JP7228828B2 - Peptide type bacterial dipeptidyl peptidase 7 inhibitor - Google Patents

Description

The present invention relates to peptide-type bacterial dipeptidyl peptidase 7 inhibitors and the like.

Antimicrobial agents in current use have mechanisms of action that block the action of pathogen-specific target molecules in bacterial cell wall synthesis, protein synthesis, nucleic acid synthesis, and metabolic processes. In order to suppress the emergence of resistant strains of these antibacterial drugs, measures are taken to ensure their proper use based on guidelines. However, due to the international movement of people and goods, it is difficult to prevent the global spread of drug-resistant bacteria. In addition to prevention and proper use, it is important to develop new antibacterial agents with mechanisms of action different from those of existing drugs.

Stenotrophomonas maltophilia (Sm), one of the multidrug-resistant bacteria, has low susceptibility to drugs such as β-lactams, aminoglycosides, and quinolones. It causes severe pneumonia and death. Sm is a non-sugar-fermenting Gram-negative bacterium that decomposes proteins and peptides instead of carbohydrates to obtain amino acids as a nutritional source. The inner membrane of Sm contains an enzyme called dipeptidyl peptidase 7 (also referred to as "DPP7" in this specification) that cleaves dipeptides from peptides, and the resulting dipeptide must permeate the inner membrane. Therefore, the function of DPP7 is essential for the proliferation of Sm. On the other hand, Porphyromonas gingivalis (Pg), which is a typical causative bacterium of periodontal disease, is said to be involved in systemic diseases such as diabetes, angina pectoris, and myocardial infarction. I know I have.

The structure of the active center of dipeptidyl aminopeptidase (DAP) BII is similar to that of SmDPP7 and PgDPP7, and the co-crystal structure with Val-Tyr dipeptide has been analyzed (Non-Patent Document 1).

SCIENTIFIC REPORT, 4, 4977 (2014)

The present inventor focused on DPP7, which is possessed only by bacteria, in the course of his research. An object of the present invention is to provide a DPP7 inhibitor.

Means for Solving the Problems As a result of intensive research in view of the problem, the present inventors have found that the compound represented by general formula (1) has DPP7 inhibitory activity. As a result of further research based on this knowledge, the present invention was completed.

That is, the present invention includes the following aspects.

Section 1. General formula (1):

[In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group. ^R3 represents a single bond or an alkylene group. R ⁴ represents an optionally substituted cycloalkyl group or an optionally substituted aryl group. ^R5 represents an optionally substituted branched alkyl group or an optionally substituted aryl group. R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different and represent a hydrogen atom or a hydrocarbon group (n represents 0 or 1). ]
A bacterial dipeptidyl peptidase 7 inhibitor containing a compound represented by or a salt, hydrate or solvate thereof.

Section 2. Item 2. The inhibitor according to Item 1, wherein the cycloalkyl group and aryl group represented by R ⁴ have 5 to 7 carbon atoms.

Item 3. Item 3. The inhibitor according to Item 1 or 2, wherein the substituent when the cycloalkyl group and aryl group represented by R ⁴ are substituted is an acid group, a halogen atom, an amino group, or a nitro group.

Section 4. Item ^4. The inhibitor according to any one of Items 1 to 3, wherein the branched alkyl group represented by R 5 has 3 to 8 carbon atoms, and the aryl group represented by R ⁵ is a phenyl group.

Item 5. Item 5. The inhibitor according to any one of Items 1 to 4, wherein when the branched alkyl group and aryl group represented by R ⁵ are substituted, the substituent is a hydroxyl group, an alkoxy group, or a halogen atom.

Item 6. Item 6. The inhibitor according to any one of Items 1 to 5, wherein both R ¹ and R ² are hydrogen atoms.

Item 7. Item ^{7. The item according to any one of Items 1 to 6, wherein in —NR 62 —} (SO ₂ ) _n —R ⁶³ represented by R 6 , R ⁶² is a hydrogen atom and R ⁶³ is a hydrocarbon group. inhibitor.

Item 8. The cycloalkyl group and aryl group represented by R ⁴ have 5 to 7 carbon atoms,
When the cycloalkyl group and aryl group represented by R ⁴ are substituted, the substituents are
a hydroxyl group, a halogen atom, an amino group, or a nitro group,
The branched alkyl group represented by R ⁵ has 3 to 8 carbon atoms,
The aryl group represented by R ⁵ is a phenyl group,
When the branched alkyl group and aryl group represented by R ⁵ are substituted, the substituent is a hydroxyl group, an alkoxy group, or a halogen atom,
-NR ⁶² -(SO ₂ ) _n -R ⁶³ represented by R ⁶ wherein both R ¹ and R ² are hydrogen atoms, and R ⁶² is a hydrogen atom and R ⁶³ is a hydrocarbon is the basis
Item 8. The inhibitor according to any one of Items 1 to 7.

Item 9. Item 9. The inhibitor according to Item 8, wherein the cycloalkyl group and aryl group represented by ^R4 are unsubstituted.

Item 10. General formula (1):

[In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group. ^R3 represents a single bond or an alkylene group. R ⁴ represents an optionally substituted cycloalkyl group or an optionally substituted aryl group. ^R5 represents an optionally substituted branched alkyl group or an optionally substituted aryl group. R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different and represent a hydrogen atom or a hydrocarbon group (n represents 0 or 1). ]
An antibacterial agent containing a compound represented by or a salt, hydrate or solvate thereof.

Item 11. General formula (1):

[In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group. ^R3 represents a single bond or an alkylene group. R ⁴ represents an optionally substituted cycloalkyl group or an optionally substituted aryl group. ^R5 represents an optionally substituted branched alkyl group or an optionally substituted aryl group. R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different and represent a hydrogen atom or a hydrocarbon group (n represents 0 or 1). ]
A prophylactic or ameliorating agent for bacterial infections containing the compound represented by or a salt, hydrate or solvate thereof.

Item 12. General formula (1):

[In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group. ^R3 represents a single bond or an alkylene group. R ⁴ represents an optionally substituted cycloalkyl group or an optionally substituted aryl group. ^R5 represents an optionally substituted branched alkyl group or an optionally substituted aryl group. R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different and represent a hydrogen atom or a hydrocarbon group (n represents 0 or 1). ]
A compound represented by (excluding compounds where -R ³ -R ⁴ is the side chain of a natural amino acid).

INDUSTRIAL APPLICABILITY According to the present invention, a compound having DPP7 inhibitory action and a DPP7 inhibitor can be provided. This compound can also be used as an antibacterial agent, an agent for preventing or improving bacterial infections, and the like.

15 shows SmDPP7 residual activity at a compound concentration of 100 μM, measured in Example 15. FIG. The vertical axis indicates residual activity. Numbers on the horizontal axis indicate the compound number of the test compound, and "No inhibitor" indicates the case where the test compound was not added.

As used herein, the expressions "contain" and "include" include the concepts "contain", "include", "consist essentially of" and "consist only of".

1. In one aspect of the present invention, a compound represented by general formula (1):

A compound represented by or a salt, hydrate or solvate thereof. This will be explained below.

<1-1. About R ¹ and R ² >
R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group.

The alkyl group represented by R ¹ or R ² includes any of linear, branched or cyclic (preferably linear or branched, more preferably linear) . The number of carbon atoms in the alkyl group is not particularly limited, and is, for example, 1-6, preferably 1-4, more preferably 1-2, still more preferably 1. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, neopentyl group, n -hexyl group, 3-methylpentyl group and the like.

R ¹ and R ² are preferably both hydrogen atoms.

<1-2. About ^R3 >
^R3 represents a single bond or an alkylene group.

The alkylene group represented by R ³ includes either straight-chain or branched-chain, preferably straight-chain. The number of carbon atoms in the alkylene group is not particularly limited, and is, for example, 1-6, preferably 1-4, more preferably 1-2, still more preferably 1. Specific examples of the alkylene group include methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group and isobutylene group.

