WO2004018453A1 - Proline derivatives - Google Patents

Abstract

Proline derivatives represented by the general formula (I) or salts thereof, useful as antibacterial drugs against multidrug-resistant bacteria: (I) (b) wherein A is a group derived from a 5- or 6-membered heterocycle which may be fused with an optionally halogenated benzene ring; p1, p2, and p3 are each an integer of 0 or 1; R1, R2 and R3 are each H, optionally substituted lower alkyl, a 5- or 6-membered saturated or unsaturated cyclic group (a), or the like; T is a single bond, methylene, or carbonyl; R4 and R5 are each H, lower alkyl, or the like; n and m are each an integer of 1 or 2; R6 and R7 are each H, OH, halogeno, or the like; X is C, S or O; Y is H, an amino-protecting group, or a group represented by the general formula (b); R8 is alkyl or cycloalkyl lower alkyl; and R9 is H, a hydroxyl-protecting group, or the like. Compounds wherein Y is H or an amino-protecting group correspond to intermediates of compounds wherein Y is a group represented by the general formula (b).

Description

 Description Proline derivative Technical field

 The present invention relates to a novel proline derivative useful as a medicine and an intermediate for producing the same. More specifically, the present invention relates to a proline derivative or a salt thereof, a production intermediate thereof, a medicament, and a pharmaceutical composition having an excellent antibacterial activity, particularly against multidrug-resistant bacteria. Background art

 Methicilin-resistant Staphylococcus aureus, abbreviated as MRSA, 196 Intractable postoperative infection, first reported in the UK in 1961, in the respiratory and gastrointestinal tracts. Known as the causative agent of infectious disease MRSA infectious disease prevailed in Europe and the United States in the late 1960s and late 1970s, and in Japan in the 1980s, attracted public attention as the main causative agent of hospital-acquired infections. It spread nationwide in the late 990s, and MRSA is now highly resistant to multiple drugs and resistant to the antibacterial agents Vancomycin and Arbekacin in MRSA infections. Strains have also emerged.

 In addition to the above MRSA, multidrug-resistant bacteria that have attracted a great deal of interest in the medical community include Penicillin-Resistant Streptococcus pneumoniae (PRSP) and Vancomycin-Resistant Enterococcus faeciwn, pneumococcus is a pneumonia-causing bacterium that is feared for its virulence, and enterococci are systemic infections and Z or urine that may be clinically isolated with MRSA. For infections caused by these multidrug-resistant bacteria, new antibacterial agents such as quinoquinone and oxazolidinone are used, but their antibacterial activities are not so strong. The emergence of strains resistant to these antibiotics has also been reported.

In the first part of the claim of WO 99/39704 pamphlet: Is described.

When the definition of each substituent in the above general formula is examined with the compound of the present invention in mind, a compound having a structure somewhat similar to that of the compound of the present invention can be assumed. Is different from The only proline derivative specifically described in the specification of this International Publication is the following compound A described in Example 12 thereof.

 Compound A Disclosure of the Invention

 The present inventors searched for a compound having a strong antibacterial activity against these multidrug-resistant bacteria, particularly MRSA, and succeeded in selecting a proline derivative described later, thus completing the present invention.

 That is, the present invention relates to a proline derivative represented by the following formula or a salt thereof.

(In the formula, ring A has 1 to 4 hetero atoms as ring constituent atoms, and is a halogen atom. It is a 5- to 6-membered heterocyclic group that may be condensed with an optionally substituted benzene ring.

 p1 is an integer of 0 or 1, p2 is an integer of 0 or 1, and p3 is an integer of 0 or 1.

Ri, R ₂ and R ₃ are bonded at any position on the A ring, and are the same or different and each has 1 to 3 halogen atoms or hydroxy groups (the hydroxy groups are protected with an acyl group). May be substituted with a lower alkyl group, a hydrogen atom, a lower alkoxy group, a lower alkylthio group, a halogen atom, a hydroxy group, an amino group, or an aminocarbonyl group (the amino group is protected or lower alkyl). May be mono- or di-substituted), a hydroxy lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkyl group, a lower alkyl group, a lower alkyl group optionally substituted with 1 to 3 halogen atoms. It means a sulfonyloxy group or a cyano group, or when pl = p 2 = l, it is bound to the same carbon atom. Fine R ₂ Gar緖since it either forms a Okiso group, or when pl = p 2 = p 3 = 1, and R ₂ is a hydrogen atom, a saturated or unsaturated in R ₃ is 5-6 membered A saturated cyclic group (a), which is directly bonded to the A ring, or bonded via a carbonyl group, an imino lower alkylene or an oxy lower alkylene; It may contain two hetero atoms, and the cyclic group (a) may be substituted with a lower alkyl group optionally substituted with a halogen atom or a halogen atom. '

 T represents a single bond, a methylene group or a heptonyl group.

R 4 and R ₅ may be the same or different and each may be a hydrogen atom or a lower alkyl group, or both bonded to the same carbon atom may be combined to form an oxo group.

 m is an integer of 1 or 2.

R ₆ and R ₇ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, a lower alkyl group, a phenyl group, a lower alkoxy group, a phenyl lower alkyloxy group, an amino group which may be protected, Both may combine to form a saturated cyclic group. X is a carbon atom (CH ₂ , CH, C), a zeo atom or an oxygen atom, and n is an integer of 1 or 2.

 Y is a hydrogen atom or an amino protecting group or a group (b) represented by the following formula.

Wherein R ₈ is an alkyl group or a cycloalkyl lower alkyl group, R ₉ is a hydrogen atom or a hydroxy protecting group, or R _9a . Here, R _9a is R _9al -CO-, R _{9a2 -0-} CO-, R _9a3- (CH ₂ ) p-, and R _9al is a lower alkyl group (the lower alkyl group is a phenyl group, Or a mono-lower alkyl-substituted amino group, or substituted with a 6-membered saturated cyclic amino group. either a saturated cyclic amino group which may 6 membered and has, optionally substituted by hydroxyl C ₆ - C io Ariru group in which force ,, or a benzene ring condensed with or 5-6 membered also It means a saturated or unsaturated heterocyclic group.

R _9a2 represents a lower alkyl group, a power which is a cycloalkyl group which may be substituted with lower alkyl, or a 5-membered saturated cyclic ester residue which may be substituted with lower alkyl.

R ₉ a3 represents a 5-membered saturated or unsaturated cyclic ester residue or cyclic carbonate residue which may be substituted with lower alkyl or condensed with a benzene ring, and p is 0 or 1. It is an integer. )

 ,

BEST MODE FOR CARRYING OUT THE INVENTION

 The compound (I) of the present invention can be divided into two groups having a common main structure but different characteristics.

The first group is a proline derivative represented by the following formula (I-A) or a salt thereof, wherein Y is a substituent W (hydrogen atom or amino protecting group).

 (In the formula, w is a hydrogen atom or an amino protecting group, and the definitions of other substituents and symbols are the same as those defined above.)

 The second group is a proline derivative (IB) or a salt thereof, wherein Y is represented by the formula (b). '

 (In the formula, the definition of each symbol and substituent is the same as the definition described above.)

Compound (I-A) is an intermediate for producing compound (I_B), and among compounds (I-B), compounds in which R ₉ is H or R _9a [hereinafter, referred to as compound (I-B) ' Has a strong antibacterial effect, especially against multidrug-resistant bacteria such as MRSA, and is useful as an antibacterial agent.

The structural features of the compound (IB) include (i) the presence of ring A, (ii) having at least three heterocyclic groups consisting of ring A, ring B, and ring C, (Iii) ring A and ring B are linked via T; (iv) N-formyl-N-〇R ₉ _ amine moiety; (V) substituent R ₈ is present And the combination of these, especially (i), (ii) and (iii), above all, (i) is the essence of the feature. Among the compounds of the present invention (I-B), a compound suitable as an antibacterial agent is represented by the following general formula (I-C) wherein R _{9 in} the general formula (I-B) is H and ring A is a ring. It is a phosphorus derivative or a salt thereof represented.

(Wherein, the definitions of R ₂ , R ₃ , R ₄ , R ₅ , n, 1, p 2, p 3 and R ₈ are the same as those defined in claim 1, and the ring has 1 to 3 rings. An unsaturated 5- to 6-membered monocyclic heterocyclic group having a double bond, and the heterocyclic group may be condensed with a benzene ring which may be substituted with a halogen atom; Z ₂ , Z ₃ and Z ₄ are the same or different and are atoms selected from a carbon atom (CH ₂ , CH or C), a nitrogen atom (NH or N), a zeolite atom and an oxygen atom. , Z ₁ Z ₂ , Z ₃ and Z ₄ may be absent, and Ri, R ₂ and R ₃ may be bonded to any of the ring-forming carbon or nitrogen atoms. shall have. R _6al and R _7Al are the same or different, a hydrogen atom, a lower alkyl group, a c androgenic atom or a lower alkoxy group, X _al is TansoHara (CH _2, CH or C) means or an oxygen atom.)

 Among the compounds of the present invention (I_C), a compound particularly suitable as an antibacterial agent is a proline derivative represented by the following general formula (I-D) or a salt thereof.

(I-D)

(Wherein, the definition of R ₈ is the same as defined above, U is a nitrogen atom or a sulfur atom, R _la is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and the two parts of Z are (It means the absence of a single bond, a double bond or a bond, so the _Ala ring is 5 or 6 members.)

When the moiety means the absence of a bond, the A _la ring shows:

Further, among the compounds (I-B) of the present invention, the compound (IE) in which R ₉ is R _9a and salts thereof also have excellent antibacterial activity.

(l-f

 (In the formula, the definition of each symbol and substituent is the same as the definition described above.) Specific examples of the compounds useful as antibacterial agents among the compounds of the present invention are shown below.

Compound D _ 1— 1

 (2S)-1-{(2R) 13-cyclopentyl 12-[(N-formyl-N-hydroxyamino) methyl] propionyl} -2-{[4- (2-pyrimidinyl) _1-piperazinyl] carbonyl} pyrrolidine;

Compound D-2— 1

 (2S) -1-{(2R) -2-[(N-formyl-N-hydroxyamino) methyl] hexanoyl} -2-{[4- (2-pyrimidinyl) 1-1-piperazinyl] carbo Nyl} pyrrolidine;

Compound D— 3— 1

 (2 S)-1-{(2R) 13 -cyclopentyl-2-[[(N-formyl- N -hydroxyamino) methyl] propionyl] 1 2-{[4- (2-thiazolyl) — 1-piperazinyl] pyrrolidine pyrrolidine;

Compound D—4-1

(2S) -1-{(2R) -2-[(N-formyl-N-hydroxyamino) methyl] hexanoyl} -2-{[4- (2-thiazolyl) -1-piperazine Nil] pyrrolidine pyrrolidine;

Compound D—5

 (2 S)-1-K2R) -2- [(N-formyl-1-N-hydroxyamino) methyl] hexanoyl}-2- {[4- (4-methyl-2-thiazolyl) -1-1-piperazinyl] Liponyl} pyrrolidine;

Compound D—6

 (1 S, 2 S, 5 R) —3—aza— 3— {(2R) -1-2 — [(N-formyl-1-N-hydroxyamino) methyl] heptanoyl} -2- {[4- (2 —Pyrimidel) — 1-piperazinyl] bicyclopropyl} bicyclo [3.1.0] hexan;

Compound D— 7 1

 (2S) -1-{(2R) -2-[(N-formyl-1-N-hydroxyamino) methyl] hepnoyl}-2--[[4- (2-thiazolyl) -1-1-piperazini Le] carbonyl} pyrrolidine;

Compound D—8

 (2 S) ― 1-{(2R) -2- [(N-formyl-N-hydroxyamino) methyl] heptanyl} — 2— {[4- (4-Methyl_ 2 _thiazolyl) -1-piperazinyl Carbonyl] pyrrolidine;

Compound D—9

 (2S) -2-{[4- (5-promo-2-thiazolyl) -1-1-piperazinyl] capillonyl}-1-{(2R) — 2 — [(N-formyl-N-hydroxyamino ) Methyl] heptanoyl} pyrrolidine;

Compound D—10

 (2 S) —2— {[4- (2-Benzothiazolyl) -1-piperazinyl] power rupoyl}-1-{(2 R)-2-[(N-formyl-N-hydroxyamino) methyl] Heptanyl} pyrrolidine;

Compound D—1 1 1 1

(2S) -1-{(2R) -1-cyclopentyl-2--2-[(N-formyl-N-hydroxyamino) methyl] propionyl} 1-2-{[4- (4-methyl-12 1-Phiazolyl) -1-piperazinyl] pyrrolidine pyrrolidine; Compound D-12

 (2 S, 3 S) ― 1-{(2 R) —2— [(N-formyl-N-hydroxyamino) methyl] hepnoyl} 1 3-methyl _ 2— {[4- (2- Pyrimidinyl) —1-piperazinyl] pyrrolidine pyrrolidine;

Compound D— 13

 (2 S) —4,4-difluoro-11-{(2 R) -2-[(N-formyl-N-hydroxyamino) methyl] hepnoyl} 1 2— {[4- (2-pyrimidinyl 1-piperazinyl] pyrrolidine pyrrolidine;

Compound D _ 14

 (2S) -1 -K2R) -2-[(N-formyl-1-N-hydroxyamino) methyl] heptanoyl} 1-2-{[4- (6-Methoxy-2-pyridyl) -1-piperazinyl] carbonyl } Pyrrolidine;

Compound D—15

 (2 S) -2- {[4- (6 _C1 -2-pyrazinyl) -1 1-piperazinyl] carbonyl}-1-{(2 R)-2-[(N-formyl- N— Hydroxyamino) methyl] hepnoyl pyrrolidine;

Compound D—16-1

 (2 S) — 1— {(2R) 13-cyclohexyl-2 -— [(N-formyl-N-hydroxyamino) methyl] propionyl} -2-{[4- (2-thiazolyl ) 1-piperazinyl] pyrrolidine pyrrolidine. Next, each substituent and symbol will be described.

Ring A in compound (I) of the present invention has 1 to 4 heteroatoms as ring-constituting atoms, and may be condensed with a benzene ring which may be substituted with a halogen atom. Is a heterocyclic group. Here, the hetero atom is selected from, for example, a nitrogen atom, an iodine atom or an oxygen atom, and preferably contains at least one nitrogen atom. Ring A may be saturated, but is preferably unsaturated. Ring A and ring B are linked via T, but nitrogen atom on ring B and carbon atom on ring A And a direct bond (hereinafter, referred to as an “N—C bond”, in which case T is a single bond).

 Specific examples of the 5- to 6-membered heterocyclic group represented by Ring A include, but are not limited to, for example, pyridyl, pyrael, chenyl, furyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, tetrahydrofuryl and the like. A monocyclic heterocyclic group having one heteroatom; a monocyclic ring having two heteroatoms such as pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, and piperazinyl Heterocyclic groups; monocyclic heterocyclic groups having 3 to 4 heteroatoms such as tetrazolyl, 1,3,5_triazinyl, 1,2,4-triazinyl, tetrazinyl, thiadiazolyl and monocyclic rings thereof A condensed heterocyclic group obtained by condensing a heterocyclic group and a benzene ring is exemplified. Examples of such a fused heterocyclic group include isoquinolyl, quinolyl, quinoxalinyl, naphthyridinyl, benzothiazolyl, and benzoxazolyl.

