [IV] thus obtained can be subjected to a removal reaction of a protecting group for a hydroxyl group, an amino group, an imino group and a carboxyl group, if necessary, by appropriately combining the removal reaction. The compound of the formula [I] can be obtained. The removal of the protecting group varies depending on the type thereof, but is carried out in accordance with a conventional method, for example, by solvolysis, ionic reduction or hydrogenation.

 In the above general formula [IV], the protecting group for the hydroxyl group and the Z or amino or imino group is, for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a nitrobenzyloxycarbonyl group; When the protecting group for the nore group is, for example, an aralkyl group such as a benzene group, a nitrobenzyl group or a benzhydryl group, a platinum catalyst such as platinum oxide, a platinum wire or platinum black; The protective group can be removed by catalytic hydrogenation using a palladium catalyst such as palladium, norudium monocarbon, and palladium hydroxide monocarbon.

 Examples of the solvent used for the catalytic hydrogenation reaction include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid and the like, or a mixed solvent of these organic solvents with a water or phosphate buffer and the like.

 The reaction is completed in 0.5 to 4 hours in a temperature range of 0 to 50 ° C under a hydrogen gas stream of 1 to 4 atm.

 In the above general formula [IV], when the protecting group for the hydroxyl group and Z or the amino or imino group is, for example, an arinoleoxycarbonyl group and the protecting group for the carboxyl group is, for example, an aryl group, The protective group can be removed by reacting an organic soluble palladium complex catalyst in an inert organic solvent containing a scavenger [McCombie et al., The Journal of Organic Chemistry (J. Org. Chem.), 47, 587-590 (1982)].

 Examples of the solvent used for the reaction include acetone, getyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride, chloroform and the like, or a mixed solvent thereof.

 Examples of the soluble palladium complex include tetrakis (triphenylphosphine) palladium.

 Examples of the scavenger for an aryl group include sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidine, and tributyltin hydride.

The reaction is performed using a catalyst of 0.01 to 0.5 mol and a nucleophile of 1 to 6 mol with respect to 1 mol of the compound of the general formula [IV], in a temperature range of 1 to 50 ° C, preferably 0 to 30 ° C. Temperature It takes about 0.5 to 3 hours.

 In the above general formula [IV], the protecting group for the hydroxyl group or the amino or imino group is 0-nitrobenzyloxycarbonyl group, and the protecting group for the carboxyl group is 0-nitrobenzyl group. In such cases, the protecting group can be removed by a photoreaction [Amit et al., The Journal of Organic Chemistry, Vol. 39, pp. 192-196 (1974). ) See].

 After completion of the reaction for removing the protecting group, the compound of the general formula [I] is subjected to an ordinary treatment method, for example, column chromatography using a silica gel or an adsorption resin, and freeze-drying or crystallizing. The compound can be isolated.

 The protective group for the carboxyl group at the 3-position of the compound of the general formula [IV] may be, for example, a lower alkenyloxy group such as an acetomethyl group or a bivaloyloxymethyl group; for example, a methoxymethyl group, indanyl group, In the case of a group or the like, such an ester is physiologically hydrolyzed in vivo, and thus can be directly administered to a human or animal without removing the protecting group.

 Starting materials represented by the general formula [II] include, for example, when R is a hydrogen atom, the method of Salzmann et al. [J. Am. Chem. Soc. Vol. 102, pp. 6161-6163 (1981)]; when R is a methyl group, see the method of Shih et al. [Heterocycles, Vol. 21, pp. 29-40 (1984)] ] Or a method analogous thereto.

 The compounds of the present invention exhibit strong antibacterial activity against various Gram-positive and Gram-negative bacteria. The antibacterial activity of the compound of the present invention exemplified in the examples as a representative example thereof was determined by the method of Bauer et al. [The American Journal of Clinical Immunol. The measurement was carried out by a disk diffusion test according to Sorodi (Amer. J. Clin. Pathol.), Vol. 45, p. 493 (1966)]. Chenamycin or imidenem was used as an internal standard.

The MIC of the test compound was calculated using the formula reported by Humphrey and Lightbown from the block diameter produced by the disc containing the test compound [The Journal of General Microbiology (J Gan. Microbiol.), Volume 7, 129 (1952)]. Calculate geometrical average of MIC for each bacterial species and calculate activity ratio with chenamycin did.

 The antibacterial efficacy is indicated by the ratio to chenamycin (= 1.0). The higher the number, the stronger the activity.

 The antibacterial activity of the inventive compound was measured using imipenem as a comparative compound. The results are shown in Table 1. Table 1 Antibacterial efficacy '>

 1) Activity ratio of test compound C / Chenamicin C

The compound of the present invention has excellent antibacterial activity against various gram-positive bacteria and gram-negative bacteria, and is useful as an antibacterial agent in the treatment and prevention of human bacterial infections caused by these pathogenic bacteria. Compound. Representative pathogens susceptible to the antibacterial agents of the present invention include, for example, Staphylococcus spp., Enterococcus spp., Escherichia spp., Enterobacter spp. Bacteria such as the genus Tia (Sia tia), the genus Proteus, and the genus Pseudomonas can be mentioned. Particularly, methicillin-resistant phycococcus varus (Methicillin resistant) is mentioned. Staphylococcus aureus) and cheenamycin resistant Pseudomonas aeruginosa.

 The compound of the present invention, which differs depending on each compound, is extremely stable to DHP-1, and has excellent physical stability and solubility in water.

The compound of the present invention is mixed with a solid or liquid excipient carrier known in the art, It can be used in the form of pharmaceutical preparations suitable for parenteral, oral and external administration. The main ones are topical or parenteral (intravenous or intramuscular) administration by injection. Examples of the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions; solid preparations such as tablets, capsules and granules; and external preparations such as ointments and suppositories. These preparations may optionally contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants and the like. Examples of the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn hard powder, magnesium stearate, talc and the like.

 The dosage depends on the patient's condition, body weight, age, sex, dosage form, number of administrations, etc., but usually the preferred daily dose for adults is about 5 to 50 mg Zkg of the active ingredient, and the preferred daily dose for children The dose ranges from about 5 to 25 mg / kg and is preferably administered once or several times a day.

 The compound of the present invention can be optionally treated with cilastatin [(Z) -7- (L-amino-2-carboxhetylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-heptoenoate ] And other DHP-IP [Japanese Patent Application Laid-Open No. 56-81518, European Patent Application No. 28,778, Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 30, p. 1074 (1987 )].

 Examples and Reference Examples

 The present invention will be described more specifically with reference to examples and reference examples, but the present invention is not limited thereto.

Thin layer chromatography of Examples and Reference Examples, Silicagel 60F ₂₄₅ a (Merck) as a plate, had use a UV detector or ninhydrin color development method as the detection method. Wakogel® C-300 (Wako Pure Chemical Industries) was used as the silica gel for the column, and LC-SORB® SP-B-ODS (Chemco) was used as the silica gel for the reverse layer column. The JASCO® 800 series (JASCO) was used as the high-speed liquid mouth chromatography. The NMR spectrum is determined using tetramethylsilane (TMS) as an internal standard when measuring with heavy dimethyl sulfoxide or heavy chloroform solution, and 2,2-dimethyl-2-silapentane when measuring with heavy aqueous solution. -Measured with 5-sulfonate (DSS) using an XL-200 (200 MHz; Varian) or R-40 (90 MHz; daily) spectrometer and showed all <5 values in ppm . The meanings of the abbreviations in NMR measurement are shown below.c

 S sink "let"

 d doublet

 Triblet

 q Committing

 ABq AB Quartet

 dd Dubnore Doublet

 m multiplet

 br broad

 J coupling constant

 Hz hertz

 DMSO-de heavy dimethyl sulfoxide

 CDCla heavy chlorophosolem

D ₂ 〇

The meanings of the abbreviations in the reaction formula are shown below.

 Ac acetyl group

 Boc tert-butyl, toxic canolebonyl group

 Cbz benzyloxycarbonyl group

 Me methyl group

 Ms methanesulfonyl group

 PNB-nitrobenzyl group

 PNZ Nitrobenzyloxycarbonyl group

TBDMS tert-butyldimethylsilinole group

Example 1

 Potassium (5i?, 6S) -6-[() -1-Hydroxyethyl] -2- (isoxazolidin-4-ylthio) -1- 1-hydroxyl- 2-em--3-carboxylate

1)

Aryl--trihydroxyethyl] -2-oxo-tribasic ruvapenam -3-carboxylate (360 mg, 1.42 mmo ^) in acetonitrile (15π ^) solution at 0 ° C in a nitrogen stream, immediately-di- Sopropylethylamine (0.743m, 4.27mmoi) and diphenylchlorophosphite (0.325m, 1.57mmoi) were added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. A solution of N-aryloxycarbonyl-4-mercaptoisoxazolidine (272 mg, 1.44 mmo ^) in acetonitrile (5 m ^) was added dropwise to the reaction mixture at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was added to ethyl acetate (70m), and the organic layer was washed with water, diluted hydrochloric acid, a 5% aqueous solution of sodium hydrogen carbonate and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel chromatography (Wakogel® C-300) and eluted with hexane-ethyl acetate: 1) to give aryl (5R, 6S) -2- (N- Arizoleoxycarbonylisoxazolidine-4-ylthio) -6-[() -1-hydroxyethynole] -carbapene-2-em-3-carboxylate (460 mg, yield: 76.6%) was obtained. Was.

IR KBr) era ¹ : 1770, 1720, 1450, 1380, 1320, 1210

 NMR (CDC) δ: 1.35 (3H, d, J = 6Hz), 3.0-4.36 (10H, m), 4,60-

 4.90 (4H, m), 5.22-5.52 (4H, m), 5.84-6.08 (2H, m)

2)

Arinole (5i?, 6S)-2-(N-aryloxycarbonylisoxazolidine-4- -Yl-)-6- [0?)-1 -Hydroxyethyl]-:! -Carcupan-2-em-3-carboxylate (450 mg, 1.07 mmoi) in acetone (20π ^) solution and ice Triphenylphosphine (84mg, 0.32mmo ^), tributyltin hydride (0.631m ^, 2.34mmo ^) and tetrakis (triphenylphosphine) palladium (23mg, 0.106mmo ^) were added in a nitrogen stream under cooling. Was. The reaction solution was stirred for 30 minutes under ice-cooling, and further for 30 minutes at room temperature. Under ice-cooling, a 0.5 M 2-ethylhexanoic acid-ethyl acetate solution (2.35 mi L175 mmo) was added dropwise to the reaction mixture. After the reaction solution was stirred for 20 minutes under ice cooling, the precipitate was collected by filtration. Water (1 ^) was added to the precipitate, and the insolubles were removed by filtration. The filtrate was subjected to reverse phase column chromatography (LC-SORB® SP-B-ODS), and eluted with water to give the title compound (176 mg, yield: 48.8%).

IR (KBr) cm— ¹ 1760, 1590, 1390

 NMR ΦζΟ) δ 1.36 (3H, dJ = 6Hz)

 HPLC

 Column YMC®-Pack ODS-A, 5, 4.6 ø x 150mm

 Mobile phase 0.01M phosphate buffer (pH6.5) / MeOH (90/10)

 l.OmiZmin

 40 ° C

 Detection: UV 290nm

 Holding time: 3.2min

Example 2

 Potassium (1,5S6S) -6-[(i?)-1-hydroxyethyl] -2- (isoxazolidin-4-ylthio) -1-methinole-1-canolebapene-2-hem-3-carboxylate 1)

Aryl (li?, 5S6S) -6-[(i?)-L-Hydroxyethynole]-:! -Methinole-2-oxo-carpenam-3 -Hydroxylate (31 Omg, 1.16mmo) The reaction was carried out in the same manner as in Example 1-1), and aryl (1 shaku 5S6S) -2- (N-aryloxycarbonylisoxazolidin-4-ylthio) -6-[(R) -trihydroxy Ethil Mech This yielded 268 mg (yield: 52.7%) of 1-hexyl lvapen-2-em-3-carboxylate.

NMR (CDC £ ₃ ) δ: 1.26 (3H, d, J = 7Hz), 1.33 (3H, d, J = 6Hz), 4.66-4.88 (4H, m), 5.14-5.52 (4H, m), 5.97 ( 2H, m)

 2)

 Aryl (1,5S, 6S) -2- (N-aryloxycarbonylisoxazolidine-

4- (4-ylthio) -6-hydroxyethyl] -trimethyl-1-hexyllvapen-2-em-3-carboxylate (268 mg, 0.61 mmoi) was reacted in the same manner as in Example 2), and Diastereomer A (22 mg, yield: 10.2%), diastereomer B (16 mg, yield: 7.4%) and a mixture thereof (1: 1, 34 mg, yield: 15.8%) were obtained.