R ³ is preferably an alkylene group.

<1-3. About ^R4 >
R ⁴ represents an optionally substituted cycloalkyl group or an optionally substituted aryl group.

The number of carbon atoms in the cycloalkyl group represented by R ⁴ is not particularly limited, and is, for example, 3-10, preferably 4-8, more preferably 5-7, still more preferably 6. Specific examples of the cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like.

The aryl group represented by R ⁴ is not particularly limited, but preferably has 6 to 12 carbon atoms, more preferably 6 to 12 carbon atoms, and even more preferably 6 to 8 carbon atoms. The aryl group can be either monocyclic or polycyclic (eg, bicyclic, tricyclic, etc.), but is preferably monocyclic. Specific examples of the aryl group include phenyl, naphthyl, biphenyl, pentalenyl, indenyl, anthranyl, tetracenyl, pentacenyl, pyrenyl, perylenyl, fluorenyl, and phenanthryl groups. and preferably a phenyl group.

The substituents that the cycloalkyl group represented by ^R4 and the aryl group represented by ^R4 may have are not particularly limited, and examples thereof include a hydroxyl group, a halogen atom, an optionally substituted amino group, and a nitro group. , an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a cyano group and the like. Among these, hydroxyl group, halogen atom, amino group, nitro group and the like are preferred, and hydroxyl group is more preferred.

Examples of the halogen atom which the cycloalkyl group represented by R ⁴ and the aryl group represented by R ⁴ may have include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The amino group which the cycloalkyl group represented by ^R4 and the aryl group represented by ^R4 may have is not particularly limited, and may be linear or branched (preferably linear). Examples include amino groups optionally substituted with 1 to 6, preferably 1 to 4, more preferably 1 to 2 alkyl groups. The number of alkyl groups substituted is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted amino groups include amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, ethylmethylamino group and the like.

The cycloalkyl group represented by R ⁴ and the alkyl group which the aryl group represented by R ⁴ may have are not particularly limited, and include halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). A linear or branched (preferably linear) alkyl group having 1 to 6, preferably 1 to 4, more preferably 1 to 2, more preferably 1 carbon atoms optionally substituted with be done. The number of substituents is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, perfluoro Examples include a methyl group and a perfluoroethyl group.

The alkoxy group that the cycloalkyl group represented by R ⁴ and the aryl group represented by R ⁴ may have is not particularly limited, and includes a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.) and the like. A linear or branched (preferably linear) alkoxy group having 1 to 6, preferably 1 to 4, more preferably 1 to 2, more preferably 1 carbon atoms optionally substituted with be done. The number of substituents is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, per A fluoromethoxy group, a perfluoroethoxy group, and the like can be mentioned.

The alkylthio group which the cycloalkyl group represented by R ⁴ and the aryl group represented by R ⁴ may have is not particularly limited, and includes a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.) and the like. A linear or branched (preferably linear) alkylthio group having 1 to 6, preferably 1 to 4, more preferably 1 to 2, more preferably 1 carbon atoms optionally substituted with be done. The number of substituents is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted alkylthio groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, A perfluoromethylthio group, a perfluoroethylthio group, and the like can be mentioned.

The number of substituents of the cycloalkyl group represented by R ⁴ and the aryl group represented by R ⁴ is, for example, 0 to 3, preferably 0 to 2, more preferably 0 to 1, still more preferably 0.

R ⁴ preferably includes an optionally substituted aryl group.

<1-4. About ^R5 >
^R5 represents an optionally substituted branched alkyl group or an optionally substituted aryl group.

The number of carbon atoms in the branched alkyl group represented by R ⁵ is not particularly limited, and is, for example, 3-10, preferably 3-8, more preferably 3-6, still more preferably 3-4. Specific examples of the branched alkyl group include isopropyl group, isobutyl group, tert-butyl group, sec-butyl group and the like.

The aryl group represented by R ⁵ is not particularly limited, but preferably has 6 to 12 carbon atoms, more preferably 6 to 12 carbon atoms, and even more preferably 6 to 8 carbon atoms. The aryl group can be either monocyclic or polycyclic (eg, bicyclic, tricyclic, etc.), but is preferably monocyclic. Specific examples of the aryl group include phenyl, naphthyl, biphenyl, pentalenyl, indenyl, anthranyl, tetracenyl, pentacenyl, pyrenyl, perylenyl, fluorenyl, and phenanthryl groups. and preferably a phenyl group.

The substituents that the branched alkyl group represented by R ⁵ and the aryl group represented by R ⁵ may have are not particularly limited. optionally substituted amino group, nitro group, optionally substituted alkyl group, optionally substituted alkylthio group, cyano group and the like. Among these, preferred are a hydroxyl group, an optionally substituted alkoxy group, a halogen atom, and the like, more preferred are a hydroxyl group, an optionally substituted alkoxy group, and the like, and further preferred is a substituted alkoxy group. good alkoxy groups.

The alkoxy group which the branched alkyl group represented by ^R5 and the aryl group represented by ^R5 may have is not particularly limited, and includes a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.) and the like. A linear or branched (preferably linear) alkoxy group having 1 to 6, preferably 1 to 4, more preferably 1 to 2 carbon atoms which may be substituted with . The number of substituents is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, per A fluoromethoxy group, a perfluoroethoxy group, and the like can be mentioned.

The halogen atom which the branched alkyl group represented by ^R5 and the aryl group represented by ^R5 may have includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, preferably an iodine atom. mentioned.

The branched alkyl group represented by R ⁵ and the amino group which the aryl group represented by R ⁵ may have are not particularly limited, and may be linear or branched (preferably linear). Examples include amino groups optionally substituted with 1 to 6, preferably 1 to 4, more preferably 1 to 2 alkyl groups. The number of alkyl groups substituted is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted amino groups include amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, ethylmethylamino group and the like.

The branched alkyl group represented by R ⁵ and the alkyl group which the aryl group represented by R ⁵ may have are not particularly limited, and include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). A linear or branched (preferably linear) alkyl group having 1 to 6, preferably 1 to 4, more preferably 1 to 2, more preferably 1 carbon atoms optionally substituted with be done. The number of substituents is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, perfluoro Examples include a methyl group and a perfluoroethyl group.

The branched alkyl group represented by R ⁵ and the alkylthio group which the aryl group represented by R ⁵ may have are not particularly limited, and include a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). A linear or branched (preferably linear) alkylthio group having 1 to 6, preferably 1 to 4, more preferably 1 to 2, more preferably 1 carbon atoms optionally substituted with be done. The number of substituents is not particularly limited, and is, for example, 0 to 3, preferably 0. Examples of such optionally substituted alkylthio groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, A perfluoromethylthio group, a perfluoroethylthio group, and the like can be mentioned.

The number of substituents of the branched alkyl group represented by R ⁵ and the aryl group represented by R ⁵ is, for example, 0-3, preferably 1-3, more preferably 1-2, still more preferably 1.

R ⁵ preferably includes an optionally substituted aryl group, more preferably general formula (X):

[Wherein, R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are the same or different and are hydrogen atom, hydroxyl group, optionally substituted alkoxy group, halogen atom, optionally substituted amino group , a nitro group, an optionally substituted alkyl group, an optionally substituted alkylthio group, and a cyano group. ]

In the general formula (X), the various substituents represented by R ³¹ , R ³² , R ³³ , R ³⁴ or R ³⁵ include the branched alkyl group represented by R ⁵ and the aryl group represented by R ⁵ . It is the same as the substituent which may be possessed.

In general formula (X), preferably R ³² , R ³³ , R ³⁴ and R ³⁵ are hydrogen atoms, and R ³¹ is a substituent other than a hydrogen atom.