Among these 5- to 6-membered heterocyclic groups represented by the ring A, more specifically, A _ia of the general formula (I-D), such as the ring A i of the general formula ( _{I_C} ) It is preferable that a nitrogen atom, which is a hetero atom, be present next to the bonding site on the C side of the N—C bond, such as a ring. The most preferred examples of such a heterocyclic group include pyrimidinyl and thiazolyl.

The substituent Ri, R ₂ or R ₃ in the compound (I) of the present invention may be substituted at any position of the ring A, but preferably binds to a carbon atom on the ring A. , R ₂ and R ₃ include, as one substituent, a lower alkyl group which may be substituted with 1 to 3 halogen atoms or a hydroxy group (the hydroxy group may be protected with acyl). There is. In this specification, the term “lower” means that the hydrocarbon moiety of the group to which this term is attached has 1 to 6 carbon atoms, unless otherwise specified. Examples of the “lower alkyl” include straight or branched ones such as methyl, ethyl, propylyl, isopropyl, butyl, isobutyl, -butyl, pentyl, and hexyl. The term “halogen atom” means fluorine, chlorine, bromine, and iodine. Accordingly, the “lower alkyl group substituted with 1 to 3 halogen atoms” includes, for example, trifluoromethyl. You. Examples of "acyl" include lower aliphatic acyl groups such as acetyl, propionyl, and piperoyl.

 In the present specification, “lower alkoxy” is a lower alkyloxy group whose lower alkyl moiety has the above-mentioned meaning, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

 In the present specification, the “lower alkylthio group” is a lower alkylthio group in which the lower alkyl moiety has the above-mentioned meaning, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, monobutylthio, pentylthio, and hexylthio. And straight-chain or branched ones.

 In the present specification, the “mono-lower alkylamino” is a mono-lower alkylamino group whose lower alkyl moiety has the above-mentioned meaning, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isoptylamino, —butylamino, pentylamino. And linear or branched ones such as hexylamino.

 In the present specification, the “di-lower alkylamino” is a di-lower alkylamino group in which the lower alkyl moiety has the above-mentioned meaning, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino. And linear or branched ones such as, di-butylamino, dipentylamino, and dihexylamino.

 In the present specification, "mono-lower alkylaminocarbonyl" is a mono-lower alkylaminocarbonyl group having a lower alkyl moiety having the above-mentioned meaning, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl. Examples thereof include linear or branched ones such as bonyl, isopropylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, t-butylaminocarbonyl, pentylaminocarbonyl, and hexylaminocarbonyl.

In the present specification, “di-lower alkylaminocarbonyl” is a di-lower alkylaminocarbonyl group in which the lower alkyl moiety has the above-mentioned meaning, for example, dimethylaminocarbonyl, getylaminocarbonyl, dipropylamino Minocarbonyl, diisopropylaminocarbonyl, dibutylaminopropyl, diiso Linear or branched ones such as butylaminopropyl, di-pentylaminopropyl, dipentylaminopropyl, dihexylaminocarbonyl and the like can be mentioned.

 In the present specification, “hydroxy lower alkylamino” is a hydroxy lower alkylamino group whose lower alkyl moiety has the above-mentioned meaning, for example, hydroxymethylamino, 2-hydroxyethylamino, 3-hydroxy Propylamino, 2-hydroxy-1-methyl-1-ethaneamine, 4-hydroxybutylamino, 2-hydroxy-1-methyl-1-propanamine, 2-hydroxy-1,1,1-dimethyl-1-ethaneamine, 5-hydroxypentylamino And linear or branched ones such as 6-hydroxyhexylamino. In the present specification, "lower alkoxycarbonyl" is a lower alkoxycarbonyl group whose lower alkyl moiety has the above-mentioned meaning, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Examples thereof include linear or branched ones such as butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

 As used herein, the term "lower alkylcarbonyloxy" refers to a lower alkylcarbonyloxy having a lower alkyl moiety having the above-mentioned meaning, and includes methylcaplonoxy, ethylcarbonyloxy, propylcarbonyloxy, and isopropoxy. Examples thereof include linear or branched ones such as pyroxycarbonyl, butylcarbonyloxy, isobutylcarbonyloxy, -butylcarbonyloxy, pentylcarbonyloxy, and hexylcarbonyloxy.

In the present specification, the “lower alkylsulfonyloxy group” is a lower alkylsulfonyloxy group in which the lower alkyl moiety has the above-mentioned meaning, such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, and isopropanol. Examples thereof include linear or branched ones such as pyrsulfonyloxy, butylsulfonyloxy, isoptylsulfonyloxy, -butylsulfonyloxy, pentylsulfonyloxy, and hexylsulfonyloxy. The “lower alkylsulfonyloxy group substituted with 1 to 3 halogen atoms” includes trifluoro A methylsulfonyloxy group is exemplified.

In the present specification, examples of the “imino lower alkylene group” include —NH (CH ₂ ) _q — (Q is an integer of 1 to 6), and an iminomethylene group is preferable.

In the present specification, examples of the “oxy lower alkylene group” include 1 O (CH ₂ ) _g − (q is an integer of 1 to 6), and an oxymethylene group is preferable.

 In the present specification, the “phenyl lower alkyloxy group” is a phenyl lower alkyloxy group whose lower alkyl moiety has the above-mentioned meaning, and is a linear or branched such as benzyloxy, phenethyloxy, 3_phenylpropyloxy and the like. One.

Examples of the saturated cyclic group formed by combining R ₆ and R ₇ include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

 In this specification, the terms “the amino group is protected”, “optionally protected amino group” or “amino protecting group” are used. As a description of "protecting group for amino group". As the "protecting group for an amino group" in the present specification, those commonly used in the field of chemistry, particularly in the field of peptide chemistry are used.

Examples of the “protecting group for an amino group” include those capable of reductive elimination and those capable of hydrolytic elimination. Examples of the "protecting group for an amino group" that can be reductively eliminated include an arylsulfonyl group such as P-toluenesulfonyl; a methyl group substituted by phenyl or benzyloxy such as benzyl, trityl and benzyloxymethyl; Benzyloxycarbonyl ゃ arylmethoxycarbonyl such as P-methoxybenzyloxycarbonyl; halogenoethoxycarbonyl groups such as 2,2,2-trichloromouth ethoxycarbonyl and 2-thioethoxycarbonyl. As On the other hand, the “protecting group for the amino group” that can be hydrolytically removed includes ethoxycarponyl ゃ B0Cίbutoxycarbonyl, benzyloxycarponyl, Ρ-methoxybenzyloxycarponyl, vinyloxycarponyl And oxycarbonyl groups such as 2-tosylethoxycarbonyl; carbonyl groups such as formyl, acetyl, 1, and rifluoroacetyl; and ο-ditrophenylsulfenyl, 1, rimethylsilyl. , Tetrahydropi Ranyl, diphenylphosphinyl and the like are exemplified.

When two amino groups are present in the same molecule, one is an "amino group protecting group" that can be hydrolytically eliminated, and the other is an "amino group protecting group" that can be reductively eliminated. It is a good idea to adopt it. For example, as the “protecting group for the amino group” in the “amino group or aminolponyl group (the amino group is protected)” for R ₂ or R _3, those that can be reductively eliminated are used. It is preferable to select a “protecting group for an amino group” that can be hydrolytically eliminated as an amino protecting group for Y.

Examples of the “5- to 6-membered saturated or unsaturated cyclic group (a)” for R ₃ include, but are not limited to, phenyl, adamantyl, pyridyl, piperazinyl, morpholinyl, morpholino, pyrazinyl, tetrahydro Examples thereof include a furyl group and the like, and these cyclic groups (a) may be substituted with a lower alkyl group such as methyl or ethyl or a halogen atom. These cyclic groups (a) are bonded to the ring A via a direct bond; a carboxylic acid; an imino lower alkylene such as iminomethylene; or an oxy lower alkylene such as oxymethylene.

The “alkyl group” defined as R ₈ may be linear or branched as long as it has 2 to 10 carbon atoms, but is preferably linear. Preferred alkyl groups are those having 4 to 7 carbon atoms, particularly preferably 13-butyl or 3-pentyl. Examples of cycloalkyl in “cycloalkyl lower alkyl” defined as R ₈ include those having 4 to 7, preferably 5 or 6 carbon atoms, and lower alkyl having 1 to 4 carbon atoms. , Preferably methyl or ethyl. Accordingly, specific examples of suitable “cycloalkyl lower alkyl” include a cyclobenzylmethyl group and a cyclohexylmethyl group.

The “hydroxy protecting group” defined as R ₉ is not particularly limited as long as it can be eliminated by chemical means, and examples include benzyl and 2,4-dimethoxyphenylmethyl. Of these, 2,4-dimethoxyphenylmethyl which is easily desorbed is preferred. The compound having a hydroxy protecting group (I-B) has no antibacterial activity.

A lower alkyl group defined as R _9al (the lower alkyl group may be one or two selected from a phenyl group, a protected amino group and a carbonyl group); May be substituted with a group) ”, for example, include a methyl group, a -butyl group, a 3-force propyloxy group, a 2-phenyl-1-(-butoxycarponyl) aminoethyl group, and the like. _{Specific examples} of the “mono-lower alkyl-substituted amino group” or the “6-membered saturated cyclic amino group which may be substituted with a 6-membered saturated cyclic amino group” for R 9al include -butylamino, 4-piperidinyl-1- And a piperidinyl group. Specific examples of the "C ₆ -C ₁₀ aryl group optionally substituted with a hydroxyl group" for R _9al include a phenyl group, a 2-hydroxyphenyl group, a 1- or 2-naphthyl group, and the like. Specific examples of the 5- or 6-membered saturated or unsaturated heterocyclic group which may be condensed with a ring include 3-pyridyl, 2-pyrrolyl, 3-quinolyl, 2-indolyl, 2- Examples include a phenyl group, a 3-furyl group, and a morpholino group.

_{Specific examples} of the “lower alkyl group” and the “cycloalkyl group _optionally substituted with lower alkyl” for R _9a2 include isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-isopropyl-5 -Methylcyclohexyl group. As an _example of the “5-membered saturated cyclic ester residue _optionally substituted with lower alkyl” in R _9a2 , a group represented by the following formula (c) is substituted with “lower alkyl” in R _9a3 . Examples of the 5-membered saturated or unsaturated cyclic ester residue or cyclic carbonate residue which may be condensed with a benzene ring include groups represented by the following formulas (d) and (e). Is mentioned.

( ^c ) (Φ (e)

The compound (I) of the present invention can form an acid addition salt between a basic nitrogen atom in the molecule and an acid. Examples of the acid addition salt include salts with an organic acid such as tartaric acid, fumaric acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, dalconic acid, and aspartic acid, or hydrochloric acid And salts with inorganic acids such as phosphoric acid and the like. Further, in the N-formyl-N-hydroxyamine portion of the compound of the present invention, a metal salt such as sodium, potassium or calcium may be formed. The compound (I) of the present invention sometimes exists as a hydrate or solvate, or as a stereoisomer such as an optical isomer or a mixture thereof, and all of them are included in the present invention. Is done.

Next, a method for producing the compound (I) of the present invention will be described. The compound of the present invention is advantageously produced, for example, according to the reaction formula shown below. In the following scheme, W 'is an amino protecting group and R ₉ ' is a hydroxy protecting group. The definitions of other substituents or symbols are the same as those defined above.

Method for producing the compound of the present invention

Process 1

 Step 1 is a step of reacting compound (1) with compound (2) (amidation reaction) to form a new compound (IA-1). This step can be performed according to a conventional method for peptide production. For example, this step is carried out in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and a reaction accelerator such as 1-hydroxybenzotriazole. It can be carried out by mixing and stirring both starting compounds in a solvent such as methylene. When the compound (2) forms an acid addition salt, the reaction is preferably performed in the presence of a base such as triethylamine. This step is performed at -10 ° C to 45 ° C for 1 hour to 3 days.

 The compound (1) is known, and the compound (2) is mostly known, and can be easily prepared from a known compound by a known method.

 Process 2

 Step 2 is a step of removing the amino protecting group W ′ of the compound (I-A-1) produced in Step 1 to give the compound (I-A-2). Elimination can be carried out reductively or hydrolytically, depending on the nature of the amino protecting group W '. Usually, it is preferably carried out by hydrolysis, preferably by acid decomposition, and it is good to select an amino protecting group W ′ suitable for acid decomposition. Boc is suitable as W ′ suitable for acid decomposition. The elimination of the amino-protecting group W 'by acidolysis can be carried out by contacting the compound (I-A-1) with an acid in a solvent at −10 ° C. to 100 ° C., preferably 0 ° C. to room temperature. Can be implemented. Examples of the acid include hydrogen chloride and trifluoroacetic acid, and examples of the solvent include ethyl acetate, 1,4-dioxane, and methylene chloride.

 The compound (I-A-2) thus obtained is used as a starting material in the next step 3. Process 3

 Step 3 can be carried out by reacting compound (3) with compound (I-A-2) in the same manner as in step 1 (amidation reaction) to give compound (IB-1). Compound (3) can be advantageously produced by the method described in Reference Examples below or a method analogous thereto.

 Process 4

Step 4 is to remove the hydroxyl-protecting group R ₉ ′ of compound (I-B-1) This is the process of making a product (I-B-2). This step is carried out by adding an acid such as trifluoroacetic acid to the compound (I-B-1) in a solvent such as methylene chloride and mixing and stirring at 110 ° C. to 45 ° C. for 1 to 20 hours. it can.

 Process 5

Step 5 is a step of modifying the hydroxy group of (I-B-2) to give compound (I-E). This step is a base such as the presence of pyridine, to (I- B- 2), for example, 9aR to 〇- teeth 1, J 9a2'0- C 0 "C 1, Rg a 3- ( by H ₂ Bruno _p - 1 (i ^ 9al, R9a2, θα3 and Ρ are as defined above) or an alkylating agent such as an alkyl halide; The compound of the present invention thus prepared can be converted to another compound of the present invention as appropriate, for example, by protecting Ri, R ₂ , R ₃ , R ₆ or R ₇ with “protection”. When an “amino group”, a lower alkoxycarbonyl group or a lower alkylcarbonyloxy group is present, these can be converted into an amino group, a propyloxyl group or a hydroxy group, or vice versa. When a mixture of stereoisomers such as optical isomers is obtained, a conventional method is used. Purification of these can be separated. The product can be carried out by solvent washing Kiyoshiya silica gel column chromatography scratch. Example

 Next, the present invention will be described in more detail with reference to Production Examples or Reference Examples. The following Production Examples or Reference Examples

 Series A: Raw material (2) and production of its Boc body,

 Series B: Production of intermediates (I-A-1)

 Series C: Production of raw material (3) and

 Series D: Production of the compound of the present invention (I-B)

The compounds produced in each step are characterized by 30 OMHz iH-NMR. Compounds produced in Series D are amorphous unless otherwise specified and must be subjected to high performance liquid chromatography under the following conditions. The physical properties may be clarified by the retention time of the raffle (the time from the injection of the compound of the present invention to the silica gel column to the discharge thereof).

Retention time (T r) measurement conditions: Dimethyl sulfoxide solution 0.11 of the compound adjusted to a concentration of 5 Omg / m 1 was columned with CAPCELL PAC C ₁₈ SG 120 (4.6 mm X 250 mm, Inc.) Injected into Shiseido (Shiseido Co., Ltd.)), and at a measurement temperature of 40 ° C, a solvent of acetonitrile: 0.05% trifluoroacetic acid water = 35:65 was flowed at a flow rate of lm1 / min, and the detection wavelength was 254 nm. The peak appearance time derived from the compound was determined, and this was defined as the retention time (Tr). The retention time (Tr) of methanol under these conditions was 2.89 minutes.

