# US 10,766,857 B2 · Compound having BLT inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient

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- Number: US 10,766,857 B2
- Document ID: US10766857B2
- Status: Granted
- Kind: B2
- Application number: 16/181,953
- Filed: 2018-11-06
- Published: 2019-03-07
- Granted: 2020-09-08
- Earliest claimed: 2015-07-24
- Assignees: Dongguk University Industry-Academic Cooperation Foundation; Korea University Research and Business Foundation
- Applicants: Dongguk University Industry-Academic Cooperation Foundation; Korea University Research and Business Foundation
- Inventors: Yongseok Choi; Jae-Hong Kim; Kyeong Lee; Hyo-Kyung Han; Jun Dong Wei; Jinsun Kwon; Ja-Il Goo
- Web page: https://patentgrep.com/patent/US10766857B2

## CPC

- C07C 311/21: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- A61P 11/06: Antiasthmatics
- A61P 35/00: Antineoplastic agents
- C07C 233/07: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 233/51: having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
- C07C 233/88: having nitrogen atoms of carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced
- C07C 235/34: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 237/42: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
- C07C 275/32: being further substituted by singly-bound oxygen atoms
- C07C 311/16: having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07D 211/06: having no double bonds between ring members or between ring members and non-ring members
- C07D 213/56: Amides
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 257/04: Five-membered rings
- C07D 265/30: not condensed with other rings
- C07D 295/185: from aliphatic carboxylic acids
- C07D 295/192: from aromatic carboxylic acids
- C07D 295/205: Radicals derived from carbonic acid
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a novel compound showing leukotriene B4 receptor 2 (BLT2) inhibitory activity and a pharmaceutical composition, for preventing or treating inflammatory diseases, having same as an active ingredient. The inventors identified a novel compound containing BTL2 inhibitory activity, and experimentally confirmed that the present novel compound had an excellent effect on the enhancement of the cancer cell death, on the inhibition of the metastasis and chemotactic mobility, and on the anti-asthma activity. Therefore, the present novel compound can be used as a very effective pharmaceutical component for treating the inflammatory-related diseases.

## Claims

### Claim 1

A method for inhibiting or treating an inflammatory disease in a subject in need thereof, comprising:
administering to the subject an effective amount of a pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
wherein,
R1 is C1 to C10 alkyl;
R2 is
wherein,
Ra is
or hydroxy;
Rb is
Rc is
Rd is hydrogen or and
and
Re is
and
R3 is hydrogen or fluorine and;
wherein the inflammatory disease is one that is responsive to inhibition of leukotriene B4 receptor 2 (BLT2) activity.

### Claim 2 (depends on 1)

The method of claim 1, wherein
R1 is n-Butyl;
R2 is
wherein,
Ra is
or hydroxy; and
Rb is

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound represented by Formula 1 is selected from the group consisting of:
tert-butyl 4-(4-(3-(N-phenylpentaneamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate;
N-phenyl-N-(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(4-ethylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)prop-2-ynyl)-N- phenylpentaneamide;
N-(3-(4-(4-cyclohexylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(4-(cyclohexylmethyl)piperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(4-isobutylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-phenyl-N-(3-(4-(4-(prop-2-ynyl)piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-(4-(4-cyanopiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
tert-butyl 4-(4-(3-(N-(3-fluorophenyl)pentaneamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate;
N-(3-fluorophenyl)-N-(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-fluorophenyl)-N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
tert-butyl 4-(4-(3-(N-(4-fluorophenyl)pentaneamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate;
N-(4-fluorophenyl)-N-(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(4-fluorophenyl)-N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-(4-(morpholine-4-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-phenyl-N-(3-(4-(piperidine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N,N-diethyl-4-(3-(N-phenylpentaneamido)prop-1-ynyl)benzamide;
N-phenyl-N-(3-(3-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-(3-(4-methylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(3-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
tert-butyl-4-(3-(3-(N-(4-fluorophenyl)pentaneamido)prop-1-ynyl)benzoyl)piperazine-1-carboxylate;
N-(4-fluorophenyl)-N-(3-(3-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(4-fluorophenyl)-N-(3-(3-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-(4-hydroxyphenyl)prop-2-ynyl)-N-phenylpentaneamide; 2-(4-(3-(N-phenylpentaneamido)prop-1-ynyl)phenoxy)acetic acid;
tert-butyl 4-(5-(3-((N-phenylpentaneamido)prop-1-yn-1-yl)picolinoyl)piperazine-1-carboxylate;
N-phenyl-N-(3-(6-(piperazine-1-carbonyl)pyridine-3-yl)prop-2-yn-1-yl)pentaneamide;
N-(3-(6-isopropylpiperazine-1-carbonyl)pyridine-3-yl)prop-2-yn-1-yl)pentaneamide;
N,N-diethyl-4-(3-(N-(3-fluorophenyl)pentaneamido)prop-1-yn-1-yl)benzamide;
N,N-diethyl-4-(3-(N-(4-fluorophenyl)pentaneamido)prop-1-yn-1-yl)benzamide;
N-(3-(4-(N,N-diethylsulfamoyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-(3-(4-(N-isopropylsulfamoyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
tert-butyl 4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzoate; 4-(3-(N-phenylpentaneamido)pro-1-yn-1-yl)benzoic acid;
N-ethyl-4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamide;
N-(2-(diethylamino)ethyl)-4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamide;
ethyl 2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)acetate;
2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)acetic acid;
methyl 2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)propanoate;
2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)propionic acid;
2-(4-(3-(N-(3-fluorophenyl)pentaneamido)prop-1-ynyl)phenoxy)acetic acid 4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzoic acid;
N-phenyl-N-(3-(4-(piperazine-l-carbonyl)phenyl)prop-2-ynyl)pentanamide;
N-(2-(dimethylamino)ethyl)-4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamide;
2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)propanoic acid; and
2-(4-(3-(N-(4-fluorophenyl)pentaneamido)prop-1-ynyl)phenoxy)acetic acid.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound represented by Formula 1 is selected from the group consisting of:
N-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-phenyl-N-(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamide;
N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N-phenyl-N-(3-(3-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(4-fluorophenyl)-N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
N-(3-(3-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide;
N,N-diethyl-4-(3-(N-phenylpentaneamido)prop-1-ynyl)benzamide;
N-(3-fluorophenyl)-N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)pentaneamide;
4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzoic acid;
N-(2-(dimethylamino)ethyl)-4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamide;
methyl 2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)propanoate; and
2-(4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzamido)propanoic acid.

### Claim 5 (depends on 1)

The method of claim 1, wherein the inflammatory disease is selected from the group consisting of asthma, atherosclerosis, pruritus, rheumatoid arthritis and inflammatory enteropathy.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition inhibits leukotriene B4 receptor 2 (BLT2) activity.

### Claim 7 (depends on 1)

The method of claim 1, wherein the inflammatory disease is a cancer, wherein the cancer is any cancer caused by the overexpression of BLT2 or Ras that is responsive to inhibition of BLT2.

### Claim 8 (depends on 7)

The method of claim 7, wherein the cancer is selected from the group consisting of kidney cancer, prostate cancer, pancreatic cancer, breast cancer, brain tumors, skin cancer and liver cancer.

### Claim 9 (depends on 7)

The method of claim 7, wherein the cancer is a breast cancer.

### Claim 10 (depends on 1)

The method of claim 1, wherein the inflammatory disease is asthma.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound represented by Formula I is
N-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentanamide,
N-phenyl-N-(3-(4-(piperazine-1-carbonyl)phenyl)prop-2-ynyl)pentanamid,
N-(3-(4-(4-isopropylpiperazine-1-carbonyl)phenyl)prop-2-ynyl)-N-phenylpentaneamide, or
4-(3-(N-phenylpentaneamido)prop-1-yn-1-yl)benzoic acid.