<1-5. About ^R6 >
R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different and represent a hydrogen atom or a hydrocarbon group indicates

The alkyl group represented by R ⁶¹ includes any of linear, branched or cyclic (preferably linear or branched, more preferably linear). The number of carbon atoms in the alkyl group is not particularly limited, and is, for example, 1-6, preferably 1-4, more preferably 1-2, still more preferably 1. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, neopentyl group, n -hexyl group, 3-methylpentyl group and the like.

R ⁶¹ is preferably an alkyl group.

The hydrocarbon group represented by R ⁶² or R ⁶³ is not particularly limited, and examples thereof include alkyl groups, aryl groups, and combinations thereof.

The alkyl group represented by ^R62 or ^R63 includes any of straight-chain, branched-chain and cyclic ones. The number of carbon atoms in the alkyl group is not particularly limited, and is, for example, 1-6, preferably 1-4. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, neopentyl group, n -hexyl group, 3-methylpentyl group and the like.

The aryl group represented by R ⁶² or R ⁶³ is not particularly limited, but preferably has 6 to 12 carbon atoms, more preferably 6 to 12 carbon atoms, and even more preferably 6 to 8 carbon atoms. The aryl group can be either monocyclic or polycyclic (eg, bicyclic, tricyclic, etc.), but is preferably monocyclic. Specific examples of the aryl group include phenyl, naphthyl, biphenyl, pentalenyl, indenyl, anthranyl, tetracenyl, pentacenyl, pyrenyl, perylenyl, fluorenyl, and phenanthryl groups. and preferably a phenyl group.

The hydrocarbon group represented by ^R62 or ^R63 is preferably an alkyl group.

Preferably, ^R62 is a hydrogen atom and ^R63 is a hydrocarbon group.

^R6 is preferably ^-OR61 .

<1-6. Isomer>
The compound represented by general formula (1) includes stereoisomers and optical isomers, and these are not particularly limited. Among the compounds represented by the general formula (1), compounds having a preferred stereostructure include the following general formula (1'):

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above. ]
The compound represented by is mentioned.

<1-7. Salts, Hydrates, Solvates>
The salt of the compound represented by formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. As the salt, both acid salts and basic salts can be employed. Examples of acid salts include mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, propionate, tartrate, fumarate, maleate, malic acid. Salts, organic acid salts such as citrate, methanesulfonate, p-toluenesulfonate, etc. Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as salts; salts with ammonia; morpholine, piperidine, pyrrolidine, monoalkylamine, dialkylamine, trialkylamine, mono(hydroxyalkyl)amine, di(hydroxyalkyl)amine, tri(hydroxyalkyl) Examples thereof include salts with organic amines such as amines.

The compound represented by general formula (1) can also be a hydrate or solvate. Solvents include, for example, pharmaceutically acceptable organic solvents (eg, ethanol, glycerol, acetic acid, etc.) and the like.

2. Manufacturing method The compound represented by the general formula (1) can be synthesized by various methods. Typically, the compound represented by general formula (1) can be obtained by a method comprising peptide bonding of two amino acids and/or amino acid derivatives according to or according to solid-phase peptide synthesis.

Examples of specific synthesis methods are shown below. In the reaction scheme below, ^RA corresponds to —(CH ₂ )—R ⁵ in general formula (1), ^RB corresponds to —R ³ —R ⁴ in general formula (1), and R ^C corresponds to —R ⁶³ in general formula (1), and R ^D corresponds to an alkoxy group which is a substituent of the aryl group represented by R ⁵ in general formula (1).

A compound having a carboxylic acid at the C-terminus can be synthesized according to the following reaction scheme by using a 2-chlorotrityl chloride resin to bind to a dipeptide by a conventional Fmoc solid-phase synthesis method, followed by deprotection and deresin.

A compound having a carboxamide structure at the C-terminus can be synthesized according to the following reaction scheme by extending to a dipeptide using Fmoc-amide resin, deresining and deprotecting.

Compounds with a C-terminal sulfonamide are condensed with a Boc-protected tyrosine using CDI in the presence of DBU followed by deprotection, followed by coupling and deprotection of the Boc amino acid according to the reaction scheme below, Can be synthesized.

C-terminal methyl ester compounds are synthesized starting with Boc-tyrosine methyl ester, removing the Boc group, condensing Boc-cyclohexylalanine to give an intermediate, deprotecting this intermediate, and synthesizing be able to. A compound in which the hydroxyl group of the tyrosine side chain is alkylated can be synthesized by alkylating an intermediate with an alkyl bromide, followed by ester hydrolysis and deprotection.

3. Uses Since the compound represented by the general formula (1) has DPP7 inhibitory activity, it can be suitably used as an active ingredient for various uses, such as DPP7 inhibitors, antibacterial agents, and prophylactic or therapeutic agents for bacterial infections. can be done. From this viewpoint, one aspect of the present invention is It relates to a preventive or ameliorating agent (in this specification, these may be collectively referred to as "the agent of the present invention").

The target DPP7 is not particularly limited as long as it is DPP7 possessed by bacteria. DPP7が由来する細菌としては、例えば Bacteroides fragilis、Bacteroides ovatus、Bacteroides thetaiotaomicron、Bacteroides uniformis、Bacteroides vulgatus、Capnocytophaga gingivalis、Capnocytophaga ochracea、 Chryseobacterium sp.、Shewanella putrefaciens、Stenotrophomonas maltophilia、Porphyromonas assaccharolytia、Porphyromonas endodontalis、Porphyromonas gingivalis、Porphyromonas Sugar-nonfermentative Gram-negative bacteria such as uenonis, Prevotella bivia, Prevotella disiens, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Prevotella oris, Pseudomonas sp., Pseudoxanthomonas mexicana, Tannerella forsythensis. When the agent of the present invention is an antibacterial agent, it can be suitably used against these bacteria.

Bacterial infections are not particularly limited as long as they are bacterial infections caused by infection with the above bacteria. Weight-weight infants and the like are included.

The content of the active ingredient in the agent of the present invention is not particularly limited as long as it is an amount capable of exhibiting DPP7 inhibitory action. The content of the active ingredient in the agent of the present invention can be about 0.0001 to 100 parts by weight based on 100 parts by weight of the entire agent of the present invention.

In the agent of the present invention, the compound represented by the general formula (1), or a salt, hydrate or solvate thereof, and other bacterial DPP (e.g., DPP-4, -5, -7, -11, etc.) ) may be used in combination. DPP inhibitors to be used in combination include, for example, anagliptin, alogliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, torelagliptin, vildagliptin, lignagliptin, berberine, DPP4 selective inhibitor 1c, K579, NVP-DPP728, 2-cyano-1-isoleu sylpyrrolidine, glycylhydroxyproline, lisinopril and the like.

The agent of the present invention can be a composition containing additives depending on the application and mode of use. Examples of additives include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, humectants, colorants, perfumes, Examples include chelating agents, rust inhibitors, metal corrosion inhibitors, antifoaming agents, rust inhibitors, extreme pressure additives, metal corrosion inhibitors, antifoaming agents, and dyes. It is preferable to select and use pharmaceutically acceptable ingredients and cosmetically acceptable ingredients among these additives according to the purpose of use.

The field of use of the DPP7 inhibitor and antibacterial agent of the present invention is not particularly limited. For example, it can be used in fields such as the medical field, the cosmetic field, the food field, the cleaning field, the oral cavity field, and the reagent field.

The form of the agent of the present invention is not particularly limited, and depending on the use of the agent of the present invention, it can take a form commonly used in each application.

As for the forms, when the application is a medicine, for example, patches (plasters, tapes such as plasters (reservoir type, matrix type, etc.), poultices, patches, microneedles, etc.), ointments, external liquids (liniments, lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, enema Formulations suitable for parenteral intake (especially formulations for external use) such as tablets; tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, jelly drops, etc.), pills, granules , Fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, and syrups), and jelly formulations suitable for oral intake (oral formulations) and external preparation forms are preferred.

Examples of forms include liquids, gels, creams, ointments, sticks, etc. when the application is cosmetics.

