# US 12,599,588 B2 · Inhibitor for V-ATPase activity, antibacterial agent, medicine, antibacterial method and screening method

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- Number: US 12,599,588 B2
- Document ID: US12599588B2
- Status: Granted
- Kind: B2
- Application number: 17/423,598
- Filed: 2020-01-15
- Published: 2022-04-07
- Granted: 2026-04-14
- Earliest claimed: 2019-01-18
- Assignees: Japan Science and Technology Agency
- Applicants: Japan Science and Technology Agency
- Inventors: Takeshi Murata; Kouki Shimizu; Fabiana Lica Yakushiji; Katsuhiko Moriyama
- Web page: https://patentgrep.com/patent/US12599588B2

## CPC

- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/4245: Oxadiazoles
- A61K 31/426: 1,3-Thiazoles
- A61K 31/515: Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Q 1/18: Testing for antimicrobial activity of a material
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

An inhibitor for Na+-translocating V-ATPase activity including a compound represented by where R1 represents a group selected from a hydroxy group, an alkoxy group, and a haloalkoxy group, each bonded to an adjacent phenyl group via oxygen, or a group selected from a dialkylamino group, a heterocyclic amine, and a carboxylic acid amide group, each bonded to an adjacent phenyl group via nitrogen, or represents bromine, iodine, or a straight-chain hydrocarbon group. R2 represents hydrogen or a haloalkoxy group. Z1 represents an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, each optionally having an arbitrary substituent and having a structure containing a double bond selected from between the group and an adjacent phenyl group. The symbol * represents a bond to the adjacent phenyl group.

## Claims

### Claim 1

A method of suppressing growth of a bacterium having V-ATPase in a subject, comprising the step of:
administering a medicine to the subject having bacterium having V-ATPase, wherein the medicine comprises:
a compound represented by the following formula (2) in an amount ranging from 1 μM to 100 mM:
where R1 represents a group selected from a hydroxy group represented by —OH; a haloalkoxy group represented by —O—R1b—Xn1, wherein Rib is an alkyl group having 1 to 3 carbon atoms, X is a halogen selected from fluorine, chlorine, bromine, and iodine, and n1 is 1 to 3; a dialkylamino group represented by —N(R1c) (R1a), wherein Ric and Ria are each independently an alkyl group having 1 to 10 carbon atoms and may be the same or different from each other; a heterocyclic amine having 2 to 6 carbon atoms represented by —N—(CH2)n2—, wherein n2 is 2 to 6; bromine represented by —Br; iodine represented by —I; or a straight-chain hydrocarbon group having 2 to 5 carbon atoms represented by —(CH2)n3—CH3, wherein n3 is 1 to 4;
R2 represents hydrogen or a haloalkoxy group represented by —O—R2a—Xn4, wherein R2a is a hydrocarbon group having 1 to 3 carbon atoms, X is a halogen selected from fluorine, chlorine, bromine, and iodine, and n4 is 1 to 3; and
R3 and R4 represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a halogen atom selected from fluorine, chlorine, bromine, and iodine, and R3 and R4 may be the same as or different from each other, and
an additive, wherein the additive is a solvent, an excipient, a binding agent, a disintegrant, a lubricating agent, a stabilizer, or a suspending agent;
wherein the compound represented by formula (2) binds to a membrane-embedded rotor ring (c ring) of the V-ATPase of the bacterium to inhibit a Na+-translocating activity of the V-ATPase,
wherein the bacterium having V-ATPase is Chlamydia trachomatis, Mycobacterium abscessus, Enterococcus faecium, Enterococcus durans, Enterococcus munditi, Enterococcus faecalis, Enterococcus malodoratus, Enterococcus cecorum, Enterococcus casseliflavus, Streptococcus agalactiae, Streptococcus sanguinis, Streptococcus constellatus, Streptococcus intermedius, Streptococcus gallolyticus, Streptococcus parasanguinis, Streptococcus anginosus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus pseudopneumoniae, Streptococcus mitis, Streptococcus canis, Streptococcus urinalis, Clostridium botulinum, Clostridium baratii, Clostridium argentinense, Clostridium chauvoei, Clostridium intestinale, Clostridium paraputrificum, Clostridium perfringens, Clostridium tetani, Clostridium difficile, Fusobacterium nucleatum, Fusobacterium necrophorum, Fusobacterium periodonticum, Abiotrophia defective, Aerococcus urinae, Aerococcus viridans, Facklamia hominis, Facklamia languida, Facklamia ignava, Facklamia sourekii, Alloiococcus otitis, Dolosigranulum pigrum, Granulicatella elegans, or Anaerotruncus colihominis.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound represented by formula (2) is:

