(19)
(11)EP 2 964 213 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
04.11.2020 Bulletin 2020/45

(21)Application number: 14712888.8

(22)Date of filing:  04.03.2014
(51)International Patent Classification (IPC): 
A61K 31/17(2006.01)
A61K 31/197(2006.01)
A61K 31/4166(2006.01)
A61K 31/42(2006.01)
A61K 31/4045(2006.01)
A61P 27/02(2006.01)
A61K 31/196(2006.01)
A61K 31/216(2006.01)
A61K 31/41(2006.01)
A61K 31/55(2006.01)
A61K 9/00(2006.01)
(86)International application number:
PCT/US2014/020245
(87)International publication number:
WO 2014/138037 (12.09.2014 Gazette  2014/37)

(54)

USE OF AGONISTS OF FORMYL PEPTIDE RECEPTOR 2 FOR TREATING OCULAR INFLAMMATORY DISEASES

VERWENDUNG VON AGONISTEN DES FORMYLPEPTIDREZEPTORS 2 ZUR BEHANDLUNG VON AUGENENTZÜNDUNGEN

UTILISATION D'AGONISTES DU RÉCEPTEUR 2 DE PEPTIDE FORMYLE POUR LE TRAITEMENT DE MALADIES INFLAMMATOIRES OCULAIRES


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 06.03.2013 US 201361773773 P

(43)Date of publication of application:
13.01.2016 Bulletin 2016/02

(73)Proprietor: ALLERGAN, INC.
Irvine, CA 92612 (US)

(72)Inventors:
  • VISWANATH, Veena
    Irvine, California 92602 (US)
  • BEARD, Richard L.
    Newport Beach, California 92660 (US)
  • DONELLO, John E.
    Dana Point, California 92629 (US)

(74)Representative: Hoffmann Eitle 
Patent- und Rechtsanwälte PartmbB Arabellastraße 30
81925 München
81925 München (DE)


(56)References cited: : 
EP-A1- 3 103 797
EP-B1- 2 770 989
WO-A1-2013/009543
WO-A1-2013/062947
WO-A1-2013/071203
WO-A2-01/14328
US-A- 5 492 896
EP-A1- 3 103 797
EP-B1- 2 770 989
WO-A1-2013/062947
WO-A1-2013/070600
WO-A1-2013/071203
US-A- 5 492 896
US-A1- 2012 142 726
  
  • BURLI R W ET AL: "Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 16, no. 14, 15 July 2006 (2006-07-15) , pages 3713-3718, XP027965631, ISSN: 0960-894X [retrieved on 2006-07-15]
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

BACKGROUND OF THE INVENTION


1. Field of the invention



[0001] The present invention relates to a method for treating ocular inflammatory diseases selected from uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet's disease, post-surgical corneal wound healing, wet and dry age-related macular degeneration (ARMD) in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of an agonist of Formyl peptide receptor 2 (FPR2) as specified in claim 1 or a pharmaceutically acceptable salt thereof.

2. Summary of the related art



[0002] The formyl peptide receptor (FPR) family is involved in host defense against pathogens, but also in sensing internal molecules that may provide signals of 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 that is expressed predominantly on inflammatory cells such as 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, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C. The lipoxin receptor ALX: Potent ligand-specific and stereoselective actions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 is an exceptionally promiscuous receptor that responds to a large array of exogenous and endogenous ligands, including serum amyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocotricoid-modulated protein annexin A1 (Chiang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C. The lipoxin receptor ALX: Potent ligand-specific and stereoselective actions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 transduces anti-inflammatory effects of LXA4 in many systems, and has been shown to play a key role in the resolution of 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 receptor (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 formyl-peptide receptor 2: Ligand-specific effects on leukocyte responses and experimental inflammation. Journal of Immunology 2010; 184: 2611-2619).

[0003] Activation of FPR2 by lipoxin A4 or its analogs and by Annexin I protein has been shown to result in anti-inflammatory activity by promoting active resolution of inflammation which involves inhibition of polymorphonuclear neutrophils (PMNs) and eosinophils migration and also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner (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 activation of T cells which further contributes to down regulation of tissue damaging inflammatory signals. FPR2/ LXA4 interaction has been shown to be beneficial in experimental models of ischemia reperfusion, angiogenesis, ocular inflammation such as endotoxin-induced uveitis, and corneal wound healing (Serhan C. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. 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. A role for the mouse 12/15-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 response 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 are hampered by inherent physicochemical properties of the natural poly-olefinic natural product. Therefore, small molecule anti-inflammatory agonists of FPR2 would have a wide variety of therapeutic benefit in inflammatory disorders especially in the eye. Targeting FPR2 selectively would also have benefits of reduced side effects as compared to more broad acting anti-inflammatories such as steroids 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 the posterior of eye, in addition to the inflammatory cells that migrate into the ocular tissues. FPR2 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in ocular diseases with excessive inflammatory responses.

[0004] US 2012/142726 A1 discloses 3,4-dihydroisoquinolin-2-(1H)-yl-3-phenylureas having FPLR1 agonist or antagonist activity. WO 2013/062947 A1 discloses compounds which are formyl peptide receptor 2 agonists and useful in the treatment of ocular inflammatory diseases. US 5 492 896 A discloses antiviral pseudopeptides which are useful in the treatment of HCMC infections.