Examples of forms include tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, jelly-like drops, etc.), when the application is health promoting agents, nutritional supplements (supplements, etc.), etc. Formulations suitable for oral intake such as pills, granules, fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, and syrups), and jellies ( oral dosage form), and the like.

As for the form, when the application is a food composition, liquid, gel or solid food such as juice, soft drink, tea, soup, soy milk, salad oil, dressing, yogurt, jelly, pudding, furikake, powdered milk for infants , cake mixes, powdered or liquid dairy products, breads, cookies, etc.

As for the form, when the application is an oral composition (including pharmaceuticals), for example, liquid (solution, milky lotion, suspension, etc.), semisolid (gel, cream, paste, etc.), solid (tablet, particle Formulations, capsules, films, kneaded products, molten solids, waxy solids, elastic solids, etc.), more specifically, dentifrices (toothpaste, liquid dentifrice, liquid dentifrice, toothpaste, etc.) ), mouth washes, gargles, liniments, patches, mouth fresheners, foods (eg, chewing gum, tablet candy, candy, gummies, films, lozenges, etc.).

As for the form, when the application is a disinfectant, for example, liquid formulations such as liquids, emulsions, suspensions, dispersions, and aerosols; solids such as wettable powders, powders, granules, microgranules, and flowables semi-solid agents and the like.

When the agent of the present invention is applied to a living body, the application (e.g., administration, ingestion, inoculation, etc.) route is not particularly limited, and oral administration and parenteral administration (e.g., intravenous injection, intramuscular injection, subcutaneous administration, rectal administration) , transdermal administration, topical administration) to mammals including humans.

When the agent of the present invention is applied to a living body, the amount of application (e.g., administration, ingestion, inoculation, etc.) is not particularly limited as long as it is an effective amount that exhibits the desired effect, and is usually expressed as the weight of the active ingredient. , generally 0.1 to 1000 mg/kg body weight per day. The above dosage is preferably administered once a day or in 2 to 3 divided doses, and can be adjusted appropriately according to age, condition and symptoms.

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited by these examples.

Example 1: Cyclohexylglycyltyrosine (Compound 1)

2-Chlorotrityl chloride resin (602 mg, 0.91 mmol), N-α-(9-fluorenylmethoxycarbonyl)-O-(tert-butyl)-L-tyrosine (545 mg , 1.19 mmol), dehydrated dichloromethane (6 mL), and diisopropylethylamine (300 μL, 1.72 mmol) were added in that order, and the mixture was shaken at room temperature for 2 hours. The reaction solvent was removed by suction filtration, washed twice with methanol (2 mL), methanol (2 mL) and diisopropylethylamine (79.4 µL, 0.46 mmol) were added in that order, and the mixture was shaken at room temperature for 15 minutes. The reaction solvent was filtered by suction, and the resin was washed with N,N-dimethylformamide, 80% N,N-dimethylformamide aqueous solution, N,N-dimethylformamide, chloroform, and methanol (2 mL each 5 times). After drying with an oil pump, N-α-(9-fluorenylmethoxycarbonyl)-O-(tert-butyl)-L-tyrosyl-2-chlorotrityl resin (962 mg, introduction rate 88%) was obtained.

N-α-(9-Fluorenylmethoxycarbonyl)-O-(tert-butyl)-L-tyrosyl-2-chlorotrityl resin (320 mg) was added to 20% piperidine/N,N-dimethylformamide solution (2 mL). ) was added and shaken for 1 minute, the reaction solvent was suction filtered. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and removal of the Fmoc group was confirmed by Kaiser test. Then 1-hydroxybenzotriazole monohydrate (140 mg, 0.91 mmol), N-α-(9-fluorenylmethoxycarbonyl)-L-cyclohexylglycine (346 mg, 0.91 mmol), 1H-benzotriazole -1-yloxytripyrrolidinophosphonium hexafluorophosphate (475 mg, 0.91 mmol), N,N-dimethylformamide (2 mL) and diisopropylethylamine (159 μL, 0.91 mmol) were added and shaken for 2 hours. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. A 20% piperidine/N,N-dimethylformamide solution (2 mL) was added to the resin and the mixture was shaken for 1 minute, after which the reaction solvent was filtered by suction. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and after confirming the removal of the Fmoc group by Kaiser test, the resin was washed with methanol (2 mL 5 times), and then vacuum pump dried with The resin was mixed with a mixed solution (2.0 mL) of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) and stirred at room temperature for 1 hour. The resin was removed by filtration, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the deposited precipitate was filtered and dried (120 mg, 90%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (82% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.25 (s, 1H), 8.57 (d, J = 7.5 Hz, 1H), 8.05 (br. s., 3H), 7.07-7.01 (m, 2H ), 6.70-6.64 (m, 2H), 4.52-4.29 (m, 1H), 3.55 (d, J = 5.1 Hz, 1H), 2.96 (dd, J = 14.1, 5.2 Hz, 1H), 2.82 (dd, J= 14.0, 8.6 Hz, 1H), 1.80-1.56 (m, 6H), 1.25-0.95 ( _m , _5H ); MS (ESI-TOF) m/ _z : calcd for _C17H25N2O4 [M +H] ⁺ 321.1809; found 321.1779.

Example 2: Phenylglycyltyrosine (Compound 2)

N-α-(9-fluorenylmethoxycarbonyl)-O-(tert-butyl)tyrosyl-2-chlorotrityl resin (321 mg) was added to 20% piperidine/N,N-dimethylformamide solution (2 mL). After shaking for 1 minute, the reaction solvent was suction filtered. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and removal of the Fmoc group was confirmed by Kaiser test. Then 1-hydroxybenzotriazole monohydrate (140 mg, 0.91 mmol), N-α-(tert-butyloxycarbonyl)-L-phenylglycine (229 mg, 0.91 mmol), 1H-benzotriazole-1 -yloxytripyrrolidinophosphonium hexafluorophosphate (475 mg, 0.91 mmol), N,N-dimethylformamide (2 mL) and diisopropylethylamine (159 μL, 0.91 mmol) were added and shaken for 2 hours. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. The resin was washed with methanol (5 x 2 mL) and then dried on a vacuum pump. The resin was mixed with a mixed solution (2.0 mL) of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) and stirred at room temperature for 1 hour. The resin was removed by filtration, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the deposited precipitate was filtered and dried (114 mg, 88%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (21% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (br, s., 1H), 9.25 (s, 1H), 8.76 (d, J = 7.7 Hz, 1H), 8.50 (br. s., 3H), 7.55-7.34 (m, 5H), 7.06-6.92 (m, 2H), 6.71-6.53 (m, 2H), 4.93 (s, 1H), 4.37 (td, J = 8.0, 5.2Hz, 1H) , 2.94 (dd, J = 14.0, 5.1 Hz, 1H), 2.82 (dd, J = 14.0, _8.4 Hz, _1H ) _; MS (ESI-TOF) m/z: calcd for _C17H19N2O4 [ M+H] ^+315.1339 ; found 315.1338.

Example 3: Cyclohexylalanyltyrosine (compound 3)

N-α-(9-fluorenylmethoxycarbonyl)-O-(tert-butyl)tyrosyl-2-chlorotrityl resin (321 mg) was added to 20% piperidine/N,N-dimethylformamide solution (2 mL). After shaking for 1 minute, the reaction solvent was suction filtered. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and removal of the Fmoc group was confirmed by Kaiser test. Next, 1-hydroxybenzotriazole monohydrate (140 mg, 0.91 mmol), N-α-(tert-butyloxycarbonyl)-L-cyclohexylalanine monohydrate (264 mg, 0.91 mmol), 1H- Add benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (475 mg, 0.91 mmol), N,N-dimethylformamide (2 mL) and diisopropylethylamine (159 μL, 0.91 mmol) and shake for 2 hours. bottom. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. The resin was washed with methanol (5 x 2 mL) and then dried on a vacuum pump. The resin was mixed with a mixed solution (2.0 mL) of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) and stirred at room temperature for 1 hour. The resin was removed by filtration, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the deposited precipitate was filtered and dried (126 mg, 92%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (48% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 8.02 (br. s., 3H), 7.55-7.34 (m, 5H ), 7.03 (d, J = 8.4 Hz, 2H), 6.69-6.65 (m, 2H), 4.93 (s, 1H), 4.41 (td, J = 8.1, 5.4 Hz, 1H), 3.77 (dd, J = 8.1, 6.2 Hz, 1H), 2.96 (dd, J = 14.0, 5.2 Hz, 1H), 2.83 (dd, J = 14.1, 8.5 Hz, 1H), 1.74-1.45 (m, 7H), 1.41-1.30 (m , 1H), 1.25-1.12 (m, 3H ₎ , 0.97-0.72 (m, _{2H )} ; MS (ESI-TOF) m/z: calcd for _C18H27N2O4 [M + H] ⁺ 335.1965; found 315.1942.

