# US 2018/0022769 A1 · Novel fluorine-containing bisphosphonic acid derivative and use thereof

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- Number: US 2018/0022769 A1
- Document ID: US20180022769A1
- Status: Published application
- Kind: A1
- Application number: 15/548,303
- Filed: 2016-02-01
- Published: 2018-01-25
- Earliest claimed: 2015-02-02
- Assignees: Nagasaki University
- Applicants: Nagasaki University
- Inventors: Yoshimasa TANAKA; Satoshi MIZUTA; Hiroshi UEDA
- Web page: https://patentgrep.com/patent/US20180022769A1

## CPC

- C07F 9/6506: having the nitrogen atoms in positions 1 and 3
- A61K 31/683: Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/42: Cancer antigens
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- C07F 9/3873: {containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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

## Abstract

A series of fluorine-containing bisphosphonic acids in which an alkylamine side chain is added, a series of fluorine-containing bisphosphonic acids in which an amino group substituted by a heterocyclic group or a heterocyclic group containing a nitrogen atom is added, to the carbon atom of P—C(F)—P, and a series of fluorine-containing bisphosphonate derivatives in which the acid moiety thereof is esterified by an alkoxymethyl group such as POM group, n-butanoyloxymethyl (BuOM) group and the like, that is, the fluorine-containing bisphosphonic acid and fluorine-containing bisphosphonate derivative represented by the following formula (I): wherein each symbol is as defined in the DESCRIPTION, can efficiently induce proliferation of peripheral blood γδ T cells that express Vγ2Vδ2 T cell receptor having superior cytotoxicity against tumor cells and virus infected cells, immunize tumor cells and virus infected cells, and can induce cytotoxicity by γδ T cells.

## Claims

### Claim at position 1

-22. (canceled)

### Claim 23

A compound represented by formula (I):
wherein Cy is an imidazolyl group, Y is a hydrogen atom, F is a fluorine atom, P is a phosphorus atom, R1 and R2 are the same or different from each other and each is an alkylcarbonyloxyalkyl group, j is a number 1, m is a number 0, and n is an integer of 1-6, or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The compound according to claim 23, wherein R1 and R2 are the same or different and each is a C2-7 alkylcarbonyloxy-C1-3 alkyl group, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 23)

The compound according to claim 23, wherein R1 and R2 are the same or different and each is pivaloyloxymethyl (POM) group, or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 23)

The compound according to claim 23, which is a compound represented by formula (5)
or a pharmaceutically acceptable salt thereof:

### Claim 27 (depends on 23)

A pharmaceutical composition comprising the compound according to claim 23, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 28 (depends on 24)

A pharmaceutical composition comprising the compound according to claim 24, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 29 (depends on 25)

A pharmaceutical composition comprising the compound according to claim 25, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 30 (depends on 26)

A pharmaceutical composition comprising the compound according to claim 26, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 31 (depends on 23)

A method of (i) treating a lymphocyte in a living body, (ii) proliferating and/or inducing a γδ T cell, (iii) suppressing proliferation of a tumor cell, or (iv) treating cancer, comprising administering an effective amount of the compound according to claim 23, or a pharmaceutically acceptable salt thereof, to a living body.

### Claim 32 (depends on 23)

A method of proliferating and/or inducing a γδ T cell, comprising reacting ex vivo the compound according to claim 23, or a pharmaceutically acceptable salt thereof, with a sample containing γδ T cells.

### Claim 33 (depends on 23)

A method of suppressing proliferation of a tumor cell, comprising a step of reacting the compound according to claim 23, or a pharmaceutically acceptable salt thereof, with a sample containing δγ T cells collected from a living body, and a step of returning the γδ T cells to the living body.