BRIEF DESCRIPTION OF THE INVENTION



[0005] The invention pertains to the ability of FPR2 agonists as specified in claim 1 to exhibit ocular anti-inflammatory activity with chemical stability and suitable for ocular delivery. These FPR2 compounds show good potency at the receptor, a subset of compounds is exemplified in the tables below, and importantly, the FPR2 compounds are active topically, and therefore could be administered in many forms, including but not limited to eye drops. These compounds may 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 ocular inflammatory diseases selected from uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet's disease, post-surgical corneal wound healing, wet and dry age-related macular degeneration (ARMD).

BRIEF DESCRIPTION OF THE DRAWINGS



[0006] 

Figure 1 FPR2 agonists show potent anti-inflammatory activity in endotoxin-induced uveitis model in rats.

Figure 2 FPR2 agonists show potent anti-inflammatory activity in endotoxin-induced uveitis model in rats.

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


DETAILED DESCRIPTION OF THE INVENTION



[0007] The present invention relates to an agonist of Formyl peptide receptor 2 (FPR2) for use in a method for treating ocular inflammatory diseases selected from uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet's disease, post-surgical corneal wound healing, wet and dry age-related macular degeneration (ARMD) in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of an agonist of FPR2 as specified in claim 1 or a pharmaceutically acceptable salt thereof.

[0008] The term "alkyl", as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (-CH2-) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can have one or more chiral centers. Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups.

[0009] 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 can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C1-8 alkyl groups, sulfoxide C1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, - OC1-8 alkyl groups, -SC1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups..

[0010] The term "cycloalkenyl", as used herein, refers to a monovalent or divalent group of 3 to 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 independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.

[0011] The term "halogen", as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.

[0012] The term "alkenyl", as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. One methylene (-CH2-) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 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 substituted by alkyl groups, as defined above or by halogen atoms.

[0013] The term "alkynyl", as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. One methylene (-CH2-) group, of the alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.

[0014] 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 heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C=O; the S and N heteroatoms can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.

[0015] 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 removal of one hydrogen atom. Aryl can be substituted by halogen atoms, sulfonyl C1-6 alkyl groups, sulfoxide C1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups. Aryls can be monocyclic or polycyclic.

[0016] The term "hydroxyl" as used herein, represents a group of formula "-OH".

[0017] The term "carbonyl" as used herein, represents a group of formula "-C(O)-".

[0018] The term "ketone" as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)Rx wherein Rx can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0019] The term "amine" as used herein, represents a group of formula "-NRxRy",wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0020] The term "carboxyl" as used herein, represents a group of formula "-C(O)O-".

[0021] The term "sulfonyl" as used herein, represents a group of formula "-SO2-".

[0022] The term "sulfate" as used herein, represents a group of formula "-O-S(O)2-O-".

[0023] The term "sulfonate" as used herein, represents a group of the formula "-S(O)2-O-".

[0024] The term "carboxylic acid" as used herein, represents a group of formula "-C(O)OH".

[0025] The term "nitro" as used herein, represents a group of formula "-NO2".

[0026] The term "cyano" as used herein, represents a group of formula "-CN".

[0027] The term "amide" as used herein, represents a group of formula "-C(O)NRxRy," wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0028] The term "sulfonamide" as used herein, represents a group of formula "-S(O)2NRxRy" wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

[0029] The term "sulfoxide" as used herein, represents a group of formula "-S(O)-".

[0030] The term "phosphonic acid" as used herein, represents a group of formula "-P(O)(OH)2".

[0031] The term "phosphoric acid" as used herein, represents a group of formula "-OP(O)(OH)2".

[0032] The term "sulphonic acid" as used herein, represents a group of formula "-S(O)2OH".

[0033] The formula "H ", as used herein, represents a hydrogen atom.

[0034] The formula "O", as used herein, represents an oxygen atom.

[0035] The formula "N ", as used herein, represents a nitrogen atom.

[0036] The formula "S ", as used herein, represents a sulfur atom.

[0037] The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.

[0038] 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, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may 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 therapy.

[0039] In another embodiment of the description, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0040] Pharmaceutical compositions of the present description can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present description, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Compounds according to the invention may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.

[0041] Pharmaceutical compositions containing compounds according to the description 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 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 a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing compounds according to the description 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) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents 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.

[0042] In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are 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 the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0043] Pharmaceutical compositions containing compounds according to the description may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.

[0044] Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present description, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.

[0045] For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major 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 may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preferred preservatives that may be used in the pharmaceutical compositions of the present description include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention.

[0046] These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.

[0047] Tonicity adjustors may 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 adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar manner 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.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.

[0048] The ingredients are usually used in the following amounts:
IngredientAmount (% w/v)
active ingredient about 0.001-5
preservative 0-0.10
vehicle 0-40
tonicity adjustor 0-10
buffer 0.01-10
pH adjustor q .s. pH 4.5-7.8
antioxidant as needed
surfactant as needed
purified water to make 100%


[0049] The actual dose of the active compounds of the present description depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present description are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may 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 units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 µl.

[0050] 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 like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

[0051] The compounds of the description may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

[0052] Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.

[0053] The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of FPR2. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of FPR2. 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 invention compound. As used herein, the term "therapeutically effective amount" means the amount of the 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 human.

Materials and Methods



[0054] FPR2 agonists would be expected to have significant effects in many different types of ocular inflammation but have been exemplified by demonstrating anti-inflammatory activity in endotoxin-induced uveitis in rats (Figures 1 and 2). Anti-inflammatory activity in this model has been exemplified with the FPR2 agonists described in Table 4.