Example 4: Cyclohexylalanyl(4-iodo)phenylalanine (Compound 4)

2-Chlorotrityl chloride resin (200 mg, 0.30 mmol) and N-α-(9-fluorenylmethoxycarbonyl)-4-iodo-L-phenylalanine (187 mg, 0.37 mmol) in a plastic column filled with nitrogen gas. , dehydrated dichloromethane (3 mL), and diisopropylethylamine (212 μL, 1.22 mmol) were sequentially added and shaken at room temperature for 2 hours. The reaction solvent was removed by suction filtration, washed twice with methanol (2 mL), methanol (2 mL) and diisopropylethylamine (79.4 µL, 0.46 mmol) were added in that order, and the mixture was shaken at room temperature for 15 minutes. The reaction solvent was filtered by suction, and the resin was washed with N,N-dimethylformamide, 80% N,N-dimethylformamide aqueous solution, N,N-dimethylformamide, chloroform, and methanol (2 mL each 5 times). Dried with an oil pump. N-α-(9-fluorenylmethoxycarbonyl)-4-iodo-L-phenylalanyl-2-chlorotrityl resin 307 mg, introduction rate 57%.

N-α-(9-Fluorenylmethoxycarbonyl)-4-iodo-L-phenylalanyl-2-chlorotrityl resin (307 mg) was diluted with 20% piperidine/N,N-dimethylformamide solution (2 mL). After adding and shaking for 1 minute, the reaction solvent was suction-filtered. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and removal of the Fmoc group was confirmed by Kaiser test. Then 1-hydroxybenzotriazole monohydrate (123 mg, 0.80 mmol), N-α-(tert-butyloxycarbonyl)cyclohexylalanine monohydrate (364 mg, 1.34 mmol), 1H-benzotriazole- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (418 mg, 0.80 mmol), N,N-dimethylformamide (3 mL) and diisopropylethylamine (280 μL, 1.61 mmol) were added and shaken for 2 hours. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. The resin was washed with methanol (5 x 2 mL) and then dried on a vacuum pump. The resin was mixed with a mixed solution (3.0 mL) of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) and stirred at room temperature for 1 hour. The resin was removed by filtration, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the deposited precipitate was filtered and dried (110 mg, 73.6%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (60% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.76 (d, J = 8.0 Hz, 1H), 8.12 (br. s., 3H), 7.69-7.57 (m, 2H), 7.12-7.00 (m , 2H), 4.49 (s, 1H), 4.49 (td, J = 8.3, 5.1 Hz, 1H), 3.82-3.71 (m, 1H), 3.08-3.00 (m, 1H), 2.95-2.88 (m, 1H) ), 1.74-1.44 (m, 7H), 1.39-1.28 (m, 1H), 1.25-1.05 (m, 3H), 0.94-0.74 (m, 2H); MS (ESI-TOF) m/z: calcd for _C18H26IN2O3 ^[ M+H] _+445.0983 ; _{found 445.0988} .

Example 5: Cyclohexylalanyltyrosylcyclopropanesulfonamide (compound 5)

N-α-(tert-butoxycarbonyl)-O-(tert-butyl)-L-tyrosine (675 mg, 2.0 mmol) was dissolved in dry N,N-dimethylformamide (7 mL) and N,N-carbonyl Diimidazole (487 mg, 3 mmol) was added and stirred at 50°C for 2 hours. N-Cyclopropylsulfonamide (364 mg, 3.0 mmol) and diazabicycloundecene (448 μL, 3.0 mmol) were added to the reaction solution, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate, washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was filtered and concentrated under reduced pressure to give a white solid (366 mg). The solid was mixed with anisole (435 μL, 4.0 mmol), 4 M hydrochloride in dioxane and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, the precipitate was filtered, and dried to give tyrosylcyclopropanesulfonamide hydrochloride as a pale yellowish white solid (274 mg, 43%). MS (ESI _- TOF) m/z: calcd for _C12H17N2O4S [M + H] ⁺ 285.0904 _{; found} 285.0896.

Tyrosylcyclopropanesulfonamide hydrochloride (64.2 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (97.8 μL, 0.7 mmol), N-α-(tert -Butyloxycarbonyl)-L-cyclohexylalanine dicyclohexylamine salt (99.6 mg, 0.22 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (115 mg, 0.22 mmol) were added in order, and the mixture was stirred at room temperature. and stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid (137 mg). The solid was mixed with anisole (43.5 μL, 0.4 mmol), trifluoroacetic acid (2 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was filtered and dried to give a brownish white solid (71.6 mg, 65%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (30% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.99 (s, 1H), 9.27 (s, 1H), 8.76 (d, J = 7.5 Hz, 1H), 8.03 (br. s., 3H), 7.10-7.08 (m, 2H), 6.72-6.62 (m, 2H), 4.57-4.49 (m, 1H), 3.78 (br.s., 1H), 2.93 (dd, J = 13.9, 5.1Hz, 1H) , 2.89-2.82 (m, 1H), 2.77 (dd, J = 14.1, 9.1 Hz, 1H), 1.72-1.51 (m, 7H), 1.41-1.27 (m, 1H), 1.22-1.01(m, 7H) , 0.94-0.81 (m ^{, 2H); MS (ESI-TOF) m/z: calcd for C21H32N3O5S [M + H]+} _{438.2057 ; found 438.2042} .

Example 6: Phenylglycyltyrosylcyclopropanesulfonamide (compound 6)

Tyrosylcyclopropanesulfonamide hydrochloride (64.2 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (97.8 μL, 0.7 mmol), N-α-(tert -Butyloxycarbonyl)-L-phenylglycine (55.3 mg, 0.22 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (115 mg, 0.22 mmol) were sequentially added and stirred overnight at room temperature. bottom. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was filtered off and concentrated under reduced pressure to give a colorless oil (59 mg). Oily anisole (43.5 μL, 0.4 mmol) was mixed with trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, the precipitate was filtered and dried to give a white solid (34.7 mg, 33%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (36% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.97 (br. s, 1H), 9.29 (s, 1H), 8.87 (d, J = 7.5 Hz, 1H), 8.55 (br. s., 3H ), 7.52-7.36 (m, 5H), 7.12-6.95 (m, 2H), 6.72-6.62 (m, 2H), 4.96 (s, 1H), 4.57-4.49 (m, 1H), 2.93-2.87 (m , 1H), 2.84-2.74 (m, _2H ) _, 1.12-0.94 (m, _{4H )} ; MS (ESI-TOF) m/z: calcd for C20H24N3O5S [M + H] ⁺ 418.1431 ;found 438.1418.