IR (KBr) cm— ¹ : 1750, 1600, 1390, 1270

NMR (D _z O) δ: 1.36 (3H, d, J = 7Hz), 1.44 (3H, d, J = 6Hz)

 HPLC;

 Column: YMS®-Pack ODS-A, 5μ, 4.6 φ x 150mm

 Mobile phase: 0.01 M phosphate buffer (pH 6.5) ZMeOH (90Z10)

 丄. Om / min

 40 ° C

 Detection: UV 290nm

 Retention time: diastereomer A 5.47min

 Diastereomer B 6.86min

 Example 3

Potassium (5, 6S)-2- (N-glycylisoxazolidin-4-ylthio)-6-JI-hydroxyethynole] -tokanolevapen-2-em-3-carboxylate 1)

Of aryl (5i?, 6S) -6-[(R) -trihydroxyethyl] -2-diphenoxyphosphoryloxy-1--1-l-lubapen-2-em-3-carboxylate (350mg, 0.72mmoi) Acetonitrile (15mi) solution in a nitrogen stream under ice-cooling in a nitrogen stream, NN-diisopropylethylamine (0.14m ^, 0.80mmo, then N- (N-aryloquine carbonyldaricyl) -4-mercaptoiso Oxazolidine (180 mg, 0.73 mmoi) in acetonitrile (5 mO solution was added dropwise. After stirring the reaction solution for 2 hours, ethyl acetate (50 m ^) was added to the reaction solution. The organic layer was washed with water and saturated saline. The residue was subjected to silica gel gel chromatography (Wakogel® C-300) and eluted with ethyl acetate to give aryl (5i?, 6S) -2- [N- (N-aryloxycarbonylglycyl) isoxazolidin-4-ylthio] -6-[() -1-hydroxyethyl] -] 1-Canolenopan-2-em-3-hexylboxylate (313 mg, yield: 90.2%) was obtained.

NMR (CDC £ ₃ ) δ: 1.31 (3H, d, J = 8Hz), 4.38 (2H, d, J = 6Hz), 5.20-5.54 (4H, m), 5.95 (2H, m)

 2)

 Arinole (5i?, 6S)-2-IN- (N-aryloxycarbonylglycinole) isoxazolidine-4-ylthio] -6-[(R)-: i-hydroxyethynole]- -2-hem-3-carboxylate (305 mg, 0.62 mmof) was reacted in the same manner as in Example 2) to give a mixture of diastereomers A and B of the title compound (5: 1, 22 mg, and 1: 1, 2). 35 mg, yield: 22.7%).

IR (KBr) cm— ¹ : 1760, 1660, 1600, 1390

NMR (D ₂ 0) δ: 1.45 (3H, d, J = 6Hz), 3.42 (2H'm), 3.63 (lH.m), 3 ・ 80〜4.10 (3H 、 m)

 HPLC;

 Column: YMC®-Pack ODS-A, 5 μ, 4.6 φ x 150 mm

 Mobile phase: 0.01 M phosphate buffer (pH 6.5) ZMeOH (90 to 10)

 LOmi / min

 40 ° C

 Detection: UV 290nm

 Retention time: diastereomer A 2.46min

 Diastereomer B 2.47min

Example 4

 Potassium (1, 5S, 6S)-2- (N-glycylisoxazolidin-4-ylthio)-6-[() -1-hydroxyethyl] -1-methyl-1-kyrpapene-2- MM-3--Power; Xylate

1)

Aryl (li?, 5S, 6S) -6-[(i?)-: I-hydroxyethyl] -trimethyl-2-oxo-1-canolebabenam-3-carboxylate (300 mg, 1.12 mmo) and The same reaction as in Example 1) was performed using N- (N-peryloxycarbonylglycyl) -4-mercaptoisoxazolidine (300 mg, 1.22 mmo; the compound of Reference Example 8). 5S, 6S) -2- [N- (N-aryloxycarbonyldaricyl) isoxazolidin-4-ylthio] -6-[(R) -1-hydroxyethyl] -1-me Cyl-1-canolebapene-2-em-3-carboxylate (229 mg, yield: 41.2%) was obtained.

IR (KBr) cm " ¹ : 1770, 1710, 1530

NMR (CDC £ ₃ ) δ: 1.26 (3H, d, J = 8Hz), 1.34 (3H, d, J = 7Hz), 5.20- 5.52 (4H, m), 5.96 (2H, m) 2)

The same reaction as in Example 1-2) was performed using the compound (227 mg, 0.46 mmc ^) obtained in the above reaction to obtain the title compound (25 mg, yield: 13.3%).

NMR (D ₂ 0) δ: 1.36 (3H, d, J = 7Ηζ), 1.42 (3H, d, J = 6Hz)

 HPLC;

 Column YMC®-Pack ODS-A, δμ, 4.6Φ 150mm

 Mobile phase 0.01M phosphate buffer (pH6.5) MeOH (80/20) Flow rate l.Omi / min

 Temperature 40 ° C

 Detection UV 290nm

 Retention time 4.35 and 485min

Example 5

 Sodium (U?, 5S, 6S)-2-[(/ ?, 5) -5 -aminocarbonylisoxazolidin-4-ylthio] -6-[(R) -l-hydroxyethyl] -1-methyl- 1-Canolebaben-2-em-3-carboxylate

 1)

A solution of (4 ^, 5) -4-acetylthio-5-aminocarbonyl-N-()-nitrobenzyloxycarbonyl) isoxazolidine (102mg, 0.276mmo) in methanol (4.0m under ice cooling) 2Ν sodium hydroxide (0.28mi, 0.56mmoi) was added and the solution was stirred for 1 hour 6Ν hydrochloric acid (0.10m ^, 0.60m) was added to the reaction solution, and then this solution was poured into water and chlorided The organic layer was dried (MgS), concentrated and the crude (4R, 5 /?)-5-aminocarbinole-4-mercapto- A residue of N- (p-nitrobenzyloxylpropionyl) isoxazolidine was obtained. Nitrobenzyl (lR, 5S, 6S) -2-diphenyloxyphosphoryloxy-6- [0?)-1-hydroxyethyl :! -Trimethyl-tocanolenopan-2-em-3-carboxylate (31 mg, 0.22 mmo ^) and acetonitrile (6.5 mi) were added and dissolved. To this solution, NN-diisopropylethylamine (46, 0.26 mmoi) was added under ice cooling. The reaction solution was warmed to room temperature, stirred overnight, and then diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO _4), and was enrichment. The resulting residue was subjected to silica gel gel column chromatography (Wakogel® C-300, 5% methanol monoacetate) to give -nitrobenzil (15S, 6S) -2-[(4R, 5i? )-5-Aminocarbonyl-N-(-dimethoxybenzoylcarbonyl) isoxazolidine-4-ylthio] -6-[() -1-hydroxyethynole] -1-methyl -1-Kirubapen-2-em-3-carboxylate (67mg, yield: 45%)

NMR CDC δ: 1.28 (3H, d, J = 6Ηζ), 1.34 (3H, d, J = 6Hz), 3.30 (2Η, m), 3.80 to 4.08 (2H, m), 4.30 (3H, m) , 4.88 (lH, d, J = 6Hz), 5.38 (2H, ABq, J _AB = 14Hz, Muri _AB = 48Hz), 7.66 (2H, d, J = 8Hz), 8.24 (2H, d, J = 8Hz) )

 2)

The compound (67 mg, O.lOmmoi) obtained in the above reaction was added to a mixture of tetrahydrofuran (6.7 mO, 0.1 M 3- (monorefolino) propanesulfonic acid buffer (pH 6.5, 6.7 ml) and ethanol (0.67 mi). The catalyst was catalytically reduced for 2 hours at room temperature using 10% palladium on carbon catalyst (70 mg) After filtering off the catalyst, the filtrate was washed with ethyl acetate and then concentrated under reduced pressure to about 3π ^. After subjecting to reverse phase silica gel chromatography (LC-SOLB® SP-B-ODS, 5% methanol), the target fraction was concentrated and lyophilized to give the title compound (33 _mg , yield: 87%) I got

IR (win) cm " ¹ : 3400, 1740, 1690, 1600, 1400 NMR (D _z O) 6: 1.10 (3H, d, J = 6Hz), 1.20 (3H, d, J = 6Hz), 3.40 (2H, m), 3.82 (lH, m), 4.08 (IH.m) , 4.20 (2H, m), 4.38 (IH.m), 4.94 (lH, d, J = 6Hz)

 HPLC;

 Column: YMC®-Pack ODS-A, 5β, 4.6Φ x 150mm

 Mobile phase: 0.01 M phosphate buffer (pH 6.5) ZMeOH (80/20) Flow rate: 0.8 miZmin

 Temperature: 40 ° C

 Detection: UV 290nm

 Holding time: 3.2min

Example 6

 Sodium (5,65) -2-[(/ ?, 5i?)-5- (dimethylaminocarbonyl) isoxazolidine-4-ylthio] -6- [CR) -1-hydroxyethynole] -1 Canoleno 'ぺ -2-M-3-carboxylate

1)

According to the method of Example 5-1), (4i?, 5) -4-acetylthio-5-dimethylaminocarbonyl-N--nitrobenzyloxycarbonyl) isoxazolidine (56 mg, O.Hmmoi ) To form a 4-mercapto compound, and then nitrobenzyl (5R, 6S) -2-diphenyloxyphosphorinoleoxy-6- [0?)-Tohydroxyethynole]-;! -Em-3-carboxylate (65mg, O.llmmoi) reacts to give nitrobenzyl (5,6S) -2- 2-[(4 «, 5i?)-5-dimethylamino carbonyl-N- ( P-Nitrobenzyloxy carbonyl) isosazozolidine-4-ylthio] -6- [0?)-1-hydroxyethynole] -1-canolebapene-2-em-3-carboxylate (63 mg, yield: 82%) was obtained.

NMR (CDCh) δ: 1.38 (3H, d, J = 6Hz), 2.92 (3H, s), 3.14 (3H, s), 3.28 (3H, m), 4.00-4.40 (4H, m), 5.02 (lH , D, J = 6 Hz), 5.38 (2H, ABq, J _AB = 14 Hz, A _AB = 46 Hz), 7.64 (2H, d, J = 8 Hz), 8.24 (2H, d, J = 8Hz)

 )

Using the compound (63 mg, 0.092 mmo ^) obtained in the above reaction, the title compound (16 mg, yield: 4%) was obtained in the same manner as in Example 5-2).

IR (KBr) cm— ¹ : 3400, 1740, 1640, 1600, 1400

NMR ( ₂₀ ) δ: 1.20 (3H, d, J = 6Hz), 2.86 (3H, s), 3.00 (3H, s), 3.08 (2H, m), 3.30 (lH, m), 4.05-4.45 ( 4H, m), 5.22 (IH.dJ = 6Hz) HPLC;

 Column: YMC®-Pack ODS-A, 5μ, 4.6Φ x 150mm

 Mobile phase: 0.01M phosphate buffer (pH 6.5) ZMeOH (90,10)

 : L.OmiZmin

 Detection: UV 290nm

 Holding time: 7.1min

Example 7

 Potassium— (5i?, 6S) -6-hydroxyethylenole] -2- (2-methyl-3-oxopyrazolidine-4-ylthio) -1-carbazin-2-em-3-force Ruboxilat 1)

Aryl (3S, 5R, 6S) -6-[(i?)-Trihydroxyethyl] -2-oxo-Toluene-lubanum-3-carboxylate (355mg, 1.40mmoi) solution in acetonitrile (15 £) Then, N, N-diisopropylethylamine (0.733 rn ^ 4.21mmo, then diphenylchlorophosphate (0.32mi, 1.54mmoi)) was added dropwise at 0 ° C in a nitrogen stream at 0 ° C. And stirred for 1.5 hours. A solution of riloxycarbonyl-4-mercapto-2-methyl-3-oxovirazolidine (305 mg, 1.42 mmol) in acetonitrile (5 m) was added dropwise at 0 ° C. After stirring at 0 ° C. for 1 hour, The reaction solution was poured into ethyl acetate (70 mi) The organic layer was washed with water, dilute hydrochloric acid and 5% aqueous sodium hydrogen carbonate in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By chromatography on a column (Wakogel® C-300) and elution with hexane-ethyl acetate (1: 2), aryl (5S 6S 2- (1-aryloxycarbonyl-2-methyl) was obtained. -3-Oxovirazolidine-4-ylthio) -6-[(R) -l-hydroxyethyl] -1-canoleva pen-2-em-3-carboxylate (460 mg, yield: 72.9% ).