[0055] FLlPR: HEK-Gα16 cells stably expressing the human FPR2 receptor was utilized. Cells were plated into 384-well poly-D-lysine coated plates at a density of 18,000 cells per well one day prior to use. The growth media 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 (HBSS/hepes buffer). The cells were then dye loaded with 2 µM Fluo-4 diluted in the HBSS/Hepes buffer and incubated at 37°C for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). 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 (*: Reference compounds)
Compound numberStructureIUPAC nameFPR2 EC50 (efficacy)
1*

1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea 3.0 (0.96)
2

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid 2 (0.91)
3

{[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid 1.98 (1.0)
4*

1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 6.7 (0.90)
5

(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoic acid 31 (0.96)
6

2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic acid 1.66 (0.91)
7

{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid 3.57 (1.0)
8

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid 0.78 (0.78)
9*

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoic acid 5.95 (0.77)
10

2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-oxoazepan-3-yl)-3-phenylpropanamide 11 nM (0.89)
11*

3-[(4-iodophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-5-ene-2-carboxylic acid 1.6 nM (1.00)
12*

3-[(4-bromophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-5-ene-2-carboxylic acid 4 nM (0.97)
13*

1-(4-acetylphenyl)-3-{3-(4-cyanophenyl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}urea 11 nM (0.80)
14*

rel-(2R,3S)-3-[(4-bromophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2-carboxylic acid 4 nM (0.90)
15*

3-[(4-iodophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2-carboxylic acid 0.60 nM (0.87)
16*

1-[2-(3-aminopropyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-[4-(methylsulfanyl)phenyl]urea 2.5 nM (0.70)
17*

1-{3-(4-cyanophenyl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7 -yl}-3-[4-(methylsulfanyl)phenyl]urea 5.5 nM (0.92)
18*

1-[2-(3-aminopropyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-[4-(methylsulfonyl)phenyl]urea 10 nM (0.86)
19*

1-{3-(4-cyanophenyl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 20 nM (1.00)
20*

3-[(4-iodophenyl)carbamoyl]-7-(propan-2-ylidene)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid 11 nM (0.94)
21*

3-[(4-bromophenyl)carbamoyl]-7,7-dimethylbicyclo[2.2.1 ]heptan e-2-carboxylic acid 10 nM (0.85)
22*

3-[(4-iodophenyl)carbamoyl]-7,7-dimethylbicyclo[2.2.1 ]heptane-2-carboxylic acid 1.7 nM (0.97)
23*

1-{3-(furan-2-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 19 nM (0.83)
24*

1-{3-(5-fluoropyridin-2-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfinyl)phenyl]urea 11.8 nM (0.93)
25*

1-{3-(5-fluoropyridin-2-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 10.5 nM (1.0)
26*

N-(4-bromophenyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-5-ene-2,3-dicarboxamide 4.8 nM (0.91)
27*

1-{3-(5-chlorofuran-2-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 17 nM (0.81)
28*

1-{3-(6-chloropyridin-3-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 6.3 nM (0.89)
29*

3-{[4-(methylsulfanyl)phenyl]carbamoyl}spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2-carboxylic acid 7 nM (0.96)
30*

N-(4-bromophenyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide 2.5 nM (0.96)
31*

3-{[4-(methylsulfanyl)phenyl]carbamoyl}spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-5-ene-2-carboxylic acid 14 nM (0.85)
32*

1-{3-(5-chloropyridin-2-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 13.5 nM (0.91)
33*

1-{3-(5-chloropyridin-2-yl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 9.5 nM (0.99)
34*

N-(4-bromophenyl)-7,7-dimethylbicyclo[2.2.1]heptane-2,3-dicarboxamide 15 nM (0.83)
35*

N-(4-iodophenyl)-7, 7-dimethylbicyclo[2.2.1 ]heptan e-2,3-dicarboxamide 2.6 nM (0.81)
36*

(+)1-[(3R)-2-(3-aminopropyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-[4-(methylsulfanyl)phenyl]urea 3.3 nM (0.97)
37*

7,7-dimethyl-N-[4-(methylsulfanyl)phenyl]bicyclo[2.2.1]heptane-2,3-dicarboxamide 17 nM (0.85)
38*

N-(4-iodophenyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide 1.9 nM (0.95)
39*

N-(4-iodophenyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-5-ene-2,3-dicarboxamide 1.6 nM (0.90)
40*

(+) tert-butyl {3-[(3R)-3-(4-cyanophenyl)-7-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]propyl}carbamate 103 nM (0.91)
41*

(+) 1-[(3R)-2-(3-aminopropyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-[4-(methylsulfinyl)phenyl]urea 10.6 nM (0.94)
42*

1-[2-(3-aminopropyl)-3-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-[4-(methylsulfanyl)phenyl]urea 15 nM (1.00)
43*

1-[2-(3-aminopropyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-(4-iodophenyl)urea 13.7 nM (0.94)
44*

(+) (2S,3R)-3-[(4-bromophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2-carboxylic acid (0.98)
45*

(-) N-(4-bromophenyl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide <1 nM (0.91)
46*

N-(4-bromophenyl)-N'-methylspiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide 8.5 nM (1.0)
47*

N-(4-bromophenyl)-N'-ethylspiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide 9.3 nM (1.0)
48*

N-(4-bromophenyl)-N'-(propan-2-yl)spiro[bicyclo[2.2.1]heptane-7,1'-cyclopropane]-2,3-dicarboxamide 6.7 nM (1.0)
49*

1-(4-bromophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea 11.5 nM (0.98)
50*