Example 7: Cyclohexylalanyl-(O-methyl)tyrosine (compound 7)

Mix N-α-(tert-butyloxycarbonyl)-L-tyrosine methyl ester (1.00 g, 3.39 mmol) with anisole (737 μL, 6.78 mmol) and trifluoroacetic acid (5 mL) and stir at room temperature for 1 hour. bottom. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue, and the precipitate was filtered and dried to give a white solid (1.08 g). The obtained trifluoroacetic acid salt was dissolved in N,N-dimethylformamide (20 mL), and with stirring under ice cooling, triethylamine (3.31 mL, 23.8 mmol), N-α-(tert-butyloxycarbonyl)-L-cyclohexyl Alanine monohydrate (1.08 mg, 3.73 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (1.94 g, 3.73 mmol) were sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was filtered off and concentrated under reduced pressure to give an amorphous solid (2.03 g). MS (ESI _{-TOF) m/z: calcd for C24H36N2NaO6 [ M} + Na] ⁺ 471.2466; _found 471.2443.

The obtained N-α-(tert-butyloxycarbonyl)cyclohexylalanyltyrosine methyl ester (256 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (4 mL) and potassium carbonate (86.7 mg, 0.63 mmol ) and methyl iodide (390 μL, 6.27 mmol) were sequentially added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a pale yellow oil (221 mg). The oil was dissolved in methanol (2 mL), 1 M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, citric acid was added to adjust the pH to 3, the mixture was extracted with ethyl acetate, washed with 10% citric acid solution and saturated brine in that order, and dried over sodium sulfate. Filter off the drying agent and concentrate under reduced pressure to give a colorless oil. The oil was mixed with trifluoroacetic acid (2 mL) and stirred at room temperature for 80 minutes. The reaction solution was concentrated under reduced pressure, the precipitate precipitated by adding diethyl ether to the residue was decanted, and the supernatant was removed. After drying, the residue was dissolved in water and freeze-dried to obtain a white powder (197 mg, 90%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (32% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.73 (d, J = 7.8 Hz, 1H), 8.11 (br. s., 3H), 7.28-7.09 (m, 2H), 6.91-6.70 (m , 2H), 4.43 (td, J = 8.0, 5.4 Hz, 1H), 3.80-3.78 (m, 1H), 3.01 (dd, J = 14.0, 5.3 Hz, 1H), 2.89 (dd, J = 14.1, 8.6 Hz, 1H), 1.75-1.45 (m, 7H), 1.40-1.30 (m, 1H), 1.26-1.02 (m, 3H), 0.94-0.73 (m, 2H); MS (ESI-TOF) m/z : calcd _{for C19H29N2O4} [ ^M+H]+ _349.2122 ; _found 349.2117.

Example 8: Cyclohexylalanyltyrosinamide (compound 8)

N-(9-Fluorenylmethoxycarbonyl)-amide resin (202 mg, 0.14 mmol) was added to 20% piperidine/N,N-dimethylformamide solution (2 mL), shaken for 1 minute, and the reaction solvent was removed. Suction filtered. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and removal of the Fmoc group was confirmed by Kaiser test. Then 1-hydroxybenzotriazole monohydrate (63.4mg, 0.41 mmol), N-α-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (190 mg, 0.41 mmol) , 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (215 mg, 0.41 mmol), N,N-dimethylformamide (2 mL) and diisopropylethylamine (72.1 μL, 0.41 mmol) were added and Shake for 1 minute. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. was added to a 20% piperidine/N,N-dimethylformamide solution (2 mL) and shaken for 1 minute, after which the reaction solvent was suction filtered. Add 20% piperidine/N,N-dimethylformamide solution (2 mL) again and shake for 20 minutes. ), washed with N,N-dimethylformamide (2 mL 3 times), and removal of the Fmoc group was confirmed by Kaiser test. Then 1-hydroxybenzotriazole monohydrate (63.4 mg, 0.41 mmol), N-(9-fluorenylmethoxycarbonyl)-L-cyclohexylalanine (163 mg, 0.41 mmol), 1H-benzotriazole-1 -yloxytripyrrolidinophosphonium hexafluorophosphate (215 mg, 0.41 mmol), N,N-dimethylformamide (2 mL) and diisopropylethylamine (72.1 μL, 0.41 mmol) were added and shaken for 90 minutes. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. The resin was washed with methanol (5 x 2 mL) and then dried on a vacuum pump. The resin was mixed with a mixed solution (2.0 mL) of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) and stirred at room temperature for 1 hour. The resin was removed by filtration, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the deposited precipitate was filtered and dried (17.6 mg, 34%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (68% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.02 (br. s., 3H), 7.48 (s, 1H), 7.06 (s, 1H), 7.09-6.98 (m, 3H), 6.69-6.60 (m, 2H), 4.42 (td, J = 8.2, 5.8 Hz, 1H), 3.84-3.72 (m, 1H), 2.87 ( dd, J = 13.9, 5.6 Hz, 1H), 2.73 (dd, J = 13.9, 8.4 Hz, 1H), 1.73-1.44 (m, 7H), 1.39-1.25 (m, 1H), 1.25-1.05 (m, 3H), 0.94-0.76 (m ^{, 2H); MS (ESI-TOF) m/z: calcd for C18H28N3O3 [M+H]+} _{334.2125 ; found 334.2134} .

Example 9: Cyclohexylalanylleucine (Compound 9)

L-Leucine methyl ester hydrochloride (36.3 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (28.0 μL, 0.2 mmol), 1-hydroxybenzotriazole (33.7 mg, 0.22 mmol), N-α-(tert-butyloxycarbonyl)-L-cyclohexylalanine monohydrate (63.7 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42.2 mg, 0.22 mmol) were sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was filtered off and concentrated under reduced pressure to give a white solid. The solid was dissolved in methanol (1.5 mL), 1M aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, citric acid was added to adjust the pH to 3, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The drying agent was filtered off and concentrated under reduced pressure to give a white solid. The solid was mixed with anisole (43.5 μL, 0.4 mmol), trifluoroacetic acid (1.5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue, and the deposited precipitate was filtered and dried to give a colorless oil (143 mg). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (40% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.63 (d, J = 8.0 Hz, 1H), 8.08 (br. s., 3H), 4.32-4.24 (m, 1H), 3.79 (t, J = 7.3 Hz, 1H), 1.77-1.48 (m, 10H), 1.43-1.31 (m, 1H), 1.28-1.02 (m, 3H), 1.01-0.75 (m, 8H); MS (ESI-TOF) m _/ z: calcd _{for C15H29N2O3} [M + H] ⁺ 285.2173; found _285.2168 .

Example 10: Cyclohexylalanyl-(O-ethyl)tyrosine (Compound 10)

N-α-(tert-Butyloxycarbonyl)cyclohexylalanyltyrosine methyl ester (44.9 mg, 0.10 mmol) was dissolved in acetonitrile (2 mL), potassium carbonate (27.6 mg, 0.2 mmol), ethyl bromide (14.9 μL). , 0.2 mmol) was sequentially added, and the mixture was stirred overnight at room temperature. Furthermore, acetonitrile (1 mL) and ethyl bromide (14.9 µL, 0.2 mmol) were added, and the mixture was stirred at 50°C for 8 hours. The reaction mixture was filtered to remove insoluble matter, concentrated under reduced pressure, the residue was dissolved in methanol (1 mL), 1M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, citric acid was added to adjust the pH to 3, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. Filter off the drying agent and concentrate under reduced pressure to give a colorless oil. The oil was mixed with anisole (21.7 μL, 0.2 mmol) and trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue, and the deposited precipitate was decanted to remove the supernatant. After drying, the residue was dissolved in water and freeze-dried to give a white powder (92 mg). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (17% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.70-8.58 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.87-6.75 (m, 2H), 4.45-4.38 (m, 1H), 3.98 (q, J = 5.6 Hz, 1H), 3.73-3.69 (m, 1H), 3.00 (dd, J = 14.1, 5.3 Hz, 1H), 2.87 (dd, J = 13.9, 8.4 Hz, 1H ), 1.72-1.43 (m, 7H), 1.40-1.25 (m, 4H), 1.23-1.05 (m, 3H), 0.92-0.78 (m, 2H); MS (ESI-TOF) m/z: calcd for _C20H31N2O4 [M+H] ⁺ _363.2278 ; found _{363.2266 .}