 The abbreviations used in the following production examples are defined as follows. WSC: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

 DMAP: 4- (N, N-dimethylamino) pyridine

 THF: tetrahydrofuran

Me: Metile

 E t: Ethil

 B u: butyl

 P h: phenyl

 Ac: Acetyl

Boc: f-butoxycarponyl

 11-: Normal,

 f- or t 6 Γt— ', Yuichi Shariichi Series A: Production of the starting compound (2) and its Boc form

Reference example A-1

4- [2-(4,6-dichloro-1,3,5-triazinyl)] piperazine 1 1-butyl ribonate

 2,4,6-Triclo 1,1,3,5-triazine 2.04 g (11.1 mmo 1) of acetonitrile solution in 100 ml of acetonitrile solution 60 ml of an acetonitrile solution containing 6 mmo 1) and 2.5 g (25.2 mmo 1) of triethylamine was added dropwise and stirred at room temperature for 3 hours. After concentration, the mixture was extracted with chloroform to obtain 3.7 g of crude crystals. This was purified by silica gel column chromatography (form-form / methanol = 250/1) to give 4- [2- (4,6-dichloro-1,3,5-triazinyl)] piperazine-1-carbonic acid —1.44 g (41% yield) of butyl ester was obtained.

_{^{X H-NMR (CDC 1 3}} ): (5 / p pm 1. 48 (9H, s), 3. 51 (4 H, t, J = 5. 1 Hz), 3. 86 (4H, t, J = 5.1 Hz). Reference examples A-2 and A-7

The following compound was obtained in the same manner as described in Reference Example A-1 _c

Production of Boc form of raw material compound (2)

Reference Example A-8

4- [2- (1,35-triazinyl)] carboxylic acid t-butyl ester

70 g of a solution of 1.44 g (4.3 mmol) of the compound obtained in Reference Example A_ 1 in 14 dioxane was cooled on ice, and 0.43 g of 10% Pd—C0 Min 1. O g (l Ommol) was added, and the mixture was catalytically reduced at room temperature under a hydrogen atmosphere. After filtering to remove the catalyst, the filtrate was concentrated to obtain a crude product. This was purified by silica gel column chromatography (Chromate form Z methanol = 100/1) to give 4- [2— (1,3,5-triazinyl)] piperazine-1 0.94 g (yield 82%) of the butyl ester was obtained.

_{^{X H-NMR (CDC 1 3}} ): 5 / P pm 1. 49 (9H, s), 3. 46- 3. 54 (4H, m), 3. 80- 3. 90 (4H, m), 8 . 54 (2H, s). Reference example A_ 9 to A_ 10

The following compound was obtained in the same manner as described in Reference Example A-8 _c

 Table 2 Production of Boc form of raw material compound (2)

Reference Example A-11

2- [4-(/-butoxycarbonyl) 1-piperazinyl] 1-5 _morpholino 1 1,3,4-oxaziazol

(1) A solution of 1 g (5.9 mmo 1) of 2-amino-5-morpholino-1,3,4-oxadiazole in acetonitrile was cooled with ice and mixed with 1.59 g of copper (II) bromide (7. lmmo 1) and 0.92 g (8.9 mmo 1) of nitrite / monobutyl were added and stirred for 30 minutes. After returning to room temperature and stirring for 1 hour, dilute aqueous hydrochloric acid and chloroform were added to the reaction solution to extract the desired product into the organic layer, which was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated, and then purified by silica gel column chromatography (cloform form Z methanol = 30/1) to give 2-promo 5-morpholino-1,3,4-oxadiazole 73 Omg (yield) 5 3%).

4 one _{NMR (CDC 1 3): 6} / p pm 3. 47 - 3. 54 (4H, m), 3. 7 6 - 3. 8 3 (4H, m).

 (2) 2- [4-(/-Butoxycarponyl) -11-piperazinyl] -5-morpholino-1,3,4-oxaziazol was obtained in the same manner as described in Reference Example A-1.

_{■ i- NMR (CDC 1 3)} : δ / ρ pm 1. 48 (9H, s), 3. 3 2 - 3. 42 (8H, m), 3. 49- 3. 5 7 (4H, m) , 3.75-3.81 (4H, m). Reference example A- 2 to A_ 13

 The following compounds were obtained in the same manner as described in Reference Example A-11. C

 Table 3 Production of Boc form of raw material compound (2)

Reference example A-14

4- {2- [4- (3-pyridyl) thiazolyl]} piperazine-1-butyl carboxylate

 Known in the literature: 4-Dithiocarbamoylpiperazine-111-Rubonic acid-Ptilester 1.31 g (5.3 mmol), diisopropylethylamine 1.86 ml (10.7 mmol) and a mixture of ethanol 24 ml 1.5 g (5.3 mmo 1) of 3- (bromoacetyl) pyridinepyridine hydrochloride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 1.86 g (yield 100%) of 4_ {2- [4- (3-pyridyl) thiazolyl: 1} piperazine-11-carboxylic acid-butyl ester was obtained. Obtained.

_{^ -i-NMR (CDC 1 3} ):. ά / ρ pm 1. 49 (9H, s), 3. 50-3 66 (8H m), 6. 89 (1H s), 7. 30 (1 H , dd J = 4.8, 7.9 Hz), 8.11 (1H, ddd, J = 1.5, 1.8, 7.9 Hz), 8.52 (1H, dd, J = 1.5, 4.8 Hz), 9.06 (1 H, d, J = 1.8 Hz). Reference example A—15 to A 17

The following compounds were obtained in the same manner as described in Reference Example A-14 _c

 Table 4 Production of Boc form of raw material compound (2)

Reference example A_ 18

4- [2-(4-Chloro-6-ethoxy-1,3,5-triazinyl)] piperazine-one-butane monobutyl ester

 2,4,6_Trichloro-1,3,5-triazine 1.98 g (10.8 mmo 1), sodium bicarbonate 2.57 g (30.6 mmo 1) and ethanol 25 ml 1 80 ml of an ethanol solution of 1.94 g (10.4 mmo 1) of rosin-l-rubinic acid monobutyl ester was added and stirred at room temperature with stirring. Water is added and the crystals are filtered, washed successively with isopropanol and diisopropyl ether, and washed with 4- [2- (4-chloro-6_ethoxy-1,3,5-triazinyl)] piperazine-1 rubourone 2.12 g (yield 61%) of acid monobutyl ester was obtained.

_{- NMR (CDC 1 3):} δ / ρ pm 1. 40 (3H, t, J = 7. 5Hz), 1. 48 (9H, s), 3. 46- 3. 55 (4H, m), 3 77— 3.90 (4 H, m), 4.41 (2H, q, J = 7.5 Hz). Reference example A 19

4- [2— (4-ethoxy-1,3,5-triazinyl)] piperazine 1-force rubonic acid monobutyl ester

 The compound obtained in Reference Example A-18 was subjected to catalytic reduction in the same manner as described in Reference Example A-8 to obtain the title compound.

^X H-NMR (CDC 1: δ / ρ pm 1.42 (3H, t, J = 7.1 Hz), 1.49 (9H, s), 3.43—3.57 (4H, m), 3 73-3.93 (4 H, brs), 4.39 (2H, q, J = 7.1 Hz), 8.35 (1H, s). Reference Example A-20

4- [2- (4_Benzyloxypyrimidinyl)] piperazine-1-carboxylic acid ブ チ ル -butyl ester, and 4- [4- (2_Benzyloxypyrimidinyl)] piperazine-1-carboxylic acid Monobutyl ester

 (1) 4.4 g (0.1 lmo 1) of 60% sodium hydride was added to a 200 ml solution of benzyl alcohol (10.8 g, 0.1 lmo 1) in 200 ml of THF under ice cooling, followed by stirring. This reaction suspension was slowly added to a solution of 15 g (0.1 ml) of 2,4-dichloropyrimidine in 200 ml of THF under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with aqueous acetic acid and concentrated under reduced pressure. To the residue was added chloroform and water, and the desired product was extracted into the organic layer. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 4-benzoyloxy 2-cyclopyrimidine and its positional isomer. A mixture of benzyloxy 41-pyrimidine 25.0 was obtained.

(2) 25.0 g of the mixture obtained above was mixed with 22.35 g (0.12 mo 1) of piperazine-1 t-butyl rubrate and 16.8 g (0.2 mol 1) of sodium hydrogen carbonate Was added and the mixture was stirred in ethanol at 80 ° C. overnight. After concentrating the reaction solution under reduced pressure, chloroform and water were added to the residue to extract the desired product into an organic layer. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography-(ethyl acetate / hexane = 1/2 to 1Z1) to give 4- [2-((4-benzyloxypyrimidinyl)). ] Piperazine-1-carboxylic acid monobutyl ester 21.1 g (57% yield) and its positional isomer, 4_ [4-1-(2-benzyloxypyrimidinyl)] piperazine-1- There were obtained 14.4 g (yield: 39%) of sodium butyl sulfonate.

4- [2- (4-benzyloxypyrimidinyl)] piperazine-1-carboxylic acid monobutyl ester _{^{: H-NM (CDC 1 3}} ): δ / ρ m 1. 49 (9H, s), 3. 45-3.

49 (4H, m), 3.76-3.80 (4H, m), 5.34 (2H, s), 6.42 (1H, d, J = 5.7 Hz), 7.30- 7. 44 (5H, m), 8.07

(1H, d, J = 5.7Hz).

4- [4- (2-benzyloxypyrimidinyl)] pirazazine

_{^{X H-NMR (CDC 1 3}} ): δ / pm 1. 48 (9 H, s), 3. 47- 3.

50 (4H, m), 3.60-3.64 (4H, m), 5.36 (2H, s), 6.16 (1H, d, J = 6.1 Hz), 7.25-7. 50 (5H, m), 8.05 (1H, d, J = 6.1 Hz). Reference Example A— 21

4- [2- (4-Hydroxypyrimidinyl)] piperazine-1-carboxylic acid t-butyl ester

 Reference Example A—A solution of 14.8 g (40 mmo 1) of 4- [2-((4-benzyloxypyrimidinyl)] piperazine-l-carboxylic acid-butyl ester obtained in Example 20) Was cooled on ice, 5 g of 10% Pd—CO. Was added, and the mixture was catalytically reduced at room temperature under a hydrogen atmosphere. After the completion of the reaction, chloroform was added to the precipitated crystals to dissolve, and then the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 13.2 g (100%) of 4- [2- (4-hydroxypyrimidinyl)] pirazine_1_carboxylic acid-butyl ester.

_{^ -NMR (CDC 1 3):} . (5 / ppm 1. 49 (9H, s), 3. 52-3 55 (4H, m), 3. 72 - 3. 75 (4H, m), 5. 77 (1H, d, J = 6.2Hz), 7.76 (1H, d, J = 6.2Hz), 12.05 (1H, brs). Reference Example A—22

4- (1,3,5-trimethyl-4_pyrazolyl) piperazine-one-butane-butyric acid mono-butyl ester ''

 (1) A mixture of bis (2-chloroethyl) amine hydrochloride 10 g (56.0 mmol), dichloromethane 84 ml and 10% aqueous sodium hydroxide solution 56 ml was mixed with di-butyl dicarbonate 12.9 ml (56. Omol) was added and stirred overnight. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was distilled off to obtain 13.8 g (100% yield) of butyl Ν, Ν-bis (2-chloroethyl) power.

_{- NMR (CDC 1 3):} S / P pm 1. 47 (9H, s), 3. 66 (8 H, m).

(2) The above product 3.04 g (12.6 mmol), 4-amino-1,3,5-trimethylvirazole 1.43 g (11.4 mmol 1), triethylamine 3.5 ml (25.lmmo l) ) And 1,4-dioxane 18 ml were heated to reflux overnight. The solvent was distilled off, water and ethyl acetate were added, and the mixture was separated. The organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off, and the crude product was purified by basic silica gel column chromatography (ethyl acetate / 1-hexane = 1/1) to give 4- (1,3,5-trimethyl-4-pyrazolyl) pidazine There was obtained 58 Omg (yield 17%) of monobutyl ribonate.

_{- NMR (CDC 1 3):} δ / ρ pm 1. 33, 1. 48 (total 9 H, bo ths), 1. 63 (3H, s), 2. 16 (3H, s), 2. 21 ( 3 H, s), 2.89 (4H, m), 3.48 (4H, m).

4— [2— (4-force rubamoylthiazolyl)] piperazine-1 1-carboxylic acid t Monobutyl ester and 4- [2- (4-cyanothiazolyl)] piperazine

 (1) In a manner similar to that described in Reference Example A-1, 2- {1_ [4-(-butoxycarbonyl) piperazinyl]} thiazo-l-uyl 4-carboxylate ethyl ester 4.65 g (yield 9 2%).

iH—NMR (CDC 13): (5 / p pm 1.37 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 3.48-3.62 (8H, m ), 4.36 (2H, q, J = 7.1 Hz), 7.47 (1H, s).

(2) Dissolve 2.23 g (6.5 mmo 1) of 2-{1-[4- (4-butoxycarbonyl) piperazinyl]} thiazole-4-carboxylic acid ethyl ester in 20 ml of methanol, 13.1 ml of a 1N aqueous sodium hydroxide solution was slowly added to the mixture, and the mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. Under ice cooling, a 10% aqueous solution of HC1 was added to make PH2, and the mixture was extracted with ethyl acetate. After washing with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added, and the precipitated crystals were collected by filtration and dried to obtain 2- [4- (1-butoxycarbonyl) -1-1-piperazinyl] thiazole-4-force 1.89 g of rubonic acid (92% yield). Was.

_{^{X H-NMR (CDC 1 3}} ): (5 / P pm 1. 49 (9H, s), 3. 46- 3. 6 1 (8H, m), 7. 5 5 (1 H, s).

(3) 2- [4- (1-butoxycarbonyl) 1-1-piperazinyl] thiazo-l-4 mono-luronic acid 1.0 g (3.2 mmo 1), WS C 7 34 mg (3.8 mmol), After stirring a mixture of 474 mg (3.5 mmol) of 1-hydroxybenzotriazole monohydrate and 10 ml of DMF for 1 hour at room temperature, 2.9 ml of a 28% aqueous ammonia solution was added, and Stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 1N aqueous solution of sodium hydroxide and water in that order, and then sulfuric anhydride, Dried with pum. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 3 Z 7-1 / 0). The crystal was recrystallized from ethyl acetate-hexane to obtain 4- [2- (4-hydroxylrubamoylthiazolyl)] piperazine-11-carboxylic acid monobutyl ester 92 Omg (yield 92%).

_{iH- NMR (CDC 1 3):} . δ / ρ pm 1. 49 (9H, s), 3. 43-3 62 (8H, m), 5. 52 (1 H, br), 6. 99 (1H , br), 7.46 (1H, s).

