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    • 专利摘要:
    use of formyl peptide 2 receptor agonists to treat inflammatory eye diseases the present invention relates to a method for treating inflammatory eye diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of hair least one formyl 2 peptide receptor agonist.
    公开号:BR112015021371B1
    申请号:R112015021371-5
    申请日:2014-03-04
    公开日:2021-04-13
    发明作者:John E. Donello；Veena Viswanath；Richard L. Beard
    申请人:Allergan, Inc；
    IPC主号:
    专利说明:

    RELATED REQUESTS
    [1] This application claims the benefit of Provisional Patent Application Serial No. US 61 / 773,773 filed on March 6, 2013, the disclosure of which is incorporated herein in its entirety by reference. BACKGROUND OF THE INVENTION 1. Field of the invention
    [2] The present invention relates to a method for the treatment of inflammatory eye diseases in a subject in need of said treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one receptor agonist. Formyl peptide 2 (FPR2). 2. Summary of related technique
    [3] The receptor of the formyl peptide family (FPR) is involved in the defense of the host against pathogens, but also in the detection of internal molecules that can provide signals of cellular dysfunction. This family includes three members in humans and one member of this family FPR2 (also known as FPRL-1, ALXA4) is a G protein coupled receptor that is expressed predominantly in inflammatory cells such as monocytes and neutrophils, as well as in T cells. shown to play a critical role in leukocyte trafficking during human inflammation and pathology (Chiang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C. The ALX receptor lipoxin : Potent ligandspecific and stereoselective actions in vivo (Pharmacological Reviews 2006; 58: 463-519). FPR2 is an exceptionally promiscuous receptor that responds to a wide variety of endogenous and exogenous ligands, including serum amyloid A (SAA), sCKβ8-1 chemokine variant, the neuroprotective human peptide, anti-inflammatory lipoxin A4 (LXA4) and protein glucocotricoid-modulated annexin A1 (Chiang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C. The lipoxin ALX receptor: Potent ligandspecific and stereoselective actions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 transduces the anti-inflammatory effects of LXA4 in many systems, and has been shown to play a key role in resolving inflammation (Dufton N, Perretti M. Therapeutic anti-inflammatory potential of formyl peptide receptor agonists. Pharmacology & Therapeutics 2010; 127: 175-188). FPR2 knockout mice show exaggerated inflammation in disease conditions as expected by the biological role of the recipient (Dufton N, Hannon R, Brancaleone V, Dalli J, Patel HB, Gray M, D'Aquisto F, Buckingham JC, Perretti M, Flower RJ. Anti-inflammatory role of the murine formylpeptide receptor 2: Ligand-specific effects on leukocyte responses and experimental inflammation. Journal of Immunology 2010; 184: 2611-2619).
    [4] The activation of FPR2 by lipoxin A4 or its analogs and by annexin I protein has been shown to result in anti-inflammatory activity, promoting the resolution of active inflammation, which involves the inhibition of polymorphonuclear neutrophils (PMNs) and migration of eosinophils and also migration stimulate monocyte migration allowing clearance of apoptotic cells from the inflammation site in a non-phlogistic way (Maderna P, Cottell DC, Toivonen T, Dufton N, Dalli J, Perretti M, Godson C. FPR2 / ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis. FASEB 2010; 24: 4240-4249; Reville K, Cream JK, Vivers S, Dransfield I, Godson C. Lipoxin A4 redistributes Mysoin IIA and Cdc42 in macrophages: Implications for phagocytosis of apoptotic leukocytes, Journal of Immunology 2006; 176: 1878-1888). In addition, FPR2 has been shown to inhibit NK cytotoxicity and promote T cell activation which further contributes to down-regulation of harmful inflammatory tissue signals. LXA4 / FPR2 interaction has been shown to be beneficial in experimental models of reperfusion of ischemia, angiogenesis, eye inflammation, such as endotoxin-induced uveitis, and corneal wound healing (Serhan C. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators Annual reviews of Immunology 2007; 25: 101-137; Medeiros R, Rodrigues GB, Figueiredo CP, Rodrigues EB, Grumman A Jr, Menezes-de-Lima O Jr, Passos GF, Calixto JB. Molecular mechanisms of topical anti -inflammatory effects of lipoxin A (4) in endotoxin-induced uveitis. Molecular Pharmacology 2008; 74: 154-161; Gronert K, Maheshwari N, Khan N, Hassan IR, Dunn M, Schwartzmann ML. 15-lipoxygenase pathways in promoting epithelial wound healing and host defense.Journal of Biological Chemistry 2005; 280: 15267-15278; Leedom A, Sullivan AB, Dong B, Lau D, Gronert K. Endogenous LXA4 circuits are determinants of pathological angiogenesis in respons and to chronic injury. American Journal of Pathology 2010; 176: 74-84; Gronert K. Lipoxins in the eye and their role in wound healing. Prostaglandins, Leukotrienes and Essential fatty Acids. 2005; 73: 221-229). Pharmaceutical utility of lipoxin A4 and its analogs is hampered by the inherent physicochemical properties of the natural polyolefin natural product. Therefore, small molecule anti-inflammatory FPR2 agonists would have a wide variety of therapeutic benefits in inflammatory diseases, especially in the eye. Targeting FPR2 selectively also has benefits of reduced side effects, compared to broader-acting anti-inflammatories such as corticosteroids or NSAIDs, which have significant side effects of elevated IOP and delays in wound healing in the eye. FPR2 is also expressed in ocular tissues in the cornea and also in the posterior chamber of the eye, in addition to inflammatory cells that migrate to ocular tissues. FPR2 thus represents an important new pro-revolutionary molecular target for the development of new therapeutic agents in eye diseases with excessive inflammatory responses. BRIEF DESCRIPTION OF THE INVENTION