Example 11: Cyclohexylalanyl Tyrosine Methyl Ester (Compound 11)

N-α-(tert-Butyloxycarbonyl)cyclohexylalanyltyrosine methyl ester (44.9 mg, 0.10 mmol) was mixed with anisole (21.7 μL, 0.2 mmol) and trifluoroacetic acid (1 mL) and incubated at room temperature for 1 hour. Stirred. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue, decantation was performed, and the supernatant was removed. After drying, the residue was dissolved in water and freeze-dried to give a white powder (40.7 mg, 88%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (36% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.29 (s, 1H), 8.84 (d, J = 7.5 Hz, 1H), 8.00 (br. s., 3H), 7.09-6.94 (m,2H ), 6.76-6.61 (m, 2H), 4.52-4.42 (m, 1H), 3.78 (dd, J = 8.1, 6.3 Hz, 1H), 3.60 (s, 3H), 2.94 (dd, J = 14.1, 6.0 Hz, 1H), 2.86 (dd, J = 14.0, 8.4 Hz, 1H), 1.77-1.46 (m, 7H), 1.58-1.40 (m, 1H), 1.26-1.08 (m, 3H), 0.94-0.79 ( m _{, 2H); MS (ESI-TOF) m/z: calcd for C19H29N2O4 [ M +} H] ⁺ 349.2122; found 349.2111.

Example 12: Phenylglycyl(4-iodo)phenylalanine (Compound 12)

2-Chlorotrityl chloride resin (202 mg, 0.30 mmol) and N-α-(9-fluorenylmethoxycarbonyl)-4-iodo-L-phenylalanine (203 mg, 0.40 mmol) in a plastic column filled with nitrogen gas. , dehydrated dichloromethane (3 mL), and diisopropylethylamine (101 μL, 0.58 mmol) were sequentially added and shaken at room temperature for 2 hours. The reaction solvent was removed by suction filtration, washed twice with methanol (2 mL), methanol (2 mL) and diisopropylethylamine (79.4 µL, 0.46 mmol) were added in that order, and the mixture was shaken at room temperature for 15 minutes. The reaction solvent was filtered by suction, and the resin was washed with N,N-dimethylformamide, 80% N,N-dimethylformamide aqueous solution, N,N-dimethylformamide, chloroform, and methanol (2 mL each 5 times). After drying with an oil pump, N-α-(9-fluorenylmethoxycarbonyl)-4-iodophenylalanyl-2-chlorotrityl resin (365 mg, introduction rate 97%) was obtained.

After adding 20% piperidine/N,N-dimethylformamide solution (3 mL) to N-α-(9-fluorenylmethoxycarbonyl)-4-iodophenylalanyl-2-chlorotrityl resin and shaking, The reaction solvent was suction filtered (twice for 3 minutes, once for 20 minutes). The resin was washed with N,N-dimethylformamide (3 mL 6 times) and removal of the Fmoc group was confirmed by Kaiser test. Then 1-hydroxybenzotriazole monohydrate (140 mg, 0.91 mmol), N-α-(tert-butyloxycarbonyl)-L-phenylglycine (229 mg, 0.91 mmol), 1H-benzotriazole-1- Iloxytripyrrolidinophosphonium hexafluorophosphate (475 mg, 0.91 mmol), N,N-dimethylformamide (2 mL) and diisopropylethylamine (618 μL, 1.82 mmol) were added and shaken for 2 hours. The reaction solvent was removed by suction filtration, the resin was washed with N,N-dimethylformamide (2 mL 5 times), and completion of coupling was confirmed by Kaiser test. The resin was washed with methanol (5 x 2 mL) and then dried on a vacuum pump. The resin was mixed with a mixed solution (2.0 mL) of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5) and stirred at room temperature for 1 hour. The resin was removed by filtration, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the deposited precipitate was filtered and dried (22.6 mg, 18%). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (44% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.78 (d, J = 7.7 Hz, 1H), 8.47 (br. s., 3H), 7.64-7.57 (m, 2H), 7.52-7.35 (m , 5H), 7.00 (d, J = 8.3 Hz, 2H), 4.91 (s, 1H), 4.44 (td, J = 8.2, 5.0 Hz, 1H), 3.02 (dd, J = 13.8, 4.7 Hz, 1H) , 2.89 (dd, _J = 13.9, 8.8 Hz, 1H); MS (ESI-TOF) m/ _z : calcd for C17H18IN2O3 [M + H] ⁺ 425.0357 _; found _245.0357 .

Example 13: Phenylalanyltyrosine (Compound 13)

L-Tyrosine methyl ester hydrochloride (100 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (60.1 μL, 0.43 mmol), 1-hydroxybenzotriazole ( 72.4 mg, 0.47 mmol), N-α-(tert-butyloxycarbonyl)-L-phenylalanine (126 mg, 0.47 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90.7 mg, 0.47 mmol) was sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid (189 mg). The solid was dissolved in methanol (1.5 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, citric acid was added to adjust the pH to 3, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. Filter off the drying agent and concentrate under reduced pressure to give a colorless oil. The oil was mixed with anisole (93.5 μL, 0.86 mmol) and 4 M hydrochloride dioxane solution (3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was filtered and dried to give a white solid (175 mg). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (74% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (br. s, 1H), 9.29 (s, 1H), 8.87 (d, J = 7.8 Hz, 1H), 8.11 (br. s., 3H ), 7.36-7.22 (m, 5H), 7.09-7.01 (m, 2H), 6.72-6.64 (m, 2H), 4.43 (td, J = 8.0, 5.3 Hz, 1H), 4.04 (dd, J = 8.2 , 4.9 Hz, 1H), 3.15 (dd, J = 14.2, 4.8 Hz, 1H), 3.01-2.81 (m, 3H); MS (ESI-TOF) m/z: calcd for C ₁₈ H ₂₁ N ₂ O ₄ [M+H] ^+329.1496 ; found 329.1486.

Example 14: Tyrosyl Tyrosine (Compound 14)

L-Tyrosine methyl ester hydrochloride (100 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (60.1 μL, 0.43 ammol), 1-hydroxybenzotriazole (72.4 mg, 0.47 mmol), N-α-(tert-butyloxycarbonyl)-L-tyrosine (133 mg, 0.47 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (90.7 mg, 0.47 mmol) was sequentially added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% citric acid solution, 5% aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over sodium sulfate. The drying agent was filtered off and concentrated under reduced pressure to give a white solid (204 mg). The solid was dissolved in methanol (1.5 mL), 1M aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, citric acid was added to adjust the pH to 3, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. Filter off the drying agent and concentrate under reduced pressure to give a colorless oil. The oil was mixed with anisole (93.5 μL, 0.86 mmol) and 4 M hydrochloride dioxane solution (3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was filtered and dried to give a white solid (193 mg). The resulting crude product was purified by reverse phase column HPLC and lyophilized to give a white powder (68% recovery).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (br. s, 1H), 9.29 (br. s, 1H), 8.81 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.70-6.69 (m, 4H), 4.45-4.38 (m, 1H), 3.91 (br.s, 1H), 3.06-2.95 (m , 2H), 2.87-2.75 (m, 2H) _; MS ( _ESI -TOF) _m /z: calcd for C18H21N2O5 [M ₊ H] ⁺ 345.1445; found 345.1431.

Example 15: Enzyme Inhibition Assay for Bacterial DPP7 To determine the enzyme specific activity value, 50 μL of enzyme solution (100 mM Na phosphate buffer pH 7.0, 10 mM EDTA, 0.01% Mix Tween20 and enzyme (SmDPP7, PgDPP7, or PmDPP7)) with 50 μL of substrate solution (200 μM Met-Leu-MCA) and measure the fluorescence value of free MCA at an excitation wavelength of 355 nm/measurement wavelength of 460 nm. Activity was measured by reacting at 25°C for 20 minutes while measuring . The amount of released MCA was calculated from a calibration curve using MCA as a standard substance, and the amount of MCA released per minute was determined as the enzyme specific activity value (μmol/min/mg). The kinetic parameters K _m (μM) and kcat (/sec) were calculated by approximating the calculated values based on the Michaelies-Menten equation by the least-squares method from the enzyme activity values obtained using multiple substrate concentrations.

