Compound having BLT inhibitory activity and composition, for preventing or treating inflammatory diseases, comprising same as active ingredient

Patent metadata

Field	Value
Publication number	US-10766857-B2
Application number	US-201816181953-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	Jul 24, 2015
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

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.

First claim

The invention claimed is:

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,
R 1 is C 1 to C 10 alkyl;
R 2 is

wherein,
R a is

or hydroxy;
R b is

R c is

R d is hydrogen or and

and
R e is

and
R 3 is hydrogen or fluorine and;
wherein the inflammatory disease is one that is responsive to inhibition of leukotriene B4 receptor 2 (BLT2) activity.

2. The method of claim 1 , wherein
R 1 is n-Butyl;
R 2 is

wherein,
R a is

or hydroxy; and
R b is

3. 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.

4. 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.

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

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

7. 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.

8. 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.

Assignees

• Univ Dongguk Ind Acad Coop
• Univ Korea Res & Bus Found

Inventors

• Choi Yongseok
• Kim Jae-Hong
• Lee Kyeong
• Han Hyo-Kyung
• Wei Jun Dong
• Kwon Jinsun
• Goo Ja-Il

Classifications

• C07C233/07 Primary

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C233/88

  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 · CPC title

• C07C275/32

  being further substituted by singly-bound oxygen atoms · CPC title

• C07D295/205

  Radicals derived from carbonic acid · CPC title

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title