    [5] The invention relates to the ability of FPR2 agonists to exhibit ocular anti-inflammatory activity with chemical stability and suitable for ocular administration. These FPR2 compounds show good potency at the receptor, a subset of compounds is exemplified in the tables below, and importantly, the compounds are topically active FPR2, and therefore can be administered in various forms, including, but not limited to, eye drops . These compounds can also be administered directly or through a local drug delivery device applied to ocular tissue, and via IV, intramuscularly, intrathecally, subcutaneously, orally, intravitreally or intraperitoneally. These compounds will be useful for the treatment of inflammatory eye diseases, including, but not limited to, uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as epitheliopathy acute multifocal placoid pigmentation, Behcet's disease, post-surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, wet and dry age-related macular degeneration (AMRD), conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration, including non-exudative age-related macular degeneration, exudative age-related macular degeneration, choroidal neovascularization, diabetic (proliferative) retinopathy, premature retinopathy (ROP), acute macular neuroretinopathy, chorioretinopathy central serosa, cystoid macular edema, and diabetic macular edema; birdshot retinochoroidopathy, infectious (syphilis, Lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white spot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and subretinal fibrosis uveitis, Vogt syndrome and Koyanagi Harada; vascular diseases / exudative diseases, such as retinal arterial occlusive disease, central retinal vein occlusion, cystoid macular edema, disseminated intravascular coagulopathy, retinal vein branch occlusion, hypertensive fundus changes, ocular ischemic syndrome, arterial microaneurysms retinal disease, Coat disease, parafoveal telangiectase, retinal vein hemi-occlusion, papillophlebitis, central retinal artery occlusion, retinal artery branch occlusion, carotid artery disease (CAD), frozen branch angeitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy and Eales disease; traumatic / surgical conditions such as sympathetic ophthalmia, diseases of the uveitic retina, retinal detachment, trauma, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy; proliferative disorders such as proliferative retinopathy of the vitreous and epiretinal membrane, and proliferative diabetic retinopathy; infectious diseases, such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroid disease associated with HIV infection, uveitic disease associated with HIV infection, viral retinitis, acute retinal necrosis, progressive external retinal necrosis, fungal diseases of the retina, ocular syphilis, ocular tuberculosis, unilateral diffuse subacute neuroretinitis and myiasis; genetic diseases such as retinitis pigmentosa, systemic diseases with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, standard retinal pigment epithelium dystrophy, X-linked retinoschisis, dystrophy background of Sorsby, benign concentric maculopathy, crystalline Bietti dystrophy, and elastic pseudoxanthoma; tears / holes in the retina such as retinal detachment, macular orifice, and giant retinal rupture; tumors, such as tumor-associated retinal disease, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined retinal hamartoma and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors from the bottom ocular, retinal astrocytoma, intraocular and lymphoid tumors; and several other diseases that affect the back of the eye, such as punctate inner choroidopathy, acute anterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigment epithelitis, corneal inflammation, blepharitis, MGD, glaucoma, vein occlusion post-surgical branch, Best vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative diseases of both photoreceptors or the retinal pigment epithelium (RPE).
    [6] In another aspect, these compounds will be useful for the treatment of inflammatory eye diseases associated with CNS disorders such as Alzheimer's disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, rheumatoid arthritis and related inflammatory diseases , alopecia, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular disorders, including coronary artery disease, neuroinflammatory, neurological disorders, pain and immune disorders, asthma, allergic diseases, inflammation, systemic lupus erythematosus. BRIEF DESCRIPTION OF THE DRAWINGS
    [7] Figure 1 FPR2 agonists show potent anti-inflammatory activity in the endotoxin-induced uveitis model in rats.
    [8] Figure 2 FPR2 agonists show potent anti-inflammatory activity in the endotoxin-induced uveitis model in rats.
    [9] Figure 3 shows accelerated healing and re-epithelialization in a rabbit model of corneal injury, as exemplified by compound 3, {[(2S, 3S) -2 - {[(4-bromophenyl) carbamoyl] acid] amino} -3-methylpentanoyl] amino} acetic. DETAILED DESCRIPTION OF THE INVENTION
    [10] The present invention relates to a method for the treatment of inflammatory eye diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one FPR2 agonist.
    [11] In another aspect, the invention provides the use of at least one FPR2 agonist for the manufacture of a medicament for the treatment of an inflammatory eye disease or FPR2-mediated condition in a mammal.
    [12] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one FPR2 agonist as disclosed in US patent application SN13 / 668,835 , as long as the binding compounds have activity at the FPR2 receptor.
    [13] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN13 / 668,835 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal, provided that the compounds have FPR2 receptor binding activity.
    [14] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN13 / 668,835 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have activity of connection to the FPR2 receiver.
    [15] The compounds described in patent application USSN13 / 668,835 are represented by Formula I:
    wherein: R1 is sec-butyl, C6-1o aryl, -CH2- (C6-10) aryl, -CH2-heterocycle, C4-8 cycloalkyl or C3-8 cycloalkenyl or heterocycle; R2 is halogen or methyl; R3 is halogen; R4 is H, methyl or halogen; R5 is OR6 or NH2; R6 is H or C2-4 alkyl.
    [16] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one FPR2 agonist as disclosed in US patent application SN13 / 523,579, provided that the compounds have FPR2 receptor binding activity.
    [17] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 523,579 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have FPR2 receptor binding activity.
    [18] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 523.579 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have activity connection to the FPR2 receiver.
    [19] The compounds described in US patent application SN 13 / 523,579 are represented by Formula II:
    where: a is 1 and b is 0; a is 0 and b is 1; a is 1 and b is 1; R1 is optionally substituted C1_8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, -NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6_10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, -OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6_10 aryl or optionally substituted C3-8 cycloalkenyl; R5 is halogen, -CF3 or - S (O) nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, -OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, -OR13, -NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6_10 aryl or optionally substituted C3-8 cycloalkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or optionally substituted by C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted by C1-8 alkyl;
    [20] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one FPR2 agonist as disclosed in US patent application SN 13 / 673,800, as long as the compounds have FPR2 receptor binding activity.
    [21] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 673,800 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal , as long as the compounds have FPR2 receptor binding activity.
    [22] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 673,800 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have binding activity to the FPR2 receptor.
    [23] The compounds described in US patent application SN 13 / 673,800 are represented by Formula III:
    R1 is halogen, hydrogen, optionally substituted by C1-8 alkyl, OR9, C (O) R10, NO2, NR13R14, CN, SR15 or SO2R16; R2 is halogen, optionally substituted by C 1-8 alkyl, CF3, OR9, C (O) R10, NO2, NR13R14, CN, SR15 or SO2R16; R3 is hydrogen, optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6_10 aryl, optionally substituted heterocycle, or together with R5 form a 10 or 11 membered polycyclic ring optionally replaced; R4 is hydrogen, optionally substituted C108 alkyl,

    substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6_10 aryl, optionally substituted heterocycle, or together with R5 form a monocyclic or polycyclic, carbocyclic or heterocyclic spiro, 5 to 10 membered saturated or unsaturated ring which is optionally substituted; R5 is hydrogen, optionally substituted C1_8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6_10 aryl, optionally substituted heterocycle, or together with R4 form a monocyclic or polycyclic carbocyclic or heterocyclic spiro, saturated or heterocyclic ring 5- to 10-membered unsaturated which is optionally substituted or together with R3 forms a 5- or 6-membered ring which is optionally substituted; R6 is halogen, hydrogen, optionally substituted by C1-8 alkyl, OR9, C (O) R10, NO2, NR13R14, CN, SR15 or SO2R16; R7 is halogen, hydrogen, optionally substituted by C1-8 alkyl, OR9, C (O) R10, NO2, NR13R14, CN, SR15 or SO2R16; R8 is halogen, hydrogen, optionally substituted by C1-8 alkyl, OR9, C (O) R10, NO2, NR13R14, CN, SR15 or SO2R16; R9 is hydrogen, C (O) (C1-8 alkyl) or optionally substituted C1-8 alkyl; R10 is hydrogen, optionally substituted by C1-8 alkyl, O (C1-8 alkyl), NR11R12 or OH; R11 is hydrogen, optionally substituted C6-10 aryl or optionally substituted C1-8 alkyl; R12 is hydrogen, optionally substituted C6-10 aryl or optionally substituted C1-8 alkyl; R13 is hydrogen, optionally substituted C6-10 aryl or optionally substituted C1-8 alkyl; R14 is hydrogen, optionally substituted C6-10 aryl, optionally substituted C1-8 alkyl, C (O) (C1-8 alkyl) or SO2 (C1-8 alkyl); R15 is hydrogen, optionally substituted by C1-8 alkyl or O (C1-8 alkyl); R16 is OH, O (C1-8 alkyl), (C1-8 alkyl) or NR11R12; R17 is hydrogen, optionally substituted C6-10 aryl or optionally substituted C1-8 alkyl; R18 is hydrogen, C (O) (C1-8 alkyl), optionally substituted C6-10 aryl, or optionally substituted C 1-8 alkyl; R19 is hydrogen, C (O) (C1-8 alkyl), optionally substituted C610 aryl or optionally substituted C 1-8 alkyl; R20 is hydrogen, optionally substituted C6_10 aryl or optionally substituted C 1-8 alkyl; R21 is hydrogen, optionally substituted C6_10 aryl or optionally substituted C1-8 alkyl; n is 1, 2, 3, 4, or 5; m is 1, 2, 3, 4, or 5.
    [24] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one FPR2 agonist as disclosed in US patent application SN 13 / 765,527, provided that the compounds have FPR2 receptor binding activity.
    [25] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13/7 65,527 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have FPR2 receptor binding activity.
    [26] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 765,527 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have binding activity to the FPR2 receptor.
    [27] The compounds described in US patent application SN 13 / 765,527 are represented by Formula IV:
    where: R1 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3 -8 substituted or unsubstituted cycloalkenyl heterocycle or substituted or unsubstituted C6-10 aryl, or together with R2 can form an optionally substituted cyclobutyl; R2 is isopropyl or together with R3 they can form a 3- to 6-membered substituted or unsubstituted heterocycle ring or together with R1 they can form an optionally substituted cyclobutyl, cyclopropyl; and R3 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C6-10 aryl or together with R2 can form a substituted or unsubstituted 3 to 6 membered heterocycle ring.
    [28] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a therapeutically effective amount of a pharmaceutical composition, which comprises at least one FPR2 agonist as disclosed in US SN patent application. 13 / 409,228, provided that the compounds have binding activity to the FPR2 receptor.
    [29] In another aspect, the invention provides for the use of at least one compound as disclosed in US patent application SN 13 / 409.228 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have FPR2 receptor binding activity.
    [30] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 409.228 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have activity connection to the FPR2 receiver.
    [31] The compounds described in US patent application SN 13 / 409,228 are represented by Formula V:
    on what:
    it is a single bond or a double bond;
    it is a single bond or a double bond; R1 is H, halogen, -S (O) R10, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3_8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl; R2 is H, halogen, -S (O) R10, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl; R3 is H, halogen, -S (O) R10, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl, C6_10 aryl or hydroxyl; R4 is H or C (O) R12; R5 is H, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl or -C2-6 alkynyl; R6 is H, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl or -C2-6 alkynyl; Y is O or S; X is O, NR, or CH2; Rb Ra is C6-10 aryl,
    , heteroaryl, C3_8 cycloalkyl, C3-8 cycloalkenyl or H; Rb is halogen; c is 0, 1 or 2;
    R7 is H, halogen, -S (O) R10, -S (O) 2R11, nitro, hydroxyl, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C (O) R12, NR13R14, C3_8 cycloalkenyl or C3-8 cycloalkyl; R8 is H, halogen, -S (O) R10, -S (O) 2R11, cyano, -OC1-6 alkyl, - SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkenyl or C3-8 cycloalkyl; R9 is H, _S (O) 2R11, _OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, C (O) R12, C3-8 cycloalkenyl or C3-8 cycloalkyl; R10 is -C1-6 alkyl, C3-8 cycloalkyl, or C3-8 cycloalkenyl; R11 is H, hydroxyl, -Ci-6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkenyl; R12 is H, hydroxyl, -C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, NR13R14 or -OC1-6 alkyl; R13 is H, -C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl SO2R11 or C (O) R15; R14 is H, -C1-6 alkyl, C3-8 cycloalkenyl, aryl, heterocycle or C3-8 cycloalkyl; R15 is H, -C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl; and R is H, -C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl; with the proviso that: when
    it is a double bond so R5 is empty; and when
    is a double bond R6 is empty.
    [32] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one FPR2 agonist as disclosed in US patent application 13 SN /370,472, provided that the compounds have binding activity to the FPR2 receptor.
    [33] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 370.472 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal , as long as the compounds have FPR2 receptor binding activity.
    [34] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 370.472 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have binding activity to the FPR2 receptor.
    [35] The compounds as described in US patent application SN 13 / 370,472 are represented by Formula VI:
    where: A is C6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl; R17 is C106 alkyl or
    B is C6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl; R1 is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2_6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R2 is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2_6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R3 is H, C1-6 alkyl or C3-8 cycloalkyl; R4 is H, C1-6 alkyl or C3-8 cycloalkyl; R5a is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R5b is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2_6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R5c is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2_6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R5d is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R6 is H, -S (O) 2R11, -C1-6 alkyl, - (CH2) n NR13R14, - (CH2) m heterocycle, C (O) R12, NR13R14, C3-8 cycloalkyl, C6-10 aryl, or heterocycle; R7 is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2 -6 alkynyl, C (O) R12, NR13R14, C3_8 cycloalkyl or hydroxyl; R8 is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R9 is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SCi-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2 -6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R10 is H, halogen, -S (O) R15, -S (O) 2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2_6 alkynyl, C (O) R12, NR13R14, C3-8 cycloalkyl or hydroxyl; X is O or S; Y is O or S; R11 is H, hydroxyl, -C1-6 alkyl, C3-8 cycloalkyl or NR13R14; R12 is H, hydroxyl, -C1-6 alkyl, hydroxyl, C3-8 cycloalkyl, NR13R14 or -OC1-6 alkyl; R13 is H, -C1-6 alkyl, C3-8 cycloalkyl, SO2R11 or C (O) R16; R14 is H, -C1-6 alkyl or C3-8 cycloalkyl; R15 is -C1-6 alkyl, or C3-8 cycloalkyl; R16 is H, -C1-6 alkyl or C3-8 cycloalkyl; n is 1-4; in is 1-4.
    [36] In another aspect, the invention provides a method for the treatment of inflammatory eye diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one FPR2 agonist as disclosed in US patent application SN 13 / 863,934, as long as the compounds have FPR2 receptor binding activity.
    [37] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 863,934 for the manufacture of a medicament for the treatment of an eye disease or condition mediated by FPR2 in a mammal , as long as the compounds have FPR2 receptor binding activity.
    [38] In another aspect, the invention provides the use of at least one compound as disclosed in US patent application SN 13 / 863,934 for the treatment of an eye disease or condition mediated by FPR2 in a mammal, as long as the compounds have binding activity to the FPR2 receptor.
    [39] The compounds as disclosed in US patent application SN 13 / 863,934 are represented by Formula VII:
    where: n is 0 or 1; R1 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, -NR8R9, -NC (O) R20, -OR10, -OC (O) R21 -SR11, -C (O) R12, CN or NO2; R2 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, -NR8R9, -NC (O) R20, -OR10, -OC (O) R21, -SR11, -C (O) R12, CN or NO2; R3 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, -NR8R9, -NC (O) R20, -OR10, -OC (O) R21, -SR11, -C (O) R12, CN, NO2, CF3 , S (O) R15 or S (O) 2R16; R4 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, -NR8R9, -NC (O) R20, -OR10, -OC (O) R21, -SR11, -C (O) R12, CN or NO2; R5 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, -NR8R9, -NC (O) R20, -OR10, -OC (O) R21, SR11, -C (O) R12, CN or NO2; R6 is hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-8 cycloalkenyl or - CH2R19; R7 is 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) 2R16 or -P (O) R17R18; R8 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C6-10 aryl; R9 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted Cβ-10 aryl; R10 is hydrogen or substituted or unsubstituted C1-8 alkyl; R11 is hydrogen, substituted or unsubstituted C1-8 alkyl or - CF3; R12 is hydrogen, substituted or unsubstituted C1-8 alkyl, hydroxyl, -OR24 or -NR8R9; R13 is -OR22; R14 is -OR23; R15 is substituted or unsubstituted C1-8 alkyl; R16 is substituted or unsubstituted C1-8 alkyl, -NR8R9, - NHS (O) 2R19 or hydroxyl; R17 is OR10 or NR8R9; R18 is OR10 or NR8R9; R19 is substituted or unsubstituted heterocycle, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C6-10 aryl or substituted or unsubstituted C3-8 cycloalkenyl; R20 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C6-10 aryl; R21 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C6-10 aryl; R22 is hydrogen, substituted or unsubstituted C1-8 alkyl, or together with R23 they can form a cycle; R23 is hydrogen, substituted or unsubstituted C1-8 alkyl, or together with R22 they can form a cycle; R24 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted Ce-10 aryl.