 NMR (CDC) δ: 1.46 (3H, d, J = 7 Hz), 3.29 (lH, s), 4.73 (4H, m), 5.10 to 5.55 (4H, m), 5.96 (2H, m)

 2)

 To a solution of the compound obtained in the previous step (450 mg, l. Ommoi) in acetone (20 m> solution, under ice-cooling and in a stream of nitrogen), trifurnylphosphine (79 mg, 0.30 mmo ^), tributyltin hydride (0.592 n ^) , 2.2 ramof) and tetrakis (triphenylphosphine) palladium (116 mg, O.lmmo) were added, and the solution was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. Potassium xanate (2.2m>) was added, the solution was stirred at the same temperature for 20 minutes, and the precipitate was collected by filtration, water (15π ^) was added to the precipitate, and the insoluble was removed by filtration. The filtrate is subjected to reversed phase column chromatography (LC-SORB® SP-B-ODS), eluted with water, and the fraction containing the target compound is lyophilized to give diastereomers A and B of the title compound. 206 mg, 56.6%).

IR (KBr) cm— ¹ : 1760, 1680, 1590, 1390

_{NMR (.D 2 0) δ:} 1.35 (3H, d, J = 7Hz), 3.12 (3H, s), 3.96 (lH.m) HPLC;

 Column: YMC®-Pack ODS-A, 5μ, 4.60 x 150mm

Mobile phase: 0.01 M phosphate buffer (pH 6.5) / MeOH (90/10) Flow speed: LOm / min

 Temperature: at 40

 Detection: UV290mm

 Retention time: 2.5min and 2.95min (1: 1)

Example 8

 Sodium (5R, 6S) -6-[(i?)-L-hydroquinethyl] -2- (trimethylpyrazolidine-4-ylthio) -1-carba-2-ene-3-carboxylate

1)

To a solution of 4-acetylthio-1-methyl-2- (p-nitrobenzyloxycarbonyl) villazolidine (338 mg, l.Ommo reference example 20-6) in methanol (6mi) was added 2N hydroxide solution. An aqueous solution of sodium (0.36n ^, 0.72mmoi) was added, and the solution was stirred at room temperature for 1 hour. After adding 6N hydrochloric acid (0. \ 2m £, 0.72mmo) to the reaction solution, the reaction solution was poured into water and extracted with methylene chloride. The organic layer was dried (MgSO _4), and concentrated in vacuo to 4-mercapto - was obtained Nitoroben Jill O alkoxycarbonyl) Birazorijin residue - 1-methyl-2.

2)

Nitrobenzyl (3,5i?, 6S) -6-[(R) -1-Hydroquinethyl] -2-oxo-1-canolebabenam-3-carboxylate (248mg, OJlmmoi) acetonitrile (5mi ) At 0 ° C, N, N-diisopropylethylamine (0.15m ^, 0.85mmoi) and diphenyl chloride phosphate (0.15mi, OJlmmoi) were added to the solution. After the reaction solution was stirred at the same temperature for 1 hour, diisopropylethylamine (0.15 mL, 0.85 ℃) and 4-mercapto-1-methyl-2-()- Nitrobenzyloxycarbonyl) A solution of the residue of pyrazolidine in acetonitrile (l.Om) was added to the reaction solution. The reaction solution was warmed to room temperature and further stirred for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried (MgSO ₄₎ and concentrated in vacuo. The obtained residue was subjected to silica gel ram chromatography (Wakogel® C-300, 30 ml £, 5% methanol-ethynole acetate) to give -Nitrobenzil (5i?, 6S) -6-[( i?)-l-Hydroxy shetinole] -2- [trimethyl-2-()-nitrobenzyloxycarbinole) virazolidin-4-ylthio] -1--1-canolebapene-2-em-3-carboxy (250 mg, yield: 40%) was obtained.

3)

 To a solution of the compound obtained in the above reaction (250 mg, 0.40 mmo of tetrahydrofuran (4.0 mi) and 0.1 M sodium 3- (morpholino) propanesulfonate buffer (2.0 mi) was added 10% palladium-carbon catalyst (100 m The solution was stirred for 1 hour under a hydrogen atmosphere The catalyst was filtered off and the resulting filtrate was washed with getyl ether and then with methylene chloride The aqueous layer was concentrated under reduced pressure at 10-20 ° C. The insoluble matter was separated by filtration, and the filtrate was subjected to reversed-phase column chromatography (LC-SORB® SP-B-ODS, Chemco, 50 mL, 10% methanol aqueous solution) to collect fractions containing the target substance. The concentrate was concentrated under reduced pressure, and then freeze-dried to obtain a powder of the title compound (20 mg, yield from 4-acetyl-l-methyl-2-(>-nitrobenzyloquinol luponyl) villazolidine: 6.4%). Was.

IR (KBr) cm— ¹ : 3400, 1760, 1620, 1400

NMR (D ₂ 0) 6: 1.22 (3H, d, J = 6Hz), 2.52 (3H, s), 2.7-3.5 (6H, m), 3.90 (2H, m), 4.18 (2H, m)

Example 9

Sodium (5i?, 6S) -2- (l-Acetylpyrazolidine-4-ylthio) -6-[()-1-hydroxyethynole] -1-caproluben-2-em-3- Carboxylates 1)

In the same manner as in Example 8-1), 1-acetyl-4-acetylthio-2-(-nitrobenzyloxycarbonyl) virazolidine (623 mg, the residue obtained from Reference Example 21-3) was used for 1- Acetinole-4-mercapto-2- (p-nitrobenzyloquincarbonyl) virazolidine residue was obtained.

2)

Nitrobenzyl (3i?, 5i, 6S) -6-[(R) -trihydroxyxetizole] -2-oxo-1-carbazin-3-carboxylate (473 mg) in the same manner as in Example 8-2). The reaction mixture was reacted with 1-acetyl-4-mercapto-2- (P-nitrobenzyloxycarbonyl) pyrazolidine obtained in the above reaction to obtain a nitrophenol. Andyl (5i?, 6S) -2- [Tracetyl-2- (ρ-ditropenedinoleoxycarbonyl) virazolidine-4-ylthio] -6-[(R) -l-Hydroxyshetinole] -2-Em-3-carboxylate (416 mg, yield: 47%) was obtained.

NMR (CDCi ₃ ) δ: 1.36 (3H, d, J = 8Ηζ), 2.08 (3H, s)

 3)

In the same manner as in Example 8-3), a powder (21 mg, yield: 9.8%) of the title compound was obtained using the compound (410 _mg , 0.626 mmoi) obtained in the above reaction. NMR (D ₂₀ ) δ: 1.20 (3H, d, J = 8Hz), 2.12 (3H, s)

Example 10

 Sodium (5i?, 6S) -2- (1-acetinol-2-glycylbirazolidine-4-ylthio) -6- [1-droxityl]-1-potinolepan-2-em- 3-carboxylate

 1)

1 PNZ Obtained with triacetyl-4-acetylthio-2- [N-(-nitrobenzyloxycarbonyl) glycyl] pyrazolidine (430 mg, l.Olmmoi, Reference Example 22-5) in the same manner as in Example 8-1). The obtained compound was used to obtain a residue of triacetyl-2- [N- (p-nitrobenzinoleoxycarbonyl) daricyl] -4-mercaptovirazolidine.

2)

1 PNZ Nitrobenzyl (3R, 5R, 6S) -6-[(R)-:!-Hydroxyshetyl] -2-oxo-1-canolebabenam-3-carboxy in the same manner as in Example 8-2) After the enol phosphatate was prepared by using a salt (317 mg, 0.91 mmai), acetinol-2--2- [N-(/>-nitrobenzoyloxycarbonyl) glycinole] -4-mercapto obtained in the above reaction was obtained. Reaction of virazolidine gives -nitrobenzyl (5R, 6S) -2- [l-acetyl-2- [N-nitrobenzyloxycarbonyl) glycinole] pyrazolidine-4-ylthio]-6-[ 0?)-1 -Hydroxyethynole]-:! -Hydrenolen-2-ene-3-carboxylate (305 mg, yield: 47%) was obtained.

NMR (CDCi ₃ ) δ: 1.36 (3H, d, J = 8Ηζ), 2.18 and 2.19 (3Η, each s), 5.22 (2H, m), 5.22-5.58 (2H, m), 7.50 to 7.70 ( 4H, m), 8.24 (4H, d, J = 8Hz) 3)

 In the same manner as in Example 8-3), the title compound (21 mg, yield: 12.5%) was obtained using the compound (300 mg, 0.42 mmoi) obtained in the above reaction.

IR (KBr) cm- ¹ : 3400, 1760, 1640, 1400

NMR (D ₂₀ ) δ: 1.24 (3H, d, J = 8Hz)

Example 11

 Sodium (5i?, 6S) -2- (l-dimethylaminocarbonylpyrazolidine-4-ylthio)-6- [(R)-1 -hydroxyethyl]-1 -canolevapen-2-em-3- Forced xylate

 1)

In the same manner as in Example 8-1), 4-acetylthio-1-dimethylaminocarbonyl-2- (P-ditrobenzyloxycarbonyl) pyrazolidine (0.78 & about 0.53 bandages 0 Reference Example 23-3) Using the resulting residue), a residue of dimethylaminocarbonyl-4-mercapto-2- (P-nitrobenzyloxycarbonyl) virazolidine was obtained.

2)

In the same manner as in Example 8-2), i> -nitrobenzyl (3R, 5R, 6S) -6-hydroxyquinethyl] -2-oxo-1-carbazin-3-carboxylate (280 mg, 0.80 mmoi) to form an enol phosphatate, and then react with 1-dimethylaminocarbonyl-4-mercapto-2-(^-ditoxylbenzyloxycarbonyl) pyrazolidine obtained in the above reaction to give p- Trobenzyl (5i?, 6S) -2-Π-dimethylaminocarboninole-2- (P-dimethoxybenzyloxycarbonyl) pyrazolidine-4-ylthio] -6-[(R) -l [-Hydroxyethynole]]-1-l-lubapen-2-em-3-carboxylate (276 mg, yield: 50%) was obtained.

NMR (CDC £ ₃ ) δ: 1.36 (3H, d, J = 6Ηζ), 3.00 (6H, s), 3.20 (3H, m), 3.60-4.50 (7H, m), 5.28 (2H, br s), 5.40 (2H, ABq, J _AB = 14Hz, A _AB = 46HZ), 7.54 (2H, d, J = 8Hz), 7.66 (2H, d, J = 8Hz), 8.24 (4H, d, J = 8Hz)

 3)

 In the same manner as in Example 8-3), a powder (24 mg, yield: 15%) of the title compound was obtained using the compound (276 mg, 0.40 mmol) obtained in the above reaction.

IR (KBr) cm " ¹ : 3400, 1760, 1620, 1500, 1440, 1400

 NMR (DzO) δ: 120 (3H, d, J = 6Hz), 2.84 (6H, s), 3.18 (6H, m), 3.94 (2H, m), 4.16 (2H, m)

Reference example 1

N-aryloxycarboninole-4-hydroxyisoxazolidine

4-Hydroquinisoxazolidine hydrochloride [1.5 g, 11.95 mmo ^; Amraiky et al., The Journal of Organic Chemistry. Org. Chem.), Vol. 47, pp. 517-523 (1982 Triethylamine (4.4m, 31.6mmoi) and Acrylcroform (1.75m ^, 16.5mmoi) were added dropwise to a suspension of methylene chloride (30m) prepared by the above method. Reaction solution After stirring at the temperature for 2 hours, methylene chloride (100 m 2) was added to the reaction solution, and the organic layer was washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel gel chromatography (Wakogel® C-300) and eluted with 2% methanol-chloroform to give the title compound (1.13 g, yield: 54.6%). .

 NMR (CDC) δ: 3.80 (2H, m), 4.00 (2H, m), 4.70 (2H, m), 4.83h H, m), 5.30 (lH, dd, J = 10,1Hz), 5.40 (lH , dd, J = 16,1Hz), 5.96h H, m)

Reference example 2

 N-Liloxycarbinyl-4-methanesulfonyloxysoxazolidin

To a solution of N-aryloxycarbonyl-4-hydroxyisoxazolidine (l.lg, 6.36 mmoi) in dry tetrahydrofuran (50 m) was added ice-cooled triethylamine (1.03 mi, 7.4 acetonitrile and methanesulfonyl chloride). (0.566 mi, 7.31 mmo) The reaction solution was stirred for 30 minutes, ethyl acetate (50m ^) was added to the reaction solution, and the organic layer was washed with water and saturated saline in this order. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.6 g, yield: 100).