1-(4-bromo-2-fluorophenyl)-3-(4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea 15.7 nM (1.0)
51*

(2S)-2-{[(4-iodophenyl)carbamoyl]amino}-3-phenylpropanoic acid 14.5 nM (1.0)
52*

1-(4-bromophenyl)-3-(2,4-dioxo-1,3-diazaspiro[4.5]dec-3-yl)urea 15.1 nM (1.0)
53*

(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoic acid 12.9 nM (0.9)
54*

1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea 5.1 nM (0.87)
55

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetic acid 7.7 nM (0.99)
56

3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]ami no}-3-phenylpropanoyl]amino}propanoic acid 18 nM (0.98)
57*

(+) 1-(4-bromophenyl)-3-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea 3.2 nM (0.93)
58

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide 7.0 nM (0.86)
59

{[(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid 5.5 nM (0.95)
60

(2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanamide 4.6 nM (0.91)
61*

1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 9.2 nM (0.97)
62

(2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanamide 10.3 nM (1.0)
63

(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamide 10.5 nM (0.97)
64*

1-(4-bromophenyl)-3-[2,5-dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea 3.8 nM (1.0)
65*

1-(4-bromophenyl)-3-(4,4-dicyclopropyl-2,5-dioxoimidazolidin-1-yl)urea 14.3 nM (1.0)
66*

(+)1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 4.3 nM (0.96)
67*

(-)1-(4-bromophenyl)-3-[4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 3.3 nM (1.0)
68

(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamide 12.4 nM (0.94)
69*

1-(4-bromo-2-fluorophenyl)-3-[4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea 13.4 nM (0.91 )
70*

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoic acid 7.1 nM (1.0)
71

(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide 15.6 nM (0.98)
72

methyl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate 16.4 nM (0.86)
73

propan-2-yl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate 14.5 nM (1.0)
74

{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid 4.1 nM (0.91)
75

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamide 13.5 nM (0.76)
76*

1-(4-bromophenyl)-3-{4-[2-(furan-2-yl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 5.2 nM (0.99)
77

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide 1.1 nM (1.0)
78

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide 4.7 nM (0.82)
79

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}pentanamide 2.5 nM (0.97)
80*

1-(4-bromophenyl)-3-{4-[2-(2-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 14.3 nM (99)
81

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanamide 5.2 nM (0.96)
82*

1-(4-bromophenyl)-3-{4-[2-(4-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 16.3 nM (1.0)
83*

1-(4-bromophenyl)-3-{4-[2-(3-fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 11.1 nM (1.0)
84

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amin o}-4-methylpentanamide 4.5 nM (0.95)
85

(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide 20 nM (0.99)
86*

1-(4-bromophenyl)-3-{4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 13.3 nM (1.0)
87

(2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]aminmethylpentanoyl]amino}propanoic acid 12.1 nM (0.95)
88*

1-(4-bromophenyl)-3-{4-methyl-2,5-dioxo-4-[2-(thiophen-2-yl)ethyl]imidazolidin-1-yl}urea 7.9 nM (0.94)
89*

1-(4-bromo-2-fluorophenyl)-3-{4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 8.7 nM (0.85)
90

(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic acid 11.6 nM (1.0)
91

(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoic acid 1.7 nM (0.97)
92

(2S)-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-2-bromophenyl)carbamoyl]amino}-4-methylpentanamide 5.8 nM (1.0)
93

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxy-2-methylpropyl)-4-methylpentanamide 2.5 nM (0.93)
94

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide 7.4 nM (0.96)
95

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-methylpentanamide 5.1 nM (0.98)
96

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamide 3.0 nM (1.0)
97*

1-(4-bromophenyl)-3-{4-methyl-4-[2-(5-methylfuran-2-yl)ethyl]-2,5-dioxoimidazolidin-1-yl}urea 3.5 nM (0.95)
98*

1-(4-bromo-2-fluorophenyl)-3-{4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 7.4 nM (0.91)
99*

1-(4-bromophenyl)-3-{4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 8.0 nM (1.0)
100

tert-butyl (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoate 13.0 nM (1.0)
101

(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoic acid 1.0 nM (0.95)
102

(2S)-N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide 7.3 nM (0.99)
103

(2S)-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoic acid 9.1 nM (1.0)
104

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N-(1H-tetrazol-5-ylmethyl)pentanamide 2.3 nM (0.81)
105*

ethyl hydrogen ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}methyl)phosphonate 0.95 nM (0.88)
106*

1-(4-bromo-2-fluorophenyl)-3-{4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 4.0 nM (0.91)
107*

1-(4-bromo-2-fluorophenyl)-3-{4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 2.2 nM (0.79)
108*

1-(4-bromophenyl)-3-{4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 2.1 nM (1.0)
109*

1-(4-bromophenyl)-3-{4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 0.97 nM (0.93)
110*

2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoic acid 19.4 nM (0.98)
111

[(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic acid 19.1 nM (0.99)
112*

diethyl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}methyl)phosphonate 0.48 nM (0.95)
113

I
(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetic acid 18.7 nM (1.0)
114*

diethyl ({[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}methyl)phosphonate 2.9 nM (1.0)
115*

ethyl hydrogen ({[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}methyl)phosphonate 2.7 nM (0.88)
116

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(3-hydroxy-1,2-oxazol-5-yl)methyl]-4-methylpentanamide 12.0 nM (1.0)
117*

diethyl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl)phosphonate 0.27 nM (1.0)
118*

diethyl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}methyl)phosphonate 16.1 nM (0.93)
119*

diethyl (2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}ethyl)phosphonate 16.1 nM (0.97)
120