(4) 4- [2-(4-l-rubamoylthiazolyl)] piperazine-1-carboxylic acid ί-butyl ester 914 mg (2.9 mmo 1), triethylamine 1.35 ml (9.7 mmo 1) and dichloromethane Trifluoromethanesulfonic anhydride 8111 (4.8 mmol) was added dropwise to the mixture of 30 ml under ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 4 days. Ice water was added to the reaction solution, the organic layer was separated, and washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography- (ethyl acetate / hexane = 1Z4-2Z3). The crystal was recrystallized from ethyl acetate-hexane to obtain 728 mg (yield: 85%) of 4- [2- (4-cyanothiazolyl)] piperazine-11-carboxylic acid_butyl ester.

_{- NMR (CDC 1 3):} . Δ / ρ pm 1. 48 (9H, s), 3. 46-3 61 (8H, m).

4— (Trifluoromethyl) pyrimidine dihydrochloride

To 0.5 g of the compound obtained in Reference Example A-2, 10 ml of a 4 mol Z 1000 m1 HC1 ethyl acetate solution was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours, concentrated and concentrated to give 2- (1-piperazinyl). A crude product of 4- (trifluoromethyl) pyrimidine dihydrochloride was obtained. This Was used in the next step without purification. Reference example A—25 to A—4 1

The following compounds were obtained in the same manner as described in Reference Example A-24. These compounds were used in the next step without purification.

Table 5 Production of hydrochloride of starting compound (2)

Table 6 Production of hydrochloride of starting compound (2) Reference Example A— 42

2- (1-piperazinyl) nicotinic acid ethyl ester

 Heat a mixture of 3.74 g (43.5 mmol) of piperazine, 1.86 g (10.Ommo 1) of 2-ethyl nicotinate nicotinate and 100 ml of Λ_butyl alcohol at 130 ° C for 2 days did. After concentration, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (formula methanol = 80/1 to 20/1) to obtain 1.68 g (yield: 72) of the desired ethyl 2- (1-piperazinyl) nicotinate. Was.

_{- NMR (CDC 1 3):} δ pm 1. 39 (3H, t, J = 7. 1Hz), 2. 90- 3. 10 (4H, m), 3. 30- 3. 50 (4H, m) , 4.35 (2 H, q, J = 7.1 Hz), 6.73 (1H, dd, J = 4.7, 7.6 Hz), 7.97 (1H, dd, J = 1.8, 7.6 Hz), 8.27 (1 H, dd, J = 1.8, 4.7 Hz). Reference example A—43 to A_45

The following compounds were obtained in the same manner as described in Reference Example A-42.

Table 7 Production of starting compound (2)

Reference Example A— 46

 4 1 2 1 (piperazinyl) thiazole

 In the presence, using bromoacetophenone as a starting material, the title compound was obtained according to the method described in Reference Example A-14.

_{^{X H-NMR (CDC 1 3}} ):. Δ / ρ pm 7. 84-7 81 (2H, m), 7. 39 - 7. 24 (3H, m), 6. 76 (1 H, s), 3.53-3.50 (4H, m), 3.02-2.98 (4H, m), 1.70 (1H, s).

 Reference example A—47 to A—49

The following compounds were obtained according to the method described in Reference Example A-11 using piperazine as a raw material. Table 8 Production of starting compound (2)

Reference example A 50

 1-Feneru 5- (1 piperazinyl) tetrazole

Commercially available mixture of 5- (4- (1-benzylpiperazinyl))-11-phenyltetrazole 1.0 g (3.12 mmol), 5% Pd—C 100 mg, tetrahydrofuran 15 ml and ethanol 15 ml The mixture was stirred at room temperature under an atmosphere for 7 hours. After filtration, the solvent was distilled off, and the crude product was purified by basic silica gel column chromatography (chloroform / methanol = 20/1) to give 1-phenyl-5- (1-piperazinyl) tetrazole. 490 mg (68% yield) were obtained.

_{iH- NMR (CDC 1 3):} . δ pm 2. 91 (4H, m), 3. 22 (4 H, m), 7. 50 - 7. 63 (5H, m) Reference Example A- 51～A — 56

The following compound was obtained in the same manner as described in Reference Example A-14. Table 8-2 Production of Boc form of raw material compound (2)

Reference Example A-57

The following compounds were obtained in the same manner as in the method described in Reference Example A-1.

_{^{X H-NMR (CDC 1 3}} ):. Δ / ppm 1. 46 (9H, s), 3. 24-3 28 (4H m), 3. 45 - 3. 50 (4H, m), 4. 57 -4.59 (2H m 4.69 (1H brs), 6.96-7.03 (1 H, m 7.18 7.33 (5H, m). Reference example A- 58

Reference Example A-23 The following compound was obtained in the same manner as described in (3).

MS (m / z): 367 (MH ⁺ ).

_{^{X H-NMR (CDC 1 3}} ): (5 / ppm 1. 48 (9H, s), 1. 82- 1. 99 (4H, m), 3. 42- 3. 68 (1 OH, m), 3.83— 3.93 (2 H, m), 7.33 (1H, s). Reference example A-59

Reference Example A-23 The compound obtained in (1) was reduced with sodium borohydride in the presence of calcium chloride to give the following compound.

 MS (m / z): 300 (MH +).

_{^{X H-NMR (CDC 1 3}} ): δ / p pm 1. 48 (9H, s), 3. 45- 3. 60 (8H, m), 4. 55 (2H, d, J = 5. 3Hz) , 6.44 (1H, t, J = 0.9Hz). Reference example A—60 to A_69

The following compounds were obtained in the same manner as described in Reference Example A-24. These compounds were used in the next step without purification.

Table 8-3 Production of raw material compound (2)

Reference example A—70 to A—72

 The following compounds were obtained in the same manner as described in Reference Example A-42. Table 8-4 Production of Starting Compound (2)

Series B: Production of Compound (I-A-1)

Example B-1

 (2 S) — 1— (_butoxycarponyl) 1 2— {[4- (2-pyrimidinyl) 1-piperazinyl] carbonyl} pyrrolidine

 N— (butoxycarbonyl) 1 L monoproline 15.0 g (69.8 mmol 1), WSC 16.0 g (83.5 mmol), 1-hydroxybenzotriazole monohydrate 9.4 g ( After stirring a mixture consisting of 61.4 mmo 1) and 150 ml of dichloromethane at room temperature for 30 minutes, 12.6 g (76.7 mmo 1) of 2-piperazinylpyrimidine was added under ice cooling, and the mixture was stirred at room temperature for 2 days. After adding water and filtering off insolubles, the filtrate was separated and the organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The crude crystals obtained by concentration were subjected to silica gel column chromatography (ethyl acetate) and further recrystallized (ethyl acetate-hexane) to give (2S) _1- (1-butoxycarbonyl) -2 -{[4- (2-pyrimidinyl) -1-1-piperazinyl] pyrrol} 20.9 g of pyrrolidine (83% yield).

_{^{X H-NMR (CDC 1 3}} ): δ / pm 1. 40 (0. 5 X 9 H, s), 1. 46 (0. 5 X 9H, s), 1. 76 - 2. 29 (4H, m), 3.30-4.05 (10H, m), 4.55-4.80 (1H, m), 6.48-6.60 (1H, m), 8.32 (0.5X 2H, d, J = 4.6 Hz), 8.34 (0.5 X 2H, d, J = 4.6 Hz). Example B—2 to B—65

The compound prepared in Reference Example of Series A was treated in the same manner as in Example B_1 to obtain the following compound. Table 11 Preparation of 1 compound (I-A-1)

Example NMR (CDC13 _; ppm)

Ζι z ₂

 3.10-3.94 (10H, m), 7.12-7.27 (2H, m),

B-10 N C-H 8.07-8.23 (IH, m), 8.32 (1H, br s).

 3.27-3.93 (10H, m), 6.60-6.73 (2H, m),

B-11 C-H N 8.27-8.40 (2H, m).

Table 12 Preparation of 2 compounds (I-A-1)

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Table 14 Production of compound (I-A-1)

1.41 and 1.46 (total 9H, both s

 1.80-2.30 (4H, m), 3.40-3.95 (10H, m), 4.56-4.75 (IH, m), 6.90 and 6.92 (total

B-35 C-H S IH, both s), 7.27-7.34 (1H, dd, J = 4.8,

 7.9 Hz), 8.10 (1H, ddd, J = 1.8, 2.0, 7.9 Hz), 8.52 (1H, dd, J = 1.8, 4.8 Hz), 9.06 (1H, br).

 1.40, 1.46 (9H, s), 1.76-2.26 (4H, m),

B-36 N 0 ό.ΔΌ o.oi) ν, ΐο ΐ, with m .5U U l, with m

 1.39, 1.44 (total 9H, both s), 1.83-2.17

B-37 N N N-Ph (4H, m), 3.17-3.76 (10H, m), 4.51-4.64

 (IH, m), 7.52-7.60 (5H, m).

 1.29 (9H, s), 1.48 (9H, s), 3.48 (4H, br s),

B-38 C-t-Bu C-H S 3.56 (, 4H, br s ,, 6.16 (.IH, s

 1.24 (3H, t, J = 7.5 Hz), 1.48 (9H, s),

B-39 C-Et C-H s 2.63 (2H, q, J = 7.5Hz), 3.42-3.52 (4H, m), 3.51-3.60 (4H, m), 6.16 (IH, s)

1.49 (9H, s), 3.53-3.63 (8H, m), 6.71 (IH,

B-40 C-H S s included 7.U -7.11 Zt ±, m included 7.77- /.84 Zi ±, m included

 1.49 (9H, s), 3.54-3.61 (8H, m), 6.78 (IH,

B-41 C-H S s), 7.47-7.51 (2H, m), 7.68-7.73 (2H, m).

 1.48 (9H, s), 1.74 (6H, br s), 1.91 (6H, br)

B-42 C-H S s), 2.04 (3H, br s), 3.44 (4H, br s),

 3.50-3.59 (4H, m), 6.11 (IH, s).

 1.40 and 1.46 (total 9H, both s),

B-43 C-CN C-H S 1.82-2.29 (4H, m), 3.35-3.95 (10H, m),

4.53-4.73 (IH, m).

Table 15 Preparation of compound (I-A-1)

Table 16 Production of compound (I-A-1)

Table 17 Production of compound (I-A-1)

 * Racemic

 Example B_ 6 6

(2 S, R) 1-11 (ί-butoxycarbonyl) —4-methoxy-2 -— {[4- (2-pyrimidinyl) 1-1-piperazinyl] carbonyl} pyrrolidine

To a solution of 90 Omg (2.4 mmo 1) of the compound obtained in Example B_55 in 3 Oml of DMF was added 14 mg (2.9 mmo 1) of 60% sodium hydride, and the mixture was stirred at room temperature for 30 minutes, and then iced. Under cooling, methyl iodide 22 2 \ (3.57 mmo 1) was added, and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the desired product was extracted into an organic layer. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Cross-form form Z methanol = 1/0 to 20Z1) (2S, 4R) — 1— (— Butoxycarpanol) _4-Methoxy 2-({4- (2-pyrimidyl) -1-piperazinyl) caprolidine} mouth lysine 76 Omg (82% yield) was obtained.

_{^ -NM (CDC 1 3):} δ / ρ pm 1. 40 (0. 5 X 9H, s), 1.

4 5 (0.5 X 9H, s), 1.97-2.32 (2H, m), 3.33 (3H, s), 3.50 -4. 1 5 (1 1 H , m), 4.68-4.88 (1H, m), 6.

5 0-6.59 (1H, m), 8.33 (2H, t, J = 4.7 Hz). Example B_ 6 7

 (2 S, 4 S) -4-acetamido-1- (—butoxycarponyl)-2-{[4- (2-pyrimidinyl) -1-piperazinyl] pyrrol} pyrrolidine

(1) 7.1 g (18.8 mmol) of the compound obtained in Example Β_55, triethylamine 4.Oml (28.7 mmol), DMAP 46 Omg (3.77 mmol) To a mixture of dichloromethane and 12 Om1 was added, under ice-cooling, 4.31 g (22.6 mmol) of p-toluenesulfonyl chloride, followed by stirring at room temperature for 4 days. Ethyl acetate was added to the residue obtained by evaporating the solvent under reduced pressure, and the residue was washed with ice-cooled diluted hydrochloric acid, diluted saline, saturated aqueous sodium hydrogen carbonate and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and (2 S, 4R) — 1- (1-butoxycarbonyl) -12-{[[4- (2-pyrimidyl) -11-piperazinyl] -caprolpin} One 4-Tosiloxy 9.83 g (98% yield) of pyrrolidine were obtained.

_{^ -NMR (CDC 1 3):} . <5 / p pm 1. 3 8, 1. 41 (total 9 H, boths), 2. 46 (3H, s), 3. 5 -4 0 (1 OH, m), 4.77 (0.5 X 1H, t, J = 7.7 Hz), 4.84 (0.5 X 1 H, t, J = 4.8 Hz), 4.98-8. 0 5 (0.5 X 1 H, m), 5.08-5.16 (0.5 X 1H, m), 6.54 (0.5 X 1 H, t, J = 4.8 Hz ), 6.57 (0.5 X 1 H, t, J = 4.8 Hz), 7.37 (2H, brd, J = 8.3 Hz), 7.80 (2H, brd, J = 8.3 Hz), 8.3 2 (0.5 X 2 H, d, J = 4.8 Hz), 8.34 (0.5 X 2H, d, J = 4.8 Hz).

(2) Add 1.80 g (27.7 mmo 1) of sodium azide and 70 ml of DMF to the compound obtained in the previous section, and heat at 60 ° C for 4 days, then at 80 ° C for 3 hours. After stirring, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.

5,4 S) 14-Azido 1- (1-butoxycarbonyl) —2-{{[4_ (2-pyrimidinyl) _1-piperazinyl] carbonyl} 8.55 g of a crude product of pyrrolidine was obtained.

_{^{X H-NMR (CDC 1 3}} ): δ / ρ pm 1. 40, 1. 46 (total 9 H, boths), 1. 9 - 2. 0 1 (1 H, m), 2. 5 - 2. 6 5 (1 H, m), 3.35-4.15 (10 H, m), 4.62 (0.5 X 1 H, dd, J =

6.6, 8.1 Hz), 4.73 (0.5 X 1 H, dd, J = 6.0, 8.4 Hz), 6.5—6.6 (1H, m), 8 2 9-8. 3 6 (2H, m).

(3) 5 mg of Pd—C 800 mg and ethanol 100 ml were added to the compound obtained in the preceding section, and the mixture was subjected to normal pressure catalytic reduction at 40 ° C. for 5 hours. Activated carbon was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a crystalline residue. After diisopropyl ether was added and the crystals were collected by filtration, the crystals were washed with a 1: 1 mixture of ethyl ethyl diisopropyl ether, dried and dried to give (2S, 4S) -4-amino-11 (ί-butoxycarpoel). '2— {[4- (2-Pyrimidinyl) 1-1-piperazinyl] carbonyl} pyrrolidi 4.81 g (yield from tosyl form: 61%) was obtained.

_{^{X H-NMR (CDC l 3}} ):.. 5 / ppm 1. 40, 1. 46 (total 9 H, bo ths), 1. 6-1 8 (1H, m), 2. 40-2 54 ( 1 H, m), 3.3-3.45 (1H, m), 3.45-4.05 (10 H, m), 4.61 (0.5 X 1 H, dd, J = 4. 8, 9.3Hz), 4.72 (0.5X 1H, dd, J = 4.2, 9.4Hz), 6.51-6.59 (1H, m), 8.3-1 8. 36 (2H, m).