IR (KBr) cm— ¹ : 1730, 1360, 1170, 1120, 1080

 NMR (CDC £ z) δ: 3.10 (3H, s), 4.02 (2H, m), 4.11 (lH, dd, J = 10,5Hz), 4.26 (lH, dd, J = 10,2Hz), 4.71 ( 2H, br d, J = 7Hz), 5.32 (lH.br d, J = 10Hz), 5.40 (lH.br d, J = 18Hz), 5.57 (lH, m), 5.98 (lH, m) Reference example 3

 4-acetylthio-N-aryloxycarbonylisoxazolidine

MsO ~ (Iichi AcS

To a solution of N-perinoleoxycarbinole-4-methanesulfonyloxyi-soxazolidin (700 mg, 2.79 mmoi) in N-dimethylformamide (20 m), add sodium iodide (400 mg, 2.6 mmo). ^) And potassium thioacetate (480 mg, 4.2 mmc ^) were added. After the reaction solution was stirred at 60 to 70 ° C for 6 hours in a nitrogen stream, ethyl acetate (lOOmi) was added to the reaction solution, and the organic layer was washed with water (3 times) and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel® C-300) and eluted with 10% ethyl acetate-hexane to give the title compound (333 mg, yield:

51.7%).

IR (KBr) cm " ¹ : 1740, 1700, 1320, 1200, 1120

NMR (CDC £ ₃ ) δ: 2.36 (3H, s), 3.63 (lH, dd, J = 12,4Hz), 3.82 (lH.q, J = 4Hz), 4.06-4.40 (3H, m), 4.69 ( 2H, br d, J = 6Hz), 5.30 (1H, d, J = 12Hz), 5.37 (lH.dJ = 20Hz), 5.97 (lH, m)

Reference example 4

 N-ylyloxycarbonyl-4-mercaptoisoxazolidine

To a solution of 4-acetylthio-N-aryloxycarbonylisoxazolidine (333 mg, 1.44 mmol) in methanol (20 m) was added a 1N aqueous sodium hydroxide solution (1.44 mi) in a nitrogen stream under ice-cooling. It was dropped. After the reaction solution was stirred at the same temperature for 15 minutes, 1N hydrochloric acid (1.59 mi) was added dropwise. The reaction solution was concentrated under reduced pressure, and ethyl acetate (70 mi) was added to the residue. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (272 mg, yield: 99.8%).

Reference example 5

N- (N-aryloxycarbonylglycyl) -4-hydroxyisoxazolidin

In a stream of nitrogen, carbonyldiimidazole (2.35 g, 14.4 mmol of N, N-dimethylformamide (25m>) was added to a solution of N-yl-linoleoxycarbonylglycine (2.0 g, 12.6 mmol) in tetrahydrofuran (25 mi). The solution was added dropwise at room temperature, and the solution was stirred at the same temperature for 1 hour.To the reaction solution was added triditylamine (1.74 mi, 12.5 mmo and 4-hydroxyisoxazolidine hydrochloride (l.Og, 7.97 mmo)). The reaction solution was stirred at room temperature for 3 hours The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (200 mi) The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The residue was subjected to silica gel chromatography (Wakogel® C-300) and eluted with 3% methanol-chloroform to give the title compound (1.0 g, yield: 54.6 g). %).

 NMR (CDC & z) δ: 3.88-4.08 (4H, m), 4.27 (2H, d, J = 6Hz), 4.60 (2H, d, J = 6Hz), 4.84 (lH, m), 5.30 (2H, m) , 5.94 (lH.m) Reference example 6

 N- (N-aryloxycarbonyldaricyl) -4-methanesulfonyloxyisoxazolidine O— (I, »-sO— I-

\-— CO eight NHCOO ^ -Ν— CO eight NHCOO

Triethylamine (0.30m ^, 2.16mmoi) was added to a solution of N- (N-aryloxycarbonylglycyl) -4-hydroxyisoxazolidinine (450mg, 1.96mmoi) in tetrahydrofuran (10mi) under ice cooling. ) And methanesulfonyl chloride (0.18m ^, 2.32mmo) were added dropwise.After stirring this solution for 30 minutes, ethyl acetate (50mi) was added to the reaction solution, and the organic layer was washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (560 mg, yield: 92.9%).

NMR (CDC £ ₃ ) 6: 3.12 (3H, s), 3.94 to 4.22 (5H, m), 4.35 (lH, d, J

10Hz), 4.60 (2H, d, J = 6Hz), 5.30 (2H, m), 5.60 (lH.m), 5.94 (H, m)

Reference Example 7

 4-Acetylthio-N- (N-aryloxycarbonylglycyl) isoxazolidin sO- AcS— <I

 -Ν—CO8 NHCOO ^ .N-COANHCOO

N_ (N-aryloxycarbonylglycyl) -4-methyl sulfonyloxyisoxazolidine (560 mg, 1.82 mmol of immediate-dimethylformamide (10 mi) solution in a nitrogen stream in a stream of nitrogen (136 mg, 0.91 mmoi) and potassium thioacetate (310 mg, 2.71 mmoi) were added, and this mixed solution was stirred for 5 hours at 60 ° C. Ethyl acetate (50 mi) was added to the reaction solution, and the organic layer was washed with water ( The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was subjected to silica gel gel chromatography (Wakogel® C-300) to give 30% Elution with ethyl acetate-hexane gave the title compound (226 mg, yield: 43.2%).

NMR (CDC £ ₃ ) δ: 2.38 (3H, s), 3.66 (lH, m), 3.89 (lH.m), 4.14 (3H, m), 4.36 (2H, m), 4.60 (2H, br d, J = 6Hz), 5.30 (2H, m), 5.95 (lH, m)

Reference Example 8

 N- (N-aryloxycarbonylglycyl) -4-mercaptoisoxazolidin

AcS- HS-

-Ν-CO8 NHCOO ^ ^ CO ANHCOO ^^

To a solution of 4-acetylthio-N- (N-aryloxycarbonyldaricyl) isoxazolidinine (226 mg, 0.785 mmoi) in methanol (lOmi) under a nitrogen stream under ice-cooling was added a 1-sodium hydroxide solution (0.785 m The reaction solution was stirred for 15 minutes, 1-hydrochloric acid (0.865m) was added dropwise, the reaction solution was concentrated under reduced pressure, and ethyl acetate (50π ^) was added to the residue. Wash with saline solution After drying over sodium sulfate and concentrating under reduced pressure, the title compound (180 mg, yield: 93.2%) was obtained.

Reference Example 9

 Methyl 3,4-0-isopropylidene-2- 0-phthalimido-L-erythreonate

Methyl 3,4-0-isopropylidene-L-threonate [2.0 g, 10.5 strokes o; synthesized by The Journal Off, 'Organic Chem., 50, 3462 (1982)], Trifle Enethylphosphine (3.31 g, 12.6 mmo ^) and N-hydroxyphthalimid (2.05 g, 12.5 nuno) in tetrahydrofuran solution (40.0 mi) were added under ice-cooling to getyl azodicarboxylate (2.0 mi, 12.7 mm). A tetrahydrofuran solution (10 mi) was added dropwise. The reaction was warmed to room temperature, stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate, separated by filtration, and the filtrate was again concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (Wakogel® C-300, ethyl ethyl hexane).

1: 5), and the residue obtained from the fraction containing the desired product was recrystallized from getyl ether-hexane to give the title compound as crystals (2.16 g, yield: 61%).

[W 27.9 ° (C 1.00, CHCi ₃ )

IR (KBr) cm— ¹ : 3450, 3000, 1800, 1730, 1610

NMR (CBC £ ₃ ) δ: 1.38 (3H, s), 1.42 (3H, s), 3.88 (3H, s), 4.26 (lH, m), 4.40-4.62 (3H, m), 7.84 (4H, m) )

 Reference Example 10

Methyl 3,4--0-isopropylidene-2--0--nitrobenzyloxycarbonylylamino) -L-erythreonate COO e

ONH-PNZ

 1) Hydrazine monohydrate (3.15m) was added to a solution of methyl 3,4-0-isopropylidene-2-0-phthalimido-L-erythreonate (17.5 & 52.2mmoi) in methylene chloride (175mi) under ice cooling. £, 62.6mmo ^) methanol solution (175mi) was added and the solution was stirred for 30 minutes. The precipitated insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue of methyl 3,4-0-isopropylidene-2-0-amino-L-erythreonate.

2) To a solution of the compound obtained in the above reaction in a formaldehyde (175 mi) solution, 4,6-dimethyl-2- (4-nitropentinoleoxycarbonylthio) pyrimidine (15.0 g, 47.0 mmoi) was added. The solution was heated at reflux for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the precipitated insoluble material was separated by filtration and washed with ethyl acetate. The filtrate was washed with 10% aqueous Natoriumu solution, dried (MgSO _4), and concentrated. The obtained residue was subjected to silica gel column chromatography (Wakogel® C-300, ethyl acetate-hexane 1: 3) to give the title compound as an oil (16.5 & yield: 82%).

NMR (CDC £ ₃ ) 6: 1.30 (3H, s), 1.42 (3H, s), 3.82 (3H, s), 4.12 (2H, m), 4.38 (lH.m), 4.46 (lH.dJ = 4Hz ), 5.26 (2H, s), 7.52 (2H, d, J = 8Hz), 8.22 (2H, d, J = 8Hz)

Reference Example 11

 Methyl 2-0-(-nitrobenzyloxycarbonylamino) -4-0-(-toluenesulfonyl) -L-erythreonate

OH

 TsO. COOMe

ONH-PNZ 1) A solution of methyl 3,4-Oisopropylidene-2-nitrobenzyloxycarbonylbonylamino) -L-erythreonate (9.6g, 24.9mmo) in metasodium solution (192mi) at room temperature with 6N sulfuric acid (8.3mi, 49.8mmoi), and the solution was added to 3.5 Stirred for hours.

The reaction was diluted with methylene chloride (500 meters>, dried with saturated aqueous sodium bicarbonate solution (LooM) was washed狰organic layer (MgSO _4), and concentrated under reduced pressure, methyl 2-0- (ί> -. Two DOO port Ben A crude powder of dinoleoxycarbonylamino) -L-erythreonate (7.9 g) was obtained 2) Toluenesulfonyl chloride was added to a solution of the compound (7.9 g) obtained in the above reaction in pyridine (70 mi) under ice-cooling. The reaction solution was returned to room temperature, stirred for 1 hour, and pyridine was distilled off under reduced pressure.The obtained residue was poured into saturated sodium bicarbonate water and extracted with ethyl acetate. and then drying the organic layer (MgS_〇 _4), and enrichment residue by silica force gel strength column chromatography (Wakogel® C- 300, hexane 1 to acetic acid Echiru: 1). to give the target compound (9.5 g , Yield: 85%).

NR (CDCi ₃ ) δ: 3.80 (3H, s), 4.10 (2H, m), 4.30 (lH, m), 4.50 (1H, d, J = 4Hz), 5.28 (2H, s), 7.36 (2H, d, J = 8Hz), 7.52 (2H, d, J = 8Hz), 7.80 (2H, d, J = 8Hz), 8.22 (2H, d, J = 8Hz) '

Reference Example 12

 (4S, 5)-5-metre-force ^ / po ^^-N_-(-Nitrobenzyloquinone-ruboninole)-4-(^ Trahydropyran- 2-inole _) isoxoxazo Lysine

Methyl 2-O-ip- (2-hydroxybenzylamino) -4--0-(-toluenesulfonyl) -L-erythreonate (9.5g, 19mmo) 4-Dihydro-2H-pyran (22.3m, 0.24mo ^) and pyridinium-toluenesulfonate (7.3g, 29mm) were added After stirring at room temperature for 6 hours, the reaction solution was poured into saturated sodium bicarbonate water. and extracted with methylene chloride. the organic layer drying (MgSO ₄₎ and concentrated under reduced pressure. dissolve the resulting residue in methylene chloride (190mi), under ice-cooling 1,8 Jiazabishikuro [5.4.0] After stirring for 3 hours, the reaction solution was washed with 0.5Ν hydrochloric acid (50 mi) and then with saturated aqueous sodium hydrogen carbonate (50 m>). The organic layer was dried. (MgSO _4), and vacuum Shimono by condensation, the residue silica force gel strength column chromatography (Wakogel® C- 300, vinegar The residue was subjected to acid ethyl hexane 1: 5) to give the title compound (5.43 yield: 69.4%).