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide 1.7 nM (0.99)
121*

(2S)-2-{[(4-iodophenyl)carbamoyl]amino}-4-methylpentanoic acid 4.0 nM (0.93)
122*

(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoic acid 10 µM (0.59)
123*

ethyl hydrogen ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl)phosphonate 1 nM (0.96)
124

{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid 1.8 nM (1.0)
125*

dipropan-2-yl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl)phosphonate 1.2 nM (1.0)
126*

ethyl hydrogen ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}methyl)phosphonate 16.0 nM (1.0)
127*

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}methanesulfonic acid 2.0 nM (0.91)
128*

(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoic acid 16.8 nM (0.92)
129*

propan-2-yl hydrogen {[(2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl)amino]methyl}phosphonate 1.87 nM (0.89)
130˙

{[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic acid 3.0 nM (1.0)
131*

dipropan-2-yl ({[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}methyl)phosphonate 4.0 nM (1.0)
132*

1-(4-bromophenyl)-3-[4-(hydroxymethyl)-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 16.2 nM (0.86)
133*

2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2-hydroxyethyl)acetamide 2.7 nM (1.0)
134*

diethyl ({[(2S)-4-methyl-2-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonate 5.5 nM (0.97)
135*

ethyl hydrogen ({[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonate 1.9 nM (0.91)
136˙

(2S)-4-methyl-N-(1 H-tetrazol-5-ylmethyl)-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanamide 3.7 nM (0.96)
237*

{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}methanesulfonic acid 1.9 nM (0.99)
138*

diethyl ({[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}methyl)phosphonate 3.5 nM (0.91)
139

2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic acid 2.5 nM (0.92)
140*

tert-butyl (2S)-2-{[(4-bromophenyl)sulfamoyl]amino}-4-methylpentanoate NA
141*

methyl 2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoate 10.3 nM (0.92)
142*

2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(1,3-dihydroxypropan-2-yl)acetamide 13.8 nM (0.92)
143*

2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoic acid 17.2 nM (1.0)
144

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetic acid 6.3 nM (0.91)
145*

3-({[1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)propanoic acid 1.0 nM (1.0)
146*

2-[2-(1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]benzoic acid 11.1 nM (1.0)
147*

3-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)propanoic acid 3.9 nM (0.99)
148*

2-[1-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2-hydroxyethyl)acetamide 6.9 nM (0.98)
149*

ethyl 3-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]propanoate 6.6 nM (0.94)
150

{[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetic acid 1.4 nM (0.98)
151*

2-{2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]ethyl}benzoic acid 5.8 nM (1.0)
152*

diethyl [2-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]acetyl}amino)ethyl]phosphonate 11 nM (1.0)
153*

ethyl 3-{[(4-bromophenyl)carbamoyl]amino}-2,4-dioxo-1,3-diazaspiro[4.5]decane-8-carboxylate 12 nM (0.99)
154˙

tert-butyl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl)amino}acetate 12 nM (0.85)
155

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl)amino}acetic acid 1.0 nM (1.0)


[0056] Immunohistochemistry: Chromagenic DAB immunohistochemistry with antibodies specific to FPR2 was used to determine localization in normal human, primate, and rat eyes. Anti-FPR2 antibody (Abcam) was used at a dilution of 1:200 to detect FPR2 protein in all species.

[0057] Endotoxin-induced uveitis in rats: Uveitis is a harmful ocular inflammatory condition in humans. Anterior uveitis is a recurrent inflammatory disease and may have potentially blinding consequence. 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 key to understanding the disease and testing novel therapies. A single low dose of lipopolysaccaride (LPS) in the footpad induces anterior uveitis in rats. This model known as endotoxin-induced uveitis serves as a useful paradigm of human anterior uveitis. Male Lewis rats (260 ± 25 grams) were purchased from Charles River Laboratory. Rats were footpad-injected (hind left side) with 100 µl of 1 mg/ml LPS (List Biological Labs) solution (in sterile 0.9% saline). Test compounds were formulated in the vehicle consisting of sodium phosphate, dibasic heptahydrate, salts, CMC and sterile water. Compounds were topically (0.1-1%) or subcutaneously (10mg/kg) dosed 2 hr after LPS. Animals were sacrificed at 24 hours following LPS injection. Aqueous humor was collected and analyzed to determine inflammatory cell counts and total protein concentrations.

[0058] Alkali burn in rabbits: Corneal epithelium plays an important role in the maintenance of corneal function and integrity. Prolonged corneal epithelial defects causes corneal opacity, neovascularization, bacterial infection and visual loss. Corneal epithelial healing is a complex process involving inflammatory response to injury, cell proliferation and migration. Animal models of corneal injury are every useful to test new anti-inflammatory and pro-wound healing therapies. 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 corneal epithelial wound in one eye was induced with a NaOH saturated filter paper containing 1.0 N NaOH for 30 seconds. The eyes were rinsed with sterile PBS. The corneal wound was confirmed by fluorescein staining with 10% sodium fluorescein (Science Lab Com) and slit lamp photography. Test compounds were formulated in the vehicle described above. For initial studies compounds were topically dosed three times a day. Quantification of corneal wound areas was done using Image J software where fluorescing stain green part was traced and converted to total pixel.