(4) A mixture consisting of the compound 20 Omg (0.53 mmo 1), acetic anhydride 60 1 (0.636 mmo l), triethylamine 1 11 1 (0.796 mmo 1) and dichloromethane 5.0 m 1 obtained in the preceding section was prepared. Stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel gel chromatography (black-form form Z ethanol = 40/1 to 20/1) to give (2S, 4S) -14-acetoamide-1 249 mg (100% yield) of — (— butoxycarbonyl) 1-2 — {[4- (2-pyrimidinyl) -1-piperazinyl] potassium} pyrrolidine were obtained.

_{^{X H-NMR (CDC 1 3}} ): (5 / P pm 1. 41, 1. 45 (total 9 H, bo ths), 1. 93, 1. 96 (total 3H, bo ths), 2. 33 - 2.53 (1 H, m), 3.45-4.0 (10 H, m), 4.64—4.84 (2H, m), 6.52—6.62 (1 H, m) , 7.82 (1 H, brd, J = 9.0 Hz), 8.30-8.36 (2H, m).

The following compounds were obtained in the same manner as in the method described in Example B-1. Table 17_2 Production of compound (I-A-l)

Series C: Production of raw materials (3)

 Reference example C_ 1

 Methoxyphenyl) methoxy] 2- (hydroxy

 (1) Known compound (4S) 14-benzyl-3-[(2R) -2-oxymethyl) hexanoyl] 12-oxazolidinone 240 g (606 mmo 1), 5% Pd-C25.0 g, ethanol 1600 ml was added, and the mixture was catalytically reduced under a hydrogen atmosphere while heating to 40 ° C. After removing the catalyst by filtration, the filtrate was concentrated to obtain a solid residue. Hexane (300 ml) was added and the mixture was once warmed and then gradually cooled with stirring. The crystals were collected by filtration, washed with hexane, and dried to give (4S) 14-benzene-3,3-[(2R) -2- (hydroxymethyl) hexanoyl] -12-oxazolidinone 177.9 g (96% yield).

One _{NMR (CDC 1 3): δ} / ρ pm 0. 89 (3H, t, 1 = 7. OHz), 1.0-1.8 (6H, m), 2.15-2.3 (1H, brs), 2.81 (1

H, dd, J = 9.3, 13.5 Hz), 3.30 (1 H, dd, J = 3.3, 13.4 Hz), 3.75-4.0 (2H, m), 4. 1-4.3 (2H, m), 4.65-4.75 (1H, m), 7.1-7.5 (5H, m).

(2) To the compound obtained in the previous section, 226 ml of 30 to 35.5% aqueous hydrogen peroxide, 350 ml of water and 1400 ml of THF were added, and while cooling with ice, 48.9 g of lithium hydroxide monohydrate ( After an aqueous solution (350 ml) of 1.17mo1) was added dropwise, the mixture was stirred at room temperature for 2 hours. Under ice cooling, 330 g of sodium sulfite was added to the reaction solution over 1.5 hours, the mixture was stirred at room temperature for 3 hours, and the solvent was distilled off. After water was added to the obtained residue and washed with chloroform four times, the pH was adjusted to pH 4 with concentrated hydrochloric acid, and the liberated target compound was extracted three times with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate, and then the solvent was distilled off to obtain 78.2 g (yield: 92%) of (2R) -2- (hydroxymethyl) hexanoic acid.

_{^ -NMR (CDC 1 3):} δ / ν pm 0. 91 (3H, t, J = 7. 0Hz), 1 · 25- 1. 48 (4H, m), 1. 48- 1. 77 (2H , m), 2.62 (1 3H, qu int, J = 6.4 Hz), 3.80 (2H, d, J = 6.2 Hz).

(3) A mixture comprising 77.3 g (529 mmo 1) of the compound obtained in the preceding section, known compound O — [(2,4-dimethoxyphenyl) methyl] hydroxylamine 119.7 g (555 mMol) and 750 ml of pyridine With ice cooling, WS C 12

I. 7 g (635 mmo 1) was added. After stirring at room temperature under reduced pressure, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. The organic layer was dried over sodium sulfate, and the solvent was distilled off. A mixed solvent of ethyl acetate and diisopropyl ether was added to 172 g of a crude product obtained, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to give (2R) -N-[(2,4-dimethoxyphenyl) methoxy] -12- (hydroxymethyl) hexaneamide. .7 g (73% yield) were obtained. Chromatography _{NMR (CDC 1 3): δ} / ρ pm 0. 88 (3 H, t, J = 6. 8Hz), 1. 2 - 1. 75 (6H, m), 2. 0- 2. 6 (1 H, m), 3.6-3.8 (2 H, m), 3.81 (3H, s), 3.83 (3H, s), 4.77-5.0 (2 H, m) , 6. 42-6.52 (2H, m), 7.1-7. 35 (1H, m).

 The compounds in Table 18 were obtained in the same manner as in the method described in Reference Example C-11. Table 18 Production of raw materials for compound (3)

Reference example C-1 5

(2R) -2-{{N — [(2,4-dimethoxyphenyl) methoxy] amino}

 (1) Reference Example C To 118.2 g (412 mmo 1) of the compound obtained in Example 11 was added 118.8 g (453 mmol) of triphenylphosphine and 1200 ml of THF, and the mixture was cooled on ice. 85.4 m 1 (412 mm o 1) was slowly added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, diisopropyl ether was added to the obtained oily crude product, the mixture was stirred gently, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure, a mixed solvent of diisopropyl ether and hexane was added to the obtained residue, and the mixture was stirred gently while cooling with ice, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure to obtain 138.4 g of a crude product.

(2) Crude product obtained in the preceding section 9. Mixed solvent of 738 び 11 and water (3: 1) 1 In a mixture of 20 ml 1, lithium hydroxide monohydrate 1.58 g (37.5 mmol) ) Was added and the mixture was stirred at room temperature overnight, and THF was distilled off under reduced pressure. After the residue was washed with ethyl acetate, the aqueous layer was made acidic with HC 1 and extracted with chloroform. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the solvent gave 7.14 g of (2R) -2-{{N-[(2,4-dimethoxyphenyl) methoxy] amino} methyl} hexanoic acid (79% yield in two steps). Was.

_{^ -NMR (CDC 1 3):} . (5 / p pm 0. 89 (3H, t, J = 7. 1Hz), 1. 5- 1. 4 (6H, m), 1. 4-1 6 ( 1H, m), 1.63—1.8 (1H, m), 2.65-2.78 (lH, m), 3.02-3.18 (2H, m), 3.81 (3H, m) s), 3.82 (3H, s), 4.70 (1H, d, J = 11.0Hz), 4.76 (1H, d, J = 11.0Hz), 6.4-6. 5 (2H, m), 7. 18-7. 23 (1H, d). Reference example C-1 to C-1

The compounds in Table 19 were obtained in the same manner as described in Reference Example C-15. Table 19 Preparation of precursor of compound (3)

Reference example C_ 9

 (2R) — 2-{{N — [(2,4-dimethoxyphenyl) methoxy] —N-formylamino} methyl} hexanoic acid

Reference Example C—5 (2R) — 2 -— {{Ν [(2,4-dimethoxyphenyl) methoxy] amino} methyl} hexanoic acid 150 g (4.8 mmo 1) 25 ml (31 Ommo 1) of acid ethyl was added, and the mixture was heated under reflux for 24 hours. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (chloroform / methanol = 100/1) to give the desired (2R) -2-{{N-[(2,4-dimethoxyphenyl). 1.35 g (82% yield) of methoxy] [1-N-formylamino} methyl} hexanoic acid were obtained.

_{^{X H-NMR (CDC 1 3}} ):. Δ / ρ pm 0. 88 (3H, t, J = 7. OHz), 1. 2- 1. 75 (6H, m), 2. 75-3 0 ( 1 H, m), 3.75-3.

9 (2H, m), 3.81 (3H, s), 3.83 (3H, s), 4.7-5.0 (2H, m), 6.42-6.5 (2H, m) , 7.1-7.2 (1H, m), 8.

10 (1 H, b rs). Reference example C_ 10 to C 2

 The compounds in Table 20 were obtained in the same manner as in the method described in Reference Example C-9.

 Table 20 Production of compound (3)

Series D: Production of Compound (I-B)

Example D—1-1

 (2 S) — 1— {(2 R) _ 3 —cyclopentyl-2 -— [(N—formyl-1-N—hydroxyamino) methyl] propionyl} 1 2— {[4- (2-pyrimidinyl) — — Piperazinyl] pyrrolidine pyrrolidine

 (1) To 582 mg (1.6 mmo 1) of the compound of Example B_1 was added 4 mol of Z 100 000 ml HC1 in ethyl acetate 8 ml, and the mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. Evaporation gave a crude product of (2S) —2-{[4- (2-pyrimidinyl) -1-piperazinyl] carbonyl} pyrrolidine dihydrochloride.

(2) Compound 588 mg (1.6 mmol) obtained in Reference Example C-111, triethylamine 1.12 ml (8.Ommol), 1-hydroxybenzotriazole monohydrate in the crude product obtained in the preceding section To the mixture were added 217 mg (1.4 mmo 1) and 20 ml of diclomethane, and WSC 37 Omg (1.9 mmo 1) was added under ice cooling. After stirring at room temperature for 18 hours, water was added and the organic layer was separated. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over magnesium sulfate. Concentrate and purify by silica gel column chromatography (ethyl acetate Z acetone = 10 / 1-5 / 1) to give (2S) -1-1 ((2R) -3-cyclopentyl-2-({{N-[( 2,4-dimethoxyphenyl) methoxy] —N-formylamino} methyl} propionyl} —2-{[4- (2-pyrimidinyl) -1-piperazinyl] pyrrolidinepyrrolidine 668 mg (68% yield) ).

_{^ -NMR (CDC l 3):} . <5 / p pm 0. 98 - 2. 20 (17 H, m), 2. 87 - 3. 17 (lH, m), 3. 46-4 12 (16H , m), 4.68 1 5.03 (3H, m), 6.47 (2H, brs), 6.53 (1H, t, J = 4.8 Hz), 7.17 (1H, brs), 7.83 (0.55 X 1H, brs), 8.11 (0.45 X 1H, brs), 8.32 (2H, brs) d, J = 4.8 Hz).

(3) To 666 mg (1.1 mmol) of the above product was added 12 ml of a 3% dichloromethane solution of trifluoroacetic acid, and the mixture was stirred at room temperature for 17 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, washed with saturated saline, and dried over magnesium sulfate. The crude product obtained by concentration is purified by silica gel column chromatography (dichloromethane Z methanol = 20 / 1-1 3/1) to obtain the desired (2S) — 1— {(2R) — 3 —Cyclopentyl-2-([N-formyl-1-N-hydroxyamino) methyl] propionyl} -12 — {[4- (2-pyrimidinyl) -11-piperazinyl] pyrrolyl} pyrrolidine 388 mg (yield 77%).

 MS (m / z): 459 (MH +).

— NMR (DMSO— c ₆ ): 5 / p pm 0.90—2.26 (18 H, m), 3.20 -4.13 (1 OH, m), 4.77—4.96 ( 1 H, m), 6.67 (1H, t, J = 4.8 Hz), 8.39 (2H, d, J = 4.8 Hz), 9.68 (0.7 x 1 H, s) , 10.03 (0.3 x 1 H, s). Preparation of salt of compound (I-B-2)

Example D—1-1—1: D—1-1 sodium salt

 (2S) -1-1K2R) —3-Cyclopentyl-2 -— [(N-formyl-N-hydroxyamino) methyl] propionyl} —2 — {[4- (2-Pyrimidinyl) -1-piperazinyl] carbo Nil} sodium salt of pyrrolidine

 Example D-To 2.0 g (4.36 mmol) of the compound of 1-1, 20 ml of methyl isobutyl ketone and 0.15 ml of a 42.8 (w / w)% aqueous sodium hydroxide solution were added at room temperature, followed by filtration. . The filtrate was stirred at room temperature overnight, and the precipitated crystals were collected by filtration. After washing with diisopropyl ether and drying, 1.68 g (79%, crystal) of the title compound was obtained.

Melting point 1 28-1 32 ° C. MS (m / z): 459 (MH +). Elemental analysis C ₄₆ H ₆₇ N ₁₂ Na_〇 ₈ · 2H ₂ 0 theory (%): C, 56. 66 ; H, 7. 34; N, 1 7. 24; Na, 2. 36. measurements (% ): C, 56.53; H, 7.22; N, 17.15; Na, 2.42.1 NMR (CDC 1: (5 / p pm 0.97-2.30 (16 H, m) , 3.17-4.05 (1 2H, m), 4.89-5.00 (IH, m), 6.52 (IH, t, 1 = 4.7 Hz), 7.65 (IH, s), 8.31 (2H, d, J = 4.7 Hz). Example D—The following salts were produced according to the method described in 1-1-1.

 Table 21 Preparation of salt of compound (I-B-2)

Example D—1 4

 (2 S)-1-{(2 R) — 3-cyclopentyl— 2— [(N-formyl _N—hydroxyamino) methyl] propionyl} -2- {[4- (2-pyrimidinyl) 1-1-piperazinyl ] Pyrolidine hydrochloride

HCI

Example D—11 A compound (903 mg, 2.Ommo 1) was dissolved in 60 ml of ethyl acetate, and 4 molno 1000 ml of HC1 ethyl acetate solution 1.2 ml was dissolved in ice under ice-cooling. I got it. After concentration under reduced pressure, the precipitate was collected by filtration and dried to give 914 mg (91%) of the desired product.

MS (m / z): 459 (MH ⁺ ). Elemental analysis. C ₂₃ H ₃₅ ClN ₆ O ₄ '0.' 8 H ₂₀ Theoretical value (%) C, 54.23; H, 7.24 N, 16.50; C 1,

6.96. Measured value (%) C, 54.47; H, 7.18; N, 16.15; C1,

7. 06 ^.: H-NMR (DMSO-d ₆ ): δ / ppm 0.97-2.21 (15H, m), 2.90 -4.60 (13H, m), 4.75 -4 95 (1 H, m), 6.70 (1 H, t, J = 4.8 Hz), 7.76 and 7.85 (tota 1 1 H, bots), 8.41 (2H, d, J = 4.8 Hz). Production of compound (I—E)

Example D—1-2

 (2S) -1-{(2R) -3-cyclopentyl-2-{[N-formyl-N— (2-naphthoyloxy) amino] methyl} propionyl} -2-{[4- (2— Pyrimidinyl) _1-piperazinyl] pyrrolidine pyrrolidine

Example 23 The compound 23 Omg (0.5 mmo 1) of D_1-1 was dissolved in 5 ml of pyridine, and 105 mg (0.55 mmo 1) of 2-naphthoyl chloride was added at room temperature, followed by stirring at the same temperature for 20 hours. After evaporating the reaction solution under reduced pressure at 40 ° C, the residue was subjected to silica gel column chromatography (chloroform / methanol = 1Z0 to 20/1), and the eluate was crystallized from methanol-water. After the precipitated crystals were collected by filtration, the crystals were washed with water. The obtained crystals are dried at 8 Ot: for 5 hours, and the desired (2 S) _1 — {(2R) —3-cyclopentyl —2 — {[Ν-formyl—Ν— (2-naphthoyloxy) amino] methyl} propio 2-l} -2-{[4- (2-pyrimidinyl) 1-1-pi Perazinyl] pyrrolyl pyrrolidine (237 mg, 77%, crystalline) was obtained. MS (m / z): 613 (MH ⁺ ).