NMR (CDC £ ₃ ) δ: 1.330 to 2.00 (6H, m), 3.40 to 4.10 (4H, m), 3.78 (3H, s), 4.70 to 4.90 (2H, m), 4.76 (lH, d, J = 2Hz), 5.34 (2H, m), 7.62 (2H, d, J = 8Hz), 8.28 (2H, d, J = 8Hz)

Reference Example 13

 (4S, 5i?)-4-bdroxy-5-hydroxymethyl-N-&-nitrobenzoyloxyl-ponyl) _isoxazolidine

(S, 5i?)-5-Methoxycarbonyl-N- (i> -nitrobenzyloxycarbonyl)-4- (tetrahydrovirane-2-inole) isoxazolidine (9.5g, 23mmoi) Lithium chloride (1.433 mmo, sodium borohydride (1.3 g, 33 mma) and ethanol (190 mi) were added to a solution of the above in tetrahydrofuran (95 m ^). mi) was added dropwise. the reaction solution was poured into saturated sodium bicarbonate water, and extracted with acetic Echiru. the organic layer was dried (MgSO _4), concentrated and the residue was dissolved in methanol (160 m). pyridinium © to this solution After stirring for 4 hours, the reaction mixture was allowed to cool, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. washed. the organic layer was dried (MgSO _4), di Echirueteru was concentrated. the residue Methylene chloride _(1: 1) with washing to give the title compound (2.44 g, yield: 35%). To give a crystalline powder yielded more than two TsugiAkira (0.97 g) mother liquor.

NMR (CDClz) δ: 3.66 (3H, m), 3.86 (lH, dd, J = 2,12Hz), 4.10 (1H, dt, J = 2,4Hz), 4.58 (lH, m), 5.32 (2H ₍ s), 7.58 (2H, d, J = 8Hz), 8.26 (2H, d, J = 8Hz)

Reference Example 14

(4S, 5i?)-5- (7 -butyldimethylsiloxy)-4-hydroxy -N- (-two-way benzyloquincarbonyl) isoxazolidine HO

 Ό-TBDMS PNZ

(4S, 5i?)-4-Hydroxy-5-hydroxymethyl-N-0> -nitrobenzyloxycarbinole) isoxazolidine (3.4g, 11.4mmo ^) and imidazole (2.3g, 33.8mmoi) Of N, N-dimethylformamide (68m solution at room temperature and iert-butyldimethylsilyl chloride (3.4g, 22.5nunol) were added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate. , washed with saturated aqueous sodium bicarbonate solution the organic layer was drying (MgSO _4), concentrated, and the resulting residue was purified by silica gel column chroma Bokugu Rafi one. (Wakogel® C-300, hexane 1 to acetic acid Echiru: 2) The title compound (2.48 g, yield: 53%) and 4-iert-butyldimethylsiloxy-butyldimethylsiloxymethyl form (2.49 g, yield: 41%) were obtained.

 NMR (CDCiz) δ: 0.06 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 3.60h H, dd,

J = 6,12Hz), 3.70 (lH, dd, J = 4,12Hz), 3.86 (lH, dd, J = 4,12Hz), 3.98 (lH, br d, J = 12Hz), 4.16 (lH.m ), 4.74 (lH, m), 5.32 (2H, s), 7.58 (2H, d, J = 8Hz), 8.24 (2H, d, J = 8Hz)

Reference Example 15

 (4 ^, 5i?)-4-Acetylthio-5- (O-rf-butyldimethylsiloxymethyl) -N--nitrobenzyloxycarbonyl) isosoxazolidine

 AcS

 Ί ° f "O-TBD S

(4S, 5i?)-5- (ri-butyldimethyloxy) -4-hydroxy-N-(-nitrobenzyloquincarbonyl) isoxazolidine (2.49g, 6.04mmo) and triphenyl To a solution of phosphine (3.2 g, 12.2 mmoi) in tetrahydrofuran (50 mi) was added dropwise a solution of getyl azodicarboxylate (1.9 m, 12 mmo) in tetrahydrofuran (8.0 mi) under ice cooling. After stirring this solution for 45 minutes, thioacetic acid (0.86 m, 12 mmo ^) was added, the solution was returned to room temperature, and further stirred for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The residue was subjected to chromatography (Wakogel® C-300, ethyl acetate-hexane 1: 5) to give the title compound (2.93 & yield: 103%, including impurities derived from getyl azodicarboxylate). .

 NMR (CDC) δ: 0.06 (3H, s), 0.08 (3H, s), 0.90 (9H, s), 2.38 (3H, s), 3.50 (lH, dd, J = 7,10Hz), 3.78 (lH , dd, J = 1,3Hz), 3.88 (lH.dd, J = 3,12Hz), 4.22-4.50 (2H, m), 7.58 (2H, d, J = 8Hz), 8.26 (2H, d, J = 8Hz)

Reference Example 16

 (4R, 5R)-4-Acetylthio-5-carboxylic acid N-(-Nitrobenzyloxykarponyl _) isoxazolidine

AcS COOH

, N

 PNZ

(4R, 5i?)-4-Acetylthio-5- (ieri-butyldimethylcyclomethyl) -N-nitrobenzyloxycarbonyl) isoxazolidine (261mg, 0.55mmo) in methanol (4.0mi ) Was added to 6Ν hydrochloric acid (0.14m, 0.84mmo). After stirring for 30 minutes at room temperature, the reaction mixture was poured into saturated sodium bicarbonate water, and extracted with of methylene chloride, the organic layer dried (MgSO _4), and concentrated. The obtained residue was dissolved in acetone (4 mi), and Jones reagent was added to this solution (until the reagent orange color remained). After confirming disappearance of the 5-hydroxymethyl compound by TLC (Silicagel 60F ₂₅₄ , ethyl acetate-hexane 1: 1), the reaction solution was diluted with ethyl acetate. The precipitate was filtered off, the filtrate was dried (MgSO _4), a crude product of the title compound was concentrated under reduced pressure (186 mg, yield: 94%) was obtained.

 NMR (CDC) δ: 2.32 (3H, s), 3.90-4.40 (2H, m), 4.60 (lH.m),

5.00 (lH, d, J = 6Hz), 5.36 (2H, s), 7.62 (2H, d, J = 8Hz), 8.30 (2H, d, J = 8Hz)

Reference Example 17

(?, 5i?)-4-Acetylthio-5-aminocarbonyl -N- (-Nittobenzyloxycarbonyl) isoxazolidine AcS. CONH _z

PNZ

(R, 5i?)-4-Acetylthio-5-carboxy-N-(-nitropentinoleoxycarbonyl) isoxazolidine (163mg, 0.44mmo £) in methylene chloride (3.2m £) in oxalyl chloride (0.1 lm ^, 1.3 mmoi) and N, N-dimethylformamide drop) were added at room temperature. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was azeotroped with benzene (twice) to remove volatiles. The obtained residue was dissolved in methylene chloride (2m), and a solution of concentrated aqueous ammonia (0.18π ^) in tetrahydrofuran (3.2m ^) was added to this solution under ice cooling. After stirring for 10 minutes, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO _4), and was enrichment. The residue was subjected to silica gel gel column chromatography (Wakogel® C-300, ethyl acetate-hexane 3: 1) to obtain the title compound (102 mg, yield: 63%).

 NMR (CDC) δ: 2.30 (3H, s), 400 (lH, dd, J = 3,12Hz), 4.08 (lH, dd, J = 6,12Hz), 4.60 (lH, m), 4.86 (IH. dJ = 8Hz), 5.32 (2H, s), 7.54 (2H, d, J = 8Hz), 8.26 (2H, d, J = 8Hz)

Reference Example 18

 (4R, 5R) -4-Acetylthio-5-dimethylaminocarbinole-N-(-ditrobenzinoleoxycarbonyl) isosazozolidine

AcS CON e ₂ 0

に 従 っ て According to the method of Reference Example 17, (4i?, 5) -4-acetylthio-5-hexyloxy-N- (P-ditropenedinoleoxycarbonyl) isoxazolidine (186 mg, 0.50 mmol of its acid chloride) Of dimethylamine hydrochloride (115mg, 1.41mmo and triethylamine (0.2 Imi, 1.4mmo) in 20% tetrahydrofuran monochloride dimethylene (5mi) The solution was added to give the title compound (56 _mg , yield: 28%). NMR (CDC £ ₃ ) δ: 2.38 (3H, s), 2.90 (3H, s), 3.08 (3H, s), 3.94 (lH.t, J = 10Hz), 4.08 (lH, t, J = lOHz) , 4.58 (lH, m), 5.16 (lH.dJ = 6Hz), 7.60 (2H, d, J = 8Hz), 8.28 (2H, d, J = 8Hz)

 Reference Example 19

 1-aryloxycarbinole-4-mercapto-2-methinole-3-pyrazolidinone

1)

CH ₂ = CHCOOEt

Hydrazine monohydroxide (12 mi, 0.25 mmoi) was added dropwise to a solution of ethyl acrylate (20 g, 0.2 mm) in ethanol (100 m ^), and the solution was stirred overnight at the same temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel® C-300) and eluted with 5% methanol-form to form 3-virazolidinone (3.44 g, yield: 20%).

NMR (CDC £ ₃ ) δ: 2.51 (2H, t, J = 8Hz), 3.50 (2H, t'J = 8Ηζ)

 2)

 A mixture of 3-virazolidinone (770 mg, 8.95 mmo ^) in tetrahydrofuran (lOrn ^) and water (5 mi) was added under ice-cooling to 2- (arinoleoxycarbonyldithio) -4,6-dimethylpyrimidine ( 2.41 g (10.7 mmo) of tetrahydrofuran (lOrn ^) solution and triethylamine (1.37 mi) were added. After stirring at the same temperature for 2.5 hours, the reaction solution was poured into ethyl acetate (lOOmi), and washed with diluted hydrochloric acid, water, and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (Wakogel® C-300) and eluted with 3% methanol-chloroform to give 1-aryloquincarbon-3-yl virazolidinone (700 mg, yield : 46%).

NMR (CDC £ s) δ: 2.63 (2H, t, J = 8Hz), 3.97 (2H, t, J = 8Hz), 4.60-4.85 (2H, m), 5.12-5.70 (2H, m), 5.97 ( lH, m) 3)

 Triaryloxycarbonyl-3-birazolidinone (.62g, 9.53mmo) (DN 'N-dimethylformamide (17π ^) solution in a nitrogen stream under anhydrous potassium carbonate (1.55 & 11.2mmo ^) and Methane (1.77m ^ 28.4mmoi) was added, and the mixture was stirred for 1.5 hours at 40 ° C. The reaction solution was concentrated under reduced pressure, and ethyl acetate (lOOrn ^) was added to the residue. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.The residue was subjected to silica gel gel column chromatography (Wakogel® C-300), and the residue was diluted with 1% methanol-chloroform. By elution, triaryloxycarbonyl-2-methyl-3-birazolidinone (1.7 g, yield: 99%) was obtained.

NMR (CDCi ₃ ) δ: 2.62 (2H, t, J = 9Ηζ), 3.27 (3H, s), 4.08 (2H, t, J = 9Ηζ),

 4.71 (2H, dt, J = 1,7Hz), 5.16 (2H, m), 5.96 (lH, m)

 Four)

In a nitrogen stream, a solution of lithium hexamethyldisilazide in tetrahydrofuran (50m ^) prepared from hexamethyldisilazane (3.22mi, 15.3mmo ^) and 1.6M? Z butyllithium hexane solution (8.7ml, 13.9mma ^) was prepared. A solution of arinoleoxycarbinole-2-methinole-3-birazolidinone (L7g, 9.2mmoi) in tetrahydrofuran (10m) was added dropwise at 78 ° C and the reaction mixture was stirred at the same temperature for 30 minutes. — A solution of 3-phenyl-2-toluenesulfonyloxaziridine (3.8 g, 13.8 mmol) in tetrahydrofuran (10 m) was added dropwise at 78 ° C, and the reaction solution was stirred at the same temperature for 1 hour. DL-10-Limphasulfonic acid (3.3 g, 14.2 mmo) was added at 78 ° C., and after 5 minutes, the reaction solution was poured into ethyl acetate (100 mL) .The organic layer was washed with a 5% sodium hydrogen carbonate solution, 1 Wash with hydrochloric acid and saturated saline in that order, Dried um, and concentrated under reduced pressure. The residue The residue was subjected to silica gel column chromatography (Wakogel® C-300) and eluted with 2% methanol-form mouth to give 1-aryloxycarbonyl-4-hydroxy-2-methyl-3-methyl-3-methyl-3-methyl-3-methyl-3- Birazolidinone (420 mg, yield: 22.7%) was obtained.

NMR (CDC £ ₃ ) δ: 3.26 (3H, s), 3.72 (lH.dd, J = 8.12Hz), 4.41h H, dd,

J = 8.12Hz), 4.57 (1H. = 8Hz), 4.69 (2H.brd, J = 6Hz), 5.34

(2H, m), 5.95 (lH.m)

 Five)

 1-Aryloxycarbonyl-4-hydroxy-2-methinole-3-birazolidinone (420mg, 2.1mmoi) in tetrahydrofuran (10m solution of nitrogen in a stream of nitrogen under ice-cooling, triethylamine (0.326m, 0.23mm) and methanesulfonyl) (0.187 mi, 2.4 mmo ^) was added dropwise, and the reaction solution was stirred at the same temperature for 1 hour.Ethyl acetate (50 m) was added to the reaction solution. The extract was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain tri-noroxycarbinole-4-methanesulfonyloxy-2-methyl-3-virazolidinone (580 mg, yield: 99%). Was.

NMR (CDC £ ₃ ) δ: 3.17 (3H, s), 3.24 (3H, s), 4.14 (lH, dd, J = 6,12Hz), 440 (lH, dd, J = 6,12Hz), 4.74 ( 2H, dt, J = 1,6Hz), 5.15 (lH, t, J-6Hz), 5.38 (2H, m), 5.97 (lH, m)

 6)

AcS, O

 , Me

 N

N-N-dimethylformamide of 1-arinolexy-propyl-4-methanesulfonyloquine-2-methyl-3-pyrazolidinone (580 mg, 2.08 mmoi) (10 m0 solution in a nitrogen stream at room temperature) Potassium acetate (310 mg, 2.71 mmoi) was added After stirring at room temperature overnight, the reaction solution was poured into ethyl acetate (50 mi) The organic layer was washed with water (3 times) and saturated saline, and then dried over anhydrous sodium sulfate. And dried under reduced pressure And concentrated. The residue was subjected to silica gel gel chromatography (Wakogel® C-300) and eluted with chloroform to give 4-acetylthio-1-aryloxycarbonyl-2-methyl-3-birazolidinone (368 mg). , Yield: 68%)

NMR (CDCi ₃ ) δ: 2.40 (3H, s), 3.31 (3H, s), 3.91 (lH, dd, J = 7,12Hz), 4.34 (lH, t, J = 7Hz), 4.51h H, dd , J = 7,12Hz)., 4.73 (2H, br d, J = 6Hz), 5.35 (lH, m), 5.96 (IH.m)

 7)

 4-Acetylthio-: l-aryloxycarbonyl-2-methyl-3-birazolidinone (365mg, 1.42mmoi) in methanol (20m0 solution, 1N sodium hydroxide aqueous solution (1.42m) in a nitrogen stream under ice-cooling Was added dropwise, and the solution was stirred at the same temperature for 15 minutes.1N hydrochloric acid (L56 ml) was added dropwise under ice-cooling, the reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (lOOrn ^). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-aryloxycarbonyl-4-mercapto-2-methyl-3-virazolidinone (305 mg, yield Rate: 99.9%).

Reference Example 20

 4-Acetylthio-1-methinole-2- (p-nitrobenzyloxycanoleponinole) villazolidine

 1)

N-I Cbz

 ,

Epiclorhydrin (31.4 mi, OAmoi) was added dropwise to Cbz hydrazine monohydrate (58 mi, \ 2 moS,) under ice cooling over 1 hour, and the solution was stirred for 2 hours. Excess hydrazine monohydrate is distilled off under high vacuum, and the resulting residue is washed with tetrahydrofuran. (800mi) and a saturated aqueous solution of sodium hydrogencarbonate (1.¾>), and a solution of benzyloxycarbonyl chloride (136mi, 0.67moi) in tetrahydrofuran (600m ^) was added at room temperature. Then, the mixture was extracted with ethyl acetate, the organic layer was dried (MgSO ₄ ), and then concentrated under reduced pressure The obtained residue was subjected to silica gel gel chromatography (Wakogel® C-300, ethyl acetate-hexane, 1: 1) to give 1,2-di (benzyloxycarbonyl) -4-hydroxypyrazolidine (44.9 g, yield: 31.5%).

NMR (CDC £ ₃ ) δ: 3.15 (lH, br dj = 12Hz), 3.22 (lH.br d, J = 12Hz), 3.94 (lH.br d, J = 12Hz), 4.10 (lH.br d, J = 12Hz), 4.60 (1H, brt, J = 3Hz), 5.18 (4H, s), 7.30 (lOH.m)

 2)

The compound (12.4 g, 34.8 mmo ^) obtained in the above reaction was dissolved in N, N-dimethylformamide (124 mO), and tert-butyldimethylsilyl chloride (6.3 g, 41.8 mmof) was dissolved at room temperature. Imidazoru (2.4g, 35.2mmo ^) was stirred between the mixture was. 3:00, the reaction was poured into saturated bicarbonate Natoriumu solution and extracted with acetic acid E Chi le. the organic layer was dried (MgSO _4), The residue was subjected to silica gel chromatography (Wakogel® C-300, ethyl acetate-hexane 1: 5) to give 1,2-dibenzyloxycarbonyl. -4-(ri-Butyldimethylsiloxy) pyrazolidine (15.4 yield: 94%) was obtained.

3)

TBDMS-0. TBDMS-0.

 ヽ ヽ

 N-Cbz

Cbz PNZ 10% palladium on carbon (0.25 g) was added to a solution of the compound (2.5 g, 5.3 mmoi) obtained in the above reaction in methanol (25 m ^), and the mixture was subjected to catalytic hydrogen reduction at room temperature for 2 hours. went. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in 0.5 g of 0.5 g of methylene-dioxane (1: 1, lOrn ^) in 4,6-dimethinole-2-nitrobenzyloxycarbonylthiol pyrimidine (790 mg) was used. , 2.5 mmoi) was added and the solution was stirred at room temperature for 1 hour. The deposited precipitate was separated by filtration, and the filtrate was concentrated. The resulting residue was subjected to silica gel gel chromatography (Wakogel® C-300, ethyl acetate-hexane 1: 1) to give 4- (iert-butyldimethylsiloxane) -2- (ρ-nitrobenzene). Ndyloxycarbonyl) birazolidine (446 mg, yield: 44%) was obtained.

 NMR (CDC) 6: 0.08 (6H, s), 0.90 (9H, s), 2.90 (lH.m), 3.00 (1H, br d, J = 12Hz), 3.30h H, d, J = 12Hz), 3.70 (lH.dd, J = 4,12Hz), 4.60 (lH, m), 5.24 (lH, d, J = 16Hz), 5.36 (lH.dJ = 16Hz), 7.60 (2H, d, J = 8Hz) , 8.24 (2H, d, J = 8Hz)

 Four)

TBD S-one O TBD S-one

H ^> k no e

 ヽ NT

PNZ PNZ 37% formalin (0.35 mi, 5.8 mmo) in a solution of the compound obtained in the above reaction (446 mg, 1.17 mmo ^) in acetonitrile (9.0 ml) at room temperature (0.35 mi, 5.8 mmo, sodium hydrogen cyanide boron (87 mg, 1.87 mmoi) ) And acetic acid (0.2 ml), and the reaction mixture was stirred for 30 minutes. Then, formalin (0.35 mi), sodium borohydride (87 mg) and acetic acid (02 pound) were added to the reaction mixture again. the solution was stirred for 30 minutes (was repeated this operation once more). the reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with acetic acid Echiru. the organic layer was dried (MgSO _4), and concentrated under reduced pressure 4- (ri-butyldimethylcyclopropyl)-: I-methyl-2-nitrobenzyloxycarbonyl) villazolidine (555m) was obtained. Five)

TBDMS

A solution of the compound obtained in the above reaction (555 m of IN tetrabutylammonium humoleolide (2.5ππ)) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Chromatography (Wakogel® C-300, 5% methanol-ethyl acetate) gave 4-hydroxy-1-methyl-2--nitrobenzinoleoxycarbonyl) villazolidine (237 mg, yield: 72%). Obtained.

NMR (C) Ci ₃ ) δ: 0.08 (6H, s), 0.92 (9H, s), 2.82 (3H, s), 3.02 (1H, dd, J = 1,12 Hz), 3.16 (lH.dd.J = 4,12Hz), 3.58 (lH.br d, J = 12Hz), 3.82 (lH, dd, J = 5,12Hz), 4.68 (lH.m), 5.28 (2H, m), 7.60 (2H, d , J = 8Hz), 8.24 (2H, dJ = 8Hz)

 6)

The compound (230 mg, 0.82 mmo) and triphenylphosphine (203 mg, 0.77 mmoi) obtained in the above reaction were dissolved in tetrahydrofuran (4.0 m ^), and the mixture was cooled under ice-cooling to form getyl azodicarboxylate (0.122 mi, 0.77 mmo ^). Was added. After the reaction solution was stirred under ice cooling for 30 minutes, thioacetic acid (0.77 mmoi) was added, and the reaction solution was stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel® C-300, ethyl acetate-hexane 1: 1), and the desired fraction was concentrated to give 4-acetylthio-1-methynole- A residue containing 2-0-nitrobenzyloxycarbonyl) birazolidine (338 mg, but containing triphenylphosphinoxide) was obtained.

NMR (CDC £ ₃ ) δ: 2.36 (3H, s), 2.66 (3H, s), 3.00 (lH.dd.J = 8,12Hz), 3.40 (lH, ddJ = 8,12Hz), 3.52 (lH.s) ddJ = 8,12Hz), 4.10 (lH.dd, J = 8,12Hz), 4.25 (lH, m), 5.30 (lH.dJ = 14Hz), 5.32 (lH, d, J = 14Hz), 7.42 (2H, dJ = 8Hz), 8.22 (2H, d, J = 8Hz)

Reference Example 21

 1-acetinole-4-acetylthio-2- [N-O-pentopenoleoxycarbinole) glycinole] virazolidine

1)

TBDMS-

To a solution of 4- (rt-butyldimethylsiloxy) -1,2-di (benzyloxycarbonyl) pyrazolidine (1.3g, 2.76mmoi) in methanol (26π ^) was added 10% palladium carbon catalyst (0.13g). This solution was subjected to catalytic hydrogenation at room temperature for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dioxane monosalt dimethylene (8m ^, 1: 1), and 4,6-dimethyl-2-nitrobenzyloxycarbonylthio) pyrimidine (0.88g, 2.76mmo) was added. After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate (20 mL), and then washed with 0.5N sodium hydroxide (6 mi). The organic layer was dried (MgSO _4), the crude was concentrated in vacuo to 4-(RI-butyl dimethyl shea port carboxymethyl) - 1 - was obtained - (p two Toro benzyl O alkoxycarbonyl) Birazorijin residue. This residue was dissolved in methylene chloride (10m), and acetyl chloride (0.24m, 3.3mmo and triethylamine (0.57m ^, 4.2mmo ^)) were added to the solution under ice cooling. poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with methylene chloride. organic layer was dried (MgSO _4), and concentrated under reduced pressure. the resulting residue was purified by silica gel force column chromatography (Wakogel® C-300, 1-acetinole-4- (ieri-butyldimethylsiloxane) -2- 2- (2->-nitrobenzyloxycarbonyl) virazolidine (554 mg, yield: 47%) ).

NMR (CDC £ ₃ ) δ: 0.04 (3H, s), 0.05 (3H, s), 0.84 (9H, s), 2.08 (3H, s), 3.24 (2H, m), 4.10 (2H, m), 4.62 (lH.m), 5.30 (2H, m), 7.56 (2H, d, J = 8Hz), 8.24 (2H, d, J = 8Hz) 2)

To a solution of the compound obtained in the above reaction (554 mg, L31 mmo) in tetrahydrofuran (5 ml) at room temperature was added a 1 M solution of tetrabutylammonium fluoride tetrahydrofuran (1.3 mi, 1.3 mmoi). Stirred for hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel® C-300, 5% methanol-ethyl acetate) to give crude triacetyl-4-hydroxy-2-(/> -Nitrobenziloxycarbonyl) villazolidine (504m was obtained.

NMR (CDC £ ₃ ) δ: 2.10 (3H, s), 3.00-3.50 (2H, m), 4.00-4.30 (2H, m), 4.65 (ΙΗ, πι), 5.34 (2H, m), 7.56 (2H , d, J = 8Hz), 8.26 (2H, d, J = 8Hz)

 3)

A solution of the compound obtained in the above reaction (500 mg, L62 mmo ^) and triphenylphosphine (865 mg, 3.24 mmo) in tetrahydrofuran (10.0 m, under ice-cooling, was added dropwise acetyl azodicarboxylate (0.52 mi, 3.24 mmo). This solution was stirred at the same temperature for 20 minutes, thioacetic acid (0.23 m, 3.24 mmo) was added to the reaction solution, and the reaction solution was further stirred for 1 hour. The residue was subjected to gel chromatography on silica gel (Wakogel® C-300, ethyl acetate-hexane), and triacetyl-4-acetylthio-2-(-nitrobenzyloxycarbonyl) pyrazolidine (623 mg; (Including impurities derived from zodicarboxylate).