[0059] The compounds below would be expected to have significant effects in many different types of ocular inflammation but have been exemplified by demonstrating anti-inflammatory activity in endotoxin-induced uveitis in rats (Figures 1 and 2). Anti-inflammatory activity in this model has been exemplified with the following FPR2 agonists:
In this model the compounds show a strong anti-inflammatory activity in blocking the infiltration of neutrophils and protein into the anterior chamber. In addition FPR2 agonists show accelerated healing and re-epithelialization in mouse models of corneal wound as exemplified by 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 efficacious anti-inflammatory agents suitable for ocular use in different models of ocular inflammation.


Claims

1. An agonist of Formyl peptide receptor 2 (FPR2) for use in a method of treating an ocular inflammatory disease, in a subject in need of such treatment,
wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of said agonist of FPR2,
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 placoid pigment epitheliopathy, Behcet's disease, post-surgical corneal wound healing, wet and dry age-related macular degeneration (ARMD); and
wherein the agonist of FPR2 is selected from:

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid;

{[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid;

(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoic acid;

2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic acid;

{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl] amino}acetic acid;

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid;

2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-oxoazepan-3-yl)-3-phenylpropanamide;

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetic acid;

3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}propanoic acid;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide;

{[(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid;

(2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanamide;

(2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanamide;

(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamide;

(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamide;

(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide;

methyl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate; propan-2-yl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;

{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamide;

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide; (2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}pentanamide;

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl] amino}pentanamide;

(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;

(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide;

(2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl] amino}propanoic acid;

(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl] amino}propanoic acid;

(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoic acid;

(2S)-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-2-{[(4-bromophenyl)carbamoyl] amino}-4-methylpentanamide;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxy-2-methylpropyl)-4-methylpentanamide;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-methylpentanamide;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamide;

tert-butyl (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoate;

(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} pentanoic acid;

(2S)-N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;

(2S)-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} (phenyl)ethanoic acid;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N-(1H-tetrazol-5-ylmethyl)pentanamide;

[(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic acid;

[(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetic acid;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(3-hydroxy-1,2-oxazol-5-yl)methyl]-4-methylpentanamide;

(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide;

{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl] amino}acetic acid;

{[(2S)-4-methyl-2-(([4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl] amino}acetic acid;

(2S)-4-methyl-N-(1H-tetrazol-5-ylmethyl)-2-({[4-(trifluoromethyl)phenyl]carbamoyl} amino)pentanamide;

2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoicacid;

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetic acid;

{[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetic acid;

tert-butyl {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl) amino}acetate; and

{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl) amino}acetic acid,

or a pharmaceutically acceptable salt thereof.
 
2. The agonist of Formyl peptide receptor 2 (FPR2) for use according to claim 1, wherein the agonist of FPR2 is {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid or a pharmaceutically acceptable salt thereof.
 
3. The agonist of Formyl peptide receptor 2 (FPR2) for use according to claim 1, wherein the agonist of FPR2 is {[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid or a pharmaceutically acceptable salt thereof.
 
4. The agonist of Formyl peptide receptor 2 (FPR2) for use according to claim 1, wherein the agonist of FPR2 is 2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic acid or a pharmaceutically acceptable salt thereof.
 
5. The agonist of Formyl peptide receptor 2 (FPR2) for use according to claim 1, wherein the agonist of FPR2 is {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid or a pharmaceutically acceptable salt thereof.
 
6. The agonist of Formyl peptide receptor 2 (FPR2) for use according to claim 1, wherein the agonist of FPR2 is {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid.
 
7. The agonist of Formyl peptide receptor 2 (FPR2) for use according to claim 1, wherein the ocular inflammatory disease is dry eye.
 


Ansprüche

1. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung in einem Verfahren zur Behandlung einer entzündlichen Augenerkrankung bei einem Subjekt mit Bedarf an einer solchen Behandlung, wobei das Verfahren die Verabreichung einer pharmazeutischen Zusammensetzung, umfassend eine therapeutisch wirksame Menge des FPR2-Agonisten, umfasst,
wobei die entzündliche Augenerkrankung ausgewählt ist aus: Uveitis, Trockenem Auge, Keratitis, allergischer Augenentzündung, infektiöser Keratitis, Herpeskeratitis, kornealer Angiogenese, Lymphangiogenese, Retinitis, Choroiditis, akuter multifokaler plakoider Pigmentempitheliopathie, Behcet-Krankheit, postoperativer kornealer Wundheilung, feuchter und trockener altersbedingter Makuladegeneration (ARMD) und
wobei der FPR2-Agonist ausgewählt ist aus:

{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}pentanoyl]amino}essigsäure,

{[(2S,3S)-2-{[(4-Bromphenyl)carbamoyl]amino}-3-methylpentanoyl]amino}essigsäure,

(2S,3S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-3-methylpentansäure,

2-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropionsäure,

{[(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}essigsäure,

{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}essigsäure,

2-{[(4-Bromphenyl)carbamoyl]amino}-N-(2-oxoazepan-3-yl)-3-phenylpropanamid,

{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}essigsäure,

3-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}propionsäure,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamid,

{[(2S,3S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-3-methylpentanoyl]amino}essigsäure,

(2S,3S)-N-(2-Amino-2-oxoethyl)-2-{[(4-bromphenyl)carbamoyl]amino}-3-methylpentanamid,

(2S,3S)-N-(2-Amino-2-oxoethyl)-2-{[(4-brom-2-fluorphenyl)carbamoyl]amino}-3-methylpentanamid,

(2S,3S)-2-{[(4-Bromphenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamid,

