C5aR1 inhibitors for use in the treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid - Patent Application 20070122997

Abstract

The present invention relates to C5aR1 inhibitors for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid.

Description

[Technical Field]

[0001] The present invention relates to C5aR1 inhibitors for use in the prevention and / or treatment of ocular mucous membrane pemphigoid (OcMMP) and / or oral mucous membrane pemphigoid. [Background technology]

[0002] Mucous membrane pemphigoid (MMP) is a systemic, scarring autoimmune disease that primarily affects the orifice mucosa, such as the conjunctiva, nasal passages, oropharynx, and genitals. Approximately 75% of patients with MMP develop antibodies against BP180 (type XVII collagen), and 25% develop antibodies against laminin 332. In less than 5% of patients with MMP, antibodies against type VII collagen or α6β4 integrin are detected (Domloge-Hultsch, N., et al., J Clin Invest, 1992. 90(4): pp. 1628-33; Oyama, N., et al., Br J Dermatol, 2006. 154(1): pp. 90-8; Schmidt, E., et al., Br J Dermatol, 2001. 145(5): pp. 778-83).

[0003] Ocular involvement occurs in approximately 70% of all MMP cases, and ocular MMP is the leading cause of cicatricial conjunctivitis in developed countries. Linear immunoglobulin A disease, mucosal-predominant epidermolysis bullosa acquisita, and anti-laminin 332 / anti-epiligrin / anti-laminin 5 pemphigoid are encompassed by ocular MMPs (OcMMPs).

[0004] The progressive inflammation and scarring characteristics of ocular MMP lead to severe visual impairment in 30% of affected eyes and bilateral blindness in 20%. Ocular MMP is often associated with oral mucosal lesions, including desquamative gingivitis, vesicles, pseudomembrane-covered sores, and ulcers.

[0005] In some cases of MMP, only the oral mucosa is affected. The basic pathophysiological mechanism of the disease is a type 2 hypersensitivity reaction to the basement epithelial membrane of the conjunctiva. Conjunctival damage is particularly important because autoantibody-induced inflammation leads to conjunctival scarring, which can progress even after the inflammatory process has ceased, leading to visual impairment and blindness.

[0006] Early diagnosis and appropriate treatment are of paramount importance to avoid inflammatory and infectious complications and possible vision loss. Several mechanisms have been proposed for the underlying pathogenesis of antibody-mediated MMP.

[0007] Management of ocular MMPs aims to control immune-mediated inflammatory disease and prevent fibrosis and disease progression. Georgoudis, P. et al., "Ocular Mucous Membrane Pemphigoid: Current State of Pathophysiology, Diagnostics, and Treatment," Ophthalmol. Ther. (2019) 8, 5-17, discloses a stepwise approach to select immunosuppressants and intensify treatment depending on disease severity (mild, moderate, severe). Medications used include dapsone, sulfapyridine, sulfasalazine, azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), cyclophosphamide, and short-term oral steroids.

[0008] CD20 monoclonal antibodies, TNFα inhibitors, and intravenous immunoglobulin (IVIg) are used to treat the disease in patients unresponsive to conventional immunosuppressive drugs.

[0009] The therapeutic mainstays are high-dose systemic corticosteroids supplemented with potential corticosteroid-sparing agents, e.g., azathioprine, mycophenolate, dapsone, antibiotics with anti-inflammatory activity, e.g., doxycycline, high-dose intravenous immunoglobulin, and the anti-CD20 antibody rituximab.

[0010] Current treatment avenues are often ineffective and associated with severe adverse events. Therefore, there is a great need for further effective and safe treatments. A variety of C5aR1 inhibitors have been developed and are well known to those skilled in the art.

[0011] WO2007 / 060215 discloses (R)-arylalkylamino derivatives and their use in treating diseases involving C5a-induced human PMN chemotaxis, such as sepsis, psoriasis, bullous pemphigoid, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, glomerulonephritis, and in the prevention and treatment of damage caused by ischemia and reperfusion. Summary of the Invention [Problem to be solved by the invention]

[0012] It is therefore an object of the present invention to provide an effective treatment for MMPs, particularly ocular and oral MMPs. [Means for solving the problem]

[0013] The present invention is directed to a C5aR1 inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid (OcMMP) and / or oral mucous membrane pemphigoid in a subject. The present invention is also directed to a pharmaceutical composition comprising a C5aR1 inhibitor and at least one pharmaceutically acceptable excipient or carrier, for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid in a subject.

[0014] The present invention is also directed to a method for preventing and / or treating ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid, comprising administering an effective amount of one or more C5aR1 inhibitor compounds of the present invention to a subject in need thereof.

[0015] The present invention is also directed to the use of the claimed C5aR1 inhibitors in the manufacture of a medicament for preventing and / or treating ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid in a subject. [Brief explanation of the drawings]

[0016] [Figure 1] This figure shows the effects of treatment with DF3966A administered by topical ocular application or methylprednisolone (MP) administered by intraperitoneal injection, compared with control treatment with vehicle administered by topical ocular administration (Vehicle), in an experimental MMP mouse model 12 days after the initial anti-mLAMα3 IgG injection. In detail: Panel A shows the effect of DF3966A or MP on palpebral conjunctival dehiscence formation on day 12, shown as conjunctival scores. Data are presented as mean + / - standard deviation. A statistically significant difference is observed between the vehicle group and DF3966A on day 12 (p=0.0016). Animals treated with IgG isolated from normal rabbit serum (NR IgG) injected sc were used as a negative control.

[0017] Data are based on 12–14 mice per group, except for NR IgG (n = 10). Asterisks indicate statistical significance (ANOVA with Holm-Sidak method for multiple comparisons).

[0018] Panel B shows semi-quantification of subepithelial inflammatory infiltrates based on hematoxylin and eosin (H&E)-stained biopsies of the palpebral conjunctiva in mice treated with DF3966A or MP. A statistically significant difference is observed between the vehicle and MP groups on day 12. Animals treated with IgG isolated from sc-injected normal rabbit serum (NR IgG) were used as negative controls.

[0019] Data are presented as mean + / - standard deviation. Data are based on 7-10 mice per group, except for NR IgG (n = 3). Asterisks indicate statistical significance (ANOVA with Holm-Sidak method for multiple comparisons). [Figure 2] FIG. 1 shows representative clinical images of H&E-stained sections of the eye and palpebral conjunctiva obtained 12 days after the initial anti-mLAMα3 IgG injection in mice treated with DF3966A by topical ocular administration or with methylprednisolone (MP) by intraperitoneal injection. [Figure 3] Figure 1 shows reduced dehiscence formation in the palpebral conjunctiva of experimental MMP mice 28 days after the initial anti-mLAMα3 IgG injection, treated with topical ocular administration of DF3966A or intraperitoneal injection of methylprednisolone (MP). In detail: Panel A shows the effect of treatment with DF3966A or MP compared to vehicle on palpebral conjunctival dehiscence formation at day 28, shown as conjunctival score. Animals treated with sc injected IgG isolated from normal rabbit serum (NR IgG) were used as negative controls.

[0020] Data are presented as mean + / - standard deviation. A statistically significant difference is observed between the vehicle group and DF3966A on day 28 (p = 0.0414). Data are based on 11–14 mice per group, except for NR IgG (n = 9). Asterisks indicate statistical significance (ANOVA with the Holm-Sidak method for multiple comparisons).

[0021] Panel B shows semi-quantification of subepithelial inflammatory infiltrates based on hematoxylin and eosin (H&E)-stained biopsies of the palpebral conjunctiva in mice treated with DF3966A or MP compared with vehicle. Animals treated with IgG isolated from normal rabbit serum (NR IgG) injected sc were used as negative controls. Data are presented as mean + / - standard deviation. A statistically significant difference is observed between the vehicle group and DF3966A on day 28 (p = 0.0188). Data are based on 7–9 mice per group, except for NR IgG (n = 5). Asterisks indicate statistical significance based on ANOVA with Dunnett's method for multiple comparisons. [Figure 4] FIG. 1 shows representative clinical images of H&E-stained sections of the eye and palpebral conjunctiva obtained 28 days after the initial anti-mLAMα3 IgG injection in mice treated with DF3966A by topical ocular administration or with methylprednisolone (MP) by intraperitoneal injection. [Figure 5] Figure 1 shows the effect of DF3996A and MP treatment on the severity of oral lesions on day 12, shown as oral score. Data are presented as mean + / - standard deviation. A statistically significant difference was observed between the vehicle group and DF3996A on day 12 (p = 0.0479). Data are based on 12-14 mice per group, except for NR IgG (n = 10). Asterisks indicate statistical significance (ANOVA with Holm-Sidak method for multiple comparisons). [Figure 6] Figure 1 shows the effect of DF3996A and MP treatment on the severity of oral lesions on day 28, expressed as oral score. Data are presented as mean + / - standard deviation. There is a statistically significant difference between the vehicle group and DF3996A on day 28 (p = 0.0372). MP treatment significantly increased oral score compared to the vehicle-treated group (p = 0.0136). Data are based on 11–14 mice per group, except for NR IgG (n = 9). Diamonds indicate statistical significance by ANOVA using Fisher's LSD test (uncorrected for multiple comparisons). DETAILED DESCRIPTION OF THE INVENTION

[0022] It has surprisingly been found that C5aR1 inhibitors are effective in preventing and / or treating ocular mucous membrane pemphigoid (OcMMP) and / or oral mucous membrane pemphigoid in subjects.

[0023] The terms "treatment" and "prevention," as used herein, refer to eradicating / ameliorating or preventing / delaying, respectively, the onset of the disorder being treated or one or more of the symptoms associated therewith, notwithstanding the fact that the patient may still be afflicted with the underlying disorder.

[0024] Thus, the present invention is directed to a C5aR1 inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid. According to a preferred embodiment, the present invention is directed to a C5aR1 inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid.

[0025] According to a further preferred embodiment, the present invention is directed to a C5aR1 inhibitor for use in the prevention and / or treatment of oral mucous membrane pemphigoid. According to a further preferred embodiment, the present invention is directed to a C5aR1 inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and oral mucous membrane pemphigoid.

[0026] The term "C5aR1 inhibitor" means, according to the present invention, any compound that interacts with C5aR1 and prevents it from binding to C5a or blocks C5aR1 signaling upon binding of C5a.

[0027] Preferably, the C5aR1 inhibitor compound is selected from a C5aR1 competitive antagonist, an anti-C5aR1 antibody capable of blocking the C5a binding site on the receptor, and a C5aR1 non-competitive allosteric inhibitor, and more preferably, the C5aR1 inhibitor compound is a non-competitive allosteric inhibitor.

[0028] According to the present invention, a "non-competitive allosteric inhibitor of the C5a receptor" means a compound that interacts with the C5a receptor located in the TM region at an allosteric site and inhibits intracellular signaling events activated by agonist binding, without affecting any binding of the endogenous ligand C5a on the receptor.

[0029] According to one preferred embodiment, the C5aR1 competitive antagonist is (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (Avacopan, Vynpenta®); - N-acetyl-L-phenylalanyl-L-ornityl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyl-L-arginine-N-5.2-C-1.6-lactam (PMX-53); - Acetylated phenylalanine-[ornithine-proline-(D)cyclohexylalanine-tryptophyl-arginine]; - L-alanyl-L-seryl-glycyl-L-alanyl-L-prolyl-L-alanyl-L-prolyl-glycyl-L-prolyl-L-alanyl-glycyl-L-prolyl-L-leucyl-L-arginyl-L-prolyl-L-methionyl-L-phenylalanine; - N,N-bis(1,3-benzodioxol-5-ylmethyl)-N-(1-butyl-2,4-diphenyl-1H-imidazol-5-ylmethyl)amine; - N-[2-(4-chlorophenyl)ethyl]-N-(1,4-dioxaspiro[4.5]dec-8-yl)-2-isobutylbenzamide; - N-[2-(4-chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)-1-benzothiophene-3-carboxamide; - N-[2-(4-chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)naphthalene-1-carboxamide; - 2-(2-ethyl-6-methylphenyl)-4-methoxy-N-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-amine; - 2-(2,6-diethylphenyl)-N-ethyl-4-methoxy-N-(1-naphthyl)-5,6,7,8-tetrahydroquinolin-5-amine; - N-[2,6-dioxohexahydropyrimidin-4(S)-ylcarbonyl]-L-phenylalanyl-L-ornityl-L-prolyl-5-methyl-L-norleucyl-4-fluoro-L-phenylalanyl-L-phenylalaninamide (JPE-1375; JSM-1375); - N-(3-phenylpropionyl)-L-ornityl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyl-L-arginine N-5.1-C-1.5-lactam (PMX-205); - N,N'-bis(4-amino-2-methylquinolin-6-yl)urea (NSC12155); - N-[4-(dimethylamino)benzyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (W54011); - L-phenylalanyl-L-ornityl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyl-L-arginine N-5.2-C-1.6-cyclic peptide; - (4aR,16aS)-6,18-dihydroxy-23(S)-[2(S)-hydroxy-2-[2(R)-hydroxy-6(R)-methyl-5(R)-[2(S)-methylbutyl]tetrahydro-2H-pyran-2-yl]propionamido]-22(S)-isopropyl-7(S),19(R)-dimethyldocosahydro-13H,22H-dipyridazino[6,1-f:6',1'o][1,4,7,10,13,16]oxapentaazacyclononadecin-5,7,11,17,20,24-hexanone (L-156602) is selected from the group consisting of:

[0030] Anti-C5aR1 antibodies are commercially available, for example they are sold by Abcam, ThermoFisher Scientific, Biocompare. According to one preferred embodiment, the anti-C5aR1 antibody or aptamer is - Abdullimab (IPH-5401) - MOR-044254, also known as anti-C5aR monoclonal antibody TJ210; - NOX-D20, a PEGylated biostable enantiomer mixed (L)RNA / DNA aptamer (Spiegelmer); - anti-C5aR1ab-C5-SiRNA conjugate, anti-C5aR1ab-protamine-C5 siRNA conjugate; - m20 / 70mlgG2a.1; - 3C5; - 7F3 is selected from the group consisting of:

[0031] According to one preferred embodiment, the non-competitive allosteric inhibitor is - (2R)-2-[3-(furan-2-carbonyl)phenyl]-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]propenamide (DF2427); - R(-)-2-[(4'-trifluoromethanesulfonyloxy)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide (DF2297X) or its chloride salt (DF2297A); and - compounds of formula (I) and (II) as described herein below is selected from.

[0032] According to a preferred embodiment, the non-competitive allosteric inhibitor is a compound having the general formula (I):

[0033] [ka]

[0034] or a pharmaceutically acceptable salt thereof, R is 2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from the group consisting of methyl, tert-butyl, or trifluoromethyl; C(Ra)=NW (W is a linear or branched C1-C4 alkyl), - CORa, SORa, SO2Ra, PORa, PO2Ra is selected from Ra is - C1-C5-alkyl, C3-C6-cycloalkyl, C2-C5-alkenyl, unsubstituted or substituted phenyl by a group selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, halo-C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino; heteroaryl radicals selected from pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole, unsubstituted or substituted by a radical selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, halo-C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino; - α- or β-carboxyalkyl residues, consisting of linear or branched C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C1-C6-phenylalkyl, optionally substituted by additional carboxy (COOH) groups; an ω-aminoalkylamino group of formula (II):

[0035] [ka]

[0036] is selected from In the formula (II), X is - linear or branched C1-C6 alkylene, C4-C6 alkenylene, C4-C6 alkynylene optionally substituted with a) or b): a) a CO2R4 group (R4 represents hydrogen, a linear or branched C1-C6 alkyl group, or a linear or branched C2-C6 alkenyl group); b) the CONHR5 group (where R5 is - hydrogen, linear or branched C2-C6 alkyl, or an OR4 group where R4 is as defined above represents); - optionally substituted by a CO2R4 or CONHR5 group as defined above (CH2) m -B-(CH2) n a group in which B is oxygen, or a sulfur atom or nitrogen atom optionally substituted by a C1-C4 alkyl group, m is 0 or an integer of 2 to 3, and n is an integer of 2 to 3; or B is a CO group, an SO group, or a CONH group, m is an integer of 1 to 3, and n is an integer of 2 to 3. is selected from R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, linear or branched C1-C6 alkyl optionally interrupted by oxygen or sulfur atoms, C3-C7 cycloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl-C1-C3-alkyl, hydroxy-C2-C3-alkyl groups; or R2 and R3 together with the N atom to which they are attached form a 3- to 7-membered nitrogen heterocyclic ring of formula (III),

[0037] [ka]

[0038] Y is a single bond, CH2, O, S or an N-R6 group, where R6 represents hydrogen, C1-C4 alkyl, C1-C4 acyl, phenyl unsubstituted or substituted by a group selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino, p represents an integer from 0 to 3; residues of the formula SO2R7, where R7 is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, aryl and heteroaryl; represents or or In the formula (II), X, together with the nitrogen atom to which it is attached and the R2 group, forms a nitrogen-containing 3-7 membered heterocyclic ring, monocyclic ring, or polycyclic ring, and R3 is selected from the group including hydrogen, C1-C4 alkyl, C1-C4 acyl, phenyl unsubstituted or substituted with a group selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino; R1 is a linear or branched C1-C5 alkyl, C3-C5 cycloalkyl; Ar is a phenyl group that is unsubstituted or substituted by one or more groups independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino, C1-C4-acylamino, halo-C1-C3-alkyl, halo-C1-C3-alkoxy, benzoyl, heteroarylcarbonyl, heteroaryl, linear or branched C1-C8-alkanesulfonate, linear or branched C1-C8-alkanesulfonamido, linear or branched C1-C8-alkylsulfonylmethyl; or a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, and indole; (selected from is.

[0039] Among the above compounds, particularly preferred is the compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein: R is 2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from the group consisting of methyl, tert-butyl or trifluoromethyl; C(Ra)=NW (W is a linear or branched C1-C4 alkyl), - CORa, SORa, or SO2Ra is selected from Ra is as defined above; Ar is 3'-Benzoylphenyl, 3'-(4-chloro-benzoyl)-phenyl, 3'-(4-methyl-benzoyl)-phenyl, 3'-acetyl-phenyl, 3'-propionyl-phenyl, 3'-isobutanoyl-phenyl, 4'-isobutyl-phenyl, 4'-trifluoromethanesulfonyloxy-phenyl, 4'-benzenesulfonyloxy-phenyl, 4'-trifluoromethanesulfonylamino-phenyl, 4'-benzenesulfonylamino-phenyl, 4'-benzenesulfonylmethyl-phenyl, 4'-acetoxyphenyl, 4'-propionyloxy-phenyl, 4'-benzoyloxy-phenyl, 4'-acetylamino-phenyl, 4'-propionylamino-phenyl, 4 '-Benzoylamino-phenyl, 3'-(furan-2-carbonyl)-phenyl, 3'-(benzofuran-2-carbonyl)-phenyl, 3'-(thiophene-2-carbonyl)-phenyl, 3'-(pyridine-2-carbonyl)-phenyl, 3'-(thiazole-2-carbonyl)-phenyl, 3'-(oxazole-2-carbonyl)-phenyl, 3'-(2-furyl)-phenyl, 3'-(2-oxazolyl)-phenyl, 3'-(3-isoxazolyl)-phenyl, 3'-(2-benzoxazolyl)-phenyl, 3'-(3-benzisoxazolyl)-phenyl, 3'-(2-thiazolyl)-phenyl, 3'-(2-pyridyl)-phenyl, 3'-(2-thiophenyl)-phenyl or selected from the group comprising; Or Ar is a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, or indole).

[0040] According to a further embodiment, the (R)-arylalkylamino derivative is a compound of formula (I) as defined above, wherein R is 2-thiazolyl, unsubstituted or substituted by a group selected from methyl or trifluoromethyl, - CORa, SO2Ra and Ra is - C1-C5-alkyl, C3-C5-cycloalkyl; - phenyl, 2-pyridyl, 2-furyl, 2-thiophenyl; - a group of formula II

[0041] [ka]

[0042] is selected from In formula II, X is Straight or branched C1-C6 alkylene represents R2 and R3 together with the N atom to which they are attached form a 4- to 6-membered nitrogen-containing heterocyclic ring of formula (III),

[0043] [ka]

[0044] Y represents CH2, and p represents an integer from 0 to 2; R1 is methyl; Ar is 3'-benzoylphenyl, 3'-(4-chloro-benzoyl)-phenyl, 3'-(4-methyl-benzoyl)-phenyl, 4'-Trifluoromethanesulfonyloxy-phenyl, 4'-benzenesulfonyloxy-phenyl, 3'-(furan-2-carbonyl)-phenyl (selected from).