NMR (CDC £ ₃ ) δ: 2.14 (3H, s), 2.35 and 2.38 (3H, each br s), 5.36 (2H, m), 8.30 (2H, d, J = 8Hz)

Reference Example 22

 1-Acetyl-4-acetylthio-2- [N-()-nitropentinoleoxycarbonyl) glycizole] virazolidine

1)

TBD S-0

 N-I Ac

 Boc

To a solution of 4- (ieri-butyldimethylsiloxy) -1,2-di (benzyloxycarbonyl) pyrazolidine (.77 g, 3.76 mmol) in methanol (35 mi) was added 10% palladium carbon catalyst (0.2 g). This solution was subjected to hydrogenolysis at room temperature for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dioxane-methylene chloride (16π ^, 1: 1), and 2- (o-rt-butoxycarbonylthio) -4,6-dimethylpyrimidine (0.88 g, 3.67 mmoi) was added to the solution. Was added, and the solution was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate (20 mi), and the solution was washed with 0.5N aqueous sodium hydroxide solution (20 m ₂ ). The organic layer was dried (MgS04) and concentrated under reduced pressure. This gave crude 1- (rt-butoxycarbonyl) -4- (ieri-butyldimethylsiloxy) virazolidine residue, which was dissolved in dimethyl chloride (17m) and acetyl chloride was added to this solution under ice-cooling. Lid (0.36ΐ) ^, 5.1mmoi) and triethylamine (1.5m, 10.8mmoi) were added, and the solution was stirred at room temperature for 30 minutes. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate (20 mi), and extracted with methylene chloride (20 m × 2). The organic layer was dried (MgSO _4), and crude Bok Asechinore concentrated in vacuo - 2- (ieri- Butokishika carbonyl) -4- (ieri- butyldimethylsiloxy) was obtained Birazorijin (1.55 g).

NMR (CDC δ: 0.04 (3H, s), 0.06 (3H, s), 0.84 (9H, s), 1.46 and 147 (9Η, each s), 2.95-3.30 (2H, m), 400 ~ 4.20 (2H, m), 4.56 (lH, m) Two

TBDMS

To a solution of the compound obtained in the above reaction (1.55 g, 4.50 mmoi) in tetrahydrofuran (15 mi) was added 1 M tetrabutylammonium fumoleolide (45 mi, 4.5 mmo). After stirring at room temperature for 1 hour, the reaction solution was diluted with ethyl acetate (50 mi), and the solution was washed with saturated saline (30 mi). The organic layer was dried (MgS ^ ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel® C-300, ethyl acetate) to give 1-acetinole-2- (ri-butoxycarbonyl) -4-hydroxyvirazolidine (51 lmg, yield : 49%).

NMR (CDC £ ₃ ) 6: 1.48 (9H, s), 2.14 (3H, s), 3.04 (lH.m), 3.28 (1H, m), 4.10 (2H, m), 4.68 (lH, m)

 3)

 In a tetrahydrofuran solution (10 mi) of the compound (510 mg, 2.22ππηαί) obtained in the above reaction, triphenylphosphine (871 mg, 3.33 mmo) and acetyl benzodicarboxylate (0.552π ^, 3.33 mmoi) were cooled on ice. The solution was added below and the solution was stirred for 30 minutes. After thioacetic acid (0.24 mi, 3.33 mmoi) was added to this solution, the reaction solution was warmed to room temperature, stirred for another 1 hour, and then concentrated under reduced pressure. The residue was subjected to gel chromatography on silica gel (Wakogel® C-300, ethyl acetate-hexane 1: 2) to give crude 1-acetyl-4-acetylthio-2- (tert-butyldimethylcycoxy) virazolidine (1.38 g, including impurities derived from triphenylphosphinoxide and getyl azodicarboxylate) were obtained.

NMR (CDCi ₃ ) δ: 1.48 (9H, s), 2.12 (3H, brs), 2.34 (3H, s) ) " ^Ac

 To a solution of the compound obtained in the above reaction (1.38 g, about 4.79 mmol) in methylene chloride (2.0 m) was added trifluoroacetic acid (2.0 m), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel gel chromatography (Wakogel® C-300, ethinole acetate) to give 1-acetinole-4-acetylacetylthiovirazolidine (281 mg, I-acetyl-4-hydroxy -Yield from 2- (p-nitrobenzylquinolone) pyrazolidine: 67%.

Five)

N-^-Nitropentinoleoxycarbinole) Oxalyl chloride (0.70mi, 8.1mmo and N-dimethylformamide (1 drop) in dimethyl chloride solution (13mi) of glycine (680mg, 2.7mmo) at room temperature The solvent was distilled off under reduced pressure, the residue was dissolved in benzene, and again distilled under reduced pressure (this operation was repeated three times). (5.0π ^) and dissolved in ice-cooled solution of triacetyl-4-hydroquin-2- (ί) -nitrobenzyloxycarbonyl) villazolidine (280mg, 1.53mmo) in methylene chloride (5.0m ^) and triethylamine (0.62mi, 4.11mmoi). The reaction solution was warmed to room temperature, stirred for further 30 minutes, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with methylene chloride. The organic layer was dried (MgSO ₄₎ and concentrated in vacuo. The residue was subjected to gel chromatography on silica gel (Wakogel® C-300, ethyl acetate-hexane 1: 1) to give 1-acetyl-4-acetylthio-2- [N- (P-nitrate). Benzyloxycarbonyl) glycyl] pyrazolidine (453 mg, yield: 68%) was obtained.

NMR (CDC £ _S ) δ: 2.20 (3H, br s), 2.38 (3H, s), 5.24 (2H, br s), 7.54 (2H, d, J = 8 Hz), 8.24 (2H, d, J = 8Hz) Reference Example 23

 4-Acetylthio-1-dimethylaminocarbinole-2-(>-dibenzobenzene) pyrazolidine

 1)

TBD S-0. TBDMS-X

N-Boc one CO 圆 e ₂

, ΝΤ

 To a solution of Boc 4- (ri-butyldimethylsiloxy) -1,2-di (benzyloquincarbonyl) pyrazolidine (1.80g, 3.83mmoi) in methanol (18mi), add 10% palladium carbon catalyst (200m, The catalyst was removed by filtration under reduced pressure, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in methylene chloride (10 mi), and triethylamine (1.6 mi, 11.4 mmol, then ice-cooled) was obtained. Under the conditions, dimethylamino carbonyl chloride (0.42mi, 4.60mmoi) was added, and the mixture was stirred at the same temperature for 30 minutes.

 N

 did. The reaction mixture was stirred under ice cooling for 30 minutes, and 4,6-dimethyl z-2- (4-ditrobenzinoleoxycarbonylthio) pyrimidine (0.97 g, 3.06 mmol) was added. The reaction mixture was poured into 0.5N hydrochloric acid, extracted with methylene chloride, and the organic layer was dried (MgSOJ, concentrated under reduced pressure), and the obtained residue was subjected to silica gel gel chromatography (Wakogel). ® C-300, ethyl acetate-hexane 1: 1) to give 4- (ieri-butyldimethylsiloxy) -1-dimethylaminocarbinole-2-nitropentinoleoxycarbonyl) birazolidine (l.Og, yield Rate: 44%).

NMR (CDC £ ₃ ) 6: 0.04 (6H, s), 0.84 (9H, s), 2.98 (6H, s), 3.28 (1H, m), 3.52 (lH, m), 3.65 (2H, m), 4.60 (lH, m), 5.25 (2H, br s),

7.30 (2H, d, J = 8Hz), 8.22 (2H, d, J = 8Hz)

 2)

TBDMS-0, HO

N-CON e ₂ N-I CO Me ₂

NT, NT

PNZ PNZ Compound (l.OOg, 1.71mmo ^) obtained in the above reaction was converted to methanol (20m ^)

Add 6N hydrochloric acid (0.57mi, 3.42mmoi) at room temperature and stir the solution for 1 hour.

Stirred. 6N hydrochloric acid (0.57π ^) is added to the reaction solution again, and the solution is stirred for 1 hour.

(This operation was repeated once more). The reaction solution is 2Ν sodium hydroxide

 -After adding aqueous solution (5.8m £, 11.6mmo ^), distill off methanol under reduced pressure

The residue was extracted with methylene chloride. The organic layer was dried (MgSO _4), concentrated, Bok dimethyl

Tyraminocarbonyl-4-hydroxy-2-nitrobenzyloxycarbonyl

G) A crude product of virazolidine was obtained as a solid (560 mg, yield: 69%).

NMR (CDC £ ₃ ) δ: 3.04 (6H, s), 3.38 (IH.dd, J = 4,12Hz), 3.46 (1H,

 d, J = 12Hz), 3.74H, d, J = 12Hz), 3.90 aH, dd, J = 4,12Hz), 4.62 (lH, m), 5.30 (2H, s), 7.54 (2H, d, J = 8Hz), 8.22 (2H, J = 8Hz)

3)

CONMe ₂

 The compound obtained in the above reaction (560 mg, L18 mmo) and triphenylphosphine

 (435mg, 1.66mmoi) in tetrahydrofuran (12mi) under ice-cooling

 Detyl azodicarboxylate (0.26m ^, 1.66mmoi) was added dropwise and the reaction mixture was added.

 Was stirred for 30 minutes. Add thioacetic acid (0.12ι 1.66mm) to the reaction mixture and react.

 After the solution was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The resulting residue

 Silica gel ram chromatography (Wakogel® C-300,

 Xane 3: 1) to give 4-acetylthio-to-dimethylaminocarbonyl-2- (

P-Nittobenzyloxycarbonyl) birazolidine (780 mg, but containing a small amount of triphenylphosphinoxide) is obtained.

NMR (CDC £ ₃ ) δ: 3.02 (6H, s), 3.35 (lH, m), 3.66 (2H, m), 3.85 (1H,

 m), 4.18 h, m), 5.30 (2H, brs), 7.50 (2H, d, J = 18 Hz), 8.15 (2H, d, J = 8 Hz)

 Industrial applicability

 The compound of the present invention is a novel compound not described in the literature, and has a gram of sensitivity and resistance.

 Strong antibacterial activity against positive and gram-negative bacteria, β-lactamase and

 Since it has excellent stability against DHP-I, it is useful as an antibacterial agent.

Claims

 (1) General formula

Contract

In the formula, R represents a hydrogen atom or a methyl group, R ¹ is a hydrogen atom, a lower alkyl group, a lower Arukanoinore group, a formyl group, Horumuimi Doyle group, Asetoimi Doyle group, § Mijino group, prolyl group or the following formula z R ⁴ Roh R ^s

i) — CO (CH ₂ ) _m N ii) COCH box

R ⁵ NH ₂

/ (CH ₂ ) _n R ⁷ R ⁸ iii) One COCH ヽ iv) ― C0 (CH ₂ ) n CH z

NH ₂ NH ₂

(Wherein R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinyl group or piperazinyl group, and R ⁶ May be substituted with a hydroxyl group, a lower alkynole group or an aryl group, R ⁷ is a carboxy group, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group, a lower alkylthio group or a guanidino group, and R ⁸ is A carboxy group, a lower alkoxycarbonyl group or an aminocarbonyl group, m is an integer of 0 to 3, n is an integer of 1 to 3, R ² is a hydrogen atom, a hydroxy lower alkyl group or formula

V) ― CON — (CH ₂ ) _n OCON

(Wherein R ⁹ and R ¹ represent a hydrogen atom or a lower alkyl group, or R ^g and R ^1D together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperidyl group, and n Has the meaning described above). A is a methylene or carbonyl group, B is an oxygen atom or a formula ^ NR ³ (where R ³ is a hydrogen atom, a lower alkyl group, a lower alkanol group, a formyl group, a formimidinole group, an acetimidoyl group, an amidino group, A prolyl group or the following formula zz R ⁶

i) — CO (CH ₂ ) _m N ii) — COCH

R ⁵ NH ₂ iii) COCH

_Two

(Wherein, R ⁴ , R ⁵ , R ⁶ , RR ⁸ , m and n have the above-mentioned meanings).} (Where RR ² and R ³ A hydrogen atom and A is a methylene group)]] or a pharmaceutically acceptable salt or ester thereof.