(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamid,

(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamid,

Methyl-{[(2S)-2-{[(4-bromphenyl)carbamoyl]amino}pentanoyl]amino}acetat,

Propan-2-yl-{[(2S)-2-{[(4-bromphenyl)carbamoyl]amino}pentanoyl]amino}acetat,

{[(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}pentanoyl]amino}essigsäure,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamid,

(2S)-N-(2-Amino-2-oxoethyl)-2-{[(4-bromphenyl)carbamoyl]amino}-4-methylpentanamid,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamid,

(2S)-N-(2-Amino-2-oxoethyl)-2-{[(4-bromphenyl)carbamoyl]amino}pentanamid,

(2S)-N-(2-Amino-2-oxoethyl)-2-{[(4-brom-2-fluorphenyl)carbamoyl]amino}pentanamid,

(2S)-N-(2-Amino-2-oxoethyl)-2-{[(4-brom-2-fluorphenyl)carbamoyl]amino}-4-methylpentanamid,

(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamid,

(2S)-2-{[(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propionsäure,

(2S)-2-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propionsäure,

(2S)-2-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutansäure,

(2S)-N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-2-{[(4-bromphenyl)carbamoyl]amino}-4-methylpentanamid,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-(2-hydroxy-2-methylpropyl)-4-methylpentanamid,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamid,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-methylpentanamid,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamid,

tert-Butyl-(2S)-2-{[(2S)-2-{[(4-bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoat,

(2S)-2-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentansäure,

(2S)-N-[(2S)-1-Amino-1-oxopentan-2-yl]-2-{[(4-bromphenyl)carbamoyl]amino}-4-methylpentanamid,

(2S)-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-(phenyl)ethansäure,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methyl-N-(1H-tetrazol-5-ylmethyl)pentanamid,

[(2-{[(4-Bromphenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]essigsäure,

[(2-{[(4-Bromphenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]essigsäure,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-[(3-hydroxy-1,2-oxazol-5-yl)methyl]-4-methylpentanamid,

(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamid,

{[(2S)-4-Methyl-2-({[4-(trifluormethyl)phenyl]carbamoyl}amino)pentanoyl]-amino}essigsäure,

{[(2S)-4-Methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}-essigsäure,

(2S)-4-Methyl-N-(1H-tetrazol-5-ylmethyl)-2-({[4-(trifluormethyl)phenyl]carbamoyl}amino)pentanamid,

2-Methyl-2-{[(2S)-4-methyl-2-({[4-(trifluormethyl)phenyl]carbamoyl}amino)pentanoyl]-amino}propionsäure,

{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}essigsäure,

{[2-{[(4-Bromphenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}essigsäure,

tert-Butyl-{[(2S)-2-{[(4-bromphenyl)carbamoyl]amino}-4-methylpentanoyl](methyl)amino}acetat und

{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl](methyl)amino}essigsäure

oder einem pharmazeutisch annehmbaren Salz davon.
 
2. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung gemäß Anspruch 1, wobei der FPR2-Agonist {[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}pentanoyl]amino}essigsäure oder ein pharmazeutisch annehmbares Salz davon ist.
 
3. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung gemäß Anspruch 1, wobei der FPR2-Agonist {[(2S,3S)-2-{[(4-Bromphenyl)carbamoyl]amino}-3-methylpentanoyl]amino}essigsäure oder ein pharmazeutisch annehmbares Salz davon ist.
 
4. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung gemäß Anspruch 1, wobei der FPR2-Agonist 2-{[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropionsäure oder ein pharmazeutisch annehmbares Salz davon ist.
 
5. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung gemäß Anspruch 1, wobei der FPR2-Agonist {[(2S)-2-{[(4-Brom-2-fluorphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}essigsäure oder ein pharmazeutisch annehmbares Salz davon ist.
 
6. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung gemäß Anspruch 1, wobei der FPR2-Agonist {[(2S)-2-{[(4-Bromphenyl)carbamoyl]amino}-4-methylpentanoyl]amino}essigsäure ist.
 
7. Formylpeptidrezeptor 2 (FPR2)-Agonist zur Verwendung gemäß Anspruch 1, wobei die entzündliche Augenerkrankung ein Trockenes Auge ist.
 


Revendications

1. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation dans un procédé de traitement d'une maladie inflammatoire oculaire, chez un sujet ayant besoin d'un traitement de ce type, dans lequel le procédé comprend l'administration d'une composition pharmaceutique comprenant une quantité thérapeutiquement efficace dudit agoniste de FPR2,
dans lequel la maladie inflammatoire oculaire est choisie parmi : uvéite, sécheresse oculaire, kératite, maladie oculaire allergique, kératite infectieuse, kératite herpétique, angiogénèse cornéenne, lymphangiogenèse, rétinite, choroïdite, épithéliopathie pigmentaire placoïde multifocale aiguë, maladie de Behcet, cicatrisation de la plaie cornéenne post-chirurgicale, dégénérescence maculaire liée à l'âge humide et sèche (DMLA) ; et
dans lequel l'agoniste de FPR2 est choisi parmi :

acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}pentanoyl]amino}acétique ;

acide {[(2S,3S)-2-{[(4-bromophényl)carbamoyl]amino}-3-méthylpentanoyl]amino} acétique ;

acide (2S,3S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-3-méthylpentanoïque ;

acide 2-{[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}-2-méthylpropanoïque ;

acide {[(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}acétique ;

acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}acétique ;

