WO2021165206A1

WO2021165206A1 - Treatment of dry amd with integrin antagonists

Info

Publication number: WO2021165206A1
Application number: PCT/EP2021/053650
Authority: WO
Inventors: Ove Pedersen; Elke Vermassen
Original assignee: Oxurion NV
Priority date: 2020-02-19
Filing date: 2021-02-15
Publication date: 2021-08-26

Abstract

The present invention relates to the use of integrin antagonists in the treatment and/or prevention of dry age-related macular degeneration (AMD) or geographic atrophy (GA), the use of a pharmaceutical composition comprising said integrin antagonists in the treatment and/or the prevention of dry AMD or GA and to a method for treating and/or preventing dry AMD or GA.

Description

Treatment of dry AMD with integrin antagonists

FIELD OF INVENTION

The present invention relates to the use of certain integrin antagonists in the treatment and/or prevention of dry age-related macular degeneration (AMD) or geographic atrophy (GA). The present invention also relates to the use of a pharmaceutical composition comprising said integrin antagonists in the treatment and/or the prevention of dry AMD or GA. The present invention further provides a method for treating and/or preventing dry AMD or GA.

BACKGROUND OF THE INVENTION

Age-related macular degeneration (AMD) is a leading cause of legal blindness and moderate to severe visual impairment in the Western world. It is a retinal degenerative disorder that typically affects people age 50 or older and is the most common cause of severe and irreversible vision loss in the world. The Centers for Disease Control and Prevention estimate that 1.8 million people have AMD and another 7.3 million are at substantial risk for vision loss from AMD. This eye disease occurs when modifications occur in the macula, a small portion of the retina. The progressive loss of central vision and visual acuity impacts on quality of life by hindering facial recognition, and the ability to read or drive.

AMD is a loss of central vision which occurs in two distinct types with different underlying mechanisms: "dry" (atrophic) and "wet" (exudative) AMD. Most patients suffering from macular degeneration have the dry form; which is characterized by soft drusen located between the retinal pigment epithelium (RPE) and the Bruch's membrane and by gradual breakdown of the RPE which can progress in geographic atrophy (GA). GA is characterized by progressive modifications of Bruch's membrane, patchy loss of the RPE, involution of the neighboring choriocapillaris and degeneration of photoreceptors, leading to progressive vision loss. It is hypothesized that multiple factors contribute to progression of dry AMD to GA. Aging is the greatest risk factor for AMD, but factors that exacerbate oxidative stress and inflammation, including cigarette smoking, also contribute to AMD initiation and progression. The precise pathological mechanisms underpinning GA remain unclear and no adequate treatments are available. Time and again, successful therapies for the treatment of wet AMD have shown to be ineffective for the treatment of dry AMD and GA. Integrins constitute a family of transmembrane cell surface receptors that can mediate cell-cell and cell-extracellular matrix interactions. Integrins are involved in various biological processes including cell differentiation, adhesion, shape, migration, motility, invasion, proliferation, and survival. Because of their role in these biological processes, integrins have also been associated with various pathological conditions, such as cancer and ophthalmic disorders. In the eye, integrins have been shown to play an important role in neovascularization, vascular permeability and vitreoretinal adhesion. For these reasons, integrin antagonists are also reviewed for the treatment of wet (neovascular) AMD.

Integrins are obligate heterodimeric receptors consisting of a non-covalently bound a and b subunit. Different combinations of the 18 a and the 8 b known subunits constitute the family of 24 heterodimeric integrin members recognized thus far. The integrin family of receptors can be broadly classified into 4 different categories depending on their ligand recognition pattern: 1) the tripeptide L- arginine-glycine-aspartic acid (RGD) binding, 2) collagen binding, 3) laminin binding and 4) leukocyte binding types of integrins.

Interaction of integrins with the extracellular matrix can lead to neovascularization of the retinal surface, which can eventually extend towards the vitreous region. Immunohistological staining on human retinal tissues derived from proliferative diabetic retinopathy (PDR) patients has shown that actively proliferating vascular endothelial cells express the integrins a_nb and a_nb , which are not highly expressed in quiescent endothelial cells (Friedlander et al., 1996; Ning et al., 2008). In addition, a_nb₃ and ^ have been shown to be expressed in fibrovascular epiretinal membranes from patients with active PDR in the fibrotic stage (Ning et al., 2008; Abu El-Asrar, Missotten and Geboes, 2010), whereas a5b1 has been shown to be overexpressed in a laser-induced mouse model of CNV (Umeda et al., 2006). In line with this, several non-clinical studies have demonstrated that inhibition of integrins attenuates leukostasis and retinal vascular permeability (Santulli et al., 2008; lliaki et al., 2009; Rao et al., 2010). Antagonism of a_nb₃ and a_nb₅ prevented retinal neovascularization but did not harm pre-existing blood vessels (Friedlander et al., 1996; Hammes et al.,1996; Lahdenranta et al., 2007; Santulli et al., 2008), whereas inhibition of a₅bi inhibited endothelial cell proliferation and produced regression of choroidal neovascular membranes in different animal models (Ramakrishnan et al., 2006; Umeda et al., 2006).

The RGD motif is very commonly found in many components of the extracellular matrix, including vitronectin, fibronectin and fibrinogen. Integrins are therefore heavily linked to extracellular matrix proteins, thereby mediating cell-extracellular matrix adhesion, for instance in the vitreoretinal interface. Analogues of the RGD motif are known to compete for the RGD motif of extracellular matrix proteins to disrupt integrin-extracellular matrix interactions and therefore loosen the attachments in in vitro experiments (Gehlsen et al 1988; Pierschbacher and Ruoslahti, 1987; Zhou, Zhang and Yue, 1996). In line with this, IVT injection of soluble RGD peptides has been shown to induce PVD in rabbit eyes (Oliveira et a I., 2002). Moreover, in humans, 3 IVT injections of the integrin antagonist ALG 1001 (Allegro Ophthalmics, LLC) have been shown to induce total PVD in 6 of 11 DME patients with no or partial PVD at baseline in an initial proof-of-concept study (Kuppermann, 2013; Boyer et al., 2014).

These observations underpin the preference for treating wet AMD using a pan-integrin antagonist that targets the different types of integrins that underlie different aspects of the wet AMD disease, most notably a_nb₃, a_nb₅ and a₅bi. The complexity is that such pan-integrin antagonists will often also antagonize other RGD-binding integrins, which may cause side effects. Most notable is the platelet integrin, cxi^₃, whose antagonism may interfere with platelet activation and aggregation.

Patent application publications WO2011/119282 Al, WO2011/094285 Al, US2006/0052398 Al and US2008/058348 Al disclose compounds as potential integrin antagonists or as potential vitronectin receptor antagonists. The compounds disclosed in these patent applications can be summarized as generally corresponding to Formula A

Formula A wherein, generally Gi represents a substituted pyridine or tetrahydro naphtyridine, Ri and R₂ are hydrogen, methyl or ethyl, and R₃ is a hydrophobic tail group. In particular, in the exemplified compounds with confirmed activity, R₃ comprises an alkyl, cycloalkyl or (hetero)aromatic end group.

Regarding the researches performed in the domain of dry AMD and the efforts made in finding efficient treatments, actual publications teach that the use of integrin antagonists is not adapted for this kind of disease because integrins were found to be important for retinal pigment epithelial (RPE) cell viability and for retina photoreceptors. Indeed, photoreceptor and RPE cells are in close contact, outer segment shedding by photoreceptors precedes a burst of phagocytosis by the RPE that efficiently clears photoreceptor outer segment fragments (POS) from the subretinal space and recycles their components (Young eta!., 1969). POS shedding and subsequent phagocytosis by RPE cells are crucial for photoreceptor cell function and survival. Failure of RPE to ingest POS causes debris accumulation and rapid photoreceptor degeneration illustrating the importance of RPE phagocytosis (Mullen eta!., 1976). Several data suggest that defective digestion of POS by RPE cells may contribute to development or progression of age-related retinal diseases such as AMD. The adhesion receptor a_nb₅ integrin has been shown to fulfill several roles in RPE phagocytosis (Finnemann et a!., 1997; Miceli et aL, 1997; Lin et aL, 1998). In particular, Nandrot et al. (2006) discloses that lack of a_nb₅ integrin receptors eliminates the rhythm of POS phagocytosis in the retina. With age, mice lacking a_nb₅ integrin progressively lose vision and their RPE accumulates lipofuscin granules. The age-related changes observed in retinas of b5 knockout mice share some characteristics of retinas of humans with age-related macular degeneration.

Further, McLaughlin et al. (2003) have shown that the complement regulatory protein CD46 associates directly with bi integrin in RPE cells from human donor eyes in situ and in primary cultures of human RPE and that the bΐ subunit of integrins partially mediate the adherence of human RPE cells to RPE-derived extracellular matrix and the basal lamina layer of human Bruch's membrane.

Although the vast majority of AMD patients have the dry form (about 85-90%), no treatment option is currently available for these patients. Thus, there is a strong unmet medical need to find dry AMD and GA treatment options, in particular treatments with an improved therapeutic efficacy and safety profile.

SUMMARY OF THE INVENTION

The inventors have now surprisingly found that certain integrin antagonists as detailed in the claims fulfil the above-mentioned need.

It is thus an object of the present invention to provide compounds according to formula (A) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof,

wherein:

G is selected from the group consisting of (B-a) to (B-e) :

each of R' and R", independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci-io alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ORu and NR₁₁R₁₂, wherein each of Ru and R₁₂, independently from each other and at each occurrence, are selected from hydrogen or Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; nl and n2 are integers in the range from 0 to 4, preferably nl and n2 are integers in the range from 0 to 2; each of R'", independently from each other and at each occurrence is selected from the group consisting of hydrogen, Ci-₁₀ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ORu and NRuRu, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents selected from halo, Ci-₆ alkyl or OCi-₆- alkyl, and wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or Ci-e alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; n3 is an integer in the range from 0 to 4, preferably n3 is an integer in the range from 0 to 2;

R_b is independently selected from hydrogen or COORu, wherein said Ru is selected from hydrogen or Ci-₆ alkyl; preferably R_b is hydrogen; each of Ri and R₂ are independently selected from the group consisting of hydrogen, halo, Ci-₆ alkyl and 0-Ci-₆alkyl;

R is independently selected from the group consisting of ORu and NR₂₂, wherein Ru is independently selected from hydrogen or Ci-₆ alkyl, and R₂₂ is selected from hydrogen or an Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more COORu, wherein said R is hydrogen or Ci_ alkyl;

R₃ is independently selected from the group consisting of hydrogen, Ci-₆ alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, COR_3I, COOR₃₂, S0₂R₃₃ and CON(R₃ )₂, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from halo,

alkyl, C_2. alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OC(R_U)₂0, N(Ru)₂and ORu; and wherein said R_3I, R₃₂, R₃₃ and R₃ , independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci_₆ alkyl, heterocyclyl, aryl and aralkyl, wherein said alkyl, heterocyclyl, aryl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu and S0₂Ri and wherein each of Ru, independently from each other and at each occurrence is hydrogen or Ci_ alkyl, for use in the treatment and/or prevention of dry AMD or GA.

In addition, in a particularly preferred embodiment, the present invention provides compounds with an improved integrin antagonistic profile. Therefore, the present invention provides compounds of formula I or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof,

Ri and R₂ are independently selected from the group consisting of hydrogen, methyl or ethyl; and

Aik is Ci^alkylene for use in the treatment and/or the prevention of dry AMD or GA. The present invention further relates to a pharmaceutical composition for use in the treatment and/or the prevention of dry AMD or GA comprising the compound of the present invention, and one or more pharmaceutically acceptable carries.

The present invention also provides a method for the treatment and/or the prevention of dry AMD or GA comprising the administration of the compound or the composition of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows EC50 ratios for cpdl, cpd2, cpd3 and comparative compounds cpdA and cpdB for integrin a_nb₃ over ai^₃ (lower values indicate a higher specificity for a_nb₃).

FIG. 2 shows amplitudes of the a-wave (Fig. 2A) and b-wave (Fig. 2B) measured in all eyes (n=4-8 eyes/group) at 4 days after blue light exposure. Administration of cpd2 (IP and IVT) improved both a-and b-wave amplitudes, as compared to vehicle-treated eyes. Data are shown as mean ± SEM.

FIG. 3 shows amplitudes of the a-wave (Fig. 3A) and b-wave (Fig. 3B) measured in the IVT injected eyes (n=2-4 eyes/group) at 4 days after blue light exposure. Administration of cpd2 (IP and IVT) improved both a-and b-wave amplitudes, as compared to vehicle-treated eyes. Data are shown as mean ± SEM. FIG. 4 shows amplitudes of the a-wave (Fig. 4A) and b-wave (Fig. 4B) measured in the non-IVT injected eyes (n=2-4 eyes/group) at 4 days after blue light exposure. Administration of cpd2 (IP) only showed minor differences in a-and b-wave amplitudes, as compared to vehicle-treated eyes. Data are shown as mean ± SEM.

FIG. 5 shows total retinal thickness measurements from the IVT injected eyes (n=2-4/group) at baseline and 7 days after blue light exposure. Administration of cpd2 (IP and IVT) showed a minor increase in retinal thickness, as compared to vehicle-treated mice. Data are shown as mean ± SEM.

FIG. 6 shows amplitudes of the a-wave (Fig. 6A-B) and b-wave (Fig. 6C-D) measured at 7.5 cd.s/m² at 4 days after blue light exposure (n=12 eyes/group). Administration of cpd2 (50 pg/eye) or cpdC (llpg/eye) improved both a-and b-wave amplitudes, as compared to the respective vehicle-treated eyes (P<0.05). The eyes treated with the lower doses of cpd2 (15 and 3.3 pg/eye) did not show any differences compared to the respective vehicle-treated eyes. Data are shown as mean ± SEM. FIG. 7 shows total retinal thickness measurements 7 days after blue light exposure (n=8-12 eyes/group). Administration of (A) cpdl (120 pg/eye) & cpd3 (63 pg/eye), (B) cpd2 (50 pg/eye) or (C) cpdC (11 pg/eye) showed an increase in retinal thickness, as compared to the respective vehicle-treated mice (P<0.05). The eyes treated with the other doses of (B) cpd2 (15 and 3.3 pg/eye) did not show any differences compared to the vehicle-treated eyes. Data are shown as mean ± SEM.

DETAILED DESCRIPTION OF THE INVENTION

It is further understood that all definitions and preferences as described for the compounds of the invention above equally apply for this embodiment and all further embodiments, as described below. As used in the foregoing and hereinafter, the following definitions apply unless otherwise noted.

The term "alkyl" - alone or in combination means an alkane-derived radical containing from 1 to 20, preferably 1 to 15 carbon atoms, more preferably 1 to 10 carbons, unless otherwise specified. For example, C_F-G alkyl defines a straight or branched alkyl radical having from F to G carbon atoms, e.g. Ci_ alkyl defines a straight or branched alkyl radical having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1-propyl, 2-propyl, l-butyl, 2-butyl, 2-methyl-l-propyl. An alkyl group may be a straight chain alkyl or branched alkyl. Preferably, straight or branched alkyl groups containing from 1-15, more preferably 1 to 8, even more preferably 1-6 and most preferably 1-4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl.

The term "alkylene", alone or in combination means an alkane-derived diradical, which may be a straight chain alkylene or branched alkylene, preferably containing from 1 to 4 carbon atoms. The straight chain or branched alkylene group is attached at any available point to produce a stable compound. According to certain embodiments C_A-B alkylene defines a straight or branched alkylene diradical having from A to B carbon atoms, e.g. Ci_ alkylene defines a straight or branched alkylene diradical having from 1 to 4 carbon atoms, such as for example methylene, ethylene, 1-propylene, 2-propylene, l-butylene, 2- butylene, 2-methyl-l-propylene.

The term "aryl", alone or in combination, refers to a monocyclic or bicyclic group comprising at least one aromatic ring structure, said aromatic ring preferably having 5 to 7 ring members and optionally being substituted with 1 to 5 group substituents. Non-limiting examples of such substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO -NH , aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -S0₂R^a, alkylthio, carboxyl, and the like, wherein R^a is alkyl or cycloalkyl. Preferably, aryl refers to a monocyclic aromatic group having 5 to 7 ring members, preferably 6 ring members, and is not substituted unless explicitly defined in the embodiments described herein.

The term "heteroaryl", alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 5 substituents. Optional substituents for heteroaryl are as defined for aryl above. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, and benzodiazepin-2-one-5-yl, and the like. Preferably, heteroaryl refers to a monocyclic aromatic group having 5 to 7 ring members, preferably 6 ring members, containing 1 or 2 heteroatoms selected from the group comprising O, S, and N, and is not substituted unless explicitly defined in the embodiments described herein.

The term "heterocyclyl", alone or in combination is intended to denote a saturated, partially unsaturated or completely unsaturated monocycle, bicycle, or tricycle having 3 to 12 carbon atoms and containing 1, 2, 3, or 4 heteroatoms each independently selected from O, S, P or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted with 1 to 5 substituents as defined for aryl. Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom. In each case the heterocyclyl may be condensed with an aryl to form a bicyclic ring system. Preferably, heterocyclic refers to a monocyclic group having 5 to 7 ring members, preferably 6 ring members, containing 1 or 2 heteroatoms selected from the group comprising O, S, and N, and is not substituted unless explicitly defined in the embodiments described herein.

The term "cycloalkyl" refers to a cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms. Preferably, cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like. Cycloalkyl is optionally substituted with 1 to 5 substituents as defined for aryl. Preferably, cycloalkyl refers to a monocyclic group having 5 to 7 carbon atoms, preferably 6 carbon atoms, and is not substituted unless explicitly defined in the embodiments described herein.

The term "aralkyl" refers to organic compounds containing an aromatic nucleus to which an alkyl radical is bonded. These alkyl radicals include methyl, ethyl, propyl, butyl, octyl, etc. radicals. The term aralkyl is thus seen to include aralkyl hydrocarbons such as the alkyl benzenes, and the various alkyl naphthalenes. From this definition of the term aralkyl compound it is seen that the term includes compounds such as benzyl, the three isomeric xylyls, the two isomeric trimethyl benzenes, ethyl benzene, p-methyl biphenyl, a-methyl naphthalene, etc.

Where reference is made to percentages, this refers to weight to weight percentages, unless the context clearly dictates otherwise.

As used herein, "treating" or "treatment" means to administer a treatment to a subject, preferably a human patient. Treating includes a treatment which acts to reduce an existing clinical symptom (such as the amount or extent of drusen present) of a present, diagnosed ocular condition (such as dry AMD), as well as prevention of deterioration of (or slowing of the rate of deterioration of) the present, diagnosed ocular condition.

As described herein before, the present invention provides compounds according to formula (A), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof,

wherein:

G is selected from the group consisting of (B-a) to (B-e) :

each of R' and R", independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci-io alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ORu and NR₁₁R₁₂, wherein each of Ru and R₁₂, independently from each other and at each occurrence, are selected from hydrogen or Ci_₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; nl and n2 are integers in the range from 0 to 4, preferably nl and n2 are integers in the range from 0 to 2; each of R'", independently from each other and at each occurrence is selected from the group consisting of hydrogen, Ci-₁₀ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ORu and NRuR , wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents selected from halo, Ci-₆ alkyl or OCi-₆- alkyl, and wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; n3 is an integer in the range from 0 to 4, preferably n3 is an integer in the range from 0 to 2; b is independently selected from hydrogen or COORu, wherein said Ru is selected from hydrogen or Ci-₆ alkyl; preferably R_b is hydrogen; each of Ri and R₂ are independently selected from the group consisting of hydrogen, halo, Ci-₆ alkyl and 0-Ci-₆alkyl;

R is independently selected from the group consisting of ORu and NR₂₂, wherein Ru is independently selected from hydrogen or Ci-₆ alkyl, and R₂₂ is selected from hydrogen or an Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more COORu, wherein said Ru is hydrogen or Ci- alkyl;

R₃ is independently selected from the group consisting of hydrogen, Ci-₆ alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, COR₃I, COOR₃₂, S0₂R₃₃ and CON(R₃ )₂, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from halo,

alkyl, C_2. alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OC(R_U)₂0, N(Ru)₂and ORu; and wherein said R₃I, R₃₂, R₃₃ and R₃ , independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci_₆ alkyl, heterocyclyl, aryl and aralkyl, wherein said alkyl, heterocyclyl, aryl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu and S0₂Ri and wherein each of Ru, independently from each other and at each occurrence is hydrogen or Ci_ alkyl. According to a preferred embodiment of the present invention, each of R' in formula (A), independently from each other and at each occurrence, is selected from the group consisting of hydrogen, Ci_₆ alkyl, aryl, heteroaryl, and NRuRu, wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or Ci_₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl. Preferably, R' is independently selected from the group consisting of hydrogen, Ci_ alkyl, aryl, heteroaryl, and NRuRu, wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or

alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl. More preferably, R' is independently selected from the group consisting of NR_UR_I2, wherein Ruand R_I2, independently from each other and at each occurrence, is selected from hydrogen or Ci alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from aryl or heteroaryl. Even more preferably, R' is H.

According to a particular embodiment of the present invention, each of R" in formula (A), independently from each other and at each occurrence, is selected from the group consisting of hydrogen, Ci alkyl, aryl, heteroaryl, and NR_UR_I2, wherein each of Ru and R_I2, independently from each other and at each occurrence, are selected from hydrogen or Ci alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl. Preferably, R' is independently selected from the group consisting of hydrogen, C_1-4 alkyl, aryl, heteroaryl, and NRuRu, wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or Ci alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl. More preferably, R' is independently selected from the group consisting of NRuRu, wherein Ruand R_I2, independently from each other and at each occurrence, are selected from hydrogen or Ci alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from aryl or heteroaryl. Even more preferably R" is H.

According to another particular embodiment of the present invention, each of R'" in formula (A), independently from each other and at each occurrence, is selected from the group consisting of hydrogen, Ci- alkyl, ORu and NRuRu, wherein said alkyl, is optionally substituted with one or more substituents selected from halo or OCi^- alkyl, and wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or Ci_ alkyl. Preferably, each of R'", independently from each other and at each occurrence, is selected from hydrogen, Ci_ alkyl or ORu, wherein Ru is methyl.

According to a preferred embodiment of the present invention, G in formula (A) is (B-b) as described above.

According to a preferred embodiment of the present invention, R_b in formula (A), is independently selected from hydrogen or COORu, wherein said Ru is selected from hydrogen or Ci_ alkyl. Preferably, R_b is selected from hydrogen or COORu, wherein said u is selected from hydrogen or ferf-butyl. More preferably R_b is hydrogen.

According to a particular embodiment of the present invention, nl is an integer in the range from 0 to 2. Preferably nl is 1.

According to a particular embodiment of the present invention, n2 is an integer in the range from 0 to 2. Preferably n2 is 1.

According to a particular embodiment of the present invention, n3 is an integer in the range from 0 to 2. Preferably n3 is 1.

According to a particular embodiment of the present invention, Ri in formula (A) is independently selected from the group consisting of hydrogen and Ci_₆ alkyl. Preferably, Ri is selected from the group consisting of hydrogen and Ci_ alkyl. More preferably, Ri selected from hydrogen, methyl of ethyl. Even more preferably, Ri is hydrogen or methyl.

According to a particular embodiment of the present invention, R₂ in formula (A) is independently selected from the group consisting of hydrogen, Ci_₄ alkyl, 0-Ci_ alkyl. Preferably, R₂ is selected from the group consisting of hydrogen and Ci_ alkyl. More preferably, R₂ is selected from the group consisting of hydrogen, methyl or ethyl.

According to a particular embodiment of the present invention, R₃ in formula (A) is independently selected from the group consisting of COR_3I, COOR₃₂, S0₂R₃₃ and CON(R₃ )₂, wherein said R_3I, R₃₂, R₃₃ and R₃₄, independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci_₆ alkyl, heterocyclyl, aryl, aralkyl, wherein said alkyl, heterocyclyl, aryl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, C_M alkyl, C_2. alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu, S0₂Ri and wherein each of Ru, independently from each other and at each occurrence is selected from the group consisting of hydrogen or Ci_ alkyl. Preferably, R₃ in formula (A) is independently selected from the group consisting of COR_3I, COOR₃₂, S0₂R₃₃ and CON(R₃₄)₂, wherein said R_3I, R₃₂, R₃₃ and R₃₄, independently from each other and at each occurrence, are Ci_₆ alkyls, wherein said alkyls is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu, S0₂Riand wherein each of Ru, independently from each other and at each occurrence is selected from the group consisting of hydrogen and Ci_ alkyl. More preferably, R₃ is independently selected from the group consisting of COR_3I, COOR₃₂, S0₂R₃₃ and CON(R₃ )2, wherein said R_3I, R₃₂, R₃₃ and R₃₄, independently from each other and at each occurrence, are Ci-₆ alkyls, wherein said alkyls are optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR11, N(R_U)₂, COOR11 and S0₂Ri and wherein each of Ru, independently from each other and at each occurrence is selected from the group consisting of hydrogen and Ci_₄ alkyl. Most preferably, R₃ is independently COR_3I, wherein said R₃₄ is independently Ci_₄ alkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, and COORuand wherein Ru, is hydrogen, methyl or ethyl.

According to a particular embodiment of the present invention, R₄ in formula (A) is independently OR11, wherein Ru is selected from hydrogen or Ci_₄ alkyl. Preferably, R₄ is ORu, wherein Ru is selected from hydrogen, methyl or ethyl. More preferably, R₄ is ORu, wherein Ru is hydrogen or methyl. Most preferably, R₄ is ORu, wherein Ru is hydrogen.

According to one preferred of the present invention, the compound is a compound of formula (A- 1), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof :

wherein R₃ has the same meaning as defined above and wherein : each of Ri and R2 are independently selected from the group consisting of hydrogen and C1-4 alkyl; R is OR11 wherein each of Ru is selected from hydrogen or Ci-₆ alkyl

According to an even more preferred embodiment of the present invention, the compound is a compound of formula (A-l-1): (Formula A-l-1) wherein Ri, R₂ and R have the same meaning as defined above and wherein :

R'₃₂ is Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu and S0₂Ri; and wherein each of Ru, independently from each other and at each occurrence is selected from the group consisting of hydrogen and C1-4 alkyl.

As described herein before, the present invention also provides compounds with an improved integrin antagonistic profile according to formula (I) for use in the treatment and/or prevention of dry AMD or GA. Therefore, in a particularly preferred embodiment, the present invention provides compounds of Formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof,

Formula I wherein Ri and R₂ are independently selected from the group consisting of hydrogen, methyl or ethyl; and Aik is Ci^alkylene for use in the treatment and/or the prevention of dry age-related macular degeneration (AMD) or geographic atrophy (GA).

According to a certain embodiment of the present invention, either Ri and R₂ in Formula I are both methyl, or Ri is hydrogen and R₂ is ethyl.

According to a preferred embodiment, the present invention provides those compounds of Formula I wherein Ri and R₂ are both methyl.

According to a certain embodiment of the present invention, Aik in Formula I is Ci-₂ alkylene.

According to a preferred embodiment of the present invention, the compound is selected from the group consisting of

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof.

The compound of the present invention, as detailed above, may have a center of chirality and exists as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the anti inflammatory compound as specified herein, may possess.

Unless otherwise mentioned or indicated, the chemical designation of the compounds, as detailed above, encompasses the mixture of all possible stereochemically isomeric forms, which said compounds may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compounds for use. All stereochemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention. In a preferred embodiment, the present invention provides the (S) enantiomeric forms of the compounds according to Formula I. Therefore, in a particular embodiment, the present invention provides a compound according to Formula II,

Formula II wherein Ri, R₂ and Aik are as defined in the application, in particular as defined in relation to Formula I.

In a further embodiment, the present invention provides a compound selected from the group consisting of

For therapeutic use, salts of the compounds for use of the present invention, as detailed above, are those wherein the counter-ion is pharmaceutically acceptable, which salts can be referred to as pharmaceutically acceptable acid and base addition salts. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds for use of the present invention, as detailed above, are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid in an anion form. Appropriate anions comprise, for example, trifluoroacetate, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and the like. The counterion of choice can be introduced using ion exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. A preferred salt is the hydrochloride salt of the compounds described herein.

The compounds for use as specified herein, containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cation form. Appropriate basic salts comprise those formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and the like; and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Conversely said salt forms can be converted by treatment with an appropriate acid into the free form. The term addition salt as used hereinabove also comprises the solvates which the compounds for use, as specified herein, as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.

As will be understood from the disclosures herein, the current invention particularly provides isolated compounds and isolated compositions. Compounds are in particular obtained by in vitro synthesis, such as by chemical synthesis. In a further embodiment, compounds of the invention have a purity of at least 85%, in particular at least 90%, more in particular at least 95%. In a particular embodiment, the present invention provides a method for providing a compound of the invention, the method comprising chemically synthesizing the compound of the invention and packaging the synthesized compound in a sterile container. In a further embodiment, the present invention provides a method for providing a compound of the invention, the method comprising chemically synthesizing the compound at a purity of at least 85%, in particular at least 90%, more in particular at least 95%. Preferably, the synthesized compound is subsequently packaged in a sterile container.

COMPOSITIONS The present invention further relates to a pharmaceutical composition for use in the treatment and/or the prevention of dry AMD or GA, the composition comprising a compound as defined above and as defined in any one of the embodiments presented herein. As is evident from the disclosure herein, particularly preferred are those compositions comprising a compound according to Formula I. In a further preferred embodiment, those according to Formula II. ln the rest of the text, the expression "compound " or "compound according to the invention" is understood, for the purposes of the present invention, both in the plural and the singular, that is to say that the inventive composition may comprise one or more than one "compound according to the invention".

In a particular embodiment, the present invention provides a pharmaceutical composition comprising the compound according to any one of the claims, and one or more pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable formulations as well as methods for making them can be found, e.g., in Remington's Pharmaceutical Sciences (e.g. 20th Edition; Lippincott, Williams & Wilkins, 2000) or in any Pharmacopeia handbook (e.g. US-, European- or International Pharmacopeia).

In another embodiment, the present invention provides a composition comprising an aqueous buffer wherein a compound of the invention has been dissolved. In a further embodiment, the present invention provides a pharmaceutical composition comprising an aqueous buffer wherein a compound of the invention and one or more pharmaceutically acceptable carriers have been dissolved. In another further embodiment, the present invention provides a pharmaceutical composition consisting of an aqueous buffer, a compound of the invention and one or more pharmaceutically acceptable carriers.

In a particular embodiment, the present invention provides a composition comprising an integrin antagonist, wherein at least 90% of the integrin antagonist compounds of the composition is a compound according to the invention. Preferably at least 95%, especially at least 99% of the integrin antagonist compounds of the invention is a compound according to the invention. In another particular embodiment, the compositions of the invention are substantially free of another integrin antagonist, such as compound A. In a further embodiment, the ratio of the compound of the invention over other integrin antagonist compounds, such as compound A, is more than 98:2, particularly more than 99:1, more particularly more than 99.9:0.1. In yet another embodiment, the present invention provides a composition as described herein, wherein the composition is substantially free of compound A, in particular wherein the composition comprises less than 3%, especially less than 2%, preferably less than 1% of compound A, more in particular with the proviso that the composition does not comprise compound A.

In another embodiment, the current invention provides a composition comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is an integrin antagonist according to the invention, and wherein the composition is substantially free of an integrin antagonist other than the first active ingredient. In particular, wherein the first active ingredient is an integrin antagonist according to Formula I and wherein the composition is substantially free of an integrin antagonist other than the first active ingredient. Integrin antagonist or integrin antagonist compound in the current application preferably refers to a compound having a half maximal effective concentration (EC50) against integrin receptors of less than 1 mM, in particular an EC50 against the a_nb₃ integrin receptor. Suitable methods for determining EC50 values are known to the skilled person. One particular method to determine the value for a particular compound is a competition ELISA assay wherein the integrin receptor under investigation (in particular human a_nb₃ integrin receptor) is coated to a multi-well plate using a 4 pg/mL solution and the wells are blocked with 5% bovine serum albumin. The fibronectin concentration to be used in the assay is determined experimentally in a separate experiment by testing the binding of various fibronectin concentrations to the coated integrin under investigation, the concentration of fibronectin for the assay being the one that gives 80% of maximal binding. The determined concentration of human fibronectin is then added to the coated and blocked wells in the presence of increasing concentrations of the compound. After 2h incubation at 37°C, the wells are washed and the bound fibronectin is detected with the help of a specific reagent, such as a detectable anti-fibronectin antibody. Quantitative analysis of the data is then performed to determine EC50 values, i.e. the concentration of the compound that reduces fibronectin binding to the coated receptor by 50%.

In another embodiment, the present invention provides a composition comprising an aqueous buffer and a compound of the invention. In a further embodiment, the present invention provides a pharmaceutical composition comprising an aqueous buffer, a compound of the invention and one or more pharmaceutically acceptable carriers. In another further embodiment, the present invention provides a pharmaceutical composition consisting of an aqueous buffer, a compound of the invention and one or more pharmaceutically acceptable carriers.

In a particular embodiment, the present invention provides a composition comprising between 0.1 and 1000 mg of a compound of the invention per ml of the composition, in particular between 1 and 500 mg/ml, more in particular between 1 and 100 mg/ml. In a further embodiment, the composition comprises between 10 and 100 mg/ml, such as between 20 and 75 mg/ml.

The present invention provides pharmaceutical compounds and compositions for treating, reducing, ameliorating, or inhibiting the progression of, dry-AMD or GA. In yet another embodiment, the compounds of the invention are provided for use as an integrin antagonist, in particular a vitronectin receptor antagonist, in vitro or in vivo. In a particular embodiment, the integrin is an RGD-binding integrin. In a further embodiment, the integrin is an integrin comprising an a_v, a₅ or a₈ subunit. In a more particular embodiment, the integrin is an a_nb₃, a_nb₅ or a₅bi receptor.

In a further embodiment, the present invention provides the compound or the composition for use in the treatment and/or prevention of dry AMD or GA, wherein said treatment is a monotherapy treatment with the integrin antagonist compound or composition comprising such.

As used herein, the term "monotherapy" is intended to mean a therapy that is administered to treat a disease, such as dry AMD or GA , without any other therapy that is directed to treat and/or prevent the disease.

As mentioned before, the present invention relates to known as well as novel compounds, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, isomers or mixtures thereof. The compound of the present invention may also be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, by parenteral or intravitreal injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets.

It is especially advantageous to formulate the aforementioned compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

In one particular embodiment, the present invention provides a package comprising a compound of the invention, and a leaflet with instructions to administer the compound to a patient having dry AMD or GA.

For performing the treatment and/or prevention, the compounds or the compositions as described herein may be administered to a patient by any method that leads to delivery of the therapeutic agent to the site of the ophthalