Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases

Patent metadata

Field	Value
Publication number	US-10899780-B2
Application number	US-201916254438-A
Country	US
Kind code	B2
Filing date	Jan 22, 2019
Priority date	Mar 6, 2013
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The present invention relates to a method for treating ocular inflammatory diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2.

First claim

What is claimed is:

1. A method of treating an ocular inflammatory disease in a subject in need of such treatment, wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one formyl peptide receptor 2 (FPR2) agonist to the subject;
wherein the ocular inflammatory disease is selected from the group consisting of uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet's disease, post-surgical corneal wound healing, wet age-related macular degeneration (ARMD) and dry ARMD; and
wherein the FPR2 agonist is a compound represented by Formula III, or a pharmaceutically acceptable salt thereof:

wherein:
R 1 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
R 2 is halogen, optionally substituted C 1-8 alkyl, CF 3 , OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
R 3 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R 5 forms a 10- or 11-membered polycyclic ring which is optionally substituted;
R 4 is hydrogen, optionally substituted C 1-8 alkyl,

optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R 5 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted;
R 5 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R 4 forms a spiro monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R 3 forms a 5 or 6 member ring which is optionally substituted;
R 6 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
R 7 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
R 8 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
R 9 is hydrogen, C(O)(C 1-8 alkyl) or optionally substituted C 1-8 alkyl;
R 10 is hydrogen, optionally substituted C 1-8 alkyl, O(C 1-8 alkyl), NR 11 R 12 or OH;
R 11 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
R 12 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
R 13 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
R 14 is hydrogen, optionally substituted C 6-10 aryl, optionally substituted C 1-8 alkyl, C(O)(C 1-8 alkyl) or SO 2 (C 1-8 alkyl);
R 15 is hydrogen, optionally substituted C 1-8 alkyl or O(C 1-8 alkyl);
R 16 is OH, O(C 1-8 alkyl), (C 1-8 alkyl) or NR 11 R 12 ;
R 17 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
R 18 is hydrogen, C(O)(C 1-8 alkyl), optionally substituted C 6-10 aryl, or optionally substituted C 1-8 alkyl;
R 19 is hydrogen, C(O)(C 1-8 alkyl), optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
R 20 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
R 21 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl;
n is 1, 2, 3, 4, or 5; and
m is 1, 2, 3, 4, or 5.

2. The method according to claim 1 , wherein the FPR2 agonist is a compound selected from:
1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea;
1-(4-bromo-2-fluorophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea;
1-(4-bromophenyl)-3-(2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl)urea;
1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;
1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-[2,5-dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-(4,4-dicyclopropyl-2,5-dioxoimidazolidin-1-yl)urea;
1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;
1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea;
1-(4-bromophenyl)-3-{4-[2-(furan-2-yl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-[2-(4-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-[2-(3-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-methyl-2,5-dioxo-4-[2-(thiophen-2-yl)ethyl]imidazolidin-1-yl}urea;
1-(4-bromo-2-fluorophenyl)-3-{4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-methyl-4-[2-(5-methylfuran-2-yl)ethyl]-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromo-2-fluorophenyl)-3-{4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromo-2-fluorophenyl)-3-{4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromo-2-fluorophenyl)-3-{4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-{4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea;
1-(4-bromophenyl)-3-[4-(hydroxymethyl)-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea;
2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2-hydroxyethyl)acetamide;
methyl 2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoate;
2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(1,3-dihydroxypropan-2-yl)acetamide;
2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoic acid;
2-[2-(1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoic acid;
3-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)propanoic acid;
2-[1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2-hydroxyethyl)acetamide;
2-{2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]ethyl}benzoic acid;
diethyl [2-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)ethyl]phosphonate;
1-(4-bromophenyl)-3-{4-[2-(2-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea; and
3-({[1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidaz

Assignees

• Allergan Inc

Inventors

• Beard Richard L
• Donello John E
• Viswanath Veena

Classifications

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/17 Primary

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61K31/198

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• A61K31/405

  Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title