[0045] Preferred compounds of formula (I) according to the invention are - 4-{(1R)-1-[(phenylsulfonyl)amino]ethyl}phenyl trifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]benzenesulfonamide; 4-{(1R)-1-[(pyridin-3-ylsulfonyl)amino]ethyl}phenyl trifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]methanesulfonamide; - N-{(1R)-1-[3-(2-furoyl)phenyl]ethyl}thiophene-2-sulfonamide; - N-{(1R)-1-[3-(2-furoyl)phenyl]ethyl}methanesulfonamide; - 4-{(1R)-1-[(thien-2-ylsulfonyl)amino]ethyl}phenyl trifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]thiophene-2-sulfonamide; - N-[(1R)-1-(3-benzoylphenyl)ethyl]-3-pyrrolidin-1-ylpropane-1-sulfonamide; - methyl 5-({[(1R)-1-(3-benzoylphenyl)ethyl]amino}sulfonyl)-2-furoate; 5-({[(1R)-1-(3-benzoylphenyl)ethyl]amino}sulfonyl)-2-furoic acid; - 4-{(1R)-2-methyl-1-[(methylsulfonyl)amino]propyl}phenyl trifluoromethanesulfonate; - N-((1R)-1-{4-[1-methyl-1-(phenylsulfonyl)ethyl]phenyl}ethyl)methanesulfonamide; - 4-[(1R)-1-(isobutyrylamino)ethyl]phenyl trifluoromethanesulfonate; - 4-{[(1R)-1-(pyridin-3-ylcarbonyl)amino]ethyl]}phenyl trifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]benzamide; - N-[(1R)-1-(3-benzoylphenyl)ethyl]-2-furamide; - N-[(1R)-1-(3-benzoylphenyl)ethyl]cyclobutanecarboxamide; - N-[(1R)-1-(4-trifluoromethanesulfonyloxy)phenylethyl]-4-piperidin-1-ylbutanamide (DF2593Y); 4-{(1R)-1-[(4-pyrrolidin-1-ylbutanoyl)amino]ethyl]}phenyl trifluoromethanesulfonate; - 3-{(1R)-1-[4-(4-trifluoromethyl-1,3-thiazol-2-yl)amino]ethyl}phenyl)(phenyl)methanone is selected from.

[0046] A particularly preferred compound of formula (I) according to the invention is N-[(1R)-1-(4-trifluoromethanesulfonyloxy)phenylethyl]-4-piperidin-1-ylbutanamide (DF2593Y) and its pharmaceutically acceptable salts, preferably the chloride salt (DF2593A).

[0047] The compound of formula (I) is described in WO2007 / 060215, which also discloses methods for its synthesis. According to a further preferred embodiment, the non-competitive allosteric inhibitor is a compound having the general formula (II):

[0048] [ka]

[0049] or a pharmaceutically acceptable salt thereof (In the formula, X is a heteroatom selected from S, O, and N; Y is H or a residue selected from the group consisting of halogen, linear or branched C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkoxy, hydroxy, -COOH, C1-C4-acyloxy, phenoxy, cyano, nitro, -NH2, C1-C4-acylamino, halo-C1-C3-alkyl, benzoyl, linear or branched C1-C8-alkanesulfonate, linear or branched C1-C8-alkanesulfonamide, linear or branched C1-C8-alkylsulfonylmethyl; Z is unsubstituted tetrazole and a heteroaryl ring selected from the group consisting of triazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, thiadiazole and oxadiazole, which is substituted by one hydroxy group and optionally further substituted by one or more groups selected from the group consisting of halogen, linear or branched C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkylamino, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-acyloxy, cyano, nitro, NH2, C1-C4-acylamino, halo-C1-C3-alkyl, halo-C1-C3-alkoxy, linear or branched C1-C8-alkanesulfonate, and linear or branched C1-C8-alkanesulfonamide).

[0050] Among the above compounds of formula (II), preferred are X is a heteroatom selected from S and O; Y is H or a residue selected from the group consisting of halogen, linear or branched C1-C4-alkyl and halo-C1-C3-alkyl; preferably a residue selected from the group consisting of trifluoromethyl, chlorine, methyl and tert-butyl; Z is an unsubstituted tetrazole and a heteroaryl ring selected from the group consisting of triazole, pyrazole, isoxazole, isothiazole, thiadiazole and oxadiazole, substituted by one hydroxy group and optionally further substituted by one or more groups selected from the group consisting of halogen, linear or branched C1-C4-alkyl, C1-C4-alkylthio and halo-C1-C3-alkyl; preferably selected from the group consisting of methyl, trifluoromethyl and chlorine. It is a compound.

[0051] Particularly preferred compounds of formula (II) according to the invention are - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]tetrazol-2-ide (DF3966Y) or its sodium salt (DF3966A); - 4-methyl-N-{4-[(1R)-1-(1H-tetrazol-5-yl)ethyl]phenyl}-1,3-thiazol-2-amine; - 4-tert-butyl-N-{4-[(1R)-1-(1H-tetrazol-5-yl)ethyl]phenyl}-1,3-thiazol-2-amine; - N-{4-[(1R)-1-(1H-tetrazol-5-yl)ethyl]phenyl}-1,3-thiazol-2-amine; - N-{4-[(1R)-1-(1H-tetrazol-5-yl)ethyl]phenyl}-4-(trifluoromethyl)-1,3-oxazol-2-amine; - 4-methyl-N-{4-[(1R)-1-(1H-tetrazol-5-yl)ethyl]phenyl}-1,3-oxazol-2-amine; 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-pyrazol-1-ol; 4-methyl-5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-pyrazol-1-ol; 5-[(1R)-1-(4-([4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-1,2,3-triazol-1-ol; 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isoxazol-3-ol; 4-methyl-5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isoxazol-3-ol; 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isothiazol-3-ol; 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1,2,5-oxadiazol-3-ol; 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1,2,5-thiadiazol-3-ol; - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H1,2,4-triazol-1-ol is selected from.

[0052] A particularly preferred compound of formula (II) is 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]tetrazol-2-ide (DF3966Y) or its sodium salt (DF3966A).

[0053] The compound of formula (II) is described in WO2009 / 050258, which also discloses its synthesis. Preferred C5aR1 inhibitors according to the present invention are avacopan, PMX-53, W54011, abduralimab, MOR-044254, PMX-205, DF2593A, DF2297A, DF2427 and DF3966A, more preferably the C5aR1 inhibitor is DF3966A.

[0054] Preferably, the C5aR1 inhibitor for use according to the invention is administered topically to the ocular surface of the subject. Preferably, the C5aR1 inhibitor for use according to the invention is formulated in the form of eye drops.

[0055] As will be discussed in the Examples section, the inventors have shown that topical application of a C5aR1 inhibitor to the ocular surface results in an improvement in both ocular and oral MMPs.

[0056] The present invention is also directed to a pharmaceutical composition comprising the above-mentioned C5aR1 inhibitor and at least one pharmaceutically acceptable excipient or carrier, for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid.

[0057] Preferably, the pharmaceutical composition is an ophthalmic composition suitable for topical application to the ocular surface. Accordingly, the present invention is further directed to an ophthalmic composition comprising a therapeutically effective amount of a C5aR1 inhibitor as described above and at least one ophthalmically acceptable excipient or carrier.

[0058] According to a preferred embodiment, the present invention is further directed to an ophthalmic composition comprising a therapeutically effective amount of the above-mentioned C5aR1 inhibitor and at least one ophthalmologically acceptable excipient or carrier, for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid.

[0059] An "ophthalmologically acceptable excipient" is an inert excipient that allows a medication to be delivered to the eye and / or eyelid to treat an ocular disease or condition without adversely affecting the eye.

[0060] In some embodiments, the ophthalmic composition may be a liquid eye drop composition for topical administration to the anterior portion of the eye. The liquid composition may be in the form of a solution, emulsion or suspension. The liquid composition may comprise a micellar agent.

[0061] In one embodiment, the liquid composition is an aqueous composition. Preferably, the liquid composition is an aqueous eye drop composition. Preferably, the liquid composition comprises an ophthalmically acceptable excipient selected from an ophthalmically acceptable viscosity enhancing agent, a penetration enhancer, a buffering agent, an osmolality adjusting agent, a preservative, and a surfactant.

[0062] The viscosity enhancing agent has the function of increasing the viscosity of the composition and improving its retention in the conjunctival sac and is preferably selected from cellulose derivatives, preferably hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose; polyvinylpyrrolidone, and gelling agents, preferably gellan, xanthan gum, and carbopol-974.

[0063] The penetration enhancer functions to enhance the permeability of the drug through the ocular membrane and is preferably selected from cyclodextrins, chelating agents, crown ethers, bile acids, and bile salts.

[0064] The buffering agent functions to provide and maintain the correct pH of the formulation, making it suitable for use in the eye, preferably comprised between 6 and 8. A preferred buffer is phosphate buffer, although other buffers capable of maintaining a pH within the desired range are also included, particularly buffers suitable for ophthalmic use.

[0065] The tonicity adjusting agent is a salt that can make the liquid composition isotonic with ocular fluid. A preferred salt is sodium chloride (NaCl), but other biologically acceptable salts, such as potassium chloride (KCl), calcium chloride (CaCl), and magnesium chloride (MgCl), and mixtures thereof, may also be used.

[0066] Preservatives inhibit microbial activity. Suitable preservatives include, for example, quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0067] The surfactant has the function of stabilizing the composition and is preferably selected from polysorbates, such as Tween 80, poloxamers, such as Pluronics F68, or proteins, such as serum albumin.

[0068] The liquid eye drop composition may be part of a kit comprising the composition, a container for holding the composition, and an eye drop dispenser. A "therapeutically effective amount" according to the present invention means an amount sufficient to achieve treatment or prevention of a disease. Determining an effective amount is well within the ability of a person skilled in the art based on achieving the desired effect. The effective amount will depend on factors, including but not limited to, the subject's weight and / or the severity of the disease or undesirable condition from which the subject suffers.

[0069] The present invention also relates to the use of a C5aR1 inhibitor as defined above in the manufacture of a medicament for the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid. The present invention is also directed to a method for preventing and / or treating ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid, comprising administering an effective amount of one or more C5aR1 inhibitors of the present invention to a subject in need thereof.

[0070] The present invention is further illustrated by the following examples. [Example]

[0071] A study was designed to investigate and demonstrate the effects of pharmacological inhibition of C5aR1 exerted by compound DF3966A in an MMP mouse model. material and method Test compound - DF3966A sodium salt (Lot LC446-81-1 GLB21001, Dompe SpA) - Vehicle (solvent, Dompe SpA) - (positive control) - Methylprednisolone (MP) (provided by UKSH, Lübeck - supplied by Sanofi) - (reference treatment) Animal Models - Mice Adult C57Bl / 6 (B6) mice (male and female) at least 6 weeks old were used. Animals were maintained in the animal facility of the University of Lübeck on a 12-h light-dark cycle. Mice were housed under specific-pathogen-free conditions and provided with acidified drinking water and standard chow ad libitum. The protocol was approved by the Animal Rights Commission of the Ministry of Agriculture and Environment of Schleswig-Holstein. Generation, isolation, and characterization of anti-mLAMα3 IgG For the production of anti-mLAMα3 IgG, New Zealand White rabbits were subcutaneously immunized with 250 μg of an equimolar mixture of two purified recombinant proteins (aa1656-1985 and aa2756-3330 of the murine laminin alpha 3 chain, produced in Escherichia coli as described by Heppe, EN, et al., J Invest Dermatol, 2017, 137, 1709-1718) suspended in complete Freund's adjuvant. Animals were boosted twice with the same protein preparation in incomplete Freund's adjuvant. Immune sera were obtained at regular intervals and characterized on frozen sections of murine skin by IF microscopy. IgG from rabbits immunized with the recombinant fragment of murine mLAMα3 and from non-immunized rabbits was purified by affinity chromatography using Protein G Sepharose (Amersham Biosciences, Heidelberg, Germany). The reactivity of the IgG fractions on murine skin was analyzed by IF microscopy (Sitaru et al., Induction of complement-fixing autoantibodies against type VII collagen results in subepidermal blistering in mice. J Immunol 2006, 177:3461-8). Furthermore, each batch of anti-mLAMα3 IgG was characterized in vivo for its ability to induce experimental MMP in C57Bl / 6 (B6) mice (WP1.1). From this experiment, the amount of antibody that leads to moderate experimental MMP was determined; that is, the amount required to induce the development of disease with moderate conjunctival damage (i.e., a score of 1-3 in up to 50% of animals on day 12) in the antibody transfer-induced MMP model. For this purpose, the intensity of conjunctival separation was assessed histologically. The affected body surface area should be between 3-8% at the concentration used. A conjunctival score was determined postmortem histologically and ranged from 0 to 4 depending on the severity of conjunctival separation. The required dose was determined to be 5 mg / injection of anti-mLAMα3 IgG. research design Induction of experimental MMP by repeated injections of anti-mLAMα3 IgG, and treatment protocol To test the effect of 0.05% DF3966A on the severity of conjunctival damage in experimental MMP, adult B6 mice were induced by repeated subcutaneous (sc) injections of anti-mLAMα3 IgG (5 mg / mouse) every other day (days 0, 2, (···), and 10) and treated with eye drops twice daily throughout the experimental period. Three drops of eye drops were administered twice daily per eye. Mice treated with vehicle via eye drops or vehicle via ip injection of methylprednisolone (MP) served as treatment controls. Mice injected sc with IgG isolated from normal rabbit serum (NR IgG) served as negative controls. Evaluation of conjunctival lesions The primary endpoint of this study was the extent of conjunctival lesions, as determined by lesion histopathology (H&E staining) on ​​days 12 and 28 according to an established scoring system (Heppe, EN, et al., J Invest Dermatol, 2017, 137, 1709-1718). Specifically, biopsies from the palpebral conjunctiva were taken on days 12 and 28 and embedded in paraffin. Three 4.5 μm-thick sections were cut from biopsies at three different depths and stained with H&E for further quantification. Among the H&E-stained histological images, those with more than 1000 μm of palpebral conjunctival epithelium were used for quantification. For this score, the length of dehiscence (dehiscence = separation of the epithelium from the underlying dermal structures) was measured. The length of the dehiscence was scored from 0 to 4, with no dehiscence = 0, less than 100 μm = 1, less than 200 μm = 2, less than 300 μm = 3, and more than 300 μm = 4. Dehiscences occurring at the edge of the tissue were excluded because they were most likely artifacts resulting from sectioning. The longest dehiscence among the nine possible sections determined the final score.

[0072] Endpoints were analyzed on day 12 in the following groups: Normal rabbit IgG (n=10) Anti-mLAMα3 IgG + vehicle (positive control) (n=14) Anti-mLAMα3 IgG + MP (reference treatment) (n=13) ·Anti-mLAMα3 IgG+DF3966A (n=12).

[0073] Endpoints were analyzed at day 28 in the following groups: Normal rabbit IgG (n=9) Anti-mLAMα3 IgG + vehicle (positive control) (n=11) Anti-mLAMα3 IgG + MP (reference treatment) (n=11) ·Anti-mLAMα3 IgG+DF3966A (n=12).

[0074] The experiment was performed at two independent time points, on days 12 and 28, respectively, and included 7 mice / group and 5 mice / normal rabbit IgG group. Assessment of oral lesion severity The extent of oral lesions was assessed by endoscopy (Videomed, Munich, Germany) on days 12 and 28 according to an established scoring system (Heppe, EN, et al., J Invest Dermatol, 2017, 137, 1709-1718). Specifically, the presence of lesions / blisters / eschars / erosions in each affected quadrant of the mouse's oral cavity was scored as 1 point. The quadrants were defined as the left buccal mucosa, right buccal mucosa, hypopharynx, and tongue. The maximum score was 4. statistical analysis For statistical analysis, GraphPad Prism (version 8.4.3) was used. ANOVA was used to compare the effects of treatments across groups. Dunnett's or Holmsidak's multiple comparisons were used, where appropriate, to isolate distinct groups. result 1. Topical application of DF3966A reduced experimental MMP-induced dehiscence in the palpebral conjunctiva. Injection of rabbit anti-mLAMα3 IgG into adult B6 mice resulted in persistent induction of experimental MMP within 4–8 days after the first IgG injection.

[0075] After 12 days of topical application of the drug twice daily as eye drops, a significant reduction in conjunctival dehiscence formation was observed in the DF3966A-treated group compared with mice receiving vehicle alone (Figure 1A). Semiquantification of subepithelial inflammatory cell infiltration in H&E-stained palpebral conjunctival biopsies taken on day 12 from DF3966A-treated mice revealed no statistically significant reduction compared with biopsies from mice receiving vehicle (Figure 1B). No conjunctival lesions were observed on day 12 in mice injected with NR-IgG compared with the other groups (Figure 2).

[0076] Treatment of mice receiving DF3966A with eye drops twice daily for 28 days led to a significant reduction in palpebral conjunctival dehiscence (Figure 3A). This was also reflected in a reduction in subepithelial inflammatory infiltrates by semiquantification of H&E-stained biopsies of the palpebral conjunctiva (Figure 3B). Mice receiving only NR-IgG from healthy rabbits showed no conjunctival lesions at day 28 compared to the other groups (Figure 4).

[0077] DF3966A reduced conjunctival dehiscence formation on both days 12 and 28 of the experiment and reduced inflammatory infiltrates after 28 days of treatment compared with mice receiving vehicle. 2. Topical application of DF3966A reduces oral lesions in experimental MMP Treatment with DF3966A reduced the severity of oral lesions after 12 days (Figure 5) and 28 days (Figure 6) of eye drop application, with statistically significant differences observed between the vehicle group and DF3966A (day 12: p=0.0479; day 28: p=0.0372). conclusion Overall, twice-daily treatment with DF3966A eye drops reduced conjunctival dehiscence already at day 12, but did not reduce the underlying inflammation in these tissues. Prolonged treatment with eye drops for up to 28 days also reduced the inflammatory infiltrate in the palpebral conjunctiva. Furthermore, a significant reduction in the severity of oral lesions is observed at both days 12 and 28.

Claims

1. A pharmaceutical composition comprising a C5aR1 inhibitor for use in the prevention and / or treatment of ocular mucosal pemphigoid and / or oral mucosal pemphigoid in a subject.

2. The pharmaceutical composition according to claim 1, which is administered topically to the surface of the eye of a target.

3. The pharmaceutical composition according to claim 1 or 2, wherein the C5aR1 inhibitor is selected from a C5aR1 competitive antagonist, an anti-C5aR1 antibody, and a C5aR1 non-competitive allosteric inhibitor.

4. The C5aR1 inhibitor is as follows: - (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (Avacopan, Vynpenta®); - N-acetyl-L-phenylalanyl-L-ornityl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyll-L-arginine-N-5,2-C-1,6-lactam (PMX-53); - Acetylated phenylalanine - [ornityl-proline-(D)cyclohexylalanine-tryptophyll-arginine]; - L-alanyl-L-ceryl-glycyl-L-alanyl-L-prolyl-L-alanyl-L-prolyl-glycyl-L-prolyl-L-alanyl-glycyl-L-prolyl-L-leucyl-L-arginyl-L-prolyl-L-methionyl-L-phenylalanine; - N,N-bis(1,3-benzodioxol-5-ylmethyl)-N-(1-butyl-2,4-diphenyl-1H-imidazole-5-ylmethyl)amine; - N-[2-(4-chlorophenyl)ethyl]-N-(1,4-dioxaspiro[4.5]deca-8-yl)-2-isobutylbenzamide; - N-[2-(4-chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)-1-benzothiophene-3-carboxamide; - N-[2-(4-chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)naphthalene-1-carboxamide; - 2-(2-ethyl-6-methylphenyl)-4-methoxy-N-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-5-amine; - 2-(2,6-diethylphenyl)-N-ethyl-4-methoxy-N-(1-naphthyl)-5,6,7,8-tetrahydroquinoline-5-amine; - N-[2,6-dioxohexahydropyrimidine-4(S)-ylcarbonyl]-L-phenylalanyl-L-ornityl-L-prolyl-5-methyl-L-norleucyl-4-fluoro-L-phenylalanyl-L-phenylalaninamide (JPE-1375; JSM-1375); - N-(3-phenylpropionyl)-L-ornityl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyll-L-arginine N-5,1-C-1,5-lactam (PMX-205); - N,N'-bis(4-amino-2-methylquinoline-6-yl)urea (NSC12155); - N-[4-(dimethylamino)benzyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (W54011); - L-phenylalanyl-L-ornityl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyll-L-arginine N-5,2-C-1,6-cyclic peptide; - (4aR,16aS)-6,18-dihydroxy-23(S)-[2(S)-hydroxy-2-[2(R)-hydroxy-6(R)-methyl-5(R)-[2(S)-methylbutyl]tetrahydro-2H-pyran-2-yl]propionamide]-22(S)-isopropyl-7(S),19(R)-dimethyldocosahydro-13H,22H-dipyridazino[6,1-f:6',1'o][1,4,7,10,13,16]oxapentazacyclononadesine-5,7,11,17,20,24-hexanone (L-156602) The pharmaceutical composition according to claim 1 or 2, wherein the C5aR1 competitive antagonist is selected from the group consisting of the following.

5. The C5aR1 inhibitor is as follows: - Abdullarimab; - MOR-044254; - NOX-D20; - Anti-C5aR1ab-C5-siRNA conjugate, anti-C5aR1ab-protamine-C5siRNA conjugate; - m20 / 70mlgG2a. 1; - 3C5; - 7F3 The pharmaceutical composition according to claim 1 or 2, wherein the anti-C5aR1 antibody or aptamer is selected from the group consisting of the following.

6. The C5aR1 inhibitor is as follows: (2R)-2-[3-(furan-2-carbonyl)phenyl]-N-[4-(trifluoromethyl)-1,3-thiazole-2-yl]propenamide (DF2427); R(-)-2-[(4'-trifluoromethanesulfonyloxy)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide (DF2297X) or its chloride salt (DF2297A); Compounds having general formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, R is, - 2-thiazolyl or 2-oxazolyl, either unsubstituted or substituted with a group selected from a methyl group, a tert-butyl group, or a trifluoromethyl group; - C(Ra) = N - W (W is a linear or branched C) １ ~C ４ (It is alkyl.) - CORa、SORa、SO ２ RO、PORO、RO ２ Rha Selected from, Ra is, -C １ ~C ５ -alkyl, C ３ ~C ６ -cycloalkyl, C ２ ~C ５ -alkenyl, unsubstituted, or halogen, C １ ~C ４ -alkyl, C １ ~C ４ -alkoxy, halo-C １ ~C ４ -alkoxy, hydroxy, C １ ~C ４ -phenyl substituted with a group selected from acyloxy, phenoxy, cyano, nitro, amino; - A heteroaryl group selected from pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, and oxazole, which is unsubstituted or halogenated, C １ ~C ４ - Alkyl, C １ ~C ４ - Alkoxy, Halo-C １ ~C ４ -alkoxy, hydroxy, C １ ~C ４ - Heteroaryl groups substituted with a group selected from acyloxy, phenoxy, cyano, nitro, or amino; - Linear or branched C １ ~C ６ - Alkyl, C ３ ~C ６ - Cycloalkyl, C ２ ~C ６ - Alkenil, C １ ~C ６ - α or β carboxyalkyl residues consisting of phenylalkyl groups, which may be substituted with further carboxy(COOH) groups; - ω-aminoalkylamino group of formula (II): 【Chemistry 2】 Selected from, In equation (II) above, X is - Linear or branched C which may be substituted by a) or b) １ ~C ６ Alkylene, C ４ ~C ６ Alkenylene, C ４ ~C ６ Alkinirene: a) CO ２ R4 group (R4 is hydrogen, or linear or branched carbon) １ ~C ６ Alkyl group, or linear or branched C ２ ~C ６ (represents an alkenyl group) b) CONHR5 units (R5 is, - Hydrogen, straight-chain or branched carbon ２ ~C ６ Alkyl or OR4 group (R4 is defined as above) (represents); - CO as defined above ２ It may be substituted with R4 or CONHR5 groups (CH ２ ) ｍ -B-(CH ２ ) ｎ The group (B is oxygen, or C) １ ~C ４ (A sulfur or nitrogen atom which may be substituted with an alkyl group, where m is 0 or an integer from 2 to 3, and n is an integer from 2 to 3; or B is a CO group, an SO group, or a CONH group, where m is an integer from 1 to 3, and n is an integer from 2 to 3) Selected from, R2 and R3 are hydrogen, straight-chain or branched carbon. １ ~C ６ Alkyl C which may be interposed by oxygen or sulfur atoms １ ~C ６ Alkyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ６ Alkenil, C ３ ~C ６ -Alkinyl, aryl-C １ ~C ３ -Alkyl, hydroxy-C ２ ~C ３ - Selected independently of alkyl groups; or R2 and R3, together with the N atom to which they are bonded, form a 3- to 7-membered nitrogen heterocyclic ring of formula (III). 【Transformation 3】 Y is, - Single bond, CH ２ , O, S, or N-R6 group (R6 is hydrogen, C) １ ~C ４ Alkyl, C １ ~C ４ Acyl, unsubstituted, or halogen, C １ ~C ４ - Alkyl, C １ ~C ４ -alkoxy, hydroxy, C １ ~C ４ (- Represents phenyl substituted with a group selected from acyloxy, phenoxy, cyano, nitro, or amino.) p represents an integer from 0 to 3. - Formula SO ２ The residue of R7 (R7 is C １ ~C ６ - Alkyl, C ３ ~C ６ - Cycloalkyl, C ２ ~C ６ (These are alkenyl, aryl, and heteroaryl compounds.) Does it represent, or In the formula (II), X together with the nitrogen atom and the R2 group to which it is attached forms a nitrogen-containing 3- to 7-membered heterocyclic ring, a monocyclic ring, or a polycyclic ring, and R3 is hydrogen, C １ -C ４ alkyl, C １ -C ４ acyl, phenyl substituted with a group selected from the group consisting of unsubstituted, or halogen, C １ -C ４ -alkyl, C １ -C ４ -alkoxy, hydroxy, C １ -C ４ -acyloxy, phenoxy, cyano, nitro, amino; R1 is a linear or branched C １ ~C ５ alkyl, C ３ ~C ５ cycloalkyl; Ar is, - Unsubstituted, or halogenated, C １ ~C ４ - Alkyl, C １ ~C ４ -alkoxy, hydroxy, C １ ~C ４ - Acyloxy, phenoxy, cyano, nitro, amino, C １ ~C ４ - Acylamino, Halo-C １ ~C ３ -Alkyl, Halo-C １ ~C ３ - Alkoxy, benzoyl, heteroarylcarbonyl, heteroaryl, linear or branched C １ ~C ８ - Alkanesulfonates, linear or branched C １ ~C ８ - Alkanesulfonamides, linear or branched C １ ~C ８ A phenyl group substituted with one or more groups independently selected from alkylsulfonylmethyl; or - A heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, and indole. (Selected from); and compounds having general formula (II) 【Chemistry 4】 or a pharmaceutically acceptable salt thereof (In the formula, X is a heteroatom selected from S, O, and N; Y is either H, or a halogen, linear, or branched C. １ ~C ４ - Alkyl, C ２ ~C ４ - Alkenil, C １ ~C ４ -alkoxy, hydroxy, -COOH, C １ ~C ４ -Acyloxy, phenoxy, cyano, nitro, -NH ２ , C １ ~C ４ - Acylamino, Halo-C １ ~C ３ - Alkyl, benzoyl, linear or branched C １ ~C ８ - Alkanesulfonates, linear or branched C １ ~C ８ - Alkanesulfonamides, linear or branched C １ ~C ８ - A residue selected from the group consisting of alkylsulfonylmethyl; Z is an unsubstituted tetrazole, as well as a halogen, linear or branched C substituted with one hydroxyl group. １ ~C ４ - Alkyl, C ２ ~C ４ - Alkenil, C １ ~C ４ - Alkylamino, C １ ~C ４ - Alkoxy, C １ ~C ４ - Alkylthio, C １ ~C ４ - Acyloxy, cyano, nitro, NH ２ , C １ ~C ４ - Acylamino, Halo-C １ ~C ３ -Alkyl, Halo-C １ ~C ３ - Alkoxy, linear, or branched C １ ~C ８ - Alkanesulfonates, and linear or branched C １ ~C ８ - A heteroaryl ring selected from the group consisting of triazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, and oxadiazole, which may be further substituted with one or more groups selected from the group consisting of alkanesulfonamides. The pharmaceutical composition according to claim 1 or 2, which is a C5aR1 non-competitive allosteric inhibitor selected from the above.

7. In the compound of formula (I), R is, - Unsubstituted or substituted with a group selected from a methyl group, a tert-butyl group, or a trifluoromethyl group, 2-thiazolyl or 2-oxazolyl, - C(Ra) = N - W (W is a linear or branched C) １ ~C ４ (It is alkyl.) - CORa, SORa, or SO ２ Ra Selected from, Ra is as defined in claim 6; Ar is, 3'-benzoylphenyl, 3'-(4-chlorobenzoyl)phenyl, 3'-(4-methylbenzoyl)phenyl, 3'-acetylphenyl, 3'-propionylphenyl, 3'-isobutanoylphenyl, 4'-isobutylphenyl, 4'-trifluoromethanesulfonyloxyphenyl, 4'-benzenesulfonyloxyphenyl, 4'-trifluoromethanesulfonylaminophenyl, 4'-benzenesulfonylaminophenyl, 4'-benzenesulfonylmethylphenyl, 4'-acetoxyphenyl, 4'-propionyloxyphenyl, 4'-benzoyloxyphenyl, 4'-acetylaminophenyl, 4'-propionylaminophenyl, 4 '-benzoylaminophenyl, 3'-(furan-2-carbonyl)-phenyl, 3'-(benzofuran-2-carbonyl)-phenyl, 3'-(thiophene-2-carbonyl)-phenyl, 3'-(pyridine-2-carbonyl)-phenyl, 3'-(thiazole-2-carbonyl)-phenyl, 3'-(oxazole-2-carbonyl)-phenyl, 3'-(2-furyl)-phenyl, 3'-(2-oxazolyl)-phenyl, 3'-(3-isoxazolyl)-phenyl, 3'-(2-benzoxazolyl)-phenyl, 3'-(3-benzoisoxazolyl)-phenyl, 3'-(2-thiazolyl)-phenyl, 3'-(2-pyridyl)-phenyl, 3'-(2-thiophenyl)-phenyl Selected from a group that includes; Alternatively, Ar is a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, or indole. The pharmaceutical composition according to claim 6.

8. The C5aR1 inhibitor is as follows: - 4-{(1R)-1-[(phenylsulfonyl)amino]ethyl}phenyltrifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]benzenesulfonamide; - 4-{(1R)-1-[(pyridine-3-ylsulfonyl)amino]ethyl}phenyltrifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]methanesulfonamide; - N-{(1R)-1-[3-(2-froyl)phenyl]ethyl}thiophene-2-sulfonamide; - N-{(1R)-1-[3-(2-Froyl)phenyl]ethyl}methanesulfonamide; - 4-{(1R)-1-[(thiene-2-ylsulfonyl)amino]ethyl}phenyltrifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]thiophene-2-sulfonamide; - N-[(1R)-1-(3-benzoylphenyl)ethyl]-3-pyrrolidine-1-ylpropane-1-sulfonamide; - Methyl 5-({[(1R)-1-(3-benzoylphenyl)ethyl]amino}sulfonyl)-2-floate; - 5-({[(1R)-1-(3-benzoylphenyl)ethyl]amino}sulfonyl)-2-furoic acid; - 4-{(1R)-2-methyl-1-[(methylsulfonyl)amino]propyl}phenyltrifluoromethanesulfonate; - N-((1R)-1-{4-[1-methyl-1-(phenylsulfonyl)ethyl]phenyl}ethyl)methanesulfonamide; - 4-[(1R)-1-(isobutyrylamino)ethyl]phenyltrifluoromethanesulfonate; - 4-{[(1R)-1-(pyridine-3-ylcarbonyl)amino]ethyl]}phenyltrifluoromethanesulfonate; - N-[(1R)-1-(3-benzoylphenyl)ethyl]benzamide; - N-[(1R)-1-(3-benzoylphenyl)ethyl]-2-flamid; - N-[(1R)-1-(3-benzoylphenyl)ethyl]cyclobutanecarboxamide; - N-[(1R)-1-(4-trifluoromethanesulfonyloxy)phenylethyl]-4-piperidine-1-ylbutanamide (DF2593Y); - 4-{(1R)-1-[(4-pyrrolidine-1-ylbutanoyl)aminoethyl]}phenyltrifluoromethanesulfonate; - 3-{(1R)-1-[4-(4-trifluoromethyl-1,3-thiazole-2-yl)amino]ethyl}phenyl)(phenyl)methanone The pharmaceutical composition according to claim 6, which is a compound of formula (I) selected from the above.

9. In the compound of formula (II), X is a heteroatom selected from S and O; Y is either H, or a halogen, linear, or branched C. １ ~C ４ -Alkyl and halo-C １ ~C ３ - A residue selected from the group consisting of alkyl groups; preferably a residue selected from the group consisting of trifluoromethyl, chlorine, methyl, and tert-butyl; Z is an unsubstituted tetrazole, as well as a halogen, linear or branched C substituted with one hydroxyl group. １ ~C ４ - Alkyl, C １ ~C ４ -Alkylthio, and Halo-C １ ~C ３ The pharmaceutical composition according to claim 6, which is a heteroaryl ring selected from the group consisting of triazole, pyrazole, isoxazole, isothiazole, thiadiazole and oxadiazole, which may be further substituted with one or more groups selected from the group consisting of alkyl; preferably, it may be further substituted with one or more groups selected from the group consisting of methyl, trifluoromethyl and chlorine.

10. The C5aR1 inhibitor is as follows: - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]tetrazole-2-oid (DF3966Y) or its sodium salt (DF3966A); - 4-methyl-N-{4-[(1R)-1-(1H-tetrazole-5-yl)ethyl]phenyl}-1,3-thiazole-2-amine; - 4-tert-butyl-N-{4-[(1R)-1-(1H-tetrazole-5-yl)ethyl]phenyl}-1,3-thiazole-2-amine; - N-{4-[(1R)-1-(1H-tetrazole-5-yl)ethyl]phenyl}-1,3-thiazole-2-amine; - N-{4-[(1R)-1-(1H-tetrazole-5-yl)ethyl]phenyl}-4-(trifluoromethyl)-1,3-oxazole-2-amine; - 4-methyl-N-{4-[(1R)-1-(1Htetrazole-5-yl)ethyl]phenyl}-1,3-oxazole-2-amine; - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]-1Hpyrazole-1-ol; - 4-methyl-5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]-1H-pyrazole-1-ol; - 5-[(1R)-1-(4-([4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]-1H-1,2,3-triazole-1-ol; - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]isoxazole-3-ol; - 4-methyl-5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]isoxazole-3-ol; - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]isothiazol-3-ol; - 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]-1,2,5-oxadiazole-3-ol; - 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]-1,2,5-thiadiazole-3-ol; - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]-1H1,2,4-triazole-1-ol The pharmaceutical composition according to claim 6, which is a compound of formula (II) selected from the above.

11. The C5aR1 inhibitor is as follows: - N-[(1R)-1-(4-trifluoromethanesulfonyloxy)phenylethyl]-4-piperidine-1-ylbutanamide (DF2593Y) and its pharmaceutically acceptable salt, preferably its chloride salt (DF2593A), - R(-)-2-[(4'-trifluoromethanesulfonyloxy)phenyl]-N-[3-(N'-pyrrolidinyl)propyl]propionamide (DF2297X) or its chloride salt (DF2297A), and - 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazole-2-yl]amino}phenyl)ethyl]tetrazole-2-oid (DF3966Y) or its sodium salt (DF3966A) A pharmaceutical composition according to claim 6, selected from the above.

12. The C5aR1 inhibitor is as follows: The pharmaceutical composition according to claim 1, selected from abacopan, PMX-53, W54011, abdralimab, MOR-044254, PMX-205, DF2593A, DF2297A, DF2427, and DF3966A.

13. The pharmaceutical composition according to claim 6, wherein the C5aR1 inhibitor is DF3966A.

14. An ophthalmic composition comprising a therapeutically effective amount of a C5aR1 inhibitor selected from a C5aR1 competitive antagonist, an anti-C5aR1 antibody, and a C5aR1 non-competitive allosteric inhibitor, and at least one ophthalmologically acceptable excipient or carrier.

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