Elemental analysis C ₃₄ H _4. N ₆ 〇 ₅ theory (%): C, 66. 65 ; H, 6. 58; N, 13. 72. measurements (%): C, 66. 54 ; H, 6. 59; N, 13. _{67. - NMR (CDC 1 3)} : δ / ρ pm 1. 00- 1. 30 (2H, m), 1. 35- 2. 25 (13H, m), 2. 75 - 3. 20 (1 H , m), 3.30-4.05 (11H, m), 4.10-4.30 (IH, m), 4.70-4.80 (1H, brs), 6.53 (1H, t, J = 4.8 Hz), 7.60-7.80 (2 H, m), 7.80-8.05 (4H, m), 8.10-8.45 (IH, brs), 8 32 (2H, d, J = 4.8 Hz), 8.68 (1H, s). Example D_ 1 _ 3 to D— 1— 9

The following compounds were obtained in the same manner as in the method described in Example D_1-2.

Table 22 Production of compound (I-E)

Example D_ 1-10

 (2S) -1-{(2R) -3-cyclopentyl-2-{[N-formyl-N- (1-naphthoyloxy) amino] methyl} propionyl} -2-{[4- (2— Pyrimidinyl) 1-piperazinyl] pyrrolidine pyrrolidine

Example D—Compound of 1-1—23 Omg (0.5 mmol). Naphthoic acid 10 To a mixture of 4 mg (0.5 mmo 1) and 10 ml of black mouth form was added 115 mg (0.5 mmo l) of WS C and 3 lmg (0.5 mmo 1) of DMAP, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform / methanol = 1/0 to 10/1), and the eluate was crystallized from methanol-water. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 274 mg (89%, crystal) of the title compound.

156-157 ° C. MS (m / z): 613 (MH +).

Elemental analysis C ₃₄ H _4. N ₆ 〇 ₅ theory (%): C, 66. 65 ; H, 6. 58; N, 13. 72. measurements (%): C, 66. 44 ; H, 6. 62; N, 13. ^{70. X H-NMR (CDC 1} 3): δ / pm 1. 00- 1. 30 (2H, m), 1. 35 - 2. 25 (13 H, m), 2. 75 - 3. 20 ( 2H, m), 3.30-4.05 (11H, m), 4.10—4.30 (1H, m), 4.70-4.80 (1H, brs), 6.54 ( 1 H, t, J = 4.8 Hz), 7.45-7.75 (3 H, m), 7.85-8.05 (1 H, m), 8.10-8.20 (1 H , m), 8.20-8.40 (1H, m) 8.32 (2H, d, 1 = 4.8Hz), 8.75-8.85 (1H, m). 1-11〜D— 1— 14

The following compounds were obtained in the same manner as in the method described in Example D-1-10.

Table 23 Production of 3 compounds (I-E)

Example D 15

 (2 S) — 1— {(2 R) 1-3-cyclopentyl— 2— UN— {[(3 S) —2, 3, 4, 5-tetrahydro—4,4-dimethyl-2-oxo-3-furyl] Oxycarbonylcarbonyl} _N-formylamino} methyl} propionyl}-2-{[4- (2-pyrimidinyl) — 1-piperazinyl] pyrrol} pyrrolidine

 (1) (L) — Pantolactone 645mg (4.96 mm o 1) \

0 ml, dichloromethane 20 ml, 4-nitrophenyl chloroformate 1.00 g (4.96 mmo 1) and 6 mg of DMAP (0.496 mmo 1) were added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, water and ethyl acetate were added, the organic layer was separated, washed with saturated saline and dried over sodium sulfate. The crude product obtained by concentration was subjected to silica gel column chromatography (ethyl acetate / 2-hexane = 1 /

Purified by 4) (3 S) — 2,3,4,5-tetrahydro_4,4-dimethylol 3-[(4-nitrophenoxy) carbonyloxy] 12-oxofuran 83 Omg (57% yield) ).

_{^{X H-NMR (CDC 1 3}} ):. Δ / ρ pm 1. 23 (3 H, s), 1. 32 (3 H, s), 4. 06-4 15 (2H, m), 5. 25 (1 H, s), 7.46 (2 H, d, J = 9.3 Hz), 8.3 1 (2H, d, J = 9.3 Hz).

(2) To 193 mg (0.654 mmo 1) of the above product, 20 Omg (0.436 mmol) of the compound obtained in Example D-1-1, 2 ml of pyridine and 5.3 mg of DMA P (0.0436 mmo 1). o 1) was added and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, the organic layer was separated, washed with saturated saline, and dried over sodium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (ethyl acetate Zn-hexane-4Z1-chloroform / methanol = 20/1) and recrystallized from water-methanol. (2 S) -1-{(2 R) 1-3-cyclopentyl-2-{{N— {[(3S) 1,2,3,4,5-tetrahydro-4,4-dimethyl-12-oxo-1-3-furyl] oxy N-formylamino} methyl} propionyl} -2-{[4- (2-pyrimidinyl) -11-piperazinyl] carbonyl} pyrrolidine 220 mg (82% yield, crystalline) Obtained.

Mp 155—157 ° C. MS (mZz): 615 (MH +).

Elemental analysis _{C 30 H 42 N 6 O 8} · 0. 25H 2 0 theory (%): C, 58. 19 ; H, 6. 92; N, 13. 43. measurements (%): C, 58. 00; H, 6. 9 0; N, 13. 97. - NMR (CDC 1 3): δ / ρ pm 1. 20 (6 H, m), 1. 30 (3H, s), 1. 47- 1.61 (6H, m), 1.71-2.17 (6H, m), 3.05 (1H, m), 3.69-4.12 (14H, m), 4.95 (1H , m), 5.15 (1H, m), 6.53 (1H, t, J = 4.8 Hz), 8.55 (1H, s), 8.32 (2H, d, J = 4 8Hz). Example D—1—16 to D—1—18

The following compounds were obtained in the same manner as in the method described in Example D-1-15.

Table 24 Production of compound (I-E)

Experimental example D— 2 'D— 2— 10

 The following compounds were obtained in the same manner as in the method described in Example D_1-1 or Example D-12. The compound of Example D-2-1-1 was produced according to the method described in Example D-1-1-1.

 Table 25 Preparation of Compound (I-B) '

The following compounds were obtained according to the method described in Example D-1-2.

Table 26 Preparation of 6 compounds (I-E) n _n9aヽ j Me Melting point, MS, elemental analysis

 Example

NMR (CDCI ₃ , ppm)

F¾aZ reagent

 MS (m / z): 519 (MH +).

 NMR: 0.91 (3H, m), 1.37 (3H, s), 1.39 (3H,

Me / Me s), 1.34-1.45 (5H, m), 1.60 (1H, m), Me?

D-2-7 0 people ₀ Me 1.86-2.23 (4H, m), 3.00 (IH, m), 3.42-4.11

 CI (12H, m), 4.87-5.02 (2H, m), 6.54 (IH, t, J

 = 4.8 Hz), 7.98 (1H, br s), 8.32 (2H, d, J = 4.8 Hz).

MS (m / z): 547 (MH ⁺ ).

 COOH NMR: 0.90 (4H, m), 1.26-1.42 (2H, m),

 2.00-2.17 (7H, m), 2.48-2.56 (4H, s), 2.91

D-2-8

 (IH, m), 3.45-4.09 (14H, m), 4.91 (IH, m),

0 6.54 (IH, m), 8.02 (0.6 x IH, s), 8.10 (0.4 x

IH), 8.33 (2H, d, J = 4.7 Hz).

Example D—3—D—16-3

The following compounds were obtained in the same manner as described in Example D_1-1 or Example D-11-10. However, D-4_3 was manufactured according to the method described in D-1-15, and D-16-3 was manufactured according to the method described in D-1-2. Further, the metal salt compound was produced according to the method described in Example D_1-1-1.

Table 27 Production of Compound (I-I) '

Example D 6-4

 (2 S)-1-{(2 R)-3-cyclohexyl- 21 {[N-formyl-1-N- (N-butylcarbamoyloxy) amino] methyl} propionyl} -2- {[ 4- (2-thiazolyl) -1-piperazinyl] pyrrolidine pyrrolidine

Example D—A compound of 16-1 15 Omg (0.314 mmol), triethylamine 881 (0.63 mmol) and toluene 2. A mixture of Oml at room temperature was added with butyl isocyanate 43 1 (0.38 mm 0 1) was added, and the mixture was stirred at the same temperature for 23 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (form-form Z-ethanol = 50 / 1-30 / 1) to give (2S) — 1— {(2R) 13 —Cyclohexyl-1 -— {[N-formyl-1-N— (N-butylcarbamoyloxy) amino] methyl} propionyl} -2-{[4- (2-thiazolyl) -1-piperazinyl] This gave 93 mg of pyrrolidine (yield 51%).

MS (m / z): 577 (MH +).

_{^{X H-NMR (CDC l 3}} ):. 5 / ppm 0. 8-2 25 (21 H, m), 0. 94 (3H, t, J = 7. 2Hz), 3. 00 - 3. 32 ( 3H, m), 3.32 -3.9 (12H, m), 4.82 (1H, dd, J = 3.3, 7.2Hz), 5.13 (1H, brs), 6.61 (1H, d, J = 3.7Hz), 7.21 (1H, d, J = 3.7Hz), 8.00 (1H, brs).

T r = 17.4 min. Example D—17 to D—79

The following compounds were obtained in the same manner as described in Example D_1-1 or Example D-11-14. The compound of Example D- 25- 1- is the same as Example D-1-1 It was manufactured according to the method described.

Table 28 Production of 8 compounds (I—B— 2)

Table 29 Production of 9 compounds (I-B-2)

 ¾) (2 -9- 1) ί # ^ 0

6L

丽 OOidf / IDd fSt8 Count 00Z ΟΛ \ Table 3 Production of 1 compound (I-B-2)

Table 32 Preparation of compound (I-B-2)

Table 33 Preparation of compound (I-B-2)

Table 34 Production of compound (I-B-2)

Table 35 Production of 5 compounds (I-B_2)

0 0

Table 36 Preparation of 6 compounds (I-B-2) Example Structure Structural NMR (CDCls, ppm)

0.82-1.05 (2H, m), 1.05-2.30 (15H, m), 4.63-5.0

D-54

 (IH, m), 6.5-6.63 (IH, m), 8.27-8.40 (2H, m).

D-55 0.86 (3H, t, J = 6.6Hz), 2.82-4.00 (11H, m). TJP2003 / 010548

 85

 Table 3 Production of 7 compounds (I-B-2)

Example D—80

 (2 S)-1-{(2 R) -2- [(N-formyl-N-hydroxyamino) methyl] heptanyl} 1 2— {[4- (4-ethoxy-2-pyrimidinyl) 1 1-piperazinyl] carbonyl} pyrrolidine

 (1) (2S) -1-{(2R) 1-2 [(2,4-dimethoxyphenyl) methoxy] 1-N-formylamino obtained in the course of Example D-29 } Methyl} hepnoyl} 1- 2-[[4- (4-hydroxy-2-pyrimidinyl) 1-1-piperazinyl] carbonyl} pyrrolidine 400 mg (0.65 mmo 1) and iodide chill 78 1 (1. Ommo 1 ) Was added to a THF solution of 180 mg (1.3 mmo 1), and the mixture was stirred at 60 ° C overnight. The reaction solution was concentrated under reduced pressure, and chloroform and water were added to the residue to extract the desired product into an organic layer. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and (2S) _1-K2R) -2-({N-[(2,4-dimethoxyphenyl) methoxy] -N-formylamino} methyl } Heptane} 1-2-{[4- (4-ethoxy-12-pyrimidinyl) -11-piperazinyl] carbonyl} pyrrolidine 38 Omg (91% yield) was obtained.

_{XH-NMR (CDC 1 3)} :. Δ ν pm 0. 79- 0. 94 (3H, m), 4. 34 (2H, d, J = 7. 1Hz), 4. 71-4 88 (2H, m), 6.00 (1 H, d, J = 5.7 Hz), 6.38-6.53 (2H, m), 7.85 (0.5 X 1 H, s), 8.05 ( 1H, d, J = 5.7Hz), 8.11 (0.5X 1H, s).

(2) In the same manner as in the method described in (3) of Example D-11, (2S) -11-{(2R) —2-[(N-formyl-1-N-hydroxyamino) methyl ] Heptanoyl} 1 2— {[4- (4-ethoxy-12-pyrimidinyl) 1-1-piperazinyl] Ponyl} pyrrolidine was obtained.

 ^ -NMR (CDC lg): (5 / ppm 0.77-0.94 (3H, m), 1.2-2.3 (12H, m), 1.38 (3H, t, J = 7 1 Hz), 2.9-3. 0, 3.12-3.23 (total 1 H, bothm), 3.4-4.05 (12H, m), 4.34 (2H, d, J = 7. lHz), 4.7-4.77 (0.30 X 1 H, brd), 4.84-4.96 (0.70 X 1 H, m), 5.98 -6.06 ( 1H, m), 8.03-8. 10 (1H, m). Example D-81

 (2S) -1-{(2R) -2-[(N-formyl-1-N-hydroxyamino) methyl] heptanol} -2-{[4- (4-methoxy-2-pyrimidinyl) -piperazinyl ] Carbonyl} pyrrolidine

The title compound was obtained according to the method described in Example D-80.

_{XH-NMR (CDC 1 3)} : δ / ρ pm 0. 89 (3H, t, J = 6. 9Hz), 3. 89 (3H, s), 6. 00 - 6. 09 (1 H, m) , 8.02—8.12 (1 H, m). T r = 4.08 min. Example D— 82

(2 S) — 11 {(2 R) -2-— {{N— [(2,4-dimethoxyphenyl) methoxy] 1 N-formylamino} methyl} heptanoyl} 1 2— {[4- (4-trifluoromethanesulfonyloxy-2-pyrimidinyl) -1-piperazinyl] pyrrolidine pyrrolidine

 (2S) -1-({2R) _2-{{N-[(2,4 dimethyloxyphenyl) methoxy] -1-N-formylamino} methyl} heptanyl} obtained in the course of Example D_29 2-{[4- (4-Hydroxy-2-pyrimidinyl) -1-1-piperazinyl] carbonyl} Methylene chloride solution containing 61 Omg (lmmo 1) and triethylamine 422 zl (3 mmo 1) in methylene chloride 12 ml Under ice-cooling, trifluoromethanesulfonic anhydride 2021 (1.2 mmol) was added thereto, followed by stirring for 4 hours. To the reaction mixture was added chloroform and water, and the desired product was extracted into an organic layer. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform form Z methanol = 1Z0 to 25/1) to give (2S) -1-1 ((2R) 1-2-UN — [( 2,4-dimethoxyphenyl) methoxy] 1-N-formylamino} methyl} hepnoyl} —2 — {[4_ (4-Trifluoromethanesulfonyloxy-2- 2-pyrimidinyl) 1-1-piperazinyl] } 30 Omg of pyrrolidine (yield 40%) was obtained.

_{^ -NMR (CDC 1 3):} .. (5 / p pm 0. 65- 0. 97 (3H, m), 4. 71-4 88 (2H, m), 6. 41-6 53 (2H, m), 6.55 (1 H, d, J = 5.0 Hz), 7.85 (0.5 X 1H, s), 8.12 (0.5 X 1 H, s), 8.17 ( 1H, d, J = 5.0Hz).

(2 S)-1-{(2 R) 1 2— [(N-formyl-1 N-hydroxyamino) methyl] heptanoyl}-2- {[4- (4-morpholino 1-2-pyrimigel) 1 1 -Piperazinyl] pyrrolidine pyrrolidine

 (1) A solution of 46 Omg (0.62 mmo 1) of the compound obtained in Example D-82 and 1 Om 1 of ethanol of morpholine 218 1 (2.5 mmo 1) was stirred overnight while heating to 70 ° C. The reaction solution was concentrated under reduced pressure, and chloroform and water were added to the residue to extract the desired product into an organic layer. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. (2 S) — 1— {(2R) -2- {{N— [(2,4-dimethoxyphenyl) methoxy] 1 N-formylamino} Methyl} Heptanoyl} -1-2-{[4- (4-Morpholino-2-pyrimidinyl) -1-piperazinyl] carbonyl} pyrrolidine 45 Omg

(100% yield).

_{- NMR (CDC 1 3):} . Δ ρ pm 0. 79 - 0. 94 (3H, m), 4. 71 -4 88 (2H, m), 5. 87 (1 H, d, J = 6. OHz), 6.41 -6.53 (2H, m), 7.85 (0.5 X 1 H, s), 7.96 (1 H, d, J = 6.OHz), 8.10 ( 0.5 X 1H, s)

(2) In the same manner as in the method described in (3) of Example D_l_l, (2S) — 1 — {(2R) -2-[(N-formyl-N-hydroxyamino) methyl] hepnoyl } —2— {[4 -— (4-Morpholino-2-pyrimidinyl) -1-piperazinyl] -force Ruponyl} pyrrolidine was obtained.

_{^ -NMR (CDC 1 3):} δ / ρ pm 0. 81- 0. 97 (3H, m), 1. 20 - 2. 30 (12H, m), 2. 95 - 3. 00, 3. 17 -3.22 (tota 1 1 H, bothm), 3.30 -4. 05 (2 OH, m), 4.70-1 4.76 (0.30 X 1H, brd), 4.82-- 4. 96 (0.70 X 1 H, m), 5.86-5.94 (lH, m), 7.97 (1 H, d, J = 5.9 Hz). Example 0-84 to 0-92 The following compounds were obtained in the same manner as in the method described in Example D-83. Table 38 Production of 8 compounds (I-B-2)

Example D—93

 (2 S)-1-{(2 R) 1 2— [(N-formyl-1 N-hydroxyamino) methyl] hepnoyl}-2- {[4- (3-carboxy-2-pyridyl) — 1-piperazinyl] pyrrolidine pyrrolidine

 1 mol / 1000 ml of NaOHlm 1 was added to 1 ml of an ethanol solution of 0.27 g (0.52 mmo 1) of the compound of Example D-20, and the mixture was stirred at room temperature for 1 day. After concentrating to remove ethanol, water and 10% acetic acid were added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated to obtain 0.22 g of a crude product. This was purified by silica gel column chromatography (form-form / methanol = 30 / 1-6 / 1) to give the desired (2S) — 1— {(2R) — 21 [(N—formyl-N— [Hydroxyamino] methyl] heptanoyl} —2-{[4- (3-caproloxy-2-pyridyl) -1-piperazinyl] carbonyl} pyrrolidine 8 Omg (31% yield) was obtained.

MS (mZz): 490 (MH +),

_{^ -NMR (CDC l 3):} .. 5 / ppm 0. 89 (3H, brt), 1. 05 -2 50 (12H, m), 2. 50-4 50 (13H, m), 4. 70 — 5.00 (lH m), 7.37 (1H brs), 8.50— 8.70 (2H, m). Example D— 94

(2 S) — 1— {(2 R) —2— [(N-formyl-N-hydroxyamino) methyl] heptanoyl} —2— {{4- [3- (N, N-dimethylcarbamoyl) ― 2-pyridyl] —1-piperazinyl} pyrrolidine pyrrolidine

 (1) (2S) -1-{(2R) -2-1 {{N-[(2,4-dimethoxyphenyl) methoxy]] N-formyl obtained in the course of Example D-20 Amino} methyl} hepnoyl} -2-{[4- (3-ethoxycarbinyl 2-pyridyl) -1-1-piperazinyl] pyrrol} pyrrolidine 1.25 g (1.87mmo

1 mol / 1000 ml NaOH 4 ml 1 was added to 2 ml ethanol solution of 1), and the mixture was stirred at room temperature for 4 days. After concentration, acetic acid and water were added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Concentrate (2 S) — 1-{(2 R) —2— {{N-[(2,4-dimethoxyphenyl) methoxy] -N-formylamino} methyl} Heptaneyl} -2- {[4- (3-Carpoxy_2-pyridyl)-1-piperazinyl] caprolponyl} 1.08 g of crude pyrrolidine was obtained.

(2) To a solution of 0.19 g (0.3 Ommo 1) of the compound obtained in the previous section in 12 ml of dichloromethane was added 9 Omg (1.Ommo 1) of 50% aqueous dimethylamine solution and 0.4 mg of WSC9 Omg (0.47 mmo 1). After stirring at room temperature for 11 days, the mixture was concentrated. To this was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. 0.23 g of the crude crystals obtained by concentration was purified by silica gel column chromatography (formaldehyde methanol = 50/1 to 20/1), and (2S) -1-1 ((2R) 1-2- {{N-

[(2,4-dimethoxyphenyl) methoxy] — N-formylamino} methyl} heptanoyl} 1-2 — {{4- [3- (N, N-dimethylcarbamoyl) —2-pyridyl] 1-1-piperazinyl} 0.113 g (yield in two steps: 66%) of pyrrolidine was obtained. (3) The compound was treated in the same manner as described in Example D-1-1, (3) to give (2S) -1-K2R) -2-[[(N-formyl-1-N-hydroxyamino) ) [Methyl] heptanoyl} 1-2-{{4- [3- (N, N-dimethylcarbamoyl) -2-pyridyl] -1-piperazinyl} carbonyl} pyrrolidine 4 lmg (41% yield) was obtained. .

 MS (m / z): 517 (MH +),

_{- NMR (CDC 1 3):} . (5 / p pm 0. 88 (3H, brt), 1. 00 -2 27 (14H, m), 2. 86 (3H, s), 3. 1 1 (3H , s), 2.50 -4.00 (12H, m), 4.73-- 5.00 (1H, m), 6.93-6.77 (1H, m), 7.47-- 7. 60 (1 H, d, J = 7.5 Hz), 8.17 -8. 30 (1 H, m).

 (2 S)-1-{(2 R) —2— [(N-formyl_N-hydroxyamino) methyl] heptanoyl} — 2— {{4- [3- (1 _pyrrolidinylcarbonyl) — 2 1-pyridyl] 1- 1-piperazinyl} pyrrolidine pyrrolidine

The title compound was obtained in the same manner as described in Example D-94.

_{^ -NMR (CDC 1 3):} . Ά / ρ pm 0. 89 (3H, brt), 1. 00 one 2. 27 (18 H, m) , 3. 07 -4 00 (16 H, m), 4. 73-5.00 (1H, m), 6.77-7.00 (lH, m), 7.50-7.63 (1H, dd, J = 1.83, 7.30 Hz), 8 17—8.30 (1 H, m). Example D—96

 (2 S)-1-{(2 R) 1 2— [(N-formyl-1 N-hydroxyamino) methyl] heptanoyl} — 2— {[4— (4-Pivaloyloxy 2-pyrimidinyl 1) 1-piperazinyl] pyrrolidine} pyrrolidine

(1) (2S) -1-{(2R) -2 -UN — [(2,4_dimethoxyphenyl) methoxy] 1 N-formylamino obtained in the course of Example D-29 } Methyl} Heptanoyl} -2-{[4- (4-Hydroxy_2-pyrimidinyl) -1-piperazinyl] carbonyl} Pyrrolidine 307 mg (0.5 mm o 1) and triethylamine 2 1 1 1 (1.5 mmo 1 ) Was added to the methylene chloride solution under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction mixture was added chloroform and water, and the desired product was extracted into an organic layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 1Z0 to 25/1) to give (2S) —1 — {(2R) —2 — {{N — [( 2, 4-dimethoxyphenyl) methoxy] —N-formylamino) methyl} heptanoyl} 1 2- {[4- (4-pivaloyloxy 1- 2-pyrimidyl) 1-1-piperazinyl] } 340 mg (100% yield) of pyrrolidine were obtained.

_{iH- NMR (CDC 1 3):} . (5 / p pm 0. 79 - 0. 97 (3H, m), 4. 7 1 -4 88 (2H, m), 6. 29 (1 H, d, J = 5.3 Hz), 6.38 -6.56 (2H, m), 7.85 (0.5 X 1 H, s), 8.12 (0.5 X 1 H, s), 8. 32 (1H, d, J = 5.3Hz).

(2) The compound was treated in the same manner as described in (3) of Example D-1-1, to give (2S) -1-({2R) -2-[(N-formyl-N- Hydroxyamino) [Hep-no-yl]}-2-{[4- (4-Viva-yloxy-2-pyrimidinyl) -1-1-piperazinyl] pyrrol} pyrrolidine.

_{^{X H-NMR (CDC 1 3}} ): (5 / pm 0. 89 (3 H, t, J = 6. 9Hz), 1. 36 (9H, s), 6. 26 - 6. 39 (1 H, m), 8.29—8.39 (1 H, m). Example D—97 to D—1 10

 The following compounds were obtained in the same manner as in the method described in Example D-1-1.

 Table 38-2 Production of Compound (I-B)

Example D 1

The following compounds were obtained in the same manner as in Example D-11 using the compounds obtained in Examples B-80.

 MS (m / z): 480 (MH +).

_{^{X H-NMR (CDC 1 3}} ):. (5 / p pm 0. 97- 2. 30 (15 H, m), 2 90-4 32 (15 H, m), 4. 71- 4. 92 ( 1H, m). Example! 2

To the compound 15 Omg (0.25 lmmo 1) obtained in Example D-110, 5 ml of ethanol and 20% Pd (OH) ₂ -C 3 Omg were added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. . The reaction mixture is filtered and concentrated, and the crude product is purified by basic silica gel column chromatography (form: methanol / methanol = 20/1) to obtain the desired product (2S) -1-{(2R) 13- Cyclopentyl-2-[[(N-formyl-1-N-hydroxyamino) methyl] propionyl} -1-{[4- (2-amino-1,3,5-difluoro-6-pyridyl) -1-piperazinyl] carbonyl } 4 Omg of pyrrolidine (31% yield) was obtained.

MS (m / z) 509 (MH +).

^X H-NMR (CD ₃ OD): (5 / p pm 0.87-2.22 (15H, m), 3.28-3.78 (13H, m), 4.82-4.85 (1 H, m), 7.16 -7.23 (1H, m), 7.80 (0.75 X 1 H, brs), 8.26 (0.25 X 1 H, brs). Example D__ 3 ~ D— 143

By the method described in the above Reference Examples and Examples or a method analogous thereto, Can be produced. 39 Production of Compound (I-B-2)

TOT

3d es o contract OAV

^ o ¹ [one a

 C COO CO

 V

One

o

I 1

 1

9 ε τ -a g ε T -a

o, _H ε τ— a ε ε T -a

SOT

df / X3d es o contract OAV

The compound (I-B) ′ of the present invention thus obtained has an excellent antibacterial activity and is useful as an antibacterial agent.

Next, the antibacterial activity of the compound (I-B) ′ of the present invention will be described. Experimental Example 1: Antibacterial activity in vitro (MIC: gZm 1): The minimum inhibitory concentration (MIC: g / m 1) was measured according to the standard method defined by The National Committee for Clinical Laboratory Standards (NCCLS). 40 results were obtained.

Table 40 Antimicrobial activity in 0 inv i tro (M I C: ^ g / ml)

MIC (iug / ml)

 Teeth

 D-1-1 D-2-1 D-3-1 D-4-1 D-5 D-6

A 0,25 0.5 0.25 0.125 0.25 0.5

B 0.125 0.25 0.125 0.125 0.125 0.25

C 0.125 0.25 0.125 0.125 0.125 0.25

D 0.25 0.5 0.25 0.25 0.25 0.5

E 0.25 0.5 0.25 0.25 0.25 0.5

F 0.25 0.5 0.25 0.25 0.25 0,5

G 0.03 0.125 0.06 0.06 0.06 0.125

H 0.25 0.5 0.125 0.25 0.25 1

1 0.5 1 0.25 1 2 0.5

J 0.125 0.5 0.125 0.5 0.25 1

K 1 2 0.25 2 1 1 0.5 2 0.5 2 1 2

M 0.125 0.5 0.125 1 0.5 0.125

Table 40 (Continued) Antibacterial activity in invitro (Mic: g / ml)

 MIC (g / ml)

Seedling holiday * 5b

 U-O U Π "1 Π II η_ιι_ι U"

A 0.25 0.25 0.125 0.5 0.25 0.5

B 0.125 0.125 0.125 0.25 0.06 0.25

C 0.25 0.125 0.125 0.25 0.125 0,25

D 0.25 0.25 0.25 0.5 0.125 0.5

E 0.5 0.25 0.25 0.5 0.125 1

F 0.25 0,25 0.25 0.5 0.125 0.5

G 0.06 0.06 0.06 0.06 0.03 0.125

H 0.25 0.25 0.125 0.06 0.125 0.5

1 0.5 0.5 0.5 0.25 0.25 1

J 0.25 0.25 0.25 0.125 0.125 0,5

K 0.5 0.5 0,5 0.25 0.125 2 s 2 1 1 2 0.25 2

M 0.25 0.125 0.25 0.5 0.125 0.125

Table 40 (Continued) Antibacterial activity in invitro (MIC: / xg / ml)

Strain A Staphylococcus aureus Smith

 Strain B Staphylococcus aureus KT0150 (MRSA)

 Strain C Staphylococcus aureus KT0130 (MRSA)

 Strain D Staphylococcus aureus KT0116 (MRSA)

 Strain E Staphylococcus aureus FDA 209P

 Strain F Staphylococcus aureus KMP9 (MRSA)

 Strain G Staphylococcus epidermidis ATCC12228

 Strain H Streptococcus pi contact n e ATCC49619

 Strain I Streptococcus pneumoniae KT2524 (PRSP)

Strain J Streptococcus pneumoniae KB2534 (PRSP) Strain K Streptococcus pyogenes ATCC12344

Strain L Enterococcus faeciuin ATCC19434

Strain M Mor axel la (B.) catarrhal is K1209 ³ ' ⁴

 1 Compound A has the structure described in Section 2 of the present specification and is a comparative control compound disclosed in Example 12 of WO99 / 39704 pamphlet. Compound B is a commercially available pyridonecarboxylic acid antibacterial agent (ciprofloxacin) having the following structure.

This strain is a clinical isolate.

 ^ This strain is a Gram-negative bacterium, the others are Gram-positive. The strains H to K were measured by the microfluidic dilution method, and the other strains were measured by the agar plate dilution method. Experimental example 2: Effect on mouse systemic infection:

Effect on mouse systemic infection _{(ED 5:. MgZk g /} d 0 se) is, ICR-strain male mice (body weight about 20 g) in 50% infection lethal dose of about 50 times the amount of the pathogen per animal (A to The live bacteria of C) were intraperitoneally administered (ip) to cause infection, and the test compound dissolved in physiological saline was subcutaneously administered (sc) twice at 1 hour and 4 hours after infection, and 7 days after infection Was calculated by the probit method from the survival rate of the mice. The results are shown in Table 41. Antibacterial action on the table 41 systemic infections _{(ED 5:. Mg / kg} / do se)

Table 40 refers to the same strain from <above, salts among, _{which 9} is hydrogen atom or 1 _{9 £ 1} Dearu compound (1 -B) 'or a physiologically acceptable compounds of the present invention It has excellent antibacterial activity and low toxicity. For example, as shown in Table 40, the compound of the present invention has better antibacterial activity in vitro than compound A, and also has a strong antibacterial activity in vivo. In addition, for example, D-1-1, D-3-1, D-7-1, D-14, D-15, D-16-1, D-17, D-25 _ 1 and D-54 The acute toxicity values (LD50, iV) for the compounds in mice are all> 100 mg / kg, and these compounds are non-toxic or extremely low. Therefore, the compound (I-B) ′ of the present invention or a physiologically acceptable salt thereof is useful as an antibacterial agent for humans and animals. The dose of the compound (I_B) 'of the present invention varies depending on the administration method, symptoms, age, etc., but is usually about 2 to 5000 mg, preferably about 5 to 500 mg, particularly preferably about 5 to 500 mg per 60 kg of body weight per day. 30-30 Omg. The route of administration may be oral, but parenteral, especially intravenous, is recommended. The compound (I-B) ′ of the present invention is generally administered in the form of a preparation. These preparations can be prepared by mixing the compound (I-B) 'with the components to be formulated. For example, as a formulation component in a liquid formulation for parenteral administration, a solvent such as water or physiological saline is an essential component, and in addition, a tonicity agent, a soothing agent, a pH regulator, a buffer, a storage agent, and the like. Auxiliary components such as agents are appropriately blended.

 Liquid preparations such as injections can be prepared by dissolving compound (I-B) 'in a solvent such as physiological saline for injection, and adding other auxiliary components before or after dissolution as required. . Lyophilized formulations can be prepared by lyophilizing such solutions and redissolving them upon administration. Potential industrial applicability

 The compound (IB) ′ of the present invention or a physiologically acceptable salt thereof has an excellent action on multidrug-resistant bacteria and is useful as an antibacterial agent. Further, the compound (IA) or a salt thereof of the present invention is useful as a direct intermediate for producing the compound (IB).

Claims

The scope of the claims

1. Proline derivative represented by the general formula (I) or a salt thereof:

 (Wherein ring A has 1 to 4 hetero atoms as ring constituent atoms and may be fused with a benzene ring which may be substituted with a halogen atom. Group.

 p1 is an integer of 0 or 1, p2 is an integer of 0 or 1, and p3 is an integer of 0 or 1.

Ri, R ₂ and R ₃ are bonded at any position on the A ring, and are the same or different and each has 1 to 3 halogen atoms or hydroxy groups (the hydroxy groups are protected with an acyl group). A lower alkyl group, a hydrogen atom, a lower alkoxy group, a lower alkylthio group, a halogen atom, a hydroxy group, an amino group, or an aminocarbonyl group which may be substituted with May be mono- or di-substituted with alkyl), hydroxy-lower-alkylamino group, carboxyl group, lower-alkoxycarbonyl group, lower-alkylcarboxy group, lower-alkyl which may be substituted by 1 to 3 halogen atoms It means sulfonyloxy group or cyano group, or when pl = p 2 = l, Or R ₂ is together form a connexion Okiso group, or when pl = p 2 = p 3 = 1, and R ₂ is a hydrogen atom, the R ₃ is a 5-6 membered saturated or unsaturated A cyclic group (a), which is directly bonded to the A ring, or bonded via a carbonyl, imino-lower alkylene or oxy-lower alkylene; and one to two constituent atoms of the cyclic group (a) The cyclic group (a) may be substituted with a lower alkyl group or a halogen atom which may be substituted with a halogen atom. T represents a single bond, a methylene group or a carbonyl group.

R ₄ and R ₅ may be the same or different and each may be a hydrogen atom or a lower alkyl group, or both bonded to the same carbon atom may be combined to form an oxo group.

 m is an integer of 1 or 2.

R ₆ and R ₇ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, a lower alkyl group, a phenyl group, a lower alkoxy group, a phenyl lower alkyloxy group, an amino group which may be protected, Both may combine to form a saturated cyclic group.

X is a carbon atom (CH ₂ , CH, C), a zeo atom or an oxygen atom, and n is an integer of 1 or 2.

 Y is a group (b) represented by the following formula.

Wherein R ₈ is an alkyl group or a cycloalkyl lower alkyl group, R ₉ is a hydrogen atom or a hydroxy protecting group, or R _9a . Here, R _9a is R _9al —CO—, R _{9a2 —O} —C O—, and R _9a3 — (CH ₂ ) p—, and R _9al is a lower alkyl group (the lower alkyl group is a phenyl group, Or a mono-lower alkyl-substituted amino group, or substituted with a 6-membered saturated cyclic amino group. May be a 6-membered saturated cyclic amino group, a C ₆ -C ₁₀ aryl group which may be substituted by a hydroxyl group, or may be condensed with a benzene ring 5 to 6-membered saturated Or an unsaturated heterocyclic group.

R _9a2 represents a lower alkyl group, a power that is a cycloalkyl group optionally substituted with lower alkyl, or a 5-membered saturated cyclic ester residue optionally substituted with lower alkyl.

R _9a3 may be substituted with lower alkyl or condensed with a benzene ring. 5-membered saturated or unsaturated cyclic ester residue or cyclic carbonate residue. And p is an integer of 0 or 1. )

 2. In the proline derivative represented by the general formula (I) or a salt thereof: p 1 and p 2 are 1, p 3 is 0,

1 ^ and R ₂ are the same or different and each may be a lower alkyl group, a hydrogen atom, a lower alkoxy group, a halogen atom, a hydroxy group, an amino group or an amino carbonyl group which may be substituted with 1 to 3 halogen atoms. Group (the amino group may be protected or mono- or di-substituted by lower alkyl), carbonyl group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, 1 to 3 hagen atoms Represents a lower alkylsulfonyloxy group or a cyano group which may be substituted with, or is a hydrogen atom, and R ₂ is a 5- to 6-membered saturated or unsaturated cyclic group (a) is a ring A And a bond directly through an imino lower alkylene or an oxy lower alkylene, and contains 1 to 2 heteroatoms as constituent atoms of the cyclic group (a). The cyclic group (a) may be substituted with a lower alkyl group.

 T means a single bond.

R ₄ and R ₅ are bonded at any position on the B ring and are the same or different and are a hydrogen atom or a lower alkyl group, or both bonded to the same carbon atom are oxo together. It may form a group.

 m is an integer of 1 or 2.

R ₆ and R ₇ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, a lower alkyl group, a phenyl group, a lower alkoxy group, a phenyl lower alkyloxy group, an amino group which may be protected, Both may combine to form a saturated cyclic group.

X is a carbon atom (CH ₂ , CH, C), a zeolite atom or an oxygen atom, and n is an integer of 1 or 2.

 Y is a group (b) represented by the following formula.

Wherein R ₈ is an alkyl group or a cycloalkyl lower alkyl group;

₉ is a hydrogen atom or a hydroxy protecting group;

The proline derivative according to claim 1, or a salt thereof.

 3. Proline derivative represented by the general formula (I-B) or a salt thereof:

 (In the formula, the definition of each symbol and substituent is the same as the definition in claim 1.)

4. The proline derivative or a salt thereof according to claim 3, wherein the compound is represented by the following formula (I-C):

(Wherein, the definitions of R ₂ , R ₃ , R ₄ , R ₅ , n, pi, p 2, p 3 and R ₈ are the same as those defined in claim 1, and the ring has 1 to 3 rings. An unsaturated 5- to 6-membered monocyclic heterocyclic group having a double bond, and the heterocyclic group may be condensed with a benzene ring which may be substituted with a halogen atom; , Z ₂ , Z ₃ and Z ₄ are the same or different and are atoms selected from a carbon atom (CH ₂ , CH or C), a nitrogen atom (NH or N), a zeolite atom and an oxygen atom, Any one of Zi, Z ₂ , Z ₃ and Z4 may be absent, and Ri, R ₂ and R ₃ are bonded to any of the ring-forming carbon or nitrogen atoms And

Real and R7al are the same or different, hydrogen atom, lower alkyl group, halogen An atom or a lower alkoxy group, X _al denotes carbon atom (CH _2, CH or C) or an oxygen atom. )

 5. The proline derivative or a salt thereof according to claim 4, wherein the compound is represented by the following formula (ID):

(Wherein the definition of R ₈ is the same as in the previous definition, U is a nitrogen atom or a sulfur atom, R1a is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, in the A _la ring = A portion means a single bond, a double bond or the absence of a bond.) '

6. The proline derivative or the salt thereof according to claim 3, wherein Ri, R ₂ and R ₃ are both hydrogen atoms.

 7. Ring A is pyridyl, bilanyl, cyenyl, furyl, pyrrolyl, pyrimigel, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, 1,3,5-triazinyl, 1,2,2 4. The proline derivative or a salt thereof according to claim 3, which is any one of 4-triazinyl, tetrazinyl, thiadiazolyl, isoquinolyl, benzothiazolyl, and benzoxazolyl.

8. The proline derivative or a salt thereof according to claim 4, wherein the ring or A _la ring is pyrimigel or thiazolyl.

9. The proline derivative or a salt thereof according to claim 3, 4 or 5, wherein R ₈ is any one of an n-pentyl group, an n_butyl group, a cyclopentylmethyl group and a cyclohexylmethyl group.

 10. The proline derivative or the salt thereof according to claim 3, wherein the compound is any of the following:

Compound D—1-1

(2 S) — 1-{(2 R) 1-cyclopentyl-2-[(N—formyl—N— [Hydroxyamino) methyl] propionyl} 1-2-{[4- (2-Pyrimidinyl) -11-piperazinyl] pyrrol} pyrrolidine;

Compound D— 2— 1

 (2 S)-1-{(2 R) -2- [(N-formyl-1-N-hydroxyamino) methyl] hexanoyl}-2-{[4- (2-pyrimidinyl) — 1-piperazinyl] Pyrrolidine} pyrrolidine;

Compound D— 3— 1

 (2 S) — 1— {(2 R) 13-cyclopentyl— 2 — [(N-formyl—N-hydroxyamino) methyl] propionyl} 1-2 — {[4- (2-thiazolyl) 1-piperazinyl] carbonyl} pyrrolidine;

Compound D—4-1

 (2 S) 1 1 1 {(2 R) —2— [(N-formyl-N-hydroxyamino) methyl] hexanoyl} -2- {[4- (2-thiazolyl) — 1-piperazinyl] Carbonyl} pyrrolidine;

Compound D—5

 (2S) -1-1 {(2R) -2-[(N-formyl-N-hydroxyamino) methyl] hexanoyl} -2-{[4- (4-methyl-2-thiazolyl) -1-piperazinyl ] Pyrolidine pyrrolidine;

Compound D—6

 (1 S, 2 S, 5 R)-3-Hazard 3-1 ((2R) 1 2-[(N-Formyl 1

N-hydroxyamino) methyl] heptanoyl} -2-{[4_ (2-pyrimidinyl) _1-piperazinyl] carbonyl} bicyclo [3,1,0] hexane;

Compound D— 7— 1

 (2 S) —11 {(2 R) -2-[(N-formyl-1-N-hydroxyamino) methyl] heptanyl} -2-{[4- (2-thiazolyl) _1—piperazinyl] force Liponyl} pyrrolidine;

Compound D _ 8

(2 S)-1-{(2 R) 1 2— [(N-formyl-N-hydroxyamino) Methyl] Heptanoyl} -2-{[4- (4-Methyl-2-thiazolyl) -1-piperazinyl] pyrrolyl} pyrrolidine;

Compound D—9

 (2 S)-2-{[4- (5-promo-2-thiazolyl) —1-piperazinyl] carbonyl} — 1— {(2 R) -2-[(N-formyl-N-hydroxyamino ) Methyl] hepnoyl} pyrrolidine;

Compound D—10

 (2 S) -2-{[4- (2-benzothiazolyl) —1-piperazinyl] power rupounyl} 1-1 1 {(2 R) -2 — [(N-formyl-N-hydroxyamino) methyl ] Hep Even Nyl} Pyrrolidine;

Compound D— 1 1 _ 1

 (2S) -1-{(2R) _3-cyclopentyl-2-[[(N-formyl-1-N-hydroxyamino) methyl] propionyl} -2-{[4_ (4-methyl-2-monothiazolyl) 1-piperazinyl] pyrrolidine} pyrrolidine; Compound D-12

 (2 S, 3 S) — 1— {(2 R)-2-[(N-formyl—N-hydroxyamino) methyl] heptanoyl} —3-methyl_2_ {[4- (2-pyrimidinyl) one 1-piperazinyl] pyrrolidine pyrrolidine;

Compound D— 13

 (2 S) -4,4-difluoro-1-1 {(2 R) -12-[(N-formyl-N-hydroxyamino) methyl] hepnoyl} -2-{[4- (2-pyrimidyl Dinyl) -1-piperazinyl] pyrrolidine pyrrolidine;

Compound D—14

 (2 S)-1-{(2 R) —2— [(N-formyl-1-N-hydroxyamino) methyl] hepnoyl} -2- {[4- (6-methoxy-12-pyridyl) —

1-piperazinyl] pyrrol} pyrrolidine;

Compound D—15

(2 S) 1 2— {[4- (6—C1—2—pyrazinyl) 1-1—piperazinyl] carbonyl}-1-{(2R) 1 2— [(N-formyl-N-hydroxy Amino) methyl] heptanyl} pyrrolidine;

Compound D—1 6 _ 1

 (2 S) — 1— {(2 R) 1-3-cyclohexyl— 2— [(N—formyl-1-N—hydroxyamino) methyl] propionyl} —2— {[4— (2-thiazo Lyl) 1-piperazinyl] carbonyl} pyrrolidine.

 11. The proline derivative according to any one of claims 1 to 10, wherein the salt is an acid addition salt or a metal salt.

12. A medicament comprising a proline derivative represented by the formula (I-B) according to claim 3 or a physiologically acceptable salt thereof as an active ingredient. Here, R 9 in the formula (IB) is a hydrogen atom or R _9a .

 13. The medicament according to claim 12, comprising the proline derivative represented by the formula (I-C) according to claim 4 or a physiologically acceptable salt thereof as an active ingredient.

 14. The medicament according to claim 12, comprising a proline derivative represented by the formula (ID) according to claim 5 or a physiologically acceptable salt thereof as an active ingredient.

 15. The medicament according to claim 12, 13, or 14, wherein the active ingredient is the proline derivative according to claim 10 or a physiologically acceptable salt thereof.

 16. The medicament according to any one of claims 13 to 15, wherein the medicament is an antibacterial agent.

 17. The medicament according to claim 16, wherein the antibacterial agent is against multidrug-resistant bacteria.

18. A pharmaceutical composition comprising a proline derivative represented by the formula (I-B) according to claim 3, or a physiologically acceptable salt thereof, and a formulation component. Here, R _{9 in} the formula (IB) is a hydrogen atom or R _9a .

 19. The pharmaceutical composition according to claim 18, wherein the form of the pharmaceutical composition is a liquid preparation or a ready-to-use preparation.