To measure residual enzyme activity, inhibition rate, IC ₅₀ and K _i , 50 μL of enzyme solution (same composition as above) and 50 μL of substrate/compound mixture (200 μM Met-Leu-MCA and 1.5625-200 μM of compound (any one of compounds 1 to 14)) was mixed, and the enzyme specific activity value was calculated by the activity measurement method described above. The IC ₅₀ was calculated from the sigmoid curve, and the K _i was calculated from the IC ₅₀ , K _m and substrate concentration (100 μM) using the Cheng-Prusoff equation assuming competitive inhibition as the inhibition mode of the compound and the enzyme. The residual activity was calculated by the following formula (A), and the inhibition rate was calculated by the following formula (B).
Formula (A) Residual activity (%) = "enzyme activity (including compound)"/"enzyme activity (without compound)" x 100
Equation (B) % inhibition = 100 - Equation (A).

FIG. 1 shows SmDPP7 residual activity at a compound concentration of 100 μM. Table 1 shows the 50% inhibitory concentrations of the compounds against SmDPP7. Table 2 shows the residual activity of bacterial DPP7 at a compound concentration of 100 μM.

As shown in FIG. 1, compounds 1-14 were found to reduce SmDPP7 residual activity. In addition, as shown in Table 1 (results of IC ₅₀ values against SmDPP7 for compounds with residual activity of less than 20%), IC ₅₀ values of compounds with residual activity of less than 20% were less than 20 μM. Among them, compound 7 and compound 11 had IC ₅₀ values of 2.0 µM and 2.5 µM, respectively, and exhibited strong SmDPP7 inhibitory activity.

As shown in Table 2, the compounds were found to reduce the residual activity of not only SmDPP7 but also PgDPP7 and PmDPP7. Compounds 2, 3, and 5 markedly reduced the residual activity of PmDPP7 similarly to SmDPP7, but reduced the residual activity moderately against PgDPP7. On the other hand, compound 4 reduced the residual activity of DPP7 of three kinds of bacteria to about 20%.

Example 16: Crystallization experiment of complex of SmDPP7 and compound 7
A purified SmDPP7 sample (5 mg/mL) and a 100% saturated solution of compound 7/80 mM Tris/HCl pH 8.5 were mixed at a ratio of 9:1 to prepare an SmDPP7/compound 7 mixed solution. A crystallization solution consisting of 200 μL of 20% (w/v) polyethylene glycol 8000, 200 mM ammonium acetate was then added to the 48-well plate. Then, 0.7 μL of each of the SmDPP7/compound 7 mixed solution and the crystallization solution dispensed into the 48-well plate was placed on a water-repellent cover glass to form one droplet. The cover glass was turned upside down so that the droplets faced downward, and the cover glass was placed over one well of the 48-well plate, sealed, and allowed to stand at 20°C. It took about 10 days to obtain tabular crystals of about 0.3 mm × 0.1 mm × 0.01 mm.

Example 17: Evaluation of antibacterial activity Porphyromonas gingivalis strain W83 was cultured in ABCM medium containing 0.001% menadione under anaerobic conditions at 37°C for 48 hours, the cells were suspended in PBS, and OD600 was measured. Each compound was dissolved in DMSO, and DMSO was added to the medium at 0.5%, 100 μM. DMSO containing no compound was added to the control at 0.5% to set the turbidity to 100%. The bacterial growth rate was calculated from the following formula (1). Table 3 shows part of the results (proliferation rate of Porphyromonas gingivalis W83 strain at 100 μM compound).
Formula (1) Proliferation rate (%) = "OD600 (with compound)"/"OD600 (without compound)" x 100.

As shown in Table 3, the growth rate was 52.6% in the presence of compound 11, suppressing the growth of bacteria.

Claims (6)

General formula (1):

[In the formula, R ¹ and R ² represent hydrogen atoms. R ³ represents a single bond or an alkylene group having 1 to 2 carbon atoms. R ⁴ represents a cycloalkyl group having 5 to 7 carbon atoms or a phenyl group optionally substituted with one hydroxyl group. R ⁵ is a branched alkyl group having 3 to 6 carbon atoms or general formula (X);

(In the formula, R ³¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms.)
represents a group represented by R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different; represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, n represents 0 or 1). ]
A bacterial dipeptidyl peptidase 7 inhibitor containing a compound represented by or a salt, hydrate or solvate thereof. Claim 1 ^{, wherein in -NR 62 -(SO 2 ) n -R 63 represented by R 6 , R 62 is a hydrogen atom and R 63 is} _{an alkyl} ^{group having 1} to 6 carbon atoms; Inhibitor according to . 3. The inhibitor according to claim 1 or 2, wherein the phenyl group represented by ^R4 is unsubstituted. General formula (1):

[In the formula, R ¹ and R ² represent hydrogen atoms. R ³ represents a single bond or an alkylene group having 1 to 2 carbon atoms. R ⁴ represents a cycloalkyl group having 5 to 7 carbon atoms or a phenyl group optionally substituted with one hydroxyl group. R ⁵ is a branched alkyl group having 3 to 6 carbon atoms or general formula (X);

(In the formula, R ³¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms.)
represents a group represented by R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different; represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, n represents 0 or 1). ]
or a salt, hydrate or solvate thereof, and the target bacterial strain is a sugar non-fermenting Gram-negative bacterium. General formula (1):

[In the formula, R ¹ and R ² represent hydrogen atoms. R ³ represents a single bond or an alkylene group having 1 to 2 carbon atoms. R ⁴ represents a cycloalkyl group having 5 to 7 carbon atoms or a phenyl group optionally substituted with one hydroxyl group. R ⁵ is a branched alkyl group having 3 to 6 carbon atoms or general formula (X);

(In the formula, R ³¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms.)
represents a group represented by R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different; represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, n represents 0 or 1). ]
A prophylactic or ameliorating agent for bacterial infections, which contains a compound represented by or a salt, hydrate or solvate thereof, and the target bacterial species is a sugar non-fermenting Gram-negative bacterium. General formula (1-X):

[In the formula, R ¹ and R ² represent hydrogen atoms. R ³ represents a single bond or an alkylene group having 1 to 2 carbon atoms. R ⁴ represents a cycloalkyl group having 5 to 7 carbon atoms or a phenyl group optionally substituted with one hydroxyl group. R ³¹ represents a hydrogen atom, a hydroxyl group, a halogen atom, or an alkoxy group having 1 to 4 carbon atoms. R ⁶ is —OR ⁶¹ (R ⁶¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or —NR ⁶² —(SO ₂ ) _n —R ⁶³ (R ⁶² and R ⁶³ are the same or different; represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, n represents 0 or 1). ] (provided that -R ³ -R ⁴ is a side chain of a natural amino acid , R ¹ and R ² are hydrogen atoms, R ³ is a single bond, and R ⁴ is free a substituted phenyl group, a compound in which R ³¹ is a hydroxyl group and R ⁶ is a methoxy group, a compound in which R ¹ and R ² are hydrogen atoms, R ³ is a single bond, and R ⁴ is an unsubstituted phenyl a compound in which R ³¹ is a hydrogen atom and R ⁶ is a methoxy group, R ¹ and R ² are hydrogen atoms, R ³ is a single bond, and R ⁴ is an unsubstituted phenyl group and R ³¹ is a hydroxyl group and R ⁶ is an ethoxy group, and R ¹ and R ² are hydrogen atoms, R ³ is a single bond, and R ⁴ is an unsubstituted phenyl group , R ³¹ is a hydrogen atom and R ⁶ is a hydroxyl group ).

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