HK40014878A - Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases - Google Patents

Description

Use of formyl peptide receptor 2 agonists for the treatment of ocular inflammatory diseases

This application is a divisional application of the invention patent application No. PCT/US2014/020245 entitled "use of formyl peptide receptor 2 agonists for treating ocular inflammatory diseases" filed 3/4/2014, originally filed 9/2/2015 into the chinese national phase, and filed 201480012204.5.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application serial No. 61/773,773, filed on 6/3/2013, the disclosure of which is hereby incorporated by reference in its entirety.

Technical Field

The present invention relates to a method for treating an ocular inflammatory disease in a subject in need of such treatment comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one formyl peptide receptor 2(FPR2) agonist.

Background

The Formyl Peptide Receptor (FPR) family is not only involved in host defense against pathogens but also in sensing internal molecules that can provide signals for cellular dysfunction, this family includes 3 members in humans, and one member of this family, FPR2 (also known as FPRL-1, ALXA4), is a G protein-coupled receptor expressed primarily on inflammatory cells (e.g., monocytes and neutrophils) as well as on T cells, and has been shown to play a critical role in leukocyte trafficking during inflammation and human pathology (Chiang N, Serian CN, Dahlen, S, Drazen JM, Hay DWP, Rovati, Shimizu T, Yokokio T, Brink, C.the promoter, Bupleur alpha, Poten Ligand fusion protein, P-derived fusion protein in vivo, Pharmacological protein No. 7, mouse protein No. 7, Lipocalization protein No. 11, Lipocalization protein No. 7, Lipocalization protein-10. A, Lipocalization protein No. 7, Lipocalization protein-10, Lipocalization protein No. 7, Lipocalization protein No. 7, Lipocalization protein No. 7, Lipocalization protein No. 7, Lip.

Activation of FPR2 by lipoxin A4 or an analog thereof and by annexin I proteins has been shown to produce anti-inflammatory activity by promoting active resolution of inflammation, which involves inhibiting polymorphonuclear neutrophils (PMN) and eosinophils from migrating, and also stimulating monocyte migration, enabling clearance of apoptotic cells from the site of inflammation in a non-inflammatory manner (Madena P, Cottlell DC, Toivonen T, Dufton N, Dali J, Perretti M, Godson C.FPR2/ALX receptor expression and interaction area crystalline for lipoxin A4and channel-derived peptide-derived cytological diagnosis. FASEB, 24: 4240: 4249; modifier K, Creutzfeld K, Vivers, Dransfield I, Goldson C.4. branched plasmid of molecular dynamics; 1888: J.52). In addition, FPR2 has been shown to inhibit NK cytotoxicity and promote activation of T cells, which further contributes to the down-regulation of tissue-damaging inflammatory signals. FPR2/LXA4 interaction has been shown to be beneficial to experimental models of ischemia-reperfusion, angiogenesis, ocular inflammation (e.g., endotoxin-induced uveitis) and corneal wound healing (Serhan C. resolution phase of inflammation: Novel endogeneous inflammation-in-flow and rendering metals and pathways. Annualrease of Immunology 2007; 25: 101. 137; Mesorosis R, Rodrigues GB, Figureideodo CP, Rodrigues EB, Grigma A Jr, Menezes-de-Lima O Jr, Passos GF, Calixto JB.molecular Chemistry of cosmetics of manipulating antibodies of tissue inflammation, strain of tissue engineering GF, J.S. J.M. J.S. 15232, J.S. J.E. J.M. J.S. J.M. J.E.E. J.E.S. J.E. Pat. 35, J.E.E.E.E. J.E. Pat. 35. J.E.E.E.M. J.S. No. 35, sullivan AB, Dong B, Lau D, Gronert K. endogenesis LXA4circuits area determining nutritional technological information in response to respiratory input. American journal Pathology 2010; 176: 74-84; lipoxins in the eye and role in the health, prostagladins, Leukotrienes and Essential fat acids, 2005; 73:221-229). The inherent physicochemical properties of natural polyalkenes hinder the pharmaceutical utility of lipoxin A4and its analogs. Thus, small molecule anti-inflammatory agonists of FPR2 would have multiple therapeutic benefits in inflammatory conditions, especially in the eye. Selectively targeting FPR2 would also have the benefit of reducing side effects compared to more broadly acting anti-inflammatory drugs such as steroids or NSAIDs which have elevated IOP and significant side effects of delayed wound healing in the eye. In addition to inflammatory cells migrating into ocular tissues, FPR2 is expressed in ocular tissues in the cornea and also in the posterior of the eye. Thus, FPR2 represents an important novel revolutionary molecular target for the development of novel therapeutics in ocular diseases with excessive inflammatory responses.

Disclosure of Invention

The present invention relates to the ability of FPR2 agonists to exhibit ocular anti-inflammatory activity and chemical stability and to be suitable for ocular delivery. These FPR2 compounds show good efficacy at the receptor, a subset of compounds is exemplified in the table below, and importantly, the FPR2 compound is topically active and therefore can be administered in many forms including, but not limited to, eye drops. These compounds may also be administered directly or via a topical drug delivery device applied to ocular tissue, as well as intravenously, intramuscularly, intrathecally, subcutaneously, orally, intravitreally, or intraperitoneally. These compounds will be useful in the treatment of ocular inflammatory diseases including, but not limited to, uveitis, dry eye, keratitis, allergic eye diseases, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis, such as acute multifocal squamous pigment epithelium disease, Behcet's disease, postoperative corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, wet and dry age-related macular degeneration (ARMD), conditions affecting the posterior segment of the eye, such as maculopathy and retinal degeneration, including non-exudative age-related macular degeneration, choroidal neovascularization, diabetic retinopathy (hyperplasia), retinopathy of prematurity (ROP), acute macular neuroretinopathy, macular degeneration, retinal degeneration, and the like, Central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; shotgun shell-like retinochoroidopathy (birdshow), infectious diseases (syphilis, lyme disease (lyme), tuberculosis, toxoplasmosis), intermediate uveitis (pars plana inflammation), multifocal choroiditis, multiple-resolution white-spot syndrome (mewds), ocular sarcoidosis, posterior scleritis, creeping choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome; vascular/exudative diseases such as retinal artery occlusive disease, central retinal vein occlusion, cystoid macular edema, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, coxsward' disease, collateral foveal telangiectasia, hemilateral retinal vein occlusion, papillary phlebitis, central retinal artery occlusion, branch retinal artery occlusion, Carotid Artery Disease (CAD), frost-like branch vasculitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy and periretinal phlebitis; traumatic/surgical conditions such as sympathetic ophthalmia, uveitis retinal disease, retinal detachment, trauma, conditions resulting from photodynamic therapy, photocoagulation, inadequate blood flow perfusion during surgery, radiation retinopathy and bone marrow transplantation retinopathy; proliferative diseases, such as proliferative vitreoretinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders, such as ocular histoplasmosis, ocular toxocariasis, Presumed Ocular Histoplasmosis Syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal diseases associated with HIV infection, uveitis diseases associated with HIV infection, viral retinitis, acute retinal necrosis, progressive lateral retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic disorders associated with retinal dystrophy, congenital quiescent night blindness, pyramidal dystrophy, Stargardt's disease and fundus macular disease, Best's disease, retinal pigment epithelial pattern dystrophy (pattern dystrophy of the retinal localized epidystrophy), X-linked retinal cleavage disease, Sorsby's fundal dystrophy, benign concentric maculopathy, bytty's crystalloid dystrophy, and elastopseudoxanthoma; retinal tears/retinal tears, such as retinal detachment, macular hole, and giant retinal tears; tumors, such as retinal diseases associated with tumors, congenital hypertrophy of the retinal pigment epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigment epithelium, retinoblastoma, ocular fundus angioproliferative tumors, retinal astrocytoma, and intraocular lymphoma; and various other diseases affecting the back of the eye such as punctate inner choroidopathy, acute posterior multifocal squamous pigment epithelium disorder, myopic retinal degeneration and acute retinal suprapigmentary dermatitis, postsurgical inflammation of the cornea, blepharitis, MGD, glaucoma, branch vein occlusion, Best's vitelliform macular degeneration (berg's vitelliform macular degeneration), retinitis pigmentosa, Proliferative Vitreoretinopathy (PVR), and any other degenerative disease of the photoreceptors or Retinal Pigment Epithelium (RPE).

In another aspect, these compounds will be useful in the treatment of ocular inflammatory diseases associated with: CNS disorders (e.g., Alzheimer's disease), arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, rheumatoid arthritis and related inflammatory disorders, alopecia, systemic inflammatory diseases (e.g., stroke), coronary artery disease, obstructive airways disease, HIV-mediated retroviral infection, cardiovascular disorders (including coronary artery disease), neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, systemic lupus erythematosus.

Drawings

Figure 1FPR2 agonist shows potent anti-inflammatory activity in an endotoxin-induced model of rat uveitis.

Figure 2FPR2 agonist shows potent anti-inflammatory activity in the endotoxin-induced model of rat uveitis.

Figure 3 shows accelerated healing and re-epithelialization in a rabbit model of corneal trauma as exemplified by the compound 3{ [ (2S,3S) -2- { [ (4-bromophenyl) carbamoyl ] amino } -3-methylpentanoyl ] amino } acetic acid.

Detailed Description

The present invention relates to a method for treating an ocular inflammatory disease in a subject in need of such treatment comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one FPR2 agonist.

In another aspect, the present invention provides the use of at least one FPR2 agonist for the manufacture of a medicament for treating an ocular inflammatory disease or condition mediated by FPR 2in a mammal.

In another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/668,835, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/668,835 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/668,835 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds disclosed in U.S. patent application s.n.13/668,835 are represented by formula I:

wherein:

R¹is sec-butyl, C_6-10Aryl, -CH₂-(C_6-10) Aryl, -CH₂-heterocycle, C_4-8Cycloalkyl or C_3-8Cycloalkenyl or heterocycle;

R²is halogen or methyl;

R³is halogen;

R⁴is H, methyl or halogen;

R⁵is OR⁶Or NH₂；

R⁶Is H or C_2-4An alkyl group.

In another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/523,579, with the proviso that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/523,579 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/523,579 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds disclosed in U.S. patent application s.n.13/523,579 are represented by formula II:

wherein:

a is 1 and b is 0;

a is 0 and b is 1;

a is 1 and b is 1;

R¹is optionally substituted C_1-8Alkyl, optionally substituted C_3-8Cycloalkyl, optionally substituted heterocycle, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl, optionally substituted C_3-8Cycloalkenyl radical, -NR¹¹R¹²OR-OR¹³；

R²Is optionally substituted C_1-8Alkyl or optionally substituted C_6-10An aryl group;

R³is hydrogen, optionally substituted C_1-8Alkyl, halogen, -COOR¹⁵、-OR¹³、-NR¹¹R¹²、NO₂Optionally substituted heterocycle, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl or optionally substituted C_3-8A cycloalkenyl group;

R⁴is hydrogen, optionally substituted C_1-8Alkyl, halogen, -COOR¹⁵、-OR¹³、-NR¹¹R¹²、NO₂Optionally substituted heterocycle, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl or optionally substituted C_3-8A cycloalkenyl group;

R⁵is halogen, -CF₃or-S (O)_nR¹⁴；

n is 0, 1 or 2;

R⁶is hydrogen, optionally substituted C_1-8Alkyl, halogen, -COOR¹⁵、-OR¹³、-NR¹¹R¹²、NO₂Optionally substituted heterocycle, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl or optionally substituted C_3-8A cycloalkenyl group;

R⁷is hydrogen, optionally substituted C_1-8Alkyl, halogen, -COOR¹⁵、-OR¹³、-NR¹¹R¹²、NO₂Optionally substituted heterocycle, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl or optionally substituted C_3-8A cycloalkenyl group;

R⁸is hydrogen, optionally substituted C_1-8Alkyl or optionally substituted C_6-10An aryl group;

R⁹is hydrogen, optionally substituted C_1-8Alkyl or optionally substituted C_6-10An aryl group;

R¹⁰is hydrogen, optionally substituted C_1-8Alkyl or optionally substituted C_6-10An aryl group;

R^9ais hydrogen, optionally substituted C_1-8Alkyl or optionally substituted C_6-10An aryl group;

R^10ais hydrogen, optionally substituted C_1-8Alkyl or optionally substituted C_6-10An aryl group;

R¹¹is hydrogen or optionally substituted C_1-8An alkyl group;

R¹²is hydrogen or optionally substituted C_1-8An alkyl group;

R¹³is hydrogen or optionally substituted C_1-8An alkyl group;

R¹⁴is hydrogen, CF₃Or optionally substituted C_1-8An alkyl group;

R¹⁵is hydrogen or optionally substituted C_1-8An alkyl group;

in another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/673,800, with the proviso that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/673,800 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/673,800 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds disclosed in U.S. patent application s.n.13/673,800 are represented by formula III:

R¹is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R²Is halogen, optionally substituted C_1-8Alkyl, CF₃、OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R³Is hydrogen, optionally substituted C_1-8Alkyl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_3-8Cycloalkenyl, optionally substituted C_6-10Aryl, optionally substituted heterocycle, or with R⁵Together form an optionally substituted 10-or 11-membered polycyclic ring;

R⁴is hydrogen, optionally substituted C_1-8Alkyl, aryl, heteroaryl, and heteroaryl,Optionally substituted C_3-8Cycloalkyl, optionally substituted C_3-8Cycloalkenyl, optionally substituted C_6-10Aryl, optionally substituted heterocycle, or with R⁵Together form a spiromonocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated, optionally substituted 5-to 10-membered ring;

R⁵is hydrogen, optionally substituted C_1-8Alkyl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_3-8Cycloalkenyl, optionally substituted C_6-10Aryl, optionally substituted heterocycle, or with R⁴Together form a spiromonocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated, optionally substituted 5-to 10-membered ring, or with R³Together form an optionally substituted 5-or 6-membered ring;

R⁶is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R⁷Is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R⁸Is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R⁹Is hydrogen, C (O) (C)_1-8Alkyl) or optionally substituted C_1-8An alkyl group;

R¹⁰is hydrogen, optionally substituted C_1-8Alkyl, O (C)_1-8Alkyl), NR)¹¹R¹²Or OH;

R¹¹is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹²is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹³is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹⁴is hydrogen, optionally substituted C_6-10Aryl, optionally substituted C_1-8Alkyl, C (O) (C)_1-8Alkyl) or SO₂(C_1-8Alkyl groups);

R¹⁵is hydrogen, optionally substituted C_1-8Alkyl or O (C)_1-8Alkyl groups);

R¹⁶is OH, O (C)_1-8Alkyl group), (C)_1-8Alkyl) or NR¹¹R¹²；

R¹⁷Is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹⁸is hydrogen, C (O) (C)_1-8Alkyl), optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹⁹is hydrogen, C (O) (C)_1-8Alkyl), optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R²⁰is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R²¹is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

n is 1, 2, 3, 4 or 5;

m is 1, 2, 3, 4 or 5.

In another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/765,527, with the proviso that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/765,527 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/765,527 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds disclosed in U.S. patent application s.n.13/765,527 are represented by formula IV:

wherein:

R¹is hydrogen, halogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_3-8Cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C_6-10Aryl, or with R²Together may form an optionally substituted cyclobutyl group;

R²is isopropyl, or with R³Together may form a substituted or unsubstituted 3-to 6-membered ring heterocycle, or with R¹Together may form an optionally substituted cyclobutyl, cyclopropyl; and is

R³Is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_3-8Cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C_6-10Aryl, or with R²Together may form a substituted or unsubstituted 3-to 6-membered ring heterocycle.

In another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/409,228, with the proviso that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/409,228 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/409,228 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds disclosed in U.S. patent application s.n.13/409,228 are represented by formula V:

wherein:

is a single bond or a double bond;

is a single bond or a double bond;

R¹is H, halogen, -S (O) R¹⁰、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl or hydroxy;

R²is H, halogen, -S (O) R¹⁰、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl or hydroxy;

R³is H, halogen, -S (O) R¹⁰、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, C_6-10Aryl or hydroxy;

R⁴is H or C (O) R¹²；

R⁵Is H, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6An alkynyl group;

R⁶is H, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl or-C_2-6An alkynyl group;

y is O or S;

x is O, NR or CH₂；

R^aIs C_6-10Aryl, heteroaryl, and heteroaryl,Heteroaryl group, C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl or H;

R^bis halogen;

c is 0, 1 or 2;

R⁷is H, halogen, -S (O) R¹⁰、-S(O)₂R¹¹Nitro, hydroxy, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkenyl or C_3-8A cycloalkyl group;

R⁸is H, halogen, -S (O) R¹⁰、-S(O)₂R¹¹Cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkenyl or C_3-8A cycloalkyl group;

R⁹is H, -S (O)₂R¹¹、-OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、C_3-8Cycloalkenyl or C_3-8A cycloalkyl group;

R¹⁰is-C_1-6Alkyl radical, C_3-8Cycloalkyl or C_3-8A cycloalkenyl group;

R¹¹is H, hydroxy, -C_1-6Alkyl radical, C_3-8Cycloalkyl or C_3-8A cycloalkenyl group;

R¹²is H, hydroxy, -C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, NR¹³R¹⁴or-OC_1-6An alkyl group;

R¹³is H, -C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radicals SO₂R¹¹Or C (O) R¹⁵；

R¹⁴Is H, -C_1-6Alkyl radical, C_3-8Cycloalkenyl, aryl, heterocyclic or C_3-8A cycloalkyl group;

R¹⁵is H, -C_1-6Alkyl radical, C_3-8Cycloalkenyl or C_3-8A cycloalkyl group; and is

R is H or-C_1-6Alkyl radical, C_3-8Cycloalkenyl or C_3-8A cycloalkyl group;

the premise is that:

when in useWhen it is a double bond, then R⁵Is absent; and is

When in useWhen it is a double bond, R⁶Is absent.

In another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/370,472, with the proviso that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/370,472 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/370,472 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds as disclosed in U.S. patent application s.n.13/370,472 are represented by formula VI:

wherein:

a is C_6-10Aryl, heterocyclic ring, C_3-8Cycloalkyl or C_3-8A cycloalkenyl group;

R¹⁷is C_1-6Alkyl or

B is C_6-10Aryl, heterocyclic ring, C_3-8Cycloalkyl or C_3-8A cycloalkenyl group;

R¹is H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R²is H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R³is H, C_1-6Alkyl or C_3-8A cycloalkyl group;

R⁴is H, C_1-6Alkyl or C_3-8A cycloalkyl group;

R^5ais H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R^5bis H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R^5cis H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R^5dis H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R⁶is H, -S (O)₂R¹¹、-C_1-6Alkyl, - (CH)₂)_n NR¹³R¹⁴、-(CH₂)_mHeterocycle, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl radical, C_6-10Aryl or heterocycle;

R⁷is H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R⁸is H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R⁹is H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

R¹⁰is H, halogen, -S (O) R¹⁵、-S(O)₂R¹¹Nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, C (O) R¹²、NR¹³R¹⁴、C_3-8Cycloalkyl or hydroxy;

x is O or S;

y is O or S;

R¹¹is H, hydroxy, -C_1-6Alkyl radical, C_3-8Cycloalkyl or NR¹³R¹⁴；

R¹²Is H, hydroxy, -C_1-6Alkyl, hydroxy, C_3-8Cycloalkyl, NR¹³R¹⁴or-OC_1-6An alkyl group;

R¹³is H, -C_1-6Alkyl radical, C_3-8Cycloalkyl, SO₂R¹¹Or C (O) R¹⁶；

R¹⁴Is H, -C_1-6Alkyl or C_3-8A cycloalkyl group;

R¹⁵is-C_1-6Alkyl or C_3-8A cycloalkyl group;

R¹⁶is H, -C_1-6Alkyl or C_3-8A cycloalkyl group;

n is 1 to 4; and is

m is 1 to 4.

In another aspect, the present invention provides a method for treating ocular inflammatory diseases comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application s.n.13/863,934, with the proviso that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/863,934 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

In another aspect, the present invention provides the use of at least one compound as disclosed in U.S. patent application s.n.13/863,934 for the treatment of an ocular disease or condition mediated by FPR 2in a mammal, provided that the compound has binding activity to the FPR2 receptor.

The compounds as disclosed in U.S. patent application s.n.13/863,934 are represented by formula VII:

wherein:

n is 0 or 1;

R¹is hydrogen, substituted or unsubstituted C_1-8Alkyl, halogen, -NR⁸R⁹、-NC(O)R²⁰、-OR¹⁰、-OC(O)R²¹、-SR¹¹、-C(O)R¹²CN or NO₂；

R²Is hydrogen, substituted or unsubstituted C_1-8Alkyl, halogen, -NR⁸R⁹、-NC(O)R²⁰、-OR¹⁰、-OC(O)R²¹、-SR¹¹、-C(O)R¹²CN or NO₂；

R³Is hydrogen, substituted or unsubstituted C_1-8Alkyl radicalHalogen, -NR⁸R⁹、-NC(O)R²⁰、-OR¹⁰、-OC(O)R²¹、-SR¹¹、-C(O)R¹²、CN、NO₂、CF₃、S(O)R¹⁵Or S (O)₂R¹⁶；

R⁴Is hydrogen, substituted or unsubstituted C_1-8Alkyl, halogen, -NR⁸R⁹、-NC(O)R²⁰、-OR¹⁰、-OC(O)R²¹、-SR¹¹、-C(O)R¹²CN or NO₂；

R⁵Is hydrogen, substituted or unsubstituted C_1-8Alkyl, halogen, -NR⁸R⁹、-NC(O)R²⁰、-OR¹⁰、-OC(O)R²¹、SR¹¹、-C(O)R¹²CN or NO₂；

R⁶Is hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted C_3-8Cycloalkenyl radical or-CH₂R¹⁹；

R⁷Is a substituted or unsubstituted heterocycle, -SR¹¹、-NR⁸R⁹、-N(H)C(O)N(H)S(O)₂R¹⁹、-BR¹³R¹⁴、-S(O)R¹⁵、-C(O)N(H)(CN)、-C(O)N(H)S(O)₂R¹⁹、-S(O)(N)(PO₃H₂)-、-S(O)₂R¹⁶or-P (O) R¹⁷R¹⁸；

R⁸Is hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C_6-10An aryl group;

R⁹is hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstitutedC of (A)_6-10An aryl group;

R¹⁰is hydrogen or substituted or unsubstituted C_1-8An alkyl group;

R¹¹is hydrogen, substituted or unsubstituted C_1-8Alkyl or-CF₃；

R¹²Is hydrogen, substituted or unsubstituted C_1-8Alkyl, hydroxy, -OR²⁴or-NR⁸R⁹；

R¹³is-OR²²；

R¹⁴is-OR²³；

R¹⁵Is substituted or unsubstituted C_1-8An alkyl group;

R¹⁶is substituted or unsubstituted C_1-8Alkyl, -NR⁸R⁹、-NHS(O)₂R¹⁹Or a hydroxyl group;

R¹⁷is OR¹⁰Or NR⁸R⁹；

R¹⁸Is OR¹⁰Or NR⁸R⁹；

R¹⁹Is a substituted or unsubstituted heterocycle, a substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_6-10Aryl or substituted or unsubstituted C_3-8A cycloalkenyl group;

R²⁰is hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C_6-10An aryl group;

R²¹is hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C_6-10An aryl group;

R²²is hydrogen, substituted or unsubstituted C_1-8Alkyl, or with R²³Together may form a ring;

R²³is hydrogen, substituted or unsubstituted C_1-8Alkyl, or with R²²Together may form a ring;

R²⁴is hydrogen, substituted or unsubstituted C_1-8Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C_6-10And (4) an aryl group.

The term "alkyl" as used herein refers to a saturated monovalent or divalent hydrocarbon moiety having straight or branched chain moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene group (-CH) of an alkyl group₂-) can be substituted by oxygen, sulfur, sulfoxyl, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C_3-8Cycloalkyl, divalent heterocyclyl or divalent aryl. The alkyl group may have one or more chiral centers. The alkyl group may be independently substituted with a halogen atom, a hydroxyl group, a cycloalkyl group, an amino group, a heterocyclic group, an aryl group, a carboxylic acid group, a phosphonic acid group, a sulfonic acid group, a phosphoric acid group, a nitro group, an amide group, or a sulfonamide group.

The term "cycloalkyl" as used herein refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups may be monocyclic or polycyclic. Cycloalkyl radicals independently being interrupted by halogen atoms, sulfonyl radicals C_1-8Alkyl, sulfoxide C_1-8Alkyl, sulfonamide, nitro, cyano, -OC_1-8Alkyl, -SC_1-8Alkyl, -C_1-8Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, keto, alkylamino, amino, aryl, C_3-8Cycloalkyl or hydroxy substituted.

The term "cycloalkenyl" as used herein refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl group having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl can be independently substituted by halogen atom, sulfonyl, sulfoxyl, nitro, cyano, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, keto, alkylamino, amino, aryl, C_3-8Cycloalkyl or hydroxy substituted.

The term "halogen" as used herein refers to chlorine, bromine, fluorine, iodine atoms.

The term "alkenyl" as used herein refers to a monovalent or divalent hydrocarbon group having at least one double bond, derived from a saturated alkyl group, having 2 to 6 carbon atoms. One methylene group (-CH) of an alkenyl group₂-) can be substituted by oxygen, sulfur, sulfoxyl, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C_3-8Cycloalkyl, divalent heterocyclyl or divalent aryl. C_2-6The alkenyl group may be in the E or Z configuration. The alkenyl group may be substituted by an alkyl group as defined above or by a halogen atom.

The term "alkynyl" as used herein refers to a monovalent or divalent hydrocarbon radical having at least one triple bond, derived from a saturated alkyl group, having 2 to 6 carbon atoms. One methylene group (-CH) of the alkynyl group₂-) can be substituted by oxygen, sulfur, sulfoxyl, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C_3-8Cycloalkyl, divalent heterocyclyl or divalent aryl. The alkynyl group may be substituted by an alkyl group as defined above or by a halogen atom.

The term "heterocycle" as used herein refers to a saturated or unsaturated 3 to 10 membered ring, which may be aromatic or non-aromatic, containing at least one heteroatom interrupting the carbocyclic ring structure, selected from oxygen, nitrogen, sulfur or a combination of at least two thereof. The heterocycle may be interrupted by C ═ O; the S and N heteroatoms may be oxidized. The heterocyclic ring may be monocyclic or polycyclic. The heterocyclic moiety being optionally substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-8Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, keto, alkylamino, amino, aryl, C_3-8Cycloalkyl or hydroxy substitution。

The term "aryl" as used herein refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by the removal of one hydrogen atom. Aryl radicals optionally substituted by halogen atoms, sulfonyl radicals C_1-6Alkyl, sulfoxide C_1-6Alkyl, sulfonamide, cyclic carboxylic acid group, C_1-6Alkyl carboxylic acid (ester) group, amide group, nitro group, cyano group, -OC_1-6Alkyl, -SC_1-6Alkyl, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, keto, aldehyde, alkylamino, amino, aryl, C_3-8Cycloalkyl or hydroxy substituted. The aryl group may be monocyclic or polycyclic.

The term "hydroxy" as used herein denotes a group of formula "-OH".

The term "carbonyl" as used herein denotes a group of formula "-c (o) -".

The term "ketone" as used herein denotes an organic compound having a carbonyl group attached to a carbon atom, such as- (CO) R^xWherein R is^xMay be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term "amine" as used herein denotes the formula "-NR^xR^y"wherein R is^xAnd R^yMay be the same or independently H, alkyl as defined above, aryl, cycloalkyl, cycloalkenyl, heterocycle.

The term "carboxy" as used herein denotes a group of formula "-c (O) O-".

The term "sulfonyl" as used herein denotes the formula "-SO₂"or a salt thereof.

The term "sulfate" as used herein denotes the formula "-O-S (O)₂-O- "group.

The term "sulfonate ester" as used herein denotes the formula "-S (O)₂-O- "group.

The term "carboxylic acid" as used herein denotes a group of formula "-c (o) OH".

The term "nitro" as used herein denotes the formula "-NO₂"or a salt thereof.

The term "cyano" as used herein denotes a group of formula "-CN".

The term "amide" as used herein denotes the formula "-C (O) NR^xR^y"wherein R is^xAnd R^yMay be the same or independently H, alkyl as defined above, aryl, cycloalkyl, cycloalkenyl, heterocycle.

The term "sulfonamide" as used herein denotes a compound of formula "-S (O)₂NR^xR^y"wherein R is^xAnd R^yMay be the same or independently H, alkyl as defined above, aryl, cycloalkyl, cycloalkenyl, heterocycle.

The term "sulfoxide" as used herein denotes a group of formula "-S (O) -".

The term "phosphonic acid" as used herein denotes the formula "-P (O) (OH)₂"or a salt thereof.

The term "phosphoric acid" as used herein denotes the formula "-OP (O) (OH)₂"or a salt thereof.

The term "sulfonic acid" as used herein denotes the formula "-S (O)₂OH'.

The formula "H" as used herein represents a hydrogen atom.

The formula "O" as used herein represents an oxygen atom.

The formula "N" as used herein represents a nitrogen atom.

The formula "S" as used herein represents a sulfur atom.

In another aspect, the FPR2 agonist is a compound selected from table 1:

TABLE 1

US 2005/0137230 a1 and US 7820673 disclose coagulation factor Xa inhibitors and are useful for the prevention and/or treatment of thromboembolic diseases and or for the treatment of tumors. 2- ({ [ (4-chlorophenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid, (2S) -2- ({ [ (4-methoxyphenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid, (2S) -3-phenyl-2- [ ({ [4- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] propanoic acid, methyl 2- ({ [ (4-iodophenyl) amino ] carbonyl } amino) -3-phenylpropionate, (2S) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid, and (2R) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid are intermediates in the synthesis of urea derivatives as inhibitors of activated blood coagulation factor x (fxa).

JP 63232846 discloses the resolution of N- (p-bromophenylcarbamoyl) derivatives ((2S) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid, (2S,3S) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-methylpentanoic acid, 2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3- (1H-indol-3-yl) propanoic acid, (2S) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-methylbutyric acid) on an HPLC column with a novel chiral stationary phase of chromatography.

Journal of Chromatography (1987),404(1),117-22 and Chromatography (1987),23(10),727-30 describe the resolution of p-bromophenylcarbamoyl derivatives ((2R) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid, (2S) -2- ({ [ (4-bromophenyl) amino ] carbonyl } amino) -3-phenylpropanoic acid) of enantiomeric amino acids by elution with an aqueous mobile phase on a novel chiral stationary phase.

Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1972),272(4),667-71 describe the compound (2S) -2- ({ [ (4-nitrophenyl) amino ] carbonyl } amino) -3-phenylpropionic acid) in poly (uridylic acid) -dependent binding of p-nitrophenyl-carbamoyl-phenylalanyl tRNA.

In another aspect, the FPR2 agonist is a compound selected from table 2:

TABLE 2

The compounds of Table 2 are commercially available from Chemical Libraries, such as Aurora Fine Chemicals. In another aspect, the FPR2 agonist is a compound selected from table 3:

TABLE 3

The compounds of Table 3 are available from Chemical Libraries, such as Chemical Block, Inc.

In yet another embodiment of the present invention, methods are provided for treating disorders associated with the modulation of FPR 2.

Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.

Therapeutic utility of FPR2 is ocular inflammatory diseases including, but not limited to, wet and dry age-related macular degeneration (ARMD), uveitis, dry eye, keratitis, allergic eye diseases, and conditions affecting the back of the eye, such as macular degeneration and retinal degeneration, including non-exudative age-related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferation), retinopathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis, such as acute multifocal squamous pigment epithelium disorder, behcet's disease, bullet-like retinal choroidopathies, infectious diseases (syphilis, lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (pars plana), multifocal choroiditis, multiple remitting white spot syndrome (newds), ocular sarcoidosis, posterior scleritis, paranoid uveitis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome; vascular/exudative diseases such as retinal artery occlusive disease, central retinal vein occlusion, cystoid macular edema, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal artery microaneurysms, korotkoff's disease, collateral foveal telangiectasia, hemilateral retinal vein occlusion, papillary phlebitis, central retinal artery occlusion, branch retinal artery occlusion, Carotid Artery Disease (CAD), frost-like branch vasculitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy and periretinal vein inflammation; traumatic/surgical conditions such as sympathetic ophthalmia, uveitis retinal disease, retinal detachment, trauma, postoperative corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, inadequate blood flow perfusion during surgery, radioactive retinopathy, and bone marrow transplanted retinopathy; proliferative disorders, such as proliferative vitreoretinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, Presumed Ocular Histoplasmosis Syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal diseases associated with HIV infection, uveitis diseases associated with HIV infection, viral retinitis, acute retinal necrosis, progressive lateral retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic disorders associated with retinal dystrophy, congenital quiescent night blindness, pyramidal dystrophy, stargardt disease and fundus macular disease, best's disease, retinal pigment epithelium pattern dystrophy, X-linked retinal cleavage disease, sosbye's fundus dystrophy, benign concentric maculopathy, bytts crystalloid dystrophy, and elastopseudoxanthoma; retinal tears/retinal tears, such as retinal detachment, macular hole, and giant retinal tears; tumors, such as retinal diseases associated with tumors, congenital hypertrophy of the retinal pigment epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigment epithelium, retinoblastoma, ocular fundus angioproliferative tumors, retinal astrocytoma, and intraocular lymphoma; and various other diseases affecting the posterior segment of the eye, such as punctate inner choroidopathy, acute posterior multifocal squamous pigment epithelium disorders, myopic retinal degeneration and acute retinal suprapigmentary dermatitis, systemic inflammatory diseases, such as stroke, coronary artery disease, obstructive airway disease, HIV-mediated retroviral infections, cardiovascular disorders, including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, systemic lupus erythematosus, psoriasis, CNS disorders, such as Alzheimer's disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina, post-operative corneal inflammation, blepharitis, MGD, skin wound healing, burn, rosacea, atopic dermatitis, acne, psoriasis, seborrhoeic viral diseases, actinic keratosis, warts, photoaging rheumatoid arthritis and related inflammatory disorders, Alopecia, glaucoma, branch vein occlusion, Besth's vitelliform macular degeneration, retinitis pigmentosa, Proliferative Vitreoretinopathy (PVR), and any other degenerative disease of the photoreceptors or RPE (Perretti, Mauro et al, Pharmacology & Therapeutics 127(2010) 175-.

These compounds are useful for treating mammals (including humans) suffering from a range of conditions and diseases that are alleviated by FPR2 modulation: including but not limited to the treatment of wet and dry age-related macular degeneration (ARMD), diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), diabetic macular edema, uveitis, dry eye, retinal vein occlusion, cystoid macular edema, glaucoma, branch vein occlusion, best's vitelliform macular degeneration, retinitis pigmentosa, Proliferative Vitreoretinopathy (PVR), and any other degenerative disease of the photoreceptors or RPEs.

In yet another embodiment of the invention, methods are provided for treating disorders associated with FPRL-1 receptor modulation. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.

The actual amount of compound administered in any given case will be determined by the physician considering the relevant circumstances such as: the severity of the condition, the age and weight of the patient, the general physical condition of the patient, the etiology of the condition, and the route of administration.

The patient will administer the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder, etc., or other route may be desirable or necessary, particularly if the patient is experiencing nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, by implantation of a stent, intrathecal, intravitreal, topical to the eye, posterior to the eye, intramuscular, intravenous, and intrarectal modes of delivery. In addition, the formulations can be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of treatment.

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound of the present invention in a pharmaceutically acceptable carrier. The phrase "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the present invention may be employed in the form of solids, solutions, emulsions, dispersions, patches, micelles, liposomes, and the like, wherein the resulting composition contains as an active ingredient one or more compounds of the present invention in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral application. The compounds of the present invention may be combined, for example, with generally non-toxic pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. Carriers that may be used include glucose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea, medium chain triglycerides, dextran and other carriers suitable for use in the manufacture of formulations in solid, semi-solid or liquid form. In addition, adjuvants, stabilizers, thickeners and colorants, as well as fragrances, may be used. The compounds of the present invention are included in the pharmaceutical compositions in amounts sufficient to produce the desired effect on the process or disease condition.

Pharmaceutical compositions containing a compound of the invention may be in a form suitable for oral use, for example, in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of: sweetening agents, such as sucrose, lactose or saccharin; flavoring agents, such as peppermint, oil of wintergreen or cherry; coloring agents and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets containing a compound of the invention in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch, potato starch or alginic acid; (3) binders, such as gum tragacanth, corn starch, gelatin or acacia; and (4) a lubricant, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein a compound of the invention is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein a compound of the invention is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions containing a compound of the invention may be in a form suitable for topical use, for example, in the form of an oily suspension, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

The pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the invention or a pharmaceutically acceptable salt thereof as active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparing a unit dose suitable for topical ocular use. The therapeutically effective amount in a liquid formulation is generally between about 0.001% (w/v) and about 5% (w/v), preferably about 0.001% (w/v) to about 2.0% (w/v).

For ophthalmic application, solutions are preferably prepared using physiological saline solution as the primary vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 using a suitable buffer system, neutral pH being preferred, but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, a variety of preferred vehicles may be used in the ophthalmic formulations of the present invention. Such vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers (poloxamers), carboxymethyl cellulose, hydroxyethyl cellulose, cyclodextrins, and purified water.

Tonicity adjusting agents may be added as needed or at the time of convenience. They include, but are not limited to, salts (in particular sodium chloride, potassium chloride), mannitol and glycerol or any other suitable ophthalmically acceptable tonicity modifier.

A variety of buffers and means for adjusting the pH may be used, so long as the resulting formulation is ophthalmically acceptable. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations can be adjusted as desired using acids or bases.

In a similar manner, ophthalmically acceptable antioxidants for use in the present invention include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components that may be included in the ophthalmic formulation are chelating agents. The preferred chelating agent is disodium edetate, although other chelating agents may also be used in place of or in combination with disodium edetate.

Ingredients are generally used in the following amounts:

the actual dosage of the active compounds of the invention depends on the particular compound and the condition to be treated; the selection of an appropriate dosage is well within the knowledge of one skilled in the art.

The ophthalmic formulations of the present invention are conveniently packaged in a form suitable for metered application, for example in containers equipped with a dropper, for application to the eye. Containers suitable for drop-by-drop application are typically made of suitable inert, non-toxic plastic materials and typically contain between about 0.5ml and about 15ml of solution. A package may contain one or more unit doses. In particular, preservative-free solutions are generally formulated in non-resealable containers containing up to about 10 unit doses, preferably up to about 5 unit doses, with typical unit doses being 1 to about 8 drops, preferably 1 to about 3 drops. One drop typically has a volume of about 20-35. mu.l.

The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides, fatty acids including oleic acid, naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil and the like, or synthetic fatty vehicles such as ethyl oleate, and the like. Buffers, preservatives, antioxidants and the like may be incorporated as required.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient such as cocoa butter, synthetic polyglycolyglycerides which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.

Because individual subjects can exhibit wide variation in symptom severity, and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed by each subject is determined at the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treating diseases and/or alleviating conditions responsive to treatment with an agonist or functional antagonist of FPR 2. Accordingly, in other embodiments of the invention, methods are provided for treating disorders associated with the modulation of FPR 2. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention. The term "therapeutically effective amount" as used herein means that amount of a pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is a human.

Materials and methods

It is expected that FPR2 agonists will have significant effects in many different types of ocular inflammation, but have been exemplified by the demonstration of anti-inflammatory activity in endotoxin-induced rat uveitis (fig. 1 and 2). The anti-inflammatory activity in this model has been exemplified using the FPR2 agonists described in table 4.

FLIPR Using HEK-G α 16 cells stably expressing the human FPR2 receptor the cells were plated at a density of 18,000 cells per well to 384-well poly-D-lysine coated plates the day before useIn (1). The growth medium was DMEM medium supplemented with 10% Fetal Bovine Serum (FBS), 1% antibiotic-antimycotic, 50 μ g/ml hygromycin and 400 μ g/ml geneticin. On the day of the experiment, cells were washed twice with Hank's balanced Salt Solution (Hank's balanced Salt Solution) supplemented with 20mM HEPES (HBSS/HEPES buffer). Cells were then loaded with 2 μ M Fluo-4 dye diluted in HBSS/Hepes buffer and incubated for 40 min at 37 ℃. Extracellular dye was removed by washing the Plate 4 times before placing the Plate in a FLIPR (fluorescent Imaging Plate Reader), Molecular Devices. The ligand was diluted in HBSS/Hepes buffer and prepared in 384-well microplates. Obtaining Ca in relative fluorescence units⁺²Data on the reaction.

TABLE 4

Immunohistochemistry: DAB immunohistochemistry using chromogenic antibody specific for FPR2 was used to determine location in normal human, primate, and rat eyes. To be provided withDilution 1:200 FPR2 protein was detected in all species using anti-FPR 2 antibody (Abcam).

Endotoxin induced uveitis in rats: uveitis is a harmful ocular inflammatory condition in humans. Anterior uveitis is a recurrent inflammatory disease and can have potentially blinding consequences. The pathogenesis of the disease is poorly understood and the anti-inflammatory therapies used are non-specific and associated with significant complications. Animal models are crucial for understanding the disease and testing for novel therapies. A single low dose of Lipopolysaccharide (LPS) in the plantar foot induced anterior uveitis in rats. This model, known as endotoxin-induced uveitis, serves as a useful paradigm for human anterior uveitis. Male Lewis rats (260. + -. 25 g) were purchased from Charles river laboratory. Rat footpad was injected (left posterior) with 100 μ l of 1mg/ml LPS (List Biological labs) solution (in sterile 0.9% saline). Test compounds were formulated in a vehicle consisting of sodium phosphate dibasic heptahydrate, CMC and sterile water. The compounds were administered either topically (0.1-1%) or subcutaneously (10mg/kg) 2 hours after LPS. Animals were sacrificed 24 hours after LPS injection. Aqueous humor was collected and analyzed to determine inflammatory cell counts and total protein concentration.

Alkali burn of rabbits: the corneal epithelium plays an important role in the maintenance of corneal function and integrity. Persistent corneal epithelial defects cause corneal clouding, neovascularization, bacterial infection, and vision loss. Corneal epithelial healing is a complex process involving inflammatory responses to injury, cell proliferation and migration. Animal models of corneal injury are available for testing new anti-inflammatory and pro-wound healing therapies. New Zealand white rabbits weighing between 2.1kg and 2.5kg were anesthetized systemically with Ketamine/Xylazine (35/5mg/kg) subcutaneously and with proparacaine (0.5%) topically. Corneal epithelial wounds in one eye were induced for 30 seconds with NaOH saturated filter paper containing 1.0N NaOH. The eyes were rinsed with sterile PBS. Corneal trauma was confirmed by fluorescein staining with 10% fluorescein sodium (Science Lab Com) and slit-lamp photography. Test compounds were formulated in the above vehicleA compound (I) is provided. For the initial study, the compounds were administered topically three times daily. Quantification of corneal wound area was performed using Image J software, where the fluorescently stained green fraction was followed and converted to total pixels.

The following compounds are expected to have significant effects in many different types of ocular inflammation, but have been exemplified by the demonstration of anti-inflammatory activity in endotoxin-induced rat uveitis (fig. 1 and 2). The anti-inflammatory activity in this model has been exemplified using the following FPR2 agonists:

in this model, the compounds show strong anti-inflammatory activity blocking neutrophil and protein infiltration into the anterior chamber. In addition, FPR2 agonists were shown to accelerate healing and re-epithelialization in a mouse model of corneal trauma, as exemplified by the compound { [ (2S,3S) -2- { [ (4-bromophenyl) carbamoyl ] amino } -3-methylpentanoyl ] amino } acetic acid in (fig. 3). These data demonstrate that FPR2 agonists are potent and potent anti-inflammatory agents suitable for ocular use in different models of ocular inflammation.

Claims (21)

1. A pharmaceutical composition for treating ocular inflammatory diseases comprising a compound represented by formula I:

wherein:

R¹is sec-butyl, C_6-10Aryl, -CH₂-(C_6-10) Aryl, -CH₂-heterocycle, C_4-8Cycloalkyl or C_3-8Cycloalkenyl or heterocycle;

R²is halogen or methyl;

R³is halogen;

R⁴is H, methyl or halogen;

R⁵is OR⁶Or NH₂(ii) a And is

R⁶Is H or C_2-4An alkyl group;

or a compound selected from:

2. the pharmaceutical composition of claim 1, wherein the compound of formula I is selected from the group consisting of:

3. the pharmaceutical composition of claim 1, wherein the compound is:

4. the pharmaceutical composition of any one of claims 1 to 3, 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 squamous pigment epithelium, Behcet's disease, postoperative corneal wound healing, wet and dry age-related macular degeneration (ARMD).

5. A method of treating an ocular inflammatory disease in a subject in need of such treatment, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one formyl peptide receptor 2(FPR2) agonist;

wherein the ocular inflammatory disease is selected from uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal squamous pigment epithelium, Behcet's disease, postoperative corneal wound healing, wet age-related macular degeneration (ARMD), and dry ARMD, and

wherein the FPR2 agonist is a compound represented by formula III:

wherein:

R¹is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R²Is halogen, optionally substituted C_1-8Alkyl, CF₃、OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R³Is hydrogen, optionally substituted C_1-8Alkyl, aryl, heteroaryl, and heteroaryl,Optionally substituted C_3-8Cycloalkyl, optionally substituted C_3-8Cycloalkenyl, optionally substituted C_6-10Aryl, optionally substituted heterocycle, or with R⁵Together form an optionally substituted 10-or 11-membered polycyclic ring;

R⁴is hydrogen, optionally substituted C_1-8Alkyl, aryl, heteroaryl, and heteroaryl,Optionally substituted C_3-8Cycloalkyl, optionally substituted C_3-8Cycloalkenyl, optionally substituted C_6-10Aryl, optionally substituted heterocycle, or with R⁵Together form a spiromonocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated, optionally substituted 5-to 10-membered ring;

R⁵is hydrogen, optionally substituted C_1-8Alkyl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_3-8Cycloalkenyl, optionally substituted C_6-10Aryl, optionally substituted heterocycle, or with R⁴Together form a spiromonocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated, optionally substituted 5-to 10-membered ring, or with R³Together form an optionally substituted 5-or 6-membered ring;

R⁶is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R⁷Is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R⁸Is halogen, hydrogen, optionally substituted C_1-8Alkyl, OR⁹、C(O)R¹⁰、NO₂、NR¹³R¹⁴、CN、SR¹⁵Or SO₂R¹⁶；

R⁹Is hydrogen, C (O) (C)_1-8Alkyl) or optionally substituted C_1-8An alkyl group;

R¹⁰is hydrogen, optionally substituted C_1-8Alkyl, O (C)_1-8Alkyl), NR)¹¹R¹²Or OH;

R¹¹is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹²is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹³is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹⁴is hydrogen, optionally substituted C_6-10Aryl, optionally substituted C_1-8Alkyl, C (O) (C)_1-8Alkyl) or SO₂(C_1-8Alkyl groups);

R¹⁵is hydrogen, optionally substituted C_1-8Alkyl or O (C)_1-8Alkyl groups);

R¹⁶is OH, O (C)_1-8Alkyl group), (C)_1-8Alkyl) or NR¹¹R¹²；

R¹⁷Is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹⁸is hydrogen, C (O) (C)_1-8Alkyl), optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R¹⁹is hydrogen, C (O) (C)_1-8Alkyl), optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R²⁰is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

R²¹is hydrogen, optionally substituted C_6-10Aryl or optionally substituted C_1-8An alkyl group;

n is 1, 2, 3, 4 or 5; and is

m is 1, 2, 3, 4 or 5.

6. The method of claim 5 wherein said FPR2 agonist is selected from the group consisting of:

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- (prop-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] decan-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- (prop-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-bicyclopropyl-2, 5-dioxoimidazolidin-1-yl) urea;

1- (4-bromophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (prop-2-yl) imidazolidin-1-yl ] urea;

1- (4-bromophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (prop-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-dioxo-imidazolidin-1-yl } urea;

1- (4-bromophenyl) -3- {4- [2- (3-fluorophenyl) ethyl ] -4-methyl-2, 5-dioxo-imidazolidin-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- (prop-2-yl) imidazolidin-4-yl ] -N- (2-hydroxyethyl) acetamide;

methyl 2- [2- (1- { [ (4-bromophenyl) carbamoyl ] amino } -4-ethyl-2, 5-dioxo-imidazolidin-4-yl) ethyl ] benzoate;

2- [1- { [ (4-bromophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] -N- (1, 3-dihydroxyprop-2-yl) acetamide;

2- [2- (1- { [ (4-bromophenyl) carbamoyl ] amino } -4-ethyl-2, 5-dioxo-imidazolidin-4-yl) ethyl ] benzoic acid;

2- [2- (1- { [ (4-bromo-2-fluorophenyl) carbamoyl ] amino } -4-ethyl-2, 5-dioxo-imidazolidin-4-yl) ethyl ] benzoic acid;

3- ({ [1- { [ (4-bromophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] acetyl } amino) propanoic acid;

2- [1- { [ (4-bromo-2-fluorophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] -N- (2-hydroxyethyl) acetamide;

2- {2- [1- { [ (4-bromophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] ethyl } benzoic acid;

diethyl [2- ({ [1- { [ (4-bromophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] acetyl } amino) ethyl ] phosphonate;

1- (4-bromophenyl) -3- {4- [2- (2-fluorophenyl) ethyl ] -4-methyl-2, 5-dioxo-imidazolidin-1-yl } urea; and

3- ({ [1- { [ (4-bromo-2-fluorophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] acetyl } amino) propanoic acid.

7. The method of claim 5 wherein said FPR2 agonist is a compound selected from the group consisting of:

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- (prop-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] decan-3-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- (prop-2-yl) imidazolidin-1-yl ] urea;

1- (4-bromophenyl) -3- [2, 5-dioxo-4, 4-di (propan-2-yl) imidazolidin-1-yl ] urea; and

1- (4-bromophenyl) -3- (4, 4-bicyclopropyl-2, 5-dioxoimidazolidin-1-yl) urea.

8. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (2-phenylethyl) imidazolidin-1-yl ] urea.

9. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (propan-2-yl) imidazolidin-1-yl ] urea.

10. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- (4, 4-diethyl-2, 5-dioxoimidazolidin-1-yl) urea.

11. The method of claim 5, wherein the FPR2 agonist is 1- (4-bromo-2-fluorophenyl) -3- (4, 4-diethyl-2, 5-dioxoimidazolidin-1-yl) urea.

12. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- (2, 4-dioxo-1, 3-diazaspiro [4.5] decan-3-yl) urea.

13. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- [ 4-methyl-2, 5-dioxo-4- (2-phenylethyl) imidazolidin-1-yl ] urea.

14. The method of claim 5, wherein the FPR2 agonist is 1- (4-bromo-2-fluorophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (prop-2-yl) imidazolidin-1-yl ] urea.

15. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- [2, 5-dioxo-4, 4-di (propan-2-yl) imidazolidin-1-yl ] urea.

16. The method of claim 5, wherein said FPR2 agonist is 1- (4-bromophenyl) -3- (4, 4-bicyclopropyl-2, 5-dioxoimidazolidin-1-yl) urea.

17. The method of claim 5 wherein said FPR2 agonist is

1- (4-chlorophenyl) -3- (2, 4-dioxo-1, 3-diazaspiro [4,5] decan-3-yl) urea;

1- (4-chlorophenyl) -3- (4-ethyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) urea; and

1- (8-methyl-2, 4-dioxo-1, 3-diazaspiro [4,5] decan-3-yl) -3- (p-tolyl) urea.

18. The method of claim 5 wherein said FPR2 agonist is a compound selected from the group consisting of:

(+) -1- (4-bromophenyl) -3- [ 4-methyl-2, 5-dioxo-4- (2-phenylethyl) imidazolidin-1-yl ] urea;

(+) -1- (4-bromophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (prop-2-yl) imidazolidin-1-yl ] urea;

(-)1- (4-bromophenyl) -3- [ 4-ethyl-2, 5-dioxo-4- (prop-2-yl) imidazolidin-1-yl ] urea; and

ethyl 3- [1- { [ (4-bromophenyl) carbamoyl ] amino } -2, 5-dioxo-4- (prop-2-yl) imidazolidin-4-yl ] propionate.

19. A method of treating an ocular inflammatory disease in a subject in need of such treatment, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one formyl peptide receptor 2(FPR2) agonist;

wherein the ocular inflammatory disease is selected from uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal squamous pigment epithelium, Behcet's disease, postoperative corneal wound healing, wet age-related macular degeneration (ARMD), and dry ARMD, and

wherein the FPR2 agonist is a compound selected from the group consisting of:

3- { [ (4-bromophenyl) carbamoyl ] amino } -2, 4-dioxo-1, 3-diazaspiro [4.5] decane-8-carboxylic acid ethyl ester;

1- [ 4-methyl-2, 5-dioxo-4- (2-phenylethyl) imidazolidin-1-yl ] -3-phenylurea; and

1- (2-fluorophenyl) -3- [ 4-methyl-2, 5-dioxo-4- (2-phenylethyl) imidazolidin-1-yl ] urea.

20. The method of claim 5, wherein the ocular inflammatory disease is dry eye.

21. The method of claim 19, wherein the ocular inflammatory disease is dry eye.