C5ar1 inhibitors for use in the treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid

Abstract

The 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

[0001] C5aRl INHIBITORS FOR USE IN THE TREATMENT OF OCULAR MUCOUS MEMBRANE PEMPHIGOID AND / OR ORAL MUCOUS MEMBRANE PEMPHIGOID

[0002] TECHNICAL FIELD

[0003] The invention relates to C5aRl inhibitors for use in the prevention and / or treatment of ocular mucous membrane pemphigoid (OcMMP) and / or oral mucous membrane pemphigoid.

[0004] BACKGROUND OF THE INVENTION

[0005] Mucous membrane pemphigoid (MMP) is a systemic cicatrizing autoimmune disease that primarily affects orificial mucous membranes, such as the conjunctiva, the nasal cavity, the oropharynx, and the genitalia.

[0006] About 75% of MMP patients generate antibodies against BP180 (type XVII collagen) and 25% of MMP patients against laminin 332. In less than 5% of MMP patients, antibodies against type VII collagen or a604 integrin are detected (Domloge-Hultsch, N., et al., J Clin Invest, 1992. 90(4): p. 1628-33; Oyama, N., et al., Br J Dermatol, 2006. 154(1): p. 90-8; Schmidt, E., et al., Br J Dermatol, 2001. 145(5): p. 778-83).

[0007] Ocular involvement occurs in about 70% of all MMP cases and ocular MMP is the leading cause of cicatrizing conjunctivitis in developed countries.

[0008] Linear immunoglobulin A disease, mucosal dominated epidermolysis bullosa acquisita, and anti-laminin 332 / anti-epiligrin / anti-laminin 5 pemphigoid are encompassed by Ocular MMP (OcMMP).

[0009] The progressive inflammatory and scarring nature of ocular MMP leads to severe visual impairment in 30% of affected eyes and bilateral blindness in 20%.

[0010] Ocular MMP is often associated with oral mucosa lesions including desquamative gingivitis, vesicles, erosions covered by pseudomembranes and ulcers.

[0011] In some cases of MMP, only the oral mucosa is involved.

[0012] The underlying pathophysiological mechanism of the disease is a type 2 hypersensitivity reaction against the basal epithelial membrane of the conjunctiva.

[0013] In particular, conjunctival involvement is critical since the autoantibody- induced inflammation results in conjunctival scarring that may even progress after the inflammatory process has halted and leads to visual impairment and blindness.

[0014] Early diagnosis and appropriate treatment are of paramount importance to avoid inflammatory and infectious complications, as well as possible visual loss.

[0015] Several mechanisms have been proposed underlying the development of antibody-mediated MMP. Ocular MMP management is aimed at controlling the immune-mediated inflammatory disease preventing fibrosis and progression of the disease.

[0016] Georgoudis, P. et al, “Ocular Mucous Membrane Pemphigoid: Current State of Pathophysiology, Diagnostics and Treatment”, Ophthalmol. Ther. (2019) 8, 5- 17, discloses that a stepladder approach is used to select immunosuppressive agents and to escalate treatment, depending on disease severity (mild, moderate, severe). The medications used are dapsone, sulphapyridine, sulphasalazine, azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), cyclophosphamide, and short courses of oral steroids.

[0017] CD20 monoclonal antibodies, TNFa inhibitors, and intravenous immunoglobulin (IVIg) are used to treat disease in patients non-responsive to conventional immunosuppressants.

[0018] The therapeutic mainstay are high-dose systemic corticosteroids supplemented with potentially corticosteroid sparing agents such as azathioprine, mycophenoles, dapsone, antibiotics with anti-inflammatory activity such as doxycycline, high-dose-intravenous immunoglobulins, and the anti-CD20 antibody rituximab.

[0019] The current treatment armamentarium is frequently not effective and associated with severe adverse events.

[0020] Thus, there is still a high need for effective and safe therapies.

[0021] Different C5aRl inhibitors have been developed and are well known to the skilled person.

[0022] W02007 / 060215 discloses (R)-arylalkylamino derivatives and their use in the treatment of diseases that involve C5a induced human PMNs 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 the treatment of injury caused by ischemia and reperfusion.

[0023] It is therefore the aim of the invention to provide an effective treatment of MMP, in particular ocular and oral MMP.

[0024] SUMMARY OF THE INVENTION

[0025] The invention is directed to C5aRl inhibitors for use in the prevention and / or treatment of ocular mucous membrane pemphigoid (OcMMP) and / or oral mucous membrane pemphigoid in a subject.

[0026] The invention is also directed to pharmaceutical compositions comprising a C5aRl 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.

[0027] The invention is also directed to a method of preventing and / or treating ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid, which comprises administering an effective amount of one or more C5aRl inhibitor compounds of the invention to a subject in need thereof.

[0028] The invention is also directed to the use of the claimed C5aRl inhibitors in the manufacture of a medicament for the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid in a subject.

[0029] BRIEF DESCRIPTION OF FIGURES

[0030] Figure 1 shows the effects of treatment with DF3966A, administered by topical ophthalmic application, or methylprednisolone (MP), administered by intraperitoneal injection, in an experimental MMP mouse model at day 12 after the initial anti-mLAMa3 IgG injection, compared to control treatment with vehicle, by topical ophthalmic administration (vehicle). In details:

[0031] Panel A shows the effect of DF3966A or MP on palpebral conjunctival split formation at day 12, expressed as conjunctiva score. Data are presented as means + / - standard deviation. On day 12 there is a statistically significant difference between the vehicle group and DF3966A (p=0.0016). Animals treated with IgG isolated from normal rabbit serum injected s.c. (NR IgG), were used as negative control.

[0032] Data are based on 12-14 mice per group, except for NR IgG (n=10). The asterisk indicates statistical significance (ANOVA with Holm Sidaks method for multiple comparisons).

[0033] Panel B shows semi-quantification of subepithelial inflammatory infiltrate based on hematoxylin and eosin (H&E) stained biopsies of the palpebral conjunctiva, in mice treated with DF3966A or MP. On day 12 there is a statistically significant difference between the vehicle group and MP group. Animals treated with IgG isolated from normal rabbit serum injected s.c. (NR IgG), were used as negative control.

[0034] Data are presented as means + / - standard deviation. Data are based on 7-10 mice per group, except for NR IgG (n=3). The asterisk indicates statistical significance (ANOVA with Holm Sidaks method for multiple comparisons).

[0035] Figure 2 shows representative clinical presentations of the eyes and H&E stained sections of the palpebral conjunctiva obtained 12 days after the initial anti-mLAMa3 IgG injection, in mice treated with DF3966A, by topical ophthalmic administration, or methylprednisolone (MP), by intraperitoneal injection.

[0036] Figure 3 shows the reduction of split formation in the palpebral conjunctiva in experimental MMP mice at day 28 after the initial anti-mLAMa3 IgG injection, treated with DF3966A, by topical ophthalmic administration, or methylprednisolone (MP), by intraperitoneal injection. In details:

[0037] Panel A shows the effect of treatment with DF3966A or MP on palpebral conjunctival split formation on day 28, expressed as conjunctiva score, compared to vehicle. Animals treated with IgG isolated from normal rabbit serum injected s.c. (NR IgG) were used as negative control.

[0038] Data are presented as means + / - standard deviation. On day 28 there is a statistically significant difference between the vehicle group and DF3966A (p=0.0414). Data are based on 11-14 mice per group, except for NR IgG (n=9). The asterisk indicates statistical significance (ANOVA with Holm Sidaks method for multiple comparisons).

[0039] Panel B shows the semi-quantification of subepithelial inflammatory infiltrate based on hematoxylin and eosin (H&E) stained biopsies of the palpebral conjunctiva in mice treated with DF3966A or MP, compared to vehicle. Animals treated with IgG isolated from normal rabbit serum injected s.c. (NR IgG) were used as negative control. Data are presented as means + / - standard deviation. On day 28 there is a statistically significant difference between the vehicle group and DF3966A (p=0.0188). Data are based on 7-9 mice per group, except for NR IgG (n=5). The asterisk indicates statistical significance based on ANOVA with Dunnetts method for multiple comparisons.

[0040] Figure 4 shows representative clinical presentations of the eyes and H&E stained sections of the palpebral conjunctiva obtained 28 days after the initial anti-mLAMa3 IgG injection, in mice treated with DF3966A, by topical ophthalmic administration, or methylprednisolone (MP), by intraperitoneal injection.

[0041] Figure 5 shows the effect of DF3996A and MP treatment on severity of oral lesions on day 12, expressed as oral score. Data are presented as means + / - standard deviation. For day 12 there is a statistically significant difference between the vehicle group and DF3966A (p=0.0479). Data are based on 12-14 mice per group, except for NR IgG (n=10). The asterisk indicates statistical significance (ANOVA with Holm Sidaks method for multiple comparisons).

[0042] Figure 6 shows the effect of DF3996A and MP treatment on severity of oral lesions on day 28, expressed as oral score. Data are presented as means + / - standard deviation. For day 28 there is a statistically significant difference between the vehicle group and DF3966A (p=0.0372). MP treatment significantly increased the oral score (p=0.0136) compared to vehicle treated group. Data are based on 11-14 mice per group, except for NR IgG (n=9). The rhombus indicates statistical significance by ANOVA with uncorrected Fishers LSD method (no correction for multiple comparisons).

[0043] DETAILED DESCRIPTION OF THE INVENTION

[0044] It has been surprisingly found that the C5aRl inhibitors are effective in the prevention and / or treatment of ocular mucous membrane pemphigoid (OcMMP) and / or oral mucous membrane pemphigoid in a subject. The terms “treatment” and “prevention” as used herein refer to the eradication / amelioration or prevention / delay in onset, respectively, of the disorder being treated or of one or more of the symptoms associated thereof, notwithstanding the fact that the patient may still be afflicted with the underlying disorder.

[0045] Accordingly, the invention is directed to a C5aRl inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid.

[0046] According to a preferred embodiment, the invention is directed to a C5aRl inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid.

[0047] According to a further preferred embodiment, the invention is directed to a C5aRl inhibitor for use in the prevention and / or treatment of oral mucous membrane pemphigoid.

[0048] According to a further preferred embodiment, the invention is directed to a C5aRl inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and oral mucous membrane pemphigoid.

[0049] The term “C5aRl inhibitor” in accordance with the present invention means any compound that interacts with C5aRl and prevents its binding to C5a or that blocks the signaling of C5aRl upon binding of C5a.

[0050] Preferably, said C5aRl inhibitor compound is selected from C5aRl competitive antagonists, anti-C5aRl antibodies able to block the C5a binding sites on the receptor and C5aRl non-competitive allosteric inhibitors, more preferably said C5aRl inhibitor compound is a non-competitive allosteric inhibitor.

[0051] “Noncompetitive allosteric inhibitor of C5a receptor” according to the present invention means a compound that interacts with C5a receptors in an allosteric site, located in the TM region, and inhibits intracellular signal transduction events activated by the agonist binding, without affecting any binding of endogen ligand C5a on its receptor.

[0052] According to one preferred embodiment, said C5aRl competitive antagonists are selected from the group consisting of:

[0053] (2R,3S)-2-[4-(Cyclopentylamino)phenyl]-l-(2-fluoro-6-methylbenzoyl)- N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (Avacopan, Vynpenta®);

[0054] N-Acetyl-L-phenylalanyl-L-ornithyl-L-prolyl-3-cyclohexyl-D-alanyl-L- tryptophyl-L-arginine-N-5.2-C-1.6-lactam (PMX-53);

[0055] Acetylated phenylalanine- [ornithyl-proline-(D)cyclohexylalanine- tryptophyl-arginine] ;

[0056] 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(l,3-benzodioxol-5-ylmethyl)-N-(l-butyl-2,4-diphenyl-lH- imidazol-5 -ylmethyl)amine ;

[0057] N-[2-(4-Chlorophenyl)ethyl]-N-(l,4-dioxaspiro[4.5]dec-8-yl)-2- i sobutylbenzamide ;

[0058] N-[2-(4-Chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)-l- benzothiophene-3 -carboxamide;

[0059] N-[2-(4-Chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)naphthalene-l- carboxamide;

[0060] 2-(2-Ethyl-6-methylphenyl)-4-methoxy-N-(5-methoxy-2-methylphenyl)- 5,6,7, 8 -tetrahydroquinolin-5 -amine ;

[0061] 2-(2,6-Diethylphenyl)-N-ethyl-4-methoxy-N-(l-naphthyl)-5, 6,7,8- tetrahydroquinolin-5-amine;

[0062] N-[2,6-Dioxohexahydropyrimidin-4(S)-ylcarbonyl]-L-phenylalanyl-L- ornithyl-L-prolyl-5-methyl-L-norleucyl-4-fluoro-L-phenylalanyl-L- phenylalaninamide (JPE-1375; JSM-1375);

[0063] N-(3-Phenylpropionyl)-L-ornithyl-L-prolyl-3-cyclohexyl-D-alanyl-L- tryptophyl-L-arginine N-5.1-C-1.5-lactam (PMX-205);

[0064] N,N'-Bis(4-amino-2-methylquinolin-6-yl)urea (NSC12155);

[0065] N-[4-(Dimethylamino)benzyl]-N-(4-isopropylphenyl)-7-methoxy- 1,2,3,4-tetrahydronaphthalene-l-carboxamide hydrochloride (W54011);

[0066] L-Phenylalanyl-L-ornithyl-L-prolyl-3-cyclohexyl-D-alanyl-L-tryptophyl- L-arginine N-5.2-C-1.6-cyclic peptide;

[0067] (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',l'o][l,4,7,10,13,16]oxapentaazacyclononadecine-5,7,l 1,17,20,24- hexanone (L- 156602).

[0068] Anti-C5aRl antibodies are commercially available, for example they are sold by Abeam, ThermoFisher Scientific, Biocompare.

[0069] According to one preferred embodiment, the anti-C5aRl antibodies or aptamers are selected from the group consisting of:

[0070] Avdoralimab (IPH-5401)

[0071] MOR-044254, also known as anti-C5aR monoclonal antibody TJ210;

[0072] NOX-D20, a PEGylated biostable mirror-image mixed (L)RNA / DNA aptamer (Spiegelmer);

[0073] Anti-C5aRlab-C5-SiRNA conjugate, anti-C5aRlab-protamine- C5siRNA conjugate;

[0074] According to one preferred embodiment, said non-competitive allosteric inhibitors are selected from:

[0075] (2R)-2-[3-(furan-2-carbonyl)phenyl]-N-[4-(trifluoromethyl)-l,3-thiazol-2- yl]propenamide (DF2427);

[0076] R(-)-2-[(4'-trifluoromethanesulfonyloxy)phenyl]-N-[3-(N'- pirrolidinyl)propyl] propionamide (DF2297X) or its chloride salt (DF2297A); and

[0077] - the compounds of formula (I) and (II) described hereinbelow.

[0078] According to a preferred embodiment, said non-competitive allosteric inhibitors are compounds having general formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0079] R is selected from:

[0080] - 2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from methyl, tert-butyl or trifluoromethyl group;

[0081] - C(Ra)=N-W wherein W is linear or branched C1-C4 alkyl,

[0082] - CORa, SORa, SO2Ra, PORa, PO2Ra, wherein Ra is selected from:

[0083] - Ci-Cs-alkyl, Ca-Ce-cycloalkyl, C2-Cs-alkenyl, unsubstituted or substituted phenyl with a group selected from halogen, Ci-C4-alkyl, Ci- C4-alkoxy, halo-Ci-C4-alkoxy, hydroxy, Ci-C4-acyloxy, phenoxy, cyano, nitro, amino;

[0084] - a heteroaryl group selected from pyridine, pyrimidine, pyrrole, thiophene, furane, indole, thiazole, oxazole, such heteroaryl being unsubstituted or substituted with a group selected from halogen, C1-C4- alkyl, Ci-C4-alkoxy, halo-Ci-C4-alkoxy, hydroxy, C1-C4- acyloxy, phenoxy, cyano, nitro, amino;

[0085] - a a or P carboxyalkyl residue consisting of straight or branched Ci- Ce-alkyl, Ca-Ce-cycloalkyl, C2-Ce-alkenyl, Ci-Ce-phenylalkyl, optionally substituted with a further carboxy (COOH) group;

[0086] - an co-aminoalkylamino group of formula (II): wherein in said formula (II) X is selected from: - linear or branched Ci-Ce alkylene, C4-C6 alkenylene, C4-C6 alkynylene, optionally substituted by: a) a CO2R4 group, wherein R4 represents hydrogen or a linear or branched Ci-Ce alkyl group or a linear or branched C2-C6 alkenyl group, or b) a C0NHR5 group wherein R5 represents

[0087] - hydrogen, linear or branched C2-C6 alkyl or an OR4 group, R4 being defined as above;

[0088] - a (CH2) m- B-(CH2)n, group, optionally substituted by a CO2R4 or C0NHR5 group, as defined above, wherein B is an oxygen, or sulfur atom, or nitrogen atom optionally substituted by a C1-C4 alkyl group, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;

[0089] R2 and R3 are independently selected form hydrogen, linear or branched Ci-Ce alkyl, optionally interrupted by an oxygen or sulfur atom, a C3-C7 cycloalkyl, C3-C6 alkenyl, Cs-Ce-alkynyl, aryl-Ci-Cs-alkyl, hydroxy-C2-C3-alkyl group; or

[0090] R2 and R3 together with the N atom to which they are bound, form a 3-7 membered nitrogen heterocyclic ring of formula (III) wherein Y represents:

[0091] - a single bond, CH2, O, S, or a N-R6 group, where R6 represents hydrogen, C1-C4 alkyl, C1-C4 acyl, unsubstituted or substituted phenyl with a group selected from halogen, Ci-C4-alkyl, C1-C4- alkoxy, hydroxy, Ci-C4-acyloxy, phenoxy, cyano, nitro, amino, and p represents an integer from 0 to 3;

[0092] - a residue of formula SO2R wherein R7 is Ci-Ce-alkyl, C3-C6- cycloalkyl, C2-Ce-alkenyl, aryl and heteroaryl; or in said formula (II), X together with the nitrogen atom to which it is bound and with the R2 group, forms a nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring, and R3 is selected from the group comprising hydrogen, C1-C4 alkyl, C1-C4 acyl, unsubstituted or substituted phenyl with a group selected from halogen, Ci-C4-alkyl, Ci-C4-alkoxy, hydroxy, C1-C4- acyloxy, phenoxy, cyano, nitro, amino; R1 is linear or branched C1-C5 alkyl, C3-C5 cycloalkyl; Ar is selected from:

[0093] -a phenyl group unsubstituted or substituted by one or more groups independently selected from halogen, Ci-C4-alkyl, Ci-C4-alkoxy, hydroxy, Ci-C4-acyloxy, phenoxy, cyano, nitro, amino, Ci-C4-acylamino, halo-Ci- C3- alkyl, halo-Ci-C3-alkoxy, benzoyl, heteroaryl carbonyl, heteroaryl, linear or branched Ci-Cs-alkanesulfonate, linear or branched Ci-Cs-alkanesulfonamides, linear or branched Ci-Cs alkyl sulfonylmethyl; or

[0094] - a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, indole.

[0095] Among the above compounds, particularly preferred are compounds of said formula (I) or pharmaceutically acceptable salts thereof, wherein:

[0096] R is selected from:

[0097] - 2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from methyl, tert-butyl or trifluoromethyl group,

[0098] - C(Ra)=N-W wherein W is linear or branched C1-C4 alkyl,

[0099] - CORa, SORa or SO2Ra, wherein Ra is as defined above; and

[0100] Ar is selected from the group comprising:

[0101] 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'- benzoylaminophenyl, 3 ’ -(furan-2-carbonyl)-phenyl, 3 ’ -(benzofuran-2-carbonyl)- phenyl, 3’-(thiophen-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; or Ar is a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan or indole.

[0102] According to a further embodiment, (R)-arylalkylamino derivatives are compounds of formula (I) as defined above, wherein:

[0103] R is

[0104] - 2-thiazolyl, unsubstituted or substituted by a group selected from methyl or trifluoro methyl; - CORa, SO2Ra, wherein Ra is selected from:

[0105] - Ci-Cs-alkyl, Ca-Cs-cycloalkyl;

[0106] - phenyl, 2-pyridyl, 2-furyl, 2-thiophenyl groups;

[0107] - a group of formula II, wherein

[0108] X represents: linear or branched Ci-Ce alkylene,

[0109] R2 and R3 together with the N atom to which they are bound, form a 4-6 membered nitrogen containing heterocyclic ring of formula (III) wherein Y represents CH2 and p represents an integer from 0 to 2;

[0110] R1 is methyl;

[0111] Ar is selected from:

[0112] 3 ’ -benzoylphenyl, 3 ’ -(4-chloro-benzoyl)-phenyl, 3 ’ -(4-methyl-benzoyl)- phenyl,

[0113] 4’-trifluoromethanesulfonyloxy-phenyl, 4’ -benzenesulfonyloxy-phenyl, 3 ’ -(furan-2-carbonyl)-phenyl.

[0114] Preferred compounds of formula (I) according to the invention are selected from:

[0115] 4-{(lR)-l-[(phenylsulfonyl)amino]ethyl}phenyl trifluoromethane sulfonate;

[0116] N-[(lR)-l-(3-benzoylphenyl)ethyl]benzenesulfonamide;

[0117] 4-{(lR)-l-[(pyridine-3- ylsulfonyl)amino] ethyl } phenyltrifluoromethane sulfonate ;

[0118] N- [( 1 R)- 1 -(3-benzoylphenyl)ethyl] methanesulfonamide ;

[0119] N-{(lR)-l-[3-(2-furoyl)phenyl]ethyl}thiophene-2-sulfonamide;

[0120] N- { ( 1 R)- 1 - [3-(2-furoyl)phenyl]ethyl } methane sulfonamide;

[0121] 4-{(lR)-l-[(thien-2-ylsulfonyl)amino]ethyl}phenyl trifluoromethane sulfonate ;

[0122] N- [( 1 R)- 1 -(3-benzoylphenyl)ethyl] thiophene-2- sulfonamide ;

[0123] N- [( 1 R)- 1 -(3-benzoylphenyl)ethyl] -3 -pyrrolidin- 1 -ylpropane- 1 - sulfonamide; methyl 5-( { [( 1 R)- 1 -(3-benzoylphenyl)ethyl] amino } sulfonyl)-2-furoate;

[0124] 5-({[(lR)-l-(3-benzoylphenyl)ethyl] amino }sulfonyl)-2-furoic acid;

[0125] - 4-{(lR)-2-methyl-l-

[0126] [(methylsulfonyl)amino]propyl}phenyltrifluoromethanesulfonate;

[0127] - N-((lR)-l-{4-[l -methyl- 1-

[0128] (phenylsulfonyl)ethyl]phenyl}ethyl)methanesulfonamide;

[0129] 4-[(lR)-l-(isobutyrylamino)ethyl]phenyltrifluoromethanesulfonate;

[0130] 4-{[(lR)-l-(pyridine-3- ylcarbonyl)amino] ethyl] Jphenyltrifluoromethanesulfonate;

[0131] N-[(lR)-l-(3-benzoylphenyl)ethyl]benzamide;

[0132] N-[(lR)-l-(3-benzoylphenyl)ethyl]-2-furamide;

[0133] N- [( 1 R)- 1 -(3 -benzoylphenyl)ethyl] cyclobutanecarboxamide;

[0134] N- [( 1 R)- 1 -(4-trifluoromethanesulfonyloxy)phenylethyl] -4-piperidin- 1 -yl butanamide (DF2593Y);

[0135] 4-{(lR)-l - [(4-pyrrolidin- 1 -ylbutanoyl)amino] ethyl] } phenyl trifluoro me thane sulfonate ;

[0136] 3 - { ( 1 R)- 1 - [4-(4-trifluoromethyl- 1 ,3 -thiazol-2-yl)amino] ethyl } phenyl) (phenyl)methanone.

[0137] Particularly preferred compounds of formula (I) according to the invention are N-[(lR)-l-(4-trifluoromethanesulfonyloxy)phenylethyl]-4-piperidin-l-yl butanamide (DF2593Y) and pharmaceutically acceptable salts thereof, preferably its chloride salt (DF2593A).

[0138] Compounds of formula (I) are described in W02007 / 060215, which also discloses their method of synthesis.

[0139] According to a further preferred embodiment, said non-competitive allosteric inhibitors are compounds having general formula (II): or pharmaceutically acceptable salts thereof, wherein

[0140] X is a heteroatom selected from S, O and N;

[0141] Y is H or a residue selected from the group consisting of halogen, linear or branched Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-alkoxy, hydroxy, -COOH, C1-C4- acyloxy, phenoxy, cyano, nitro, -NH2, Ci-C4-acylamino, halo-Ci-Ca-alkyl, benzoyl, linear or branched Ci-Cs-alkanesulfonate, linear or branched Ci-Cs- alkanesulfonamides, linear or branched Ci-Cs-akyl sulfonylmethyl;

[0142] Z is an heteroaryl ring selected from the group consisting of unsubstituted tetrazole and triazole, pyrazole, oxazole, thiazole, isooxazole, 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 Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-alkylamino, Ci- C4-alkoxy, Ci-C4-alkylthio, Ci-C4-acyloxy, cyano, nitro, NH2, C1-C4- acylamino, halo-Ci-Ca-alkyl, halo-Ci-Ca-alkoxy, linear or branched Ci-Cs- alkanesulfonate and linear or branched Ci-Cs-alkanesulfonamides.

[0143] Among the above compounds of formula (II), preferred are compounds wherein: X is a heteroatom selected from S and O;

[0144] Y is H or a residue selected from the group consisting of halogen, linear or branched Ci-C4-alkyl and halo-Ci-Ca-alkyl; preferably selected from the group consisting of trifluoromethyl, chlorine, methyl and tert-butyl;

[0145] Z is an heteroaryl ring selected from the group consisting of unsubstituted tetrazole and triazole, pyrazole, isooxazole, 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 Ci-C4-alkyl, Ci-C4-alkylthio and halo-Ci-Ca-alkyl; preferably selected from the group consisting of methyl, trifluoromethyl and chlorine.

[0146] Particularly preferred compounds of formula (II) according to the invention are selected from:

[0147] - 5-[( 1R)~ 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2- yl]amino}phenyl)ethyl]tetrazol-2-ide (DF3966Y) or its sodium salt (DF3966A);

[0148] - 4-methyl-N-{4-[(lR)-l-(lH-tetrazol-5-yl)ethyl]phenyl}-l,3-thiazol-2-amine;

[0149] 4-tert-butyl-N-{4-[(lR)-l-(lH-tetrazol-5-yl)ethyl]phenyl}-l,3-thiazol-2- amine;

[0150] - N- { 4-[( 1 R)- 1 -( 1 H-tetrazol-5-yl)ethyl]phenyl } - 1 ,3-thiazol-2-amine;

[0151] N- { 4-[( 1 R)- 1 -( 1 H-tetrazol-5-yl)ethyl]phenyl } -4-(trifluoromethyl)- 1,3- oxazol-2-amine;

[0152] - 4-methyl-N- {4-[(lR)-l-(lH tetrazol-5-yl)ethyl]phenyl}-l,3-oxazol-2-amine;

[0153] - 5-[(lR)-l-(4-{ [4-(trifluoromethyl)-l,3-thiazol-2-yl]amino}phenyl)ethyl]-lH pyrazol-l-ol;

[0154] - 4-methyl-5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino Jphenyl) ethyl] - 1 H-pyrazol- 1 -ol ;

[0155] - 5 - [( 1 R)- 1 -(4-( [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino } phenyl)ethyl] - 1 H- 1,2,3-triazol-l-ol;

[0156] 5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] isoxazol-3-ol;

[0157] - 4-methyl-5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino Jphenyl) ethyl]isoxazol-3-ol;

[0158] 5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] isothiazol-3-ol;

[0159] 4-[( 1 R)- 1 -(4- { [4- (trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] - l,2,5-oxadiazol-3-ol;

[0160] 4-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] - 1,2,5 -thiadiazol-3 -ol ;

[0161] - 5-[(lR)-l-(4-{ [4-(trifluoromethyl)-l,3-thiazol-2-yl]amino}phenyl)ethyl]-lH 1,2,4-triazol-l-ol.

[0162] A particular preferred compound of formula (II) is 5-[(lR)-l-(4-{ [4- ( trifluoromethyl)-!, 3-thiazol-2-yl] amino }phenyl)ethyl]tetrazol-2-ide (DF3966Y) or its sodium salt (DF3966A).

[0163] Compounds of formula (II) are described in W02009 / 050258, which also discloses their method of synthesis.

[0164] Preferred C5aRl inhibitors according to the invention are Avacopan, PMX-53, W54011, Avdoralimab, MOR-044254, PMX-205, DF2593A, DF2297A, DF2427 and DF3966A, more preferably the C5aRl inhibitor is DF3966A.

[0165] Preferably, the C5aRl inhibitor for use according to the present invention is administered topically to the surface of the eye of a subject. Preferably, the C5aRl inhibitor for use according to the present invention is formulated in form of eyedrops.

[0166] As will be discussed in the experimental section, the present inventors have shown that topical application of a C5aRl inhibitor to the surface of the eye results in amelioration of both ocular and oral MMP.

[0167] The invention is also directed to a pharmaceutical composition comprising a C5aRl inhibitor, as above described, 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.

[0168] Preferably, the pharmaceutical composition is an ophthalmic composition suitable for topical application to the surface of the eye.

[0169] Accordingly, the invention is further directed to an ophthalmic composition comprising a therapeutically effective amount of a C5aRl inhibitor, as above described, and at least one ophthalmologically acceptable excipient or carrier. According to a preferred embodiment, the invention is further directed to an ophthalmic composition comprising a therapeutically effective amount of a C5aRl inhibitor, as above described, 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.

[0170] An "ophthalmologically acceptable excipient" is an inert excipient which allows delivery of a medicament to the eye and / or eyelids, to treat an ocular disease or condition without deleterious effects on the eye.

[0171] According to an embodiment, said ophthalmic composition may be a liquid, eye drop composition for topical administration to the anterior segment of the eye. Said liquid composition may be in form of a solution, emulsion, or suspension. Said liquid composition may include micelles.

[0172] In one embodiment, the liquid composition is an aqueous composition. Preferably, the liquid composition is an aqueous eye drop composition. Preferably, said liquid composition comprises ophthalmologically acceptable excipients selected from ophthalmologically acceptable viscosity enhancers, penetration enhancers, buffering agents, osmolarity regulators, preservatives and surfactants.

[0173] Viscosity enhancers have the function to increase viscosity of the composition and to improve its retention in the conjunctival sac and are preferably selected from cellulose derivatives, preferably hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose; polyvinylpyrrolidone and gelling agents, preferably gellan, xanthan gum and carbopol-974.

[0174] Penetration enhancers have the function of enhancing drug permeability across ocular membranes and are preferably selected from cyclodextrins, chelating agent, crown ethers, bile acids and bile salts.

[0175] Buffering agents have the function of providing and maintaining the correct pH of the formulation to be compatible for use in the eye, preferably at a pH comprised between 6 and 8. The preferred buffer is phosphate buffer, but other buffers capable of maintaining the pH within the desired range, especially buffers suitable for ophthalmic use, are also included.

[0176] Osmolarity regulators are salts able to make the liquid composition isotonic with ocular fluids. The preferred salt is sodium chloride (NaCl) but other biologically acceptable salts may be used, such as for instance potassium chloride (KC1), calcium chloride (CaCh) and magnesium chloride (MgCh) and their admixtures.

[0177] Preservatives inhibit microbial activity. Suitable preservatives include for instance quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0178] Surfactants have the function of making the composition stable and are preferably selected from polysorbates such as Tween 80, poloxamers such as Pluronics F68 or proteins such as serum albumin.

[0179] Said liquid, eye drop composition can be part of a kit comprising the composition, a container for holding the composition and a drop dispenser.

[0180] A “therapeutically effective amount” according to the present invention means an amount sufficient to achieve treatment or prevention of the disease. Determination of the effective amounts is well within the capability of those skilled in the art based upon the achievement of a desired effect. An effective amount will depend on factors including, but not limited to, the weight of a subject and / or the degree of the disease or unwanted condition from which a subject suffers.

[0181] The invention relates also to the use of the above C5aRl inhibitors in the manufacture of a medicament for the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid.

[0182] The invention is also directed to a method of preventing and / or treating ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid, which comprises administering an effective amount of one or more C5aRl inhibitors of the invention to a subject in need thereof.

[0183] The invention is further illustrated by the following example.

[0184] EXAMPLE

[0185] A study was designed to investigate and show the effect of pharmacological inhibition of C5aRl exerted by the compound DF3966A in a mouse model of MMP.

[0186] Materials and methods

[0187] Test compounds

[0188] - DF3966A Sodium Salt (Lot. LC446-81-1 GLB21001, Dompe S.p.A.)

[0189] - Vehicle (solvent, Dompe S.p.A.) - (positive control)

[0190] - Methylprednisolone (MP) (sourced by UKSH, Lubeck - Supplier Sanofi) - (reference treatment)

[0191] Animal model - Mice

[0192] Adult C57B1 / 6 (B6) mice (male and female) aged at least 6 weeks old were used. Animals were maintained on a 12-h light-dark cycle at the animal facility of the University of Lubeck. Mice were held under SPF conditions and fed acidified drinking water and standard chow ad libitum. Protocols were approved by the Animal Rights Commission of the Ministry of Agriculture and Environment, Schleswig-Holstein.

[0193] Generation, isolation and characterization of anti-mLAMa3 IgG

[0194] For production of anti-mLAMa3 IgG, New Zealand White rabbits were immunized subcutaneously with 250pg of an equimolar mixture of the 2 purified recombinant proteins (aal656-1985 and aa2756-3330 of murine Laminin alpha3 chain, produced in E. coli as disclosed by Heppe, E.N., et al., J Invest Dermatol, 2017, 137, 1709-1718) suspended in complete Freund’s adjuvant. The animals were boosted twice with the same protein preparation in incomplete Freund’s adjuvant. Immune sera were obtained at regular intervals and characterized by IF microscopy on cryosections of murine skin. IgG from rabbits immunized with recombinant fragments of murine mLAMa3 and from non-immunized rabbits was purified by affinity chromatography using protein G sepharose affinity chromatography (Amersham Biosciences, Heidelberg, Germany). Reactivity of IgG fractions was analyzed by IF microscopy on murine skin (Sitaru et al., Induction of complement -fixing autoantibodies against type VII collagen results in subepidermal blistering in mice. J Immunol 2006, 177: 3461-8). In addition, each batch of anti-mLAMa3 IgG was characterized in vivo regarding its capability to induce experimental MMP in C57B1 / 6 (B6) mice (WP1.1). From this experiment, the amount of antibodies that leads to moderate experimental MMP was determined; i.e. the amount needed to induce disease development with moderate involvement of the conjunctiva (i.e. score of 1-3 in a maximum of 50% of the animals on day 12) in the model of antibody transfer-induced MMP. For this purpose, the intensity of the separation of the conjunctiva is determined histologically. The body surface area affected should be between 3-8% at the concentration used. The conjunctiva score was set histologically post-mortem and was in a range of 0- 4, depending on the intensity of the separation of the conjunctiva. The amount needed was determined to be 5 mg / injection of anti-mLAMa3 IgG.

[0195] Study design

[0196] Induction of experimental MMP by repetitive injections of anti-mLAMa3 IgG and treatment protocol

[0197] To test DF3966A at 0.05% effects on the severity of conjunctival involvement in experimental MMP, the disease was induced by repetitive subcutaneous (s.c.) injections of anti-mLAMa3 IgG (5mg / mouse) on alternating days (0, 2, (...) and 10) into adult B6 mice, which were treated throughout the entire experiment twice a day via eyedrops. Three eyedrops per eye were given twice daily. Mice treated with solvent via eyedrops or methylprednisolone (MP) via i.p. injections were used as treatment controls. Mice s.c. injected with IgG isolated from normal rabbit serum (NR IgG) served as negative control.

[0198] Evaluation of conjunctival lesions

[0199] The primary endpoint of this experiment was the extent of conjunctival lesions as determined by lesional histopathology (H&E stain) on day 12 and 28 following an established scoring system (Heppe, E.N., et al., J Invest Dermatol, 2017, 137, 1709-1718). In detail, biopsies from the palpebral conjunctiva were taken on day 12 and day 28 and paraffine embedded. 4.5pm thick sections from 3 different depths of the biopsies were cut in triplicate and H&E stained for further quantification. Among the H&E stained histologies those with a palpebral conjunctival-epithelium with more than 1000pm were used for quantification. For this score the length of the split formation (split = epithelia separation from the underlying dermal structures) is measured. The split length is categorized to a score of 0-4 with no split = 0, less than 100pm = 1, less than 200pm = 2, less than 300pm = 3, more or equal 300pm = 4. Splits that occurred at the end of the tissue were excluded, because they were most likely to be of artificial nature due to the cutting. The longest split out of 9 possible sections is decisive for the final score. The endpoint was analyzed on day 12 in the following groups:

[0200] ■ normal rabbit IgG (n=10)

[0201] ■ Anti-mLAMa3 IgG + solvent (positive control) (n=14)

[0202] ■ Anti-mLAMa3 IgG + MP (reference treatment) (n=13)

[0203] ■ Anti-mLAMa3 IgG + DF3966A (n=12)

[0204] The endpoint was analyzed on day 28 in the following groups:

[0205] ■ normal rabbit IgG (n=9)

[0206] ■ Anti-mLAMa3 IgG + solvent (positive control) (n=l l)

[0207] ■ Anti-mLAMa3 IgG + MP (reference treatment) (n=l l)

[0208] ■ Anti-mLAMa3 IgG + DF3966A (n=12)

[0209] The experiments were performed at two independent time points for each day 12 and day 28, including 7 mice / group and 5 mice / normal rabbit IgG.

[0210] Evaluation of severity of oral lesions

[0211] The extent of oral lesions was determined by endoscopy (Videomed, Miinchen, Germany) at day 12 and 28, following an established scoring system (Heppe, E.N., et al., J Invest Dermatol, 2017, 137, 1709-1718). In detail, each affected mouth-quarter of the mouse is counted as one point if there are lesions / blisters / crusts / erosions. The quarters are defined as: left buccal mucosa, right buccal mucosa, hypopharynx, tongue. The maximum score is 4.

[0212] Statistical analysis

[0213] For statistical analysis GraphPad Prism (version 8.4.3) was used. For comparison of treatment effects in multiple groups ANOVA was used. To isolate the group or groups that differ from others, Dunnett's or Holm Sidaks multiple comparison were used when appropriate.

[0214] Results

[0215] 1. Local application of DF3966A reduced split formation in the palpebral conjunctiva in experimental MMP

[0216] Injection of rabbit anti-mLAMa3 IgG into adult B6 mice persistently lead to induction of experimental MMP within 4-8 days after the first IgG injection.

[0217] After 12 days of twice daily local application of the drug as eyedrops a significant reduction of the conjunctival split formation for the group treated with DF3966A was observed, compared to mice that received the sole vehicle (figure 1A). No statistically significant reduction was seen in the subepithelial inflammatory cell infiltrate by semi-quantification of H&E stained palpebral conjunctival biopsies taken on day 12 of mice treated with DF3966A compared to those biopsies of mice that received the vehicle (figure IB). In mice injected with NR-IgG no conjunctival lesions were observed compared to the other groups on day 12 (figure 2).

[0218] Treatment over 28 days twice daily via eyedrops lead to a significant reduction of palpebral conjunctival split formation in mice receiving DF3966A (figure 3A). This is also reflected in a decreased subepithelial inflammatory infiltrate by semi-quantification of H&E stained biopsies of the palpebral conjunctiva (figure 3B). Mice that just received NR-IgG from healthy rabbits did not show conjunctival lesions compared to the other groups on day 28 (figure 4). DF3966A reduced the conjunctival split formation on both 12 and 28 experimental days and decreased the inflammatory infiltrate after 28 days of treatment, compared to mice that received the solvent.

[0219] 2. Local application of DF3966A reduces oral lesions in experimental MMP Treatment with DF3966A decreased severity of oral involvement after 12 days (Figure 5) and 28 days (Figure 6) of eyedrops application, with a statistically significant difference between the vehicle group and DF3966A (day 12: p=0.0479; day 28: p=0.0372).

[0220] Conclusions

[0221] Overall, treatment with DF3966A twice daily via eyedrops reduced conjunctival split formation already on day 12 without reducing the underlying inflammation in these tissues. A longer lasting treatment until day 28 via eyedrops also decreased the inflammatory infiltrate in the palpebral conjunctiva. Furthermore, at both day 12 and 28 significant decrease in severity of oral lesions is observed.

Claims

CLAIMS1. A C5aRl inhibitor for use in the prevention and / or treatment of ocular mucous membrane pemphigoid and / or oral mucous membrane pemphigoid in a subject.

2. A C5aRl inhibitor for use as claimed in claim 1, wherein said C5aRl inhibitor is administered topically to the surface of the eye of the subject.

3. A C5aRl inhibitor for use according to claim 1 or claim 2, wherein said C5aRl inhibitor is selected from C5aRl competitive antagonists, anti-C5aRl antibodies and C5aRl non-competitive allosteric inhibitors.

4. A C5aRl inhibitor for use according to any one of claims 1 to 3, wherein said C5aRl inhibitor is a C5aRl competitive antagonist selected from the group consisting of:(2R,3S)-2-[4-(Cyclopentylamino)phenyl]-l-(2-fluoro-6-methylbenzoyl)- N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (Avacopan, Vynpenta®);N-Acetyl-L-phenylalanyl-L-ornithyl-L-prolyl-3-cyclohexyl-D-alanyl-L- tryptophyl-L-arginine-N-5.2-C-1.6-lactam (PMX-53);Acetylated phenylalanine- [ornithyl-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(l,3-benzodioxol-5-ylmethyl)-N-(l-butyl-2,4-diphenyl-lH- imidazol-5 -ylmethyljamine ;N-[2-(4-Chlorophenyl)ethyl]-N-(l,4-dioxaspiro[4.5]dec-8-yl)-2- isobutylbenzamide ;N-[2-(4-Chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)-l- benzothiophene-3 -carboxamide;N-[2-(4-Chlorophenyl)ethyl]-N-(4-hydroxycyclohexyl)naphthalene-l- 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-(l-naphthyl)-5, 6,7,8- tetrahydroquinolin-5-amine;N-[2,6-Dioxohexahydropyrimidin-4(S)-ylcarbonyl]-L-phenylalanyl-L- ornithyl-L-prolyl-5-methyl-L-norleucyl-4-fluoro-L-phenylalanyl-L- phenylalaninamide (JPE-1375; JSM-1375);N-(3-Phenylpropionyl)-L-ornithyl-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-l -carboxamide hydrochloride (W54011);L-Phenylalanyl-L-ornithyl-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', l'o] [ 1 ,4,7, 10, 13 , 16]oxapentaazacyclononadecine-5 ,7, 11 , 17,20,24- hexanone (L- 156602).

5. A C5aRl inhibitor for use according to any one of claims 1 to 3, wherein said C5aRl inhibitor is an anti-C5aRl antibody or aptamer selected from the group consisting of:Avdoralimab;MOR-044254;NOX-D20;Anti-C5aRlab-C5-SiRNA conjugate, anti-C5aRlab-protamine- C5siRNA conjugate; m20 / 70 mlgG2a.l;3C5;7F3.

6. A C5aRl inhibitor for use according to any one of claims 1 to 3, wherein said C5aRl inhibitor is a C5aRl non-competitive allosteric inhibitor selected from: (2R)-2-[3-(furan-2-carbonyl)phenyl]-N-[4-(trifluoromethyl)-l,3-thiazol-2- yl]propenamide (DF2427);R(-)-2-[(4'-trifluoromethanesulfonyloxy)phenyl]-N-[3-(N'-pirrolidinyl)propyl] propionamide (DF2297X) or its chloride salt (DF2297A); a compound having general formula (I):or a pharmaceutically acceptable salt thereof, whereinR is selected from:- 2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from methyl, tert-butyl or trifluoromethyl group;C(Ra)=N-W wherein W is linear or branched C1-C4 alkyl,- CORa, SORa, SO2Ra, PORa, PO2Ra, wherein Ra is selected from:- Ci-Cs-alkyl, Ca-Ce-cycloalkyl, C2-Cs-alkenyl, unsubstituted or substituted phenyl with a group selected from halogen, Ci-C4-alkyl, Ci-C4-alkoxy, halo-Ci-C4-alkoxy, hydroxy, Ci-C4-acyloxy, phenoxy, cyano, nitro, amino;- a heteroaryl group selected from pyridine, pyrimidine, pyrrole, thiophene, furane, indole, thiazole, oxazole, such heteroaryl being unsubstituted or substituted with a group selected from halogen, Ci-C4-alkyl, Ci-C4-alkoxy, halo-Ci-C4-alkoxy, hydroxy, C1-C4- acyloxy, phenoxy, cyano, nitro, amino;- a a or P carboxyalkyl residue consisting of straight or branched Ci- Ce-alkyl, Ca-Ce-cycloalkyl, C2-Ce-alkenyl, Ci-Ce-phenylalkyl, optionally substituted with a further carboxy (COOH) group;- an (D-aminoalkylamino group of formula (II):wherein in said formula (II) X is selected from:- linear or branched Ci-Ce alkylene, C4-C6 alkenylene, C4-C6 alkynylene, optionally substituted by: a) a CO2R4 group, wherein R4 represents hydrogen or a linear or branched Ci- Ce alkyl group or a linear or branched C2-C6 alkenyl group, or b) a C0NHR5 group wherein R5 represents- hydrogen, linear or branched C2-C6 alkyl or an OR4 group, R4 being defined as above;- a (CH2)m-B-(CH2)n, group, optionally substituted by a CO2R4 or C0NHR5 group, as defined above, wherein B is an oxygen, or sulfur atom, or nitrogen atom optionally substituted by a C1-C4 alkyl group, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;R2 and R3 are independently selected form hydrogen, linear or branched Ci-Ce alkyl, optionally interrupted by an oxygen or sulfur atom, a C3-C7 cycloalkyl, C3-C6 alkenyl, Cs-Ce-alkynyl, aryl-Ci-Cs-alkyl, hydroxy-C2-C3-alkyl group; or R2 and R3 together with the N atom to which they are bound, form a 3-7 membered nitrogen heterocyclic ring of formula (III) wherein Y represents:- a single bond, CH2, O, S, or a N-R6 group, where R6 represents hydrogen, Ci-C4 alkyl, C1-C4 acyl, unsubstituted or substituted phenyl with a group selected from halogen, Ci-C4-alkyl, C1-C4- alkoxy, hydroxy, Ci-C4-acyloxy, phenoxy, cyano, nitro, amino, and p represents an integer from 0 to 3;- a residue of formula SO2R7 wherein R7 is Ci-Ce-alkyl, Ca-Ce-cycloalkyl, C2- Ce-alkenyl, aryl and heteroaryl; or in said formula (II), X together with the nitrogen atom to which it is bound and with the R2 group, forms a nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring, and R3 is selected from the group comprising hydrogen, C1-C4 alkyl, C1-C4 acyl, unsubstituted or substituted phenyl with a group selected from halogen, Ci-C4-alkyl, Ci-C4-alkoxy, hydroxy, C1-C4- acyloxy, phenoxy, cyano, nitro, amino;R1 is linear or branched C1-C5 alkyl, C3-C5 cycloalkyl; Ar is selected from:-a phenyl group unsubstituted or substituted by one or more groups independently selected from halogen, Ci-C4-alkyl, Ci-C4-alkoxy, hydroxy, Ci- C4-acyloxy, phenoxy, cyano, nitro, amino, Ci-C4-acylamino, halo-Ci- C3- alkyl, halo-Ci-Cs-alkoxy, benzoyl, heteroaryl carbonyl, heteroaryl, linear or branched Ci-Cs-alkanesulfonate, linear or branched Ci-Cs-alkanesulfonamides, linear or branched Ci-Cs alkyl sulfonylmethyl; or- a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan, indole; and a compound having general formula (II)or pharmaceutically acceptable salts thereof, whereinX 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 Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-alkoxy, hydroxy, -COOH, C1-C4- acyloxy, phenoxy, cyano, nitro, -NH2, Ci-C4-acylamino, halo-Ci-Cs-alkyl, benzoyl, linear or branched Ci-Cs-alkanesulfonate, linear or branched Ci-Cs- alkanesulfonamides, linear or branched Ci-Cs-alkyl sulfonylmethyl;Z is an heteroaryl ring selected from the group consisting of unsubstituted tetrazole and triazole, pyrazole, oxazole, thiazole, isooxazole, 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 Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-alkylamino, Ci- C4-alkoxy, Ci-C4-alkylthio, Ci-C4-acyloxy, cyano, nitro, NH2, C1-C4- acylamino, halo-Ci-Cs-alkyl, halo-Ci-Cs-alkoxy, linear or branched Ci-Cs- alkanesulfonate and linear or branched Ci-Cs-alkanesulfonamides.

7. A C5aRl inhibitor for use according to claim 6, wherein in said compound of formula (I)R is selected from:- 2-thiazolyl or 2-oxazolyl, unsubstituted or substituted by a group selected from methyl, tert-butyl or trifluoromethyl group,- C(Ra)=N-W wherein W is linear or branched C1-C4 alkyl,- CORa, SORa or SO2Ra, wherein Ra is as defined in claim 6; andAr is selected from the group comprising: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 ’ -(thiophen-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 ; or Ar is a heteroaryl ring selected from pyridine, pyrrole, thiophene, furan or indole.

8. A C5aRl inhibitor for use according to claim 6 or 7, wherein said C5aRl inhibitor is a compound of formula (I) selected from:4-{(lR)-l - [(phenylsulfonyl)amino] ethyl } phenyl trifluoromethanesulfonate ;N-[(lR)-l-(3-benzoylphenyl)ethyl]benzenesulfonamide;4-{(lR)-l-[(pyridine-3- ylsulfonyl)amino]ethyl}phenyltrifluoromethanesulfonate;N- [( 1 R)- 1 -(3 -benzoylphenyl)ethyl] methane sulfonamide ;N- { ( 1R)- 1 - [3 -(2-furoyl)phenyl] ethyl } thiophene-2- sulfonamide ; N-{(lR)-l-[3 - (2-furoy l)pheny 1] ethyl } methane sulfonamide ;4-{(lR)-l-[(thien-2-ylsulfonyl)amino]ethyl}phenyl trifluoro me thane sulfonate ;N- [( 1 R)- 1 -(3 -benzoylphenyl)ethyl] thiophene-2-sulfonamide ;N- [( 1 R)- 1 -(3 -benzoylphenyl)ethyl] -3 -pyrrolidin- 1 -ylpropane- 1 - sulfonamide; methyl 5-( { [( 1 R)- 1 -(3-benzoylphenyl)ethyl] amino } sulfonyl)-2-furoate;5-({[(lR)-l-(3-benzoylphenyl)ethyl] amino }sulfonyl)-2-furoic acid;- 4-{(lR)-2-methyl-l- [(methylsulfonyl)amino]propyl}phenyltrifluoromethanesulfonate;- N-(( lR)-l-{4-[l -methyl- 1-(phenylsulfonyl)ethyl]phenyl}ethyl)methanesulfonamide;4-[(lR)-l-(isobutyrylamino)ethyl]phenyltrifluoromethanesulfonate;4-{[(lR)-l-(pyridine-3- ylcarbonyl)amino] ethyl] Jphenyltrifluoromethanesulfonate;N-[(lR)-l-(3-benzoylphenyl)ethyl]benzamide;N-[(lR)-l-(3-benzoylphenyl)ethyl]-2-furamide;N- [( 1 R)- 1 -(3 -benzoylphenyl)ethyl] cyclobutanecarboxamide;N- [( 1 R)- 1 -(4-trifluoromethanesulfonyloxy)phenylethyl] -4-piperidin- 1 -yl butanamide (DF2593Y);4-{(lR)-l - [(4-pyrrolidin- 1 -ylbutanoyl)amino] ethyl] } phenyl trifluoro me thane sulfonate ;3 - { ( 1 R)- 1 - [4-(4-trifluoromethyl- 1 ,3 -thiazol-2-yl)amino] ethyl } phenyl) (phenyl)methanone.

9. A C5aRl inhibitor for use according to claim 6, wherein in said compound of formula (II)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 Ci-C4-alkyl and halo-Ci-Ca-alkyl; preferably selected from the group consisting of trifluoromethyl, chlorine, methyl and tert-butyl;Z is an heteroaryl ring selected from the group consisting of unsubstituted tetrazole and triazole, pyrazole, isooxazole, 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 Ci-C4-alkyl, Ci-C4-alkylthio and halo-Ci-Ca-alkyl; preferably selected from the group consisting of methyl, trifluoromethyl and chlorine.

10. A C5aRl inhibitor for use according to claim 6 or 9, wherein said C5aRl inhibitor is a compound of formula (II) selected from:- 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-[(lR)-l-(lH-tetrazol-5-yl)ethyl]phenyl}-l,3-thiazol-2-amine;4-tert-butyl-N-{4-[(lR)-l-(lH-tetrazol-5-yl)ethyl]phenyl}-l,3-thiazol-2- amine;- N- { 4-[( 1 R)- 1 -( 1 H-tetrazol-5-yl)ethyl]phenyl } - 1 ,3-thiazol-2-amine;N- { 4-[( 1 R)- 1 -( 1 H-tetrazol-5-yl)ethyl]phenyl } -4-(trifluoromethyl)- 1,3- oxazol-2-amine;- 4-methyl-N- {4-[(lR)-l-(lH tetrazol-5-yl)ethyl]phenyl}-l,3-oxazol-2-amine;- 5-[(lR)-l-(4-{ [4-(trifluoromethyl)-l,3-thiazol-2-yl]amino}phenyl)ethyl]-lH pyrazol-l-ol;- 4-methyl-5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino Jphenyl) ethyl] - 1 H-pyrazol- 1 -ol ;- 5 - [( 1 R)- 1 -(4-( [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino } phenyl)ethyl] - 1 H-1.2.3-triazol-l-ol;5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] isoxazol-3-ol;- 4-methyl-5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino Jphenyl) ethyl]isoxazol-3-ol;5-[( 1 R)- 1 -(4- { [4-(trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] isothiazol-3-ol;4-[( 1 R)- 1 -(4- { [4- (trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] - l,2,5-oxadiazol-3-ol;4-[( 1 R)- 1 -(4- { [4- (trifluoromethyl)- 1 ,3-thiazol-2-yl] amino }phenyl)ethyl] - 1,2,5 -thiadiazol-3 -ol ;- 5-[(lR)-l-(4-{ [4-(trifluoromethyl)-l,3-thiazol-2-yl]amino}phenyl)ethyl]-lH1.2.4-triazol-l-ol.

11. A C5aRl inhibitor for use according to any one of claims 6 to 10, selected from:N- [( 1 R)- 1 -(4-trifluoromethanesulfonyloxy)phenylethyl] -4-piperidin- 1 -yl butanamide (DF2593Y) and pharmaceutically acceptable salts thereof, preferably its chloride salt (DF2593A),R(-)-2-[(4'-trifluoromethanesulfonyloxy)phenyl]-N-[3-(N'- pirrolidinyl)propyl] propionamide (DF2297X) or its chloride salt (DF2297A), and5-[(lR)-l-(4-{[4-(trifluoromethyl)-l,3-thiazol-2- yl]amino}phenyl)ethyl]tetrazol-2-ide (DF3966Y) or its sodium salt (DF3966A).

12. A C5aRl inhibitor for use according to claims 1-11, selected from: Avacopan, PMX-53, W54011, Avdoralimab, MOR-044254, PMX-205, DF2593A, DF2297A, DF2427 and DF3966A.

13. A C5aRl inhibitor for use according to claims 6 to 12, which is DF3966A.

14. An ophthalmic composition comprising a therapeutically effective amount of a C5aRl inhibitor as defined in claims 3-13 and at least one ophthalmologically acceptable excipient or carrier.

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