2-{[(4-bromophényl)carbamoyl]amino}-N-(2-oxoazépan-3-yl)-3-phénylpropanamide ;

acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-3-phénylpropanoyl]amino}acétique ;

acide 3-{[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-3-phénylpropanoyl]amino}propanoïque ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-(2-hydroxyéthyl)-3-phénylpropanamide ;

acide {(2S,3S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-3-méthylpentanoyl]amino}acétique ;

(2S,3S)-N-(2-amino-2-oxoéthyl)-2-{[(4-bromophényl)carbamoyl]amino}-3-méthylpentanamide ;

(2S,3S)-N-(2-amino-2-oxoéthyl)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-3-méthylpentanamide ;

(2S,3S)-2-{[(4-bromophényl)carbamoyl]amino}-3-méthyl-N-(2-oxopropyl)pentanamide ;

(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-N-(2-oxopropyl)-3-phénylpropanamide ;

(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-N-(2-hydroxyéthyl)-3-phénylpropanamide ;

acétate de méthyle {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-pentanoyl]amino} ;

acétate de propan-2-yle {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}pentanoyl]amino};

acide {[(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}pentanoyl]amino}acétique ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-(2-hydroxyéthyl)-4-méthylpentanamide ;

(2S)-N-(2-amino-2-oxoéthyl)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanamide ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthyl-N-(2-oxopropyl)pentanamide ;

(2S)-N-(2-amino-2-oxoéthyl)-2-{[(4-bromophényl)carbamoyl]amino}pentanamide ;

(2S)-N-(2-amino-2-oxoéthyl)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}pentanamide ;

(2S)-N-(2-amino-2-oxoéthyl)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-4-méthylpentanamide ;

(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-4-méthyl-N-(2-oxopropyl)pentanamide ;

acide (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}propanoïque ;

acide (2S)-2-{[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}propanoïque ;

acide (2S)-2-{[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}-3-méthylbutanoïque ;

(2S)-N-[(2S)-1-amino-3-méthyl-1-oxobutan-2-yl]-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanamide ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-(2-hydroxy-2-méthylpropyl)-4-méthylpentanamide ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-méthylpentanamide ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-méthylpentanamide ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl)-4-méthylpentanamide ;

tert-butyle (2S)-2-{[(2S)-2-{[4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}pentanoate ;

acide (2S)-2-{[(2S)-2-{[4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}pentanoïque ;

(2S)-N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[4-bromophényl)carbamoyl]amino}-4-méthylpentanamide ;

acide (2S)-{[(2S)-2-{[4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}(phényl)éthanoïque ;

(2S)-2-{[4-bromophényl)carbamoyl]amino}-4-méthyl-N-(1H-tétrazol-5-ylméthyl)pentanamide ;

acide [(2-{[(4-bromophényl)carbamoyl]amino}-2,4-diméthylpentanoyl)amino]acétique ;

acide [(2-{[4-bromophényl)carbamoyl]amino}-2-éthylbutanoyl)amino]acétique ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-[(3-hydroxy-1,2-oxazol-5-yl)méthyl]-4-méthylpentanamide ;

(2S)-2-{[(4-bromophényl)carbamoyl]amino}-N-[(2-(diméthylamino)-2-oxoéthyl]-4-méthylpentanamide ;

acide {[(2S)-4-méthyl-2-{[(4-trifluorométhyl)phényl]carbamoyl]amino}pentanoyl]amino}acétique ;

acide {[(2S)-4-méthyl-2-{[(4-méthylsulfanyl)phényl]carbamoyl]amino)pentanoyl]amino}acétique ;

(2S)-4-méthyl-N-(1H-tétrazol-5-ylméthyl)-2-({[4-trifluorométhyl)phényl]carbamoyl}amino)pentanamide ;

acide 2-méthyl-2-{[(2S)-4-méthyl-2-({[4-trifluorométhyl)phényl]carbamoyl}amino)pentanoyl]amino}propanoïque ;

acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-(méthylsulfanyl)butanoyl]amino}acétique ;

acide {[2-{[(4-bromophényl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acétique ;

acétate de tert-butyle {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl](méthyl)amino}; et

acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl](méthyl)amino}acétique,

ou un sel pharmaceutiquement acceptable de celui-ci.
 
2. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation selon la revendication 1, dans lequel l'agoniste de FPR2 est l'acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}pentanoyl]amino}acétique ou un sel pharmaceutiquement acceptable de celui-ci.
 
3. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation selon la revendication 1, dans lequel l'agoniste de FPR2 est l'acide {[(2S,3S)-2-{[(4-bromophényl)carbamoyl]amino}-3-méthylpentanoyl]amino}acétique ou un sel pharmaceutiquement acceptable de celui-ci.
 
4. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation selon la revendication 1, dans lequel l'agoniste de FPR2 est l'acide 2-{[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}-2-méthylpropanoïque ou un sel pharmaceutiquement acceptable de celui-ci.
 
5. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation selon la revendication 1, dans lequel l'agoniste de FPR2 est l'acide {[(2S)-2-{[(4-bromo-2-fluorophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}acétique ou un sel pharmaceutiquement acceptable de celui-ci.
 
6. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation selon la revendication 1, dans lequel l'agoniste de FPR2 est l'acide {[(2S)-2-{[(4-bromophényl)carbamoyl]amino}-4-méthylpentanoyl]amino}acétique.
 
7. Agoniste du récepteur 2 de peptide formyle (FPR2) destiné à une utilisation selon la revendication 1, dans lequel la maladie inflammatoire oculaire est la sécheresse oculaire.
 




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Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description