 (2) General formula

Wherein R is a hydrogen atom or a methyl group, R ² is a hydrogen atom, a hydroxy lower alkyl group or

R ⁹

V) — CON vi) — (CH ₂ ) _n C0N z vii) — (CH ₂ ) _n 0C0N

(Wherein R ⁹ and R ^1Q represent a hydrogen atom or a lower alkyl group, or R ⁹ and R ¹⁰ together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinole group or piperidyl group, and n is R ¹⁰⁰ represents a hydrogen atom, a lower alkyl group, a formimidoyl group, an acetimidoyl group, an amidino group, a prolyl group or a group represented by the following formula:

R ⁸ no

iv) — C0 (CH ₂ ) _n CH viii) — C0 (CH ₂ ) _n N

NH ₂

(In the formula, R ⁶ is a lower alkyl group or an aryl group which may be substituted by a hydroxyl group; R ⁷ is a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group, a lower alkylthio group or a guanidino group. R ⁸ is a carboxyl group, a lower alkoxycarbonyl group or an aminocarbonyl group, R ⁴ ° and R ⁵ are a hydrogen atom or a lower alkyl group, and n has the meaning described above. Or a general formula

[In the formula, R ¹ and R ³ is a hydrogen atom, a lower alkyl group, a lower Arukanoinore group, e mill group, Horumuimi Dinore group, Asetoimi Doyle group, amidino group, proline group or formula Roh R ⁴ R ⁶

i) — CO (CH ₂ ) _m N ii) — COCH

R ⁵ NH ₂

/ (CH ₂ ) _n R ⁷ no R ⁸ ίϋ) COCH iv) ― CO (CH ₂ ) nCH

NH 2 NH ₂

(Wherein R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group, or R ⁴ and R together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperazinyl group, and R ⁶ is a hydroxyl group R ⁷ is a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group, a lower alkylthio group or a guanidino group, R ⁸ is a carboxyl group, A is a lower alkoxycarbonyl group or an aminocarbonyl group, m is an integer of 0 to 3, n has the above-mentioned meaning), A represents a methylene group or a carbonyl group, and R has the above-mentioned meaning. Have That (however, R ¹ and R ³ are both excluded in the case of hydrogen atoms) in the first claim, wherein a compound represented by the compound _R4.

(3) R ¹⁰⁰ is a hydrogen atom or one C0 (CH ₂ ) _n N (wherein R ⁴ and R ⁵ ° are

The compound according to claim 2, wherein the compound is a hydrogen atom or a lower alkyl group, and n is an integer of 1 to 3.

(4) R ² is a hydrogen atom or one CON:

ヽ_R , 0 (wherein, R ⁹ and R ¹⁰ represent a hydrogen atom or a lower alkyl group, or R ⁹ and R ^1D together with an adjacent nitrogen atom represent an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, or a piperidyl group. 3. The compound according to claim 2, which forms a group).

(5) The compound according to claim 2, wherein R, R ² and R ¹⁰⁰ are hydrogen atoms.

(6) R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanoinole group or one CO (CH ₂ ) _m N (wherein R ⁴ and R ⁵ are a hydrogen atom or a lower alkyl

Or shows a R ⁵ Le group, R ⁴ and R ⁵ together with the adjacent nitrogen atom, form an aziridinyl group, § Zechijiniru group, a pyrrolidinyl group or a piperazinyl group, m is 0 to an integer of 3) The compound according to claim 2.

 (7) — The compound according to claim 1, wherein the configuration of the compound of the general formula [I] is (5R, 6S) or (li ?, 5S, 6S).

 (8) (5R, 6S) -6-[() -1-Hydroxyethyl] -2- (isosoxazolidine-4-ylthio) -canolebapene-2-em-3-3-capillonic acid,

 (1,5S, 6S) -6-[(R) -l-Hydroquinethyl] -2- (isoxazolidin-4-ylthio) -1-methyl-1-alkenyl-2-em -3-Power Ruponic acid,

 (5R, 6S) -2- (N-glycylisoxoxazolidine-4-ylthio) -6-[(R) -1-Hydroxyschetinole] -1-1-l-lebapen-2-em-3-carboxylic acid ,

(.1R, 5S, 6S-2- (N-g,) silisoxazolidine-4-ylthio) -6-trihydroxyethyl] -1-methyl-1-canolevapene-2-em-3 -Carboxylic acid, 5R, 6S)-2-[(4,5S) -5- (Dimethylaminocarbonyl) isoxazolidin-4-ylthio] -6-hydroxyhydroxyl]-1 -force -2-em- 3- carboxylic acid,

 (1R, 5S, 6S) -2-i (R, 5S) -5-aminocarbonylisoxazolidin-4-ylthio] -6-[(R)-: i-hydroxyethyl] -1 -Methyl-tricarbapene-2-em-3-carboxylic acid,

 (5R, 6S) -6-[(R) -1-Hydroxyethynole] -2- (2-methynole-3-oxovirazolidin-4-ylthio) -1_canolebapen-2-em-3-carvone Acid,

 (5R, 6S) -6- [0?)-L-hydroxyethyl] -2- (1-methylbiazolidine-4-ylthio)-1-canolebapene-2-em-3 -Capillonic acid ,

 (5R, 6S) -2- (Tracetylpyrazolidine-4-ylthio) -6-[(R)-: i-hydroxyshethyl] -1-1-L-carbene-2-em-3-carbone Acid,

 (5R, 6S)-2- (1 -Acetyl-2-glycylpyrazolidine-4-ylthio)-6- [(R)-trihydroxyethynole] -1 -Canolebapen-2-em-3 -Power rubonic acid and

 (5R, 6S) -2- (1-Dimethylaminocarbonylpyrazolidine-4-ylthio) -6- 1-hydroxyethynole] -1-carbyl-2-em-3-carboxylic acid The compound according to claim 1.

 (9) — General formula

[Wherein, R represents a hydrogen atom or a methyl group, R ¹¹ represents a hydrogen atom or a carboxyl group protecting group, and R ¹² represents a hydrogen atom or a hydroxyl group protecting group] or a reactive derivative thereof. formula

[Wherein, R ²¹ is a hydrogen atom, an optionally protected hydroxy lower alkyl group, or a compound represented by the following formula: R ⁹ R ⁹

v)-CON vi)-(CH ₂ ) _n CON vii)-(CH ₂ ) _n OCON

R ¹ R '

(Wherein R ⁹ and R ^1Q represent a hydrogen atom or a lower alkyl group, or R ⁹ and together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinyl group or piperidyl group, and II represents 1 to 1 R ¹¹⁰ is a hydrogen atom, a protecting group for an imino group, a lower alkyl group, a lower alkanoyl group, a formyl group, or a formyl group which may be protected, a formimidyl group, an acetoimidinole group , An amidino group or a prolyl group or the following formula

R ⁴ 'z R ⁶ ' i ') — CO (CH ₂ ) _m N ヽ, ii') — COCH ヽ

R ⁵¹ NHR 13

/ (CH ₂ ) _n R ⁷¹ R ⁸ 'iii') ― COCH iv ') ― C0 (CH ₂ ) n CH

NHR 'NHR ¹³

(Wherein, R ¹³ is a hydrogen atom or a protecting group for an amino or imino group, R ⁴¹ and R ⁵¹ are a hydrogen atom, a lower alkyl group or a protecting group for an amino or imino group, or R ”and R ⁵¹ are Forming an aziridinyl group, a azetidinyl group, a pyrrolidinyl group or an optionally protected piperazinyl group together with an adjacent nitrogen atom, wherein R ⁶¹ is a lower alkyl group which may be substituted by an optionally protected hydroxyl group; Or an aryl group, R ⁷¹ is an optionally protected canoleboxyl group, a lower alkoxycarbonyl group, an aminocarboxy group, an optionally protected amino group, a lower alkylthio group or an optionally protected guanidino group, R ⁸¹ is an optionally protected carboxyl group, lower alkoxyl propyl group or aminoamino group, m is 0 to 3 A is a methylene group or a carbonyl group, B ¹ is an oxygen atom or a formula> NR ³¹ (where R ³¹ is a hydrogen atom, an imino group protecting group A lower alkyl group, a lower alkanoisole group, a formyl group or an optionally protected formimidoyl group, an acetimidoyl group, an amidino group or a prolyl group or a group represented by the following formula:

R ⁴ 'R 6' 1

i ') — CO (CH ₂ ) _m N ϋ') — COCH

R ^5! NHR '

z (CH ₂ ) _n R ⁷¹

iii ') — COCH z R ⁸¹

iv ') ― C0 (CH ₂ ) _n CH

NHR ' ³ \

NHR ' (Wherein, R ¹³ , R ⁴¹ , R ⁵¹ , R ⁶¹ , RR ⁸¹ , m and n have the above-mentioned meanings)), wherein R ^I1Q and R ³¹ Excluding the case where R ²¹ is a hydrogen atom and A is a methylene group) with a compound represented by the general formula

Wherein R ヽ R ", R ¹² , R ²¹ , R ¹¹⁰ , A and B ¹ have the above-mentioned meanings, and the protective group of the compound of the general formula [IV] is removed if necessary. A general formula

[Wherein, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanoinole group, a formyl group, a formimidinole group, an acetimidoyl group, an amidino group, a prolinole group or the following A

R ⁴

i) CO (CH ₂ ) _m N z R ⁶

 ii)-COCH

R ⁵ NH ₂

/ (CH ₂ ) _n R ⁷ z R ⁸ iu) COCH iv) ― C0 (CH ₂ ) _n CH

NH ₂ NH ₂

(Wherein R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinyl group or piperazinyl group, and R ⁶ May be substituted by a hydroxyl group R ⁷ is a carboxyl group, a lower alkoxycarbonyl group, an aminocanolebonyl group, an amino group, a lower alkylthio group or a guanidino group, R ⁸ is a carboxyl group, a lower alkoxycarbonyl group or an aminocarbo group. R ² is a hydrogen atom, a hydroxy lower alkyl group or a group represented by the following formula:

V) — CON vi) — (CH ₂ ) nC0N

Wherein R ⁹ , R ^1Q and n have the above-mentioned meanings, B is an oxygen atom or a formula> NR ^{3 in the} formula, R ³ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, Hosoleminole group, formimidinole group, acetateimidinole group, amidino group, propylinole group or the following formula

FT R ⁶

i) — CO (CH ₂ ) _m N ii) — COCH

R ⁵ NH ₂ iii) COCH

_Two

(Wherein, R ⁴ , R ⁵ , R \ RR ⁸ , m and n have the above-mentioned meanings), and R and A have the above-mentioned meanings (provided that , R ¹ , R ² and R ³ are each a hydrogen atom and A is a methylene group)]] or a pharmaceutically acceptable salt or ester thereof. H 0) —general formula

Wherein R is a hydrogen atom or a methyl group, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a formyl group, a formimidinole group, an acetimidoyl group, an amidino group, a prolyl group, or a group represented by the following formula: Four

i) — CO (CH ₂ ) _m N z R

ii)-COCH z R ⁶

R ⁵ NH ₂ iii) — COCH

_Two

(Wherein R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom form an aziridinyl group, azetidinyl group, pyrrolidinyl group or piperazinyl group, and R ⁶ May be substituted with a hydroxyl group, a lower alkyl group or an aryl group, R ⁷ is a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group, an amino group, a lower alkylthio group or a guanidino group, R ⁸ is a carboxy group, a lower alkoxycarbonyl group or an aminocarbonyl group, m is an integer of 0 to 3, n is an integer of 1 to 3, R ² is a hydrogen atom, a hydroxy lower alkyl group Or the following formula

R ⁹

 v) — CON

10 vi) — (CH ₂ ) _n CON vii) — (CH ₂ ) _n 0C0N z R ⁹

 R '

(Wherein R ⁹ and R ^1Q represent a hydrogen atom or a lower alkyl group, or R ⁹ and R ′ ° together with an adjacent nitrogen atom form an aziridinyl, azetidinyl, pyrrolidinyl or piperidyl group, and n Has the meaning described above).

A is a methylene group or a carbonyl group, B is an oxygen atom or a formula NR ³ (wherein, R ³ is a hydrogen atom, a lower alkyl group, a lower alkanol group, a forminole group, a formimidoyl group, an acetimidinole group, an amidino group, a prolyl group Group or the following formula

R ⁴ R ⁶

i) — CO (CH ₂ ) _m N ii) — COCH

R ⁵ NH ₂

/ (CH ₂ ) _n R ⁷ R ⁸

iii) — COCH iv) — C0 (CH ₂ ) nCH z

NH ₂ NH ₂

^{(Wherein, R 4, R 5, R} 6, R 7, R 8, m and n are as defined above) a group represented by the group} represented by (wherein, RR ² and R ³ Wherein both are hydrogen atoms and A is a methylene group)]] or a pharmaceutically acceptable salt or ester thereof as an active ingredient.