USE OF AGONISTS OF FORMYL PEPTIDE RECEPTOR 2 FOR TREATING DERMATOLOGICAL DISEASES

Abstract

The present invention relates to a method for treating dermal inflammation and dermal diseases by local or systemic delivery, in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

Description

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a method for treating dermal inflammation and dermal diseases by local or systemic delivery, in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

Summary of the Related Art

The formyl peptide receptor (FPR) family belongs to the seven transmembrane domain G-protein-coupled receptor (GPCR) family. This family includes 3 members in humans and one member of this family FPR2 (also known as FPRL-1, ALXA4) 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 C N, Dahlen, S, Drazen J M, 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 menagerie of structurally diverse exogenous and endogenous ligands, including serum amyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocorticoid-modulated protein annexin A1 (Chiang N, Serhan C N, Dahlen, S, Drazen J M, 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 has been shown to transduce anti-inflammatory effects of arachidonic acid derived Lipoxin A4 (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 H B, Gray M, D'Aquisto F, Buckingham J C, Perretti M, Flower R J. 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. Gavins FNE, Hughes E L, Buss NAPS, Holloway P M, Getting S J, Buckingham J C. Leukocyte recruitment in the brain in sepsis: involvement of the annexin1 FPR2/ALX anti-inflammatory system. FASEB 2012; 26: 1-13).

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 (Gavins FNE, Hughes E L, Buss NAPS, Holloway P M, Getting S J, Buckingham J C. Leukocyte recruitment in the brain in sepsis: involvement of the annexin1 FPR2/ALX anti-inflammatory system. FASEB 2012; 26: 1-13, Maderna P, Cotten D C, 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). In addition, FPR2 has been shown to inhibit natural killer (NK) cytotoxicity and promote activation of T cells which further contributes to down regulation of tissue damaging inflammatory signals. FPR2 interaction with LXA4 and Annexin has been shown to be beneficial in experimental models of dermal inflammation, angiogenesis, epithelial migration, edema, alopecia and corneal wound healing. (Reville K, Cream J K, Vivers S, Dransfield I, Godson C. Lipoxin A4 redistributes Myosin IIA and Cdc42 in macrophages: Implications for phagocytosis of apoptotic leukocytes. Journal of Immunology 2006; 176: 1878-1888; Serhan C. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual reviews of Immunology 2007; 25: 101-137; Takano T, Fiore S, Maddox J F, Brady H R, Petasis N A, Serhan C N. Aspirin-triggered 15-epi-lipoxin A4 and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. Journal of Experimental Medicine 1997; 185: 1693-1704; Leoni G, Alam A, Neumann P A, Lambeth J D, Cheng G, McCoy J, Hilgarth R S, Kundu K, Murthy N, Kusters D, Reutelingsperger C, Perretti M, Parkos C A, Neish A S, Nusrat A. Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. Journal of Clinical Investigation. 2013; 123:443-54; Leedom A, Sullivan A B, 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; Tsuruki T, Takahata K, Yoshikawa M. Mechanism of the protective effect of intraperitoneally administered agonists for formyl peptide receptors against chemotherapy-induced alopecia. Biosci Biotechnology Biochemistry. 2007; 71:1198-202).

Targeting FPR2 selectively would also have benefits in skin wound healing given its potent anti-inflammatory and pro-epithelial repair role. In addition, some skin diseases have been shown to have an abnormal expression of LL37, a pro-inflammatory cathelicidin which has been shown to be a natural ligand of FPR2. In the chronic inflammatory disease Rosacea, LL37 is highly expressed and is believed to play a key role in the pathogenesis (Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner R A, Bonnart C, Descargues P, Hovnanian A, Morhenn V B, Gallo R L. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nature Medicine. 2007; 13:975-80).

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating dermal inflammation and dermal diseases by local or systemic delivery, in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

Given the anti-inflammatory axis of LXA4-FPR2 we propose that FPR2 agonists will be useful in inhibiting LL-37-mediated inflammatory diseases such as Rosacea. 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 skin. FPR2 is widely expressed in human skin and its appendages. FPR2 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in dermatological diseases with excessive inflammatory responses.

The invention pertains to the ability of FPR2 agonists to exhibit dermal anti-inflammatory activity with chemical stability and suitable for topical dermal delivery. These FPR2 compounds show good potency at the receptor and, importantly, the FPR2 compounds are topically active, and therefore could be administered in many forms, including but not limited to creams, lotions, gels, solutions, sprays, and foams. These compounds may also be administered IV, intramuscularly, intrathecally, subcutaneously, orally or intraperitoneally. These compounds will be useful for the treatment of dermatological diseases including, but not limited to, rosacea, rosacea fulminans, sunburn, psoriasis, menopause-associated hot flashes, flushing and redness associated with hot flashes, erythema associated with hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, treatment of redness and itch from insect bites, photoaging, seborrheic dermatitis, acne, allergic dermatitis, telangiectasia (dilations of previously existing small blood vessels) of the face, angioectasias, rhinophyma (hypertrophy of the nose with follicular dilation), acne-like skin eruptions (may ooze or crust), burning or stinging sensation, erythema of the skin, cutaneous hyperactivity with dilation of blood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome, local itching and discomfort associated with hemorrhoids, hemorrhoids, erythema multiforme minor, erythema multiforme major, erythema nodosum, eye puffiness, urticaria, pruritis, purpura, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, stasis dermatitis, lichen simplex chronicus, perioral dermatitis, pseudofolliculitis barbae, granuloma annulare, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, eczema, dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, other disorders of pigmentation, and alopecia (scarring and non-scarring forms). The compounds below would be expected to have therapeutic effects in many different types of skin disease, but have been exemplified by demonstrating accelerated wound healing activity in a mouse dermal wound healing model (FIG. 1), and reduction of LL-37-induced inflammation in mice (FIG. 2) and human keratinocytes (FIG. 2). Anti-inflammatory activity in the LL-37-induced rosacea mouse model has been exemplified with three FPR2 agonists: {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid, {[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic acid, {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic acid. Skin penetration of FPR2 agonists following topical administration has also been demonstrated (FIG. 3).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 FPR2 agonists show potent wound healing in a mouse model of punch dermal wound.

FIG. 2 FPR2 agonists block inflammation induced by LL-37 in mouse ears p<0.05 vs. vehicle, at all-time points.

FIG. 3. Absorption of FPR2 agonists in an in vitro human skin penetration model.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating dermatological inflammation and dermatological diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

In another aspect, the invention provides the use of at least one agonist of FPR2 for the manufacture of a medicament for the treatment of a dermatological inflammation disease or condition mediated by FPR2 in a mammal

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/668,835, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/668,835 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/668,835 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/668,835 are represented by Formula I:

wherein:R¹ is sec-butyl, C_6-10 aryl, —CH₂—(C_6-10)aryl, —CH₂-heterocycle, C_4-8 cycloalkyl or C_3-8 cycloalkenyl or heterocycle;R² is halogen or methyl;R³ is halogen;R⁴ is H, methyl or halogen;R⁵ is OR⁶ or NH₂; andR⁶ is H or C_2-4 alkyl.

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/523,579, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/523,579 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/523,579 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/523,579 are represented by Formula II:

wherein:a is 1 and b is 0;a is 0 and b is 1;a is 1 and b is 1;R¹ is optionally substituted C_1-8 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl, optionally substituted C_3-8 cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C_1-8 alkyl or optionally substituted C_6-10 aryl;R³ is hydrogen, optionally substituted C_1-8 alkyl, halogen, —COOR¹⁵, —OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl or optionally substituted C_3-8 cycloalkenyl;R⁴ is hydrogen, optionally substituted C_1-8 alkyl, halogen, —COOR¹⁵, —OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl or optionally substituted C_3-8 cycloalkenyl;R⁵ is halogen, —CF₃ or —S(O)_nR¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C_1-8 alkyl, halogen, —COOR¹⁵, —OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl or optionally substituted C_3-8 cycloalkenyl;R⁷ is hydrogen, optionally substituted C_1-8 alkyl, halogen, —COOR¹⁵, —OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionally substituted C_3-8 cycloalkyl, optionally substituted C_6-10 aryl or optionally substituted C_3-8 cycloalkenyl;R⁸ is hydrogen, optionally substituted C_1-8 alkyl or optionally substituted C_6-10 aryl;R⁹ is hydrogen, optionally substituted C_1-8 alkyl or optionally substituted C_6-10 aryl;R¹⁰ is hydrogen, optionally substituted C_1-8 alkyl or optionally substituted C_6-10 aryl;R^9a is hydrogen, optionally substituted C_1-8 alkyl or optionally substituted C_6-10 aryl;R^10a is hydrogen, optionally substituted C_1-8 alkyl or optionally substituted C_6-10 aryl;R¹¹ is hydrogen or optionally substituted C_1-8 alkyl;R¹² is hydrogen or optionally substituted C_1-8 alkyl;R¹³ is hydrogen or optionally substituted C_1-8 alkyl;R¹⁴ is hydrogen, CF₃ or optionally substituted C_1-8 alkyl; andR¹⁵ is hydrogen or optionally substituted C_1-8 alkyl.

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/673,800, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least a compound as disclosed in U.S. patent application Ser. No. 13/673,800 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least a compound as disclosed in U.S. patent application Ser. No. 13/673,800 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/673,800 are represented by Formula III:

wherein:R¹ is halogen, hydrogen, optionally substituted C_1-8 alkyl, OR⁹, C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R² is halogen, optionally substituted C_1-8 alkyl, CF₃, OR⁹, C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R³ is hydrogen, optionally substituted C_1-8 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_3-8 cycloalkenyl, optionally substituted C_6-10 aryl, optionally substituted heterocycle, or together with R⁵ forms a 10- or 11-membered polycyclic ring which is optionally substituted;R⁴ is hydrogen, optionally substituted C_1-8 alkyl,

optionally substituted C_3-8 cycloalkyl, optionally substituted C_3-8 cycloalkenyl, optionally substituted C_6-10 aryl, optionally substituted heterocycle, or together with R⁵ forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted;R⁵ is hydrogen, optionally substituted C_1-8 alkyl, optionally substituted C_3-8 cycloalkyl, optionally substituted C_3-8 cycloalkenyl, optionally substituted C_6-10 aryl, optionally substituted heterocycle, or together with R⁴ forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R³ forms a 5 or 6 member ring which is optionally substituted;R⁶ is halogen, hydrogen, optionally substituted C_1-8 alkyl, OR⁹, C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R⁷ is halogen, hydrogen, optionally substituted C_1-8 alkyl, OR⁹, C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R⁸ is halogen, hydrogen, optionally substituted C_1-8 alkyl, OR⁹, C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R⁹ is hydrogen, C(O)(C_1-8 alkyl) or optionally substituted C_1-8 alkyl;R¹⁰ is hydrogen, optionally substituted C_1-8 alkyl, O(C_1-8 alkyl), NR¹¹R¹² or OH;R¹¹ is hydrogen, optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;R¹² is hydrogen, optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;R¹³ is hydrogen, optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;R¹⁴ is hydrogen, optionally substituted C_6-10 aryl, optionally substituted C_1-8 alkyl, C(O)(C_1-8 alkyl) or SO₂(C_1-8 alkyl);R¹⁵ is hydrogen, optionally substituted C_1-8 alkyl or O(C_1-8 alkyl);R¹⁶ is OH, O(C_1-8 alkyl), (C_1-8 alkyl) or NR¹¹R¹²;R¹⁷ is hydrogen, optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;R¹⁸ is hydrogen, C(O)(C_1-8 alkyl), optionally substituted C_6-10 aryl, or optionally substituted C_1-8 alkyl;R¹⁹ is hydrogen, C(O)(C_1-8 alkyl), optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;R²⁰ is hydrogen, optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;R²¹ is hydrogen, optionally substituted C_6-10 aryl or optionally substituted C_1-8 alkyl;n is 1, 2, 3, 4, or 5; andm is 1, 2, 3, 4, or 5.

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/765,527, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/765,527 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/765,527 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/765,527 are represented by Formula IV:

wherein:R¹ is hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted C_3-8 cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C_6-10 aryl, or together with R² can form an optionally substituted cyclobutyl;R² is isopropyl or together with R³ can form a substituted or unsubstituted 3 to 6 member ring heterocycle or together with R¹ can form an optionally substituted cyclobutyl, cyclopropyl; andR³ is hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted C_3-8 cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C_6-10 aryl or together with R² can form a substituted or unsubstituted 3 to 6 member ring heterocycle.

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a therapeutically effective amount of a pharmaceutical composition, comprising at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/409,228, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/409,228 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/409,228 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

wherein:

is a single bond or a double bond;

is a single bond or a double bond;R¹ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl, C_3-8 cycloalkenyl or hydroxyl;R² is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl, C_3-8 cycloalkenyl or hydroxyl;R³ is H, halogen, —S(O)R¹⁹, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl, C_3-8 cycloalkenyl, C_6-10 aryl or hydroxyl;R⁴ is H or C(O)R¹²;R⁵ is H, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl or —C_2-6 alkynyl;R⁶ is H, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl or —C_2-6 alkynyl;

Y is O or S;

X is O, NR, or CH₂;

R^a is C_6-10 aryl,

heteroaryl, C_3-8 cycloalkyl, C_3-8 cycloalkenyl or H;R^b is halogen;c is 0, 1 or 2;

R⁷ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, hydroxyl, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkenyl or C_3-8 cycloalkyl;R⁸ is H, halogen, —S(O)R¹⁹, —S(O)₂R¹¹, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkenyl or C_3-8 cycloalkyl;R⁹ is H, —S(O)₂R¹¹, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², C_3-8 cycloalkenyl or C_3-8 cycloalkyl;R¹⁰ is —C_1-6 alkyl, C_3-8 cycloalkyl, or C_3-8 cycloalkenyl;R¹¹ is H, hydroxyl, —C_1-6 alkyl, C_3-8 cycloalkyl or C_3-8 cycloalkenyl;R¹² is H, hydroxyl, —C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkenyl, NR¹³R¹⁴ or —OC_1-6 alkyl;R¹³ is H, —C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkenyl, SO₂R¹¹ or C(O)R¹⁵;R¹⁴ is H, —C_1-6 alkyl, C_3-8 cycloalkenyl, aryl, heterocycle or C_3-8 cycloalkyl;R¹⁵ is H, —C_1-6 alkyl, C_3-8 cycloalkenyl or C_3-8 cycloalkyl; andR is H, —C_1-6 alkyl, C_3-8 cycloalkenyl or C_3-8 cycloalkyl;with the proviso:when “” is a double bond then R⁵ and R⁶ are void.

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/370,472, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/370,472 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/370,472 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent application Ser. No. 13/370,472 are represented by Formula VI:

wherein:A is C_6-10 aryl, heterocyle, C_3-8 cycloalkyl or C_3-8 cycloalkenyl;R¹⁷ is C_1-6 alkyl or

B is C_6-10 aryl, heterocyle, C_3-8 cycloalkyl or C_3-8 cycloalkenyl;R¹ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R² is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R³ is H, C_1-6 alkyl or C_3-8 cycloalkyl;R⁴ is H, C_1-6 alkyl or C_3-8 cycloalkyl;R^5a is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6alkyl, —C_1-6alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R^5b is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R^5c is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6alkyl, —C_1-6alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R^5d is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R⁶ is H, —S(O)₂R¹¹, —C_1-6 alkyl, —(CH₂)_nNR¹³R¹⁴, —(CH₂)_m heterocycle, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl, C_6-10 aryl, or heterocycle;R⁷ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R⁸ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R⁹ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;R¹⁰ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC_1-6 alkyl, —SC_1-6 alkyl, —C_1-6 alkyl, —C_2-6 alkenyl, —C_2-6 alkynyl, C(O)R¹², NR¹³R¹⁴, C_3-8 cycloalkyl or hydroxyl;

X is O or S;

Y is O or S;

R¹¹ is H, hydroxyl, —C_1-6 alkyl, C_3-8 cycloalkyl or NR¹³R¹⁴;R¹² is H, hydroxyl, —C_1-6 alkyl, hydroxyl, C_3-8 cycloalkyl, NR¹³R¹⁴ or —OC_1-6 alkyl;R¹³ is H, C_3-8 cycloalkyl, SO₂R¹¹ or C(O)R¹⁶;R¹⁴ is H, —C_1-6 alkyl or C_3-8 cycloalkyl;R¹⁵ is —C_1-6 alkyl, or C_3-8 cycloalkyl;R¹⁶ is H, —C_1-6 alkyl or C_3-8 cycloalkyl;n is 1-4; andm is 1-4.

In another aspect, the invention provides a method for treating dermatological inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application Ser. No. 13/863,934, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/863,934 for the manufacture of a medicament for the treatment of a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least one compound as disclosed in U.S. patent application Ser. No. 13/863,934 for treating a dermatological disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent application Ser. No. 13/863,934 are represented by Formula VII:

wherein:n is 0 or 1;R¹ is hydrogen, substituted or unsubstituted C_1-8 alkyl, halogen, —NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN or NO₂;R² is hydrogen, substituted or unsubstituted C_1-8 alkyl, halogen, —NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN or NO₂;R³ is hydrogen, substituted or unsubstituted C_1-8 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 C_1-8 alkyl, halogen, —NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN or NO₂;R⁵ is hydrogen, substituted or unsubstituted C_1-8 alkyl, halogen, —NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, SR¹¹, —C(O)R¹², CN or NO₂;R⁶ is hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted C_3-8 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 C_1-8 alkyl, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C_6-10 aryl;R⁹ is hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C_6-10 aryl;R¹⁰ is hydrogen or substituted or unsubstituted C_1-8 alkyl;R¹¹ is hydrogen, substituted or unsubstituted C_1-8 alkyl or —CF₃;R¹² is hydrogen, substituted or unsubstituted C_1-8 alkyl, hydroxyl, —OR²⁴ or —NR⁸R⁹;R¹³ is —OR²²;R¹⁴ is —OR²³;R¹⁵ is substituted or unsubstituted C_1-8 alkyl;R¹⁶ is substituted or unsubstituted C_1-8 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 C_3-8 cycloalkyl, substituted or unsubstituted C_6-10 aryl or substituted or unsubstituted C_3-8 cycloalkenyl;R²⁰ is hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C_6-10 aryl;R²¹ is hydrogen, substituted or unsubstituted C_1-8 alkyl substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C_6-10 aryl;R²² is hydrogen, substituted or unsubstituted C_1-8 alkyl, or together with R²³ can form a cycle;R²³ is hydrogen, substituted or unsubstituted C_1-8 alkyl, or together with R²² can form a cycle; andR²⁴ is hydrogen, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C_6-10 aryl.

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.

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 C_1-8 alkyl groups, sulfoxide C_1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, —OC_1-8 alkyl groups, —SC_1-8 alkyl groups, —C_1-8 alkyl groups, —C_2-6 alkenyl groups, —C_2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C_3-8 cycloalkyl groups or hydroxyl groups.

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, —OC_1-6 alkyl groups, —SC_1-6 alkyl groups, —C_1-6 alkyl groups, —C_2-6 alkenyl groups, —C_2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C_3-8 cycloalkyl groups or hydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.

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.

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.

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, —OC_1-6 alkyl groups, —SC_1-6 alkyl groups, —C_1-8 alkyl groups, —C_2-6 alkenyl groups, —C_2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C_3-8 cycloalkyl groups or hydroxyl groups.

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 C_1-6 alkyl groups, sulfoxide C_1-6 alkyl groups, sulfonamide groups, carboxylic acid groups, C_1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, —OC_1-6 alkyl groups, —SC_1-6 alkyl groups, —C_1-6 alkyl groups, —C_2-6 alkenyl groups, —C_2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C_3-8 cycloalkyl groups or hydroxyl groups. Aryls can be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula “—C(O)—”.

The term “ketone” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —(CO)R^x, wherein R^x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “amine” as used herein, represents a group of formula “—NR^xR^y”, wherein R^x and R^y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂⁻”.

The term “sulfate” as used herein, represents a group of formula “—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula “—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula “—C(O)NR^xR^y” wherein R^x and R^y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “sulfonamide” as used herein, represents a group of formula “—S(O)₂NR^xR^y” wherein R^x and R^y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “sulfoxide” as used herein, represents a group of formula “—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula “—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula “—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

In another aspect, agonists of FPR2 are compounds selected from Table 1:

TABLE 1
		FPRL-1
		Ga16-CHO
		EC50
Structure	IUPAC name	(efficacy)
	2-({[(4- chlorophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid	110 nM (1.0)
	(2S)-2-({[(4- methoxyphenyl)amino]carbonyl}amino)-3- phenylpropanoic acid	1754 nM (0.90)
	(2S)-3-phenyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl) amino]propanoic acid	120 nM (0.97)
	(2S)-2-({[(3,4- dichlorophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid	10 □M (0.57)
	(2S)-2-({[(4- nitrophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid	574 nM (0.82)
	3-phenyl-2-[({[4- (tririuoromethoxy)phenyl]amino}carbonyl) amino]propanoic acid	1572 nM (0.79)
	2-({[(3,4- dimethoxyphenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid	2793 nM (0.72)
	methyl 2-({[(4- iodophenyl)amino]carbonyl}amino)-3- phenylpropanoate	14.3 nM (1.0)
	(2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid	31 nM (1.0)
	(2R)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid	1819 nM (0.99)
	3-phenyl-2-{[(pyridin-3- ylamino)carbonyl]amino}propanoic acid
	(2S,3S)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- methylpentanoic acid	4.1 nM (0.89)
	(2S)-({[(4- bromophenyl)amino]carbonyl}amino) (phenyl)acetic acid	25.8 nM (0.94)
	2-({[(4- bromophenyl)amino]carbonyl}amino)-3- (lH-indol-3-yl)propanoic acid	67.0 nM (0.89)
	(2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- methylbutanoic acid	72 nM (0.91)
	(2S)-2-({[(4-bromo-2- fluorophenyl)amino]carbonyl}amino)-3- methylbutanoic acid	152 nM (0.91)

US 2005/0137230 A1 and U.S. Pat. No. 7,820,673 disclose inhibitors of coagulation Factor Xa and can be employed 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-(trifluoromethyl)phenyl]amino}carbonyl)amino]propanoic acid, methyl 2-({[(4-iodophenyl)amino]carbonyl}amino)-3-phenylpropanoate, (2S)-2-({[(4-bromophenyl) amino]carbonyl}amino)-3-phenylpropanoic acid, (2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid, are intermediates in the synthesis of urea derivatives as activated blood coagulation factor X (FXa) inhibitors.

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-indol-3-yl)propanoic acid, (2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylbutanoic acid) on HPLC column with novel chromatographic chiral stationary phases.

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

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

In another aspect, agonists of FPR2 are compounds selected from Table 2:

TABLE 2
		FPRL-1
		Ga16-CHO
		EC50
Structure	IUPAC name	(efficacy)
	1-(4-chlorophenyl)-3-(2,4-dioxo-1,3- diazaspiro[4,5]decan-3-yl)urea	49 nM (0.98)
	1-(4-chlorophenyl)-3-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1- yl)urea	157 nM (0.96)
	1-[4-methyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1-yl]-3- phenylurea	223 nM (1.0)
	1-(8-methyl-2,4-dioxo-1,3- diazaspiro[4,5]decan-3-yl)-3-(p- tolyl)urea	363 nM (0.91)
	1-(2-fluorophenyl)-3-[4-methyl-2,5- dioxo-4-(2- phenylethyl)imidazolidin-1-yl]urea	258 nM (0.94)

Compounds of Table 2 are available from Chemical Libraries such as Aurora Fine Chemicals.

In another aspect, agonists of FPR2 are compounds selected from Table 3:

TABLE 3
		FPRL-1
		Ga16-CHO
		EC50
Structure	IUPAC name	(efficacy)
	N-(4-bromophenyl)-2-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)acetamide	719 nM (0.94)
	N-(4-bromophenyl)-2-(4,4-diethyl-2,5- dioxoimidazolidin-1-yl)acetamide	96 nM (0.98)
	N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.5]dec-3-yl)acetamide	738 nM (0.89)
	N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.4]non-3-yl)acetamide	322 nM (0.96)
	N-(4-bromophenyl)-2-(2,5-dioxo-4,4- dipropylimidazolidin-1-yl)acetamide	645 nM (0.98)
	N-(4-bromophenyl)-2-(4-ethyl-2,5- dioxo-4-phenylimidazolidin-1- yl)acetamide	523 nM (0.83)
	N-(4-bromophenyl)-2-(4-cyclopropyl-4- methyl-2,5-dioxoimidazolidin-1- yl)acetamide	166 nM (0.84)
	N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.6]undec-3-yl)acetamide	679 nM (0.96)
	N-(4-bromophenyl)-2-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1- yl)acetamide	485 nM (1.0)
	N-(4-chlorophenyl)-2-(4,4-diethyl-2,5- dioxoimidazolidin-1-yl)acetamide	314 nM (0.79)
	2-(4,4-diethyl-2,5-dioxoimidazolidin-1- yl)-N-(4-fluorophenyl)acetamide	2771 nM (0.67)
	N-(4-bromophenyl)-2-[4-methyl-2,5- dioxo-4-(2-phenylethyl)imidazolidin-1- yl]acetamide	860 nM (0.88)
	N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-4,7-methano-2H- isoindole-2-acetamide	575 (0.90)
	N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-2H-isoindole-2- acetamide	395 (0.98)

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

In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of the N-formyl peptide receptor like-1 receptor.

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

Therapeutic utilities of the N-formyl peptide receptor like-1 receptor modulators are dermatological inflammation and diseases including, but not limited to, dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, other disorders of pigmentation, and alopecia (scarring and non-scarring forms).

These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by the N-formyl peptide receptor like-1 receptor modulation: dermatological inflammation and diseases including, but not limited to, dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma, post-inflammatory hyperpigmentation, other disorders of pigmentation, and alopecia (scarring and non-scarring forms).

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

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.

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.

In another embodiment of the invention, 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.

Pharmaceutical compositions of the present invention 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 invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds 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.

Pharmaceutical compositions containing invention compounds 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 invention compounds 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.

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.

Pharmaceutical compositions containing invention compounds 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.

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.

The compounds of the invention 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.

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.

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 the N-formyl peptide receptor like-1 (FPRL-1) receptor. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of the N-formyl peptide receptor like-1 (FPRL-1) receptor. 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

FPR2 agonists would be expected to have significant effects in many different types of dermatological inflammation, but have been exemplified by demonstrating wound healing in a mouse model of punch dermal wound (FIG. 2). Anti-inflammatory activity in this model has been exemplified with the FPR2 agonists described in Table 4.

FLIPR: 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
Com-			FPR2
pound			EC50
number	Structure	IUPAC name	(% eff)
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]heptane- 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- l,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]heptane- 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	<1 nM (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]amino}- 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- fluorophenylcarbamoyl]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]amino}- 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]amino}- 4- methylpentanoyl]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-{[(4- bromophenyl)carbamoyl]amino}- 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-fIuorophenyl)-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		(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 □M (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-({[4- (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-(1H-tetrazol-5- ylmethyl)-2-({[4- (trifluoromethyl)phenyl] carbamoyl}amino)pentanamide	3.7 nM (0.96)
137		{[(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- bromopheml)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)

Immunohistochemistry: Fluorescent immunohistochemistry with antibodies specific to FPR2 was used to determine localization in normal human skin. Anti-FPR2 antibody (Abcam) was used at a dilution of 1:200 to detect FPR2 protein.

Dermal wound healing model: Groups of 5 ICR male mice weighing 24-28 g were used.

During the study, the tested animals were housed in individual cages. Under hexobarbital (90 mg/kg, i.p.) anesthesia, the shoulder and back region of each animal was shaved. A sharp punch (ID 12 mm) was applied to remove the skin including panniculus carnosus and adherent tissues. The wound area, traced onto clear plastic sheets, was measured by use of an Image—ProPlus (Media Cybernetics, Version 4.5.0.29) on days 1, 3, 5, 7, 9 and 11. Test substances and vehicle (Placebo, 20 μL/mouse) were administered topically (TOP) once daily post skin punch for a total of 10 consecutive days. The positive control of CGS-21680 in 0.5% CMC/PBS, pH 7.4 was given topically as the same regimen. The percent closure of the wound (%) was calculated, and wound half-closure time (CT50) was analyzed by linear regression using Graph-Prism (Graph Software USA). One-way ANOVA followed by Dunnett's test was applied for comparison between the treated and vehicle groups at each measurement time point. Differences are considered significant at P<0.05.

LL37-induced model of rosacea in mice: Prior to dosing, animals are lightly anaesthetized with isofluorane and baseline right and left ear thickness measurements are made with a digital caliper (Mitutoyo 293-340). At t=−1 hrs, animals are lightly anaesthetized with isoflurane to allow topical application (dorsal side) of 10 μL of FPR2 agonist formulated in a vehicle consisting of PBS:ethanol (50:50), or vehicle control to both ears. At t=0 hr, mice are re-anaesthetized. Following ear thickness measurements, 20 uL of LL-37 (100 μM) is injected into the right ear, while PBS is injected into the left ear. Additional ear thickness measurements are taken at t=3 and 6 hours. After the last time point, mice are euthanized by CO₂ inhalation and ears collected for additional analyses.

In vitro human skin penetration model: Briefly, split-thickness human abdominal skin (˜0.50 mm) sections from two donors were mounted in flow-through diffusion cells (PermeGear). FPR2 agonists are applied at a dose of 10 μL to a surface area of 0.64 cm² (n=7 per compound). PBS is pumped beneath the skin at a constant flow rate of ˜42 μL/min. Receptor fluid samples are collected at 1, 3, 6, 12, and 24 hrs and analyzed by LC/MS/MS.

Claims

1. A method of treating dermal inflammation or a dermal disease in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a formyl peptide receptor 2 (FPR2) agonist of Formula I:

2. The method of claim 1, wherein the compound of Formula I is:

3. The method of claim 1, wherein the compound is

4. The method of claim 1, wherein the local delivery is topical dermal delivery.

5. The method of claim 2, wherein the local delivery is topical dermal delivery.

6. The method of claim 3, wherein the local delivery is topical dermal delivery.

7. The method of claim 4, wherein the pharmaceutical composition is in a form selected from the group consisting of a cream, a lotion, a gel, a solution, a spray, a foam, a suspension and an emulsion.

8. The method of claim 5, wherein the pharmaceutical composition is in a form selected from the group consisting of a cream, a lotion, a gel, a solution, a spray, a foam, a suspension and an emulsion.

9. The method of claim 6, wherein the pharmaceutical composition is in a form selected from the group consisting of a cream, a lotion, a gel, a solution, a spray, a foam, a suspension and an emulsion.