    [40] The term "alkyl", as used herein, refers to saturated, monovalent or divalent hydrocarbon radicals of which they have linear or branched units or combinations and contain 1 to 8 carbon atoms. A methylene group (-CH 2 -), of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, with a divalent C 8/3 cycloalkyl, with a divalent heterocycle, or by a divalent aryl group. Alkyl groups can have one or more chiral centers. Alkyl groups can be substituted, independently, by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulfonic acid groups, phosphoric acid groups, nitro groups , amide groups, sulfonamide groups.
    [41] The term "cycloalkyl", as used herein, refers to a monovalent or divalent group of 3-8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be substituted, independently, by halogen atoms, C1-8 alkyl sulfonyl groups, C1-8 alkyl sulfoxide groups, sulfonamide groups, nitro groups, cyano groups, - OC1-8 alkyl groups, -SC1-8 alkyl groups, groups -C1-8 alkyl, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.
    [42] The term "cycloalkenyl", as used herein, refers to a monovalent or divalent group of 3-8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted, independently, by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, - OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2 groups -6 alkenyl, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.
    [43] The term "halogen", as used herein, refers to a chlorine, bromine, fluorine, iodine atom.
    [44] The term "alkenyl", as used herein, refers to a monovalent or divalent hydrocarbon radical containing 2 to 6 carbon atoms, derived from a saturated alkyl group, having at least one double bond. A methylene group (-CH2 -), of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be replaced by alkyl groups, as defined above, or by halogen atoms.
    [45] The term "alkynyl", as used herein, refers to a monovalent or divalent hydrocarbon radical containing 2 to 6 carbon atoms, derived from a saturated alkyl group, having at least one triple bond. A methylene group (-CH2-), from alkynyl, can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be replaced by alkyl groups, as defined above, or by halogen atoms.
    [46] The term "heterocycle" as used herein, refers to a 3- to 10-membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one selected heteroatom forms oxygen, nitrogen, sulfur , or combinations of at least two of the same, disrupts the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C = O group; heteroatoms N and S can be oxidized. Heterocycles can be monocyclic or polycyclic. The heterocyclic ring moieties may be replaced by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, groups - C1-8 alkyl, groups -C2- 6 alkenyl, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C38 cycloalkyl groups or hydroxyl groups.
    [47] The term "aryl" as used herein, refers to an organic radical derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removing one hydrogen atom. Aryl can be replaced by halogen atoms, C1-6 alkyl sulfonyl groups, C1-6 alkyl groups, sulfonamide groups, sulfoxide carboxylic acid groups, C1-6 alkyl (ester) carboxylate groups, amide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1 groups -6 alkyl, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, groups C3-8 cycloalkyl or hydroxyl groups. Aryl groups can be monocyclic or polycyclic.
    [48] The term "hydroxyl", as used herein, represents a group of the formula "-OH".
    [49] The term "carbonyl", as used herein, represents a group of the formula "-C (O) -".
    [50] The term "ketone" as used herein, represents an organic compound having a carbonyl group attached to a carbon atom, such as - (CO) Rx where Rx can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle, as defined above.
    [51] The term "amine", as used herein, represents a group of the formula "-NRxRy", where Rx and Ry can be the same or, independently, H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle, such as defined above.
    [52] The term "carboxyl" as used herein, represents a group of the formula "-C (O) O-".
    [53] The term "sulfonyl", as used herein, represents a group of the formula "-SO2 ~".
    [54] The term "sulfate", as used herein, represents a group of the formula "-OS (O) 2-O-".
    [55] The term "sulfonate" as used herein, represents a group of the formula "S (O) 2-O-".
    [56] The term "carboxylic acid", as used herein, represents a group of the formula "-C (O) OH".
    [57] The term "nitro", as used herein, represents a group of the formula "-NO2".
    [58] The term "cyan", as used herein, represents a group of the formula "CN".
    [59] The term "amide" as used herein, represents a group of the formula "-C (O) NRxRy" in which Rx and Ry can be the same or, independently, H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle, as defined above.
    [60] The term "sulfonamide", as used herein, represents a group of the formula "-S (O) 2 NRxRy" in which Rx and Ry can be the same or, independently, H, alkyl, aryl, cycloalkyl, cycloalkenyl , heterocycle, as defined above.
    [61] The term "sulfoxide", as used herein, represents a group of the formula "S (O) -".
    [62] The term "phosphonic acid", as used herein, represents a group of the formula "-P (O) (OH) 2".
    [63] The term "phosphoric acid", as used herein, represents a group of the formula "OP (O) (OH) 2".
    [64] The term "sulfonic acid", as used herein, represents a group of the formula "S (O) 2OH".
    [65] The formula "H", as used herein, represents a hydrogen atom.
    [66] The formula "O", as used here, represents an oxygen atom.
    [67] The formula "N", as used here, represents a nitrogen atom.
    [68] The formula "S", as used here, represents a sulfur atom.
    [69] In another aspect, FPR2 agonists are compounds selected from Table 1: Table 1



    [70] US 2005/0137230 A1 and US 7820673 disclose clotting factor Xa inhibitors and can be used for the prophylaxis and / or therapy of thromboembolic diseases and or 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- (trifluormethyl) phenyl] amino} carbonyl) amino] propanoic acid, methyl 2 - ({[(4-iodophenyl) amino] carbonyl} amino) -3-phenylpropanoate, (2S) -2- ({[(4-bromophenyl) amino] carbonyl} amino) -3-phenylpropanoic, (2R) - 2 - ({[(4-bromophenyl) amino] carbonyl} amino) -3-phenylpropanoic , are intermediates in the synthesis of urea derivatives as inhibitors of activated blood coagulation factor X (FXa).
    [71] JP 63232846 discloses the resolution of N- (p-bromophenylcarbamyl) 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-indole-3- il) propanoic acid (2S) —2 - ({[(4— bromophenyl) amino] carbonyl} amino) -3-methylbutanoic) in HPLC column with new chiral chromatographic stationary phases.
    [72] Journal of Chromatography (1987), 404 (1), 117-22 and Chromatographia (1987), 23 (10), 727-30 describes the resolution of p-Bromophenylcarbamyl derivatives of acidic enantiomeric protein ((2R ) -2 - ({[(4-bromophenyl) amino] carbonyl} amino) -3-phenylpropanoic acid (2S) - 2 - ({[(4-bromophenyl) amino] carbonyl} amino) -3-phenylpropanoic), in a new chiral stationary phase by elution in an aqueous mobile phase.
    [73] Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis (1972), 272 (4), 667-71 describes acid compound (2S) -2 - ({[(4-nitrophenyl) amino] carbonyl} amino) -3 -phenylpropanoic) in poly (uridyl acid) dependent binding for nitrophenyl-carbamyl-phenylalanyl tRNA.
    [74] In another aspect, FPR2 agonists are compounds selected from Table 2: Table 2

    [75] Compounds from Table 2 are available from Chemical Libraries as Aurora Fine Chemicals.
    [76] In another aspect, FPR2 agonists are compounds selected from Table 3: Table 3



    [77] The compounds in Table 3 are available from chemical libraries, such as Chemical Block Ltd.
    [78] In another embodiment of the invention, methods are provided for treating disorders associated with FPR2 modulation.
    [79] Such methods can be carried out, 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.
    [80] Therapeutic utilities of FPR2 are inflammatory eye diseases, including, but not limited to, wet and dry age-related macular degeneration (ARMD), uveitis, dry eye, keratitis, allergic eye disease and conditions affecting the back of the eye , such as maculopathies and retinal degeneration, including non-exudative age-related macular degeneration, exudative age-related macular degeneration, choroidal neovascularization, diabetic (proliferative) retinopathy, premature retinopathy (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 placoid pigment epitheliopathy, Behcet's disease, birdshot infectious retinochoroidopathy (syphilis, lyme, tuberculosis); , multifocal choroiditis, multiple white evanescent syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome; vascular diseases / exudative diseases, such as retinal arterial occlusive disease, central retinal vein occlusion, cystoid macular edema, disseminated intravascular coagulation, retinal vein branch occlusion, hypertensive fundus changes, ocular ischemic syndrome, arterial microaneurysms retinal disease, Coat disease, parafoveal telangiectasis, retinal vein hemi-occlusion, papillophlebitis, central retinal artery occlusion, retinal artery branch occlusion, carotid artery disease (CAD), frozen branch angeitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy and Eales disease; traumatic / surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, post-surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, retinopathy by radiation, and bone marrow transplantation retinopathy; proliferative disorders such as proliferative retinopathy of the vitreous and epiretinal membrane, and proliferative diabetic retinopathy; infectious diseases, such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroid disease associated with HIV infection, uveitic disease associated with HIV infection, viral retinitis, acute retinal necrosis, progressive external retinal necrosis, fungal diseases of the retina, ocular syphilis, ocular tuberculosis, unilateral diffuse subacute neuroretinitis and myiasis; genetic diseases such as retinitis pigmentosa, systemic diseases with associated retinal dystrophies, stationary congenital night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, standard retinal pigmented epithelium dystrophy, X-linked retinoschisis, dystrophy background of Sorsby, benign concentric maculopathy, crystalline Bietti dystrophy, and elastic pseudoxanthoma; tears / holes in the retina such as retinal detachment, macular orifice, and giant retinal rupture; tumors, such as tumor-associated retinal disease, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined retinal hamartoma and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the fundus ocular, retinal astrocytoma, intraocular and lymphoid tumors; and several other diseases that affect the back of the eye, such as interior punctuated choroidopathy, acute anterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigment epithelitis, systemic inflammatory diseases such as stroke, arterial disease coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular diseases, including coronary artery disease, neuroinflammatory neurological disorders, pain and immune disorders, asthma, allergic diseases, inflammation, systemic lupus erythematosus, psoriasis, CNS disorders, such such as disease, arthritis, sepsis, inflammatory bowel disease of Alzheimer's, cachexia, angina pectoris, inflammation, blepharitis, MGD, dermal wound healing of the corneal post-surgery, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis , actinic keratoses, viral warts, photoaging of rheumatoid arthritis oide and related inflammatory diseases, alopecia, glaucoma, vein branch occlusion, Best vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other photoreceptor degenerative disease or RPE (Perretti, Mauro et al. [artial] Pharmacology & Therapeutics 127 (2010) 175-188.)
    [81] These compounds are useful for the treatment of mammals, including humans, with a range of diseases and conditions that are alleviated by FPR2 modulation: including, but not limited to, wet and dry age-related macular degeneration (ARMD) ), diabetic (proliferative) retinopathy, retinopathy of prematurity (ROP), macular edema, uveitis, dry eye, retinal vein occlusion, cystoid macular edema, glaucoma, branch vein occlusion, Best vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative photoreceptor disease or RPE.
    [82] In yet another embodiment of the invention, methods are provided to treat disorders associated with FPRL-1 receptor modulation. Such methods can be carried out, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystalline forms and the individual isomers, enantiomers, and diastereoisomers thereof.
    [83] The actual amount of compound to be administered in any given case will be determined by a doctor taking into account 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 cause condition, and route of administration.
    [84] The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, through stenting, intrathecal, intravitreal, topical ocular, back to the eye, intramuscular, intravenous, intrarectal and delivery modes. In addition, formulations can be designed to delay the release of the active compound over a period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
    [85] In another embodiment of the invention, pharmaceutical compositions are provided including at least one compound of the 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 harmful to its container.
    [86] The pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a spot, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. The compounds of the invention can be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, lozenges, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. Vehicles that can be used include glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain triglycerides, dextrans , and other carriers suitable for use in the manufacture of preparations, in solid, semi-solid or liquid form. In addition, auxiliary agents, stabilizers, thickeners and dyes and perfumes can be used. The compounds of the invention are included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.
    [87] Pharmaceutical compositions containing the compounds of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring binding agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and tasty preparations. Tablets containing the compounds of the invention in admixture with non-toxic and pharmaceutically acceptable excipients can also be manufactured by known methods. The excipients used can be, for example, (1) inert diluents, such as calcium carbonate, calcium phosphate lactose or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as tragacanth gum, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
    [88] In some cases, formulations for oral use may be in the form of hard gelatin capsules, in which the compounds of the invention are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. These can also be in the form of soft gelatin capsules, in which the compounds of the invention are mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil.
    [89] The pharmaceutical compositions containing the compounds of the invention may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or non-aqueous liquids, or as liquid oil-in-water emulsions or water-in-oil.
    [90] Pharmaceutical compositions can be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by a dosage preparation unit suitable for topical ocular use. The therapeutically effective amount is typically between about 0.001 and about 5% (w / v), preferably about 0.001 to about 2.0% (w / v), in liquid formulations.
    [91] For ophthalmic application, solutions are preferably prepared using a physiological saline solution as the main vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0, with an appropriate buffer system, a neutral pH, being preferred, but not essential. The formulations can also contain conventional acceptable preservatives, stabilizers and pharmaceutically acceptable surfactants.
    [92] Preferred preservatives that can 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.
    [93] A preferred surfactant is, for example, Tween 80. Likewise, several preferred vehicles can be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose, hydroxyethylcellulose cyclodextrin and purified water.
    [94] Tonicity adjusters can be added as needed or convenient. They include, but are not limited to, salts, particularly, sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity regulator.
    [95] Various buffers and means for adjusting the pH may be used, provided the resulting preparation is ophthalmically acceptable. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases can be used to adjust the pH of these formulations, if necessary.
    [96] Similarly, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
    [97] Other excipient components that can be included in ophthalmic preparations are chelating agents. The preferred chelating agent is disodium edentate, although other chelating agents may also be used instead of or in conjunction with it.
    [98] The ingredients are normally used in the following quantities:

    [99] The effective dose of the active compounds of the present invention depends on the specific compound and the condition to be treated; selection of the appropriate dose is within the skill of the person skilled in the art. The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for a dosed application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for drip application are usually made of suitable inert material, non-toxic plastic, and generally contain between about 0.5 and about 15 ml of solution. A package can contain one or more unit doses. Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to, about five dose units, where a typical unit dose is one to about 8 drops, preferably one about 3 drops. The volume of a drop is usually about 20-35 μl.
    [100] The pharmaceutical compositions can be in the form of a sterile injectable suspension. This suspension can be formulated according to known methods using dispersing or wetting agents and suspending agents. The sterile injectable preparation can 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 soft fixed oil can be used including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc. , or synthetic fatty vehicles such as ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as needed.
    [101] The compounds of the invention can 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 invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at normal temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug .
    [102] Since patients can have a wide variation in the severity of symptoms and each drug has its own unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the doctor's discretion.
    [103] The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for the treatment of diseases and / or attenuations of conditions that respond to treatment by functional FPR2 agonists or antagonists. Thus, in other embodiments of the invention, methods are provided to treat a disorder associated with FPR2 modulation. Such methods can be carried out, 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. As used herein, the term "therapeutically effective amount" means the amount of the pharmaceutical composition that will trigger the biological or medical response of a subject in need of that subject that is being sought by the investigator, veterinarian, physician or other clinician. In some embodiments, the subject in need of it is a mammal. In some embodiments, the mammal is human. Materials and methods
    [104] FPR2 agonists would be expected to have a significant impact on many different types of eye inflammation, but have been exemplified, demonstrating anti-inflammatory activity in endotoxin-induced uveitis in rats (Figures 1 and 2). The anti-inflammatory activity in this model was exemplified with the FPR2 agonists described in Table 4.
    [105] FLIPR: HEK-Gα16 cells stably expressing the human FPR2 receptor were used. The cells were plated on 384-well poly-D-lysine coated plates at a density of 18,000 cells per well, one day before use. The growth medium was DMEM medium supplemented with 10% fetal bovine serum (FBS), 1% antibiotic-antimycotic, 50 μg / ml hygromycin and 400 μg / ml geneticin. On the day of the experiment, the cells were washed twice with Hank's balanced salt solution supplemented with 20 mM HEPES (HEPES / HBSS buffer). The cells were then loaded with 2μm of Fluo-4 dye diluted in the HBSS / Hepes buffer and incubated at 37 o C for 40 minutes. Extracellular dye was removed by washing the cell plates four times before placing the plates in the FLIPR (Fluorimetric Image Plate Reader, Molecular Devices). The ligands were diluted in HBSS / Hepes buffer and prepared in 384-well microplates. Data for Ca + 2 responses were obtained in relative fluorescence units. Table 4























    [106] Immunohistochemistry: Immunohistochemistry of chromogenic DAB with specific antibodies to FPR2 was used to determine the location in normal human, primate, and rat eyes. The anti-FPR2 antibody (Abcam) was used at a dilution of 1: 200 to detect the FPR2 protein in all species.
    [107] Endotoxin-induced uveitis in rats: Uveitis is a harmful eye inflammatory disease in humans. Anterior uveitis is a recurrent inflammatory disease and can potentially lead to blindness. The pathogenesis of the disease is poorly understood, and the anti-inflammatory therapy used is non-specific and is associated with significant complications. Animal models are the key to understanding the disease and testing new therapies. A single low dose of lipopolysaccharide (LPS) in the footpad induces 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 grams) were purchased from Charles River Laboratory. The rats were injected with a foot pad (left rear) with 100 μl of 1 mg / ml of LPS solution (List Biological Labs) (in sterile 0.9% saline). The test compounds were formulated in the vehicle consisting of sodium phosphate, dibasic heptahydrate, salts, CMC and sterile water. The compounds were dosed topically (0.1-1%) or subcutaneously (10 mg / kg) 2 hours after LPS. The animals were sacrificed at 24 hours after LPS injection. Aqueous humor was collected and analyzed to determine inflammatory cell counts and total protein concentrations.
    [108] Alkali burn in rabbits: Corneal epithelium plays an important role in maintaining corneal function and integrity. Prolonged corneal epithelial defects cause corneal opacity, neovascularization, bacterial infection and visual loss. Corneal epithelial healing is a complex process that involves an inflammatory response to an injury, cell proliferation and migration. Animal models of corneal injury are useful for testing new anti-inflammatory and wound healing treatments. New Zealand white rabbits weighing between 2.1 and 2.5 kg were anesthetized systemically with ketamine / xylazine (35/5 mg / kg) subcutaneously and topically with proparacaine (0.5%). The wound of the corneal epithelium of an eye was induced with a saturated NaOH filter paper containing 1.0 N NaOH for 30 seconds. The eyes were washed with sterile PBS. The corneal wound was confirmed by fluorescein staining with 10% sodium fluorescein (Science Lab Com) and slit lamp photography. The test compounds were formulated in the vehicle described above. For the initial compound studies, they were dosed topically three times a day. Quantification of corneal wound areas was done using the Image J software where the green part of the fluorescent spot was tracked and converted to the total pixels.
    [109] The compounds below would be expected to have a significant impact on many different types of eye inflammation, but have been exemplified, demonstrating anti-inflammatory activity in endotoxin-induced uveitis in rats (Figures 1 and 2). The anti-inflammatory activity in this model was exemplified with the following FPR2 agonists: In this model, the compounds have a strong anti-inflammatory activity in blocking the infiltration of neutrophils and protein in the anterior chamber. In addition, FPR2 agonists show healing and re-epithelialization in accelerated corneal wound mouse models as exemplified by the acid compound {[(2S, 3S) -2 - {[(4-bromophenyl) carbamoyl] amino} - 3-methylpentanoyl] amino} acetic acid in (Figure 3). These data demonstrate that FPR2 agonists are potent and effective anti-inflammatory agents suitable for ocular use in different models of ocular inflammation.
    权利要求:
    Claims (3)
    [0001]
    1. Use of a pharmaceutical composition comprising a therapeutically effective amount of at least one Formyl 2 peptide receptor agonist (FPR2) characterized in that it is in the preparation of a medicament to treat an inflammatory eye disease, in an individual in need of treatment, in that inflammatory eye 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 placid pigment epitheliopathy, Behc disease , post-surgical corneal wound healing, wet and dry age-related macular degeneration (ARMD), and because the FPR2 agonist is a compound selected from the group consisting of:
    [0002]
    2. Use according to claim 1, characterized in that the FPR2 agonist is the compound
    [0003]
    3. Use according to claim 1, characterized in that the FPR2 agonist is the compound
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-09-24| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-03-02| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-04-13| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 04/03/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201361773773P| true| 2013-03-06|2013-03-06|
    US61/773,773|2013-03-06|
    PCT/US2014/020245|WO2014138037A1|2013-03-06|2014-03-04|Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases|BR122017004254-8A| BR122017004254B1|2013-03-06|2014-03-04|USE OF FORMIL PEPTIDE 2 RECEPTOR AGONISTS TO TREAT EYE INFLAMMATORY DISEASES|
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