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound represented by formula (2) is:

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound represented by formula (2) is:

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound represented by formula (2) is:

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound represented by formula (2) is:

### Claim 7

A method of suppressing growth of a bacterial flora containing a bacterium having V-ATPase and a bacterium having no V-ATPase in a subject, comprising the step of:
administering a medicine to the subject having the bacterial flora containing the bacterium having V-ATPase and the bacterium having no V-ATPase, wherein the medicine comprises:
a compound represented by the following formula (2) in an amount ranging from 1 μM to 100 mM:
where R1 represents a group selected from a hydroxy group represented by —OH; a haloalkoxy group represented by —O—R1b—Xn1, wherein Rib is an alkyl group having 1 to 3 carbon atoms, X is a halogen selected from fluorine, chlorine, bromine, and iodine, and n1 is 1 to 3; a dialkylamino group represented by —N(R1c)(R1a), wherein R1c and R1d are each independently an alkyl group having 1 to 10 carbon atoms and may be the same or different from each other; a heterocyclic amine having 2 to 6 carbon atoms represented by —N—(CH2)n2—, wherein n2 is 2 to 6; bromine represented by —Br; iodine represented by —I; or a straight-chain hydrocarbon group having 2 to 5 carbon atoms represented by —(CH2)n3—CH3, wherein n3 is 1 to 4;
R2 represents hydrogen or a haloalkoxy group represented by —O—R2a—Xn4, wherein R2a is a hydrocarbon group having 1 to 3 carbon atoms, X is a halogen selected from fluorine, chlorine, bromine, and iodine, and n4 is 1 to 3; and
R3 and R4 represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a halogen atom selected from fluorine, chlorine, bromine, and iodine, and R3 and R4 may be the same as or different from each other, and
an additive, wherein the additive is a solvent, an excipient, a binding agent, a disintegrant, a lubricating agent, a stabilizer, or a suspending agent;
wherein the compound represented by formula (2) binds to a membrane-embedded rotor ring (c ring) of the V-ATPase of the bacterium to inhibit a Na+-translocating activity of the V-ATPase to selectively reduce the bacterium having V-ATPase from the bacterial flora containing the bacterium having V-ATPase and the bacterium having no V-ATPase,
wherein the bacterium having V-ATPase is Chlamydia trachomatis, Mycobacterium abscessus, Enterococcus faecium, Enterococcus durans, Enterococcus munditi, Enterococcus faecalis, Enterococcus malodoratus, Enterococcus cecorum, Enterococcus casseliflavus, Streptococcus agalactiae, Streptococcus sanguinis, Streptococcus constellatus, Streptococcus intermedius, Streptococcus gallolyticus, Streptococcus parasanguinis, Streptococcus anginosus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus pseudopneumoniae, Streptococcus mitis, Streptococcus canis, Streptococcus urinalis, Clostridium botulinum, Clostridium baratii, Clostridium argentinense, Clostridium chauvoei, Clostridium intestinale, Clostridium paraputrificum, Clostridium perfringens, Clostridium tetani, Clostridium difficile, Fusobacterium nucleatum, Fusobacterium necrophorum, Fusobacterium periodonticum, Abiotrophia defective, Aerococcus urinae, Aerococcus viridans, Facklamia hominis, Facklamia languida, Facklamia ignava, Facklamia sourekii, Alloiococcus otitis, Dolosigranulum pigrum, Granulicatella elegans, or Anaerotruncus colihominis.

### Claim 8 (depends on 7)

The method according to claim 7, wherein
the compound represented by formula (2) is:

### Claim 9 (depends on 7)

The method according to claim 7, wherein the compound represented by formula (2) is:

### Claim 10 (depends on 7)

The method according to claim 7, wherein the compound represented by formula (2) is:

### Claim 11 (depends on 7)

The method according to claim 7, wherein the compound represented by formula (2) is:

### Claim 12 (depends on 7)

The method according to claim 7, wherein the compound represented by formula (2) is: