US20140256685A1 - Use of agonists of formyl peptide receptor 2 for treating dermatological diseases - Google Patents

Use of agonists of formyl peptide receptor 2 for treating dermatological diseases Download PDF

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US20140256685A1
US20140256685A1 US14/196,155 US201414196155A US2014256685A1 US 20140256685 A1 US20140256685 A1 US 20140256685A1 US 201414196155 A US201414196155 A US 201414196155A US 2014256685 A1 US2014256685 A1 US 2014256685A1
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amino
bromophenyl
carbamoyl
optionally substituted
alkyl
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US14/196,155
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Richard L. Beard
John E. Donello
Veena Viswanath
Edward Hsia
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Allergan Inc
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Allergan Inc
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Priority to US14/196,155 priority Critical patent/US20140256685A1/en
Assigned to ALLERGAN, INC. reassignment ALLERGAN, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DONELLO, JOHN E., HSIA, EDWARD, VISWANATH, VEENA, BEARD, RICHARD L.
Publication of US20140256685A1 publication Critical patent/US20140256685A1/en
Priority to US15/490,127 priority patent/US10434112B2/en
Priority to US16/566,682 priority patent/US10799518B2/en
Priority to US17/028,440 priority patent/US20210008085A1/en
Priority to US17/028,416 priority patent/US20210000846A1/en
Abandoned legal-status Critical Current

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof

Definitions

  • 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).
  • FPR2 Formyl peptide receptor 2
  • 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 D W P, Rovati E, Shimizu T, Yokomizo T, Brink, C.
  • the lipoxin receptor ALX Potent ligand-specific and stereoselective actions in vivo.
  • 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 sCK ⁇ 8-1, 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 D W P, Rovati E, Shimizu T, Yokomizo T, Brink, C.
  • SAA serum amyloid A
  • LXA4 anti-inflammatory eicosanoid lipoxin A4
  • glucocorticoid-modulated protein annexin A1 Choang N, Serhan C N, Dahlen, S, Drazen J M, Hay D W P, Rovati E, Shimizu T, Yokomizo T, Brink, C.
  • 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. Pharamcology & 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.
  • FPR2 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 F N E, Hughes E L, Buss N A P S, 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.
  • PMNs polymorphonuclear neutrophils
  • eosinophils migration also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner
  • FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.
  • FASEB 2010; 24: 4240-4249 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.
  • NK natural killer
  • 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.
  • Asprin-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.
  • LL37 a pro-inflammatory cathelicidin which has been shown to be a natural ligand of FPR2.
  • 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).
  • 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).
  • FPR2 Formyl peptide receptor 2
  • 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.
  • 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.
  • 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, ery
  • 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 ).
  • 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.
  • 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).
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).
  • FPR2 Formyl peptide receptor 2
  • 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
  • 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.
  • 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.
  • 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.
  • R 1 is sec-butyl, C 6-10 aryl, —CH 2 —(C 6-10 )aryl, —CH 2 -heterocycle, C 4-8 cycloalkyl or C 3-8 cycloalkenyl or heterocycle;
  • R 2 is halogen or methyl;
  • R 3 is halogen;
  • R 4 is H, methyl or halogen;
  • R 5 is OR 6 or NH 2 ;
  • R 6 is H or C 2-4 alkyl.
  • 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.
  • 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.
  • 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.
  • R 1 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, —NR 11 R 12 or —OR 13 ;
  • R 2 is optionally substituted C 1-8 alkyl or optionally substituted C 6-10 aryl;
  • R 3 is hydrogen, optionally substituted C 1-8 alkyl, halogen, —COOR 15 , —OR 13 , —NR 11 R 12 , NO 2 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl or optionally substituted C 3-8 cycloalkenyl;
  • R 4 is hydrogen, optionally substituted C 1-8 alkyl
  • 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.
  • 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.
  • 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.
  • R 1 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
  • R 2 is halogen, optionally substituted C 1-8 alkyl, CF 3 , OR 9 , C(O)R 10 , NO 2 , NR 13 R 14 , CN, SR 15 or SO 2 R 16 ;
  • R 3 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R 5 forms a 10- or 11-membered polycyclic ring which is optionally substituted;
  • R 4 is hydrogen, optionally substituted C 1-8 alkyl,
  • R 5 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R 5 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted;
  • R 5 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R 4 forms a spiro monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R 3 forms a 5 or 6 member ring which is optionally substituted;
  • R 6 is halogen, hydrogen, optionally
  • 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.
  • 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.
  • 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.
  • R 1 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 R 2 can form an optionally substituted cyclobutyl; R 2 is isopropyl or together with R 3 can form a substituted or unsubstituted 3 to 6 member ring heterocycle or together with R 1 can form an optionally substituted cyclobutyl, cyclopropyl; and R 3 is hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C
  • 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.
  • 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.
  • 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.
  • the invention provides a method for treating dermatological
  • 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.
  • 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.
  • A is C 6-10 aryl, Heterocyle, C 3-8 cycloalkyl or C 3-8 cycloalkenyl;
  • R 17 is C 1-6 alkyl or
  • B is C 6-10 aryl, heterocyle, C 3-8 cycloalkyl or C 3-8 cycloalkenyl;
  • R 1 is H, halogen, —S(O)R 15 , —S(O) 2 R 11 , nitro, cyano, —OC 1-6 alkyl, —SC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C(O)R 12 , NR 13 R 14 , C 3-8 cycloalkyl or hydroxyl;
  • R 2 is H, halogen, —S(O)R 15 , —S(O) 2 R 11 , nitro, cyano, —OC 1-6 alkyl, —SC 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C(O)R 12 , NR 13 R 14 , C
  • X is O or S
  • Y is O or S
  • R 11 is H, hydroxyl, —C 1-6 alkyl, C 3-8 cycloalkyl or NR 13 R 14 ;
  • R 12 is H, hydroxyl, —C 1-6 alkyl, hydroxyl, C 3-8 cycloalkyl, NR 13 R 14 or —OC 1-6 alkyl;
  • R 13 is H, —C 1-6 alkyl, C 3-8 cycloalkyl, SO 2 R 11 or C(O)R 16 ;
  • R 14 is H, —C 1-6 alkyl or C 3-8 cycloalkyl;
  • R 15 is —C 1-6 alkyl, or C 3-8 cycloalkyl;
  • R 16 is H, —C 1-6 alkyl or C 3-8 cycloalkyl;
  • the invention provides a method for treating dermatological
  • 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
  • FPR2 disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.
  • 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.
  • n is 0 or 1;
  • R 1 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NC(O)R 20 , —OR 10 , —OC(O)R 21 —SR 11 , —C(O)R 12 , CN or NO 2 ;
  • R 2 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NC(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , CN or NO 2 ;
  • R 3 is hydrogen, substituted or unsubstituted C 1-8 alkyl, halogen, —NR 8 R 9 , —NC(O)R 20 , —OR 10 , —OC(O)R 21 , —SR 11 , —C(O)R 12 , CN,
  • R 13 is ⁇ OR 22 ;
  • R 14 is ⁇ OR 23 ;
  • R 15 is substituted or unsubstituted C 1-8 alkyl
  • R 16 is substituted or unsubstituted C 1-8 alkyl, —NR 8 R 9 , —NHS(O) 2 R 19 or hydroxyl;
  • R 17 is OR 16 or NR 8 R 9 ;
  • R 18 is OR 16 or NR 8 R 9 ;
  • R 19 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;
  • R 20 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;
  • R 21 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;
  • R 22 is hydrogen, substituted or unsubstituted C 1-8 alkyl, or together with R 23 can form a cycle;
  • R 23 is hydrogen, substituted or
  • alkyl 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 (—CH 2 —) 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.
  • cycloalkyl 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.
  • cycloalkenyl 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.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine.
  • alkenyl 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 (—CH 2 —) 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.
  • alkynyl 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 (—CH 2 —) 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.
  • heterocycle 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.
  • aryl 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, carboxcyclic 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.
  • hydroxyl as used herein, represents a group of formula “—OH”.
  • carbonyl as used herein, represents a group of formula “—C(O)—”.
  • ketone 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.
  • amine as used herein, represents a group of formula “—NR x R y ⁇ , wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
  • sulfonyl as used herein, represents a group of formula “—SO 2 ⁇ ”.
  • sulfonate represents a group of the formula “—S(O) 2 —O—”.
  • carboxylic acid as used herein, represents a group of formula “—C(O)OH”.
  • nitro as used herein, represents a group of formula “—NO 2 ”.
  • cyano as used herein, represents a group of formula “—CN”.
  • amide as used herein, represents a group of formula “—C(O)NR x R y ,” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
  • sulfonamide represents a group of formula “—S(O) 2 NR x R y ” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
  • sulfoxide as used herein, represents a group of formula “—S(O)—”.
  • phosphonic acid as used herein, represents a group of formula “—P(O)(OH) 2 ”.
  • phosphoric acid as used herein, represents a group of formula “—OP(O)(OH) 2 ”.
  • sulphonic acid as used herein, represents a group of formula “—S(O) 2 OH”.
  • N represents a nitrogen atom
  • agonists of FPR2 are compounds selected from Table 1:
  • 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.
  • 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.
  • agonists of FPR2 are compounds selected from Table 2:
  • agonists of FPR2 are compounds selected from Table 3:
  • the compounds of Table 3 are available from Chemical Libraries such as Chemical Block Ltd.
  • 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.
  • 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).
  • dermatological inflammation and diseases including, but not limited to, dermal wound healing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic ker
  • methods for treating disorders associated with modulation of the FPRL-1 receptor 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.
  • 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.
  • 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.
  • compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof.
  • 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.
  • 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.
  • Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • 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.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FPRL-1 N-formyl peptide receptor like-1
  • methods for treating a disorder associated with modulation of the N-formyl peptide receptor like-1 (FPRL-1) receptor 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.
  • 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.
  • the subject in need thereof is a mammal. In some embodiments, the mammal is human.
  • 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.
  • HEK-G ⁇ 16 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 ⁇ g/ml hygromycin, and 400 ⁇ g/ml geneticin.
  • FBS fetal bovine serum
  • HBSS/hepes buffer Hank's Balanced Salt Solution supplemented with 20 mM HEPES
  • the cells were then dye loaded with 2 ⁇ M Fluo-4 diluted in the HBSS/Hepes buffer and incubated at 37° C.
  • Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates. Data for Ca +2 responses were obtained in relative fluorescence units.
  • 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.
  • mice 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 ⁇ L/mouse) were administered topically (TOP) once daily post skin punch for a total of 10 consecutive days.
  • TOP topically
  • PBS is pumped beneath the skin at a constant flow rate of ⁇ 42 ⁇ L/min.
  • Receptor fluid samples are collected at 1, 3, 6, 12, and 24 hrs and analyzed by LC/MS/MS.

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US10799518B2 (en) 2020-10-13
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WO2014138046A1 (en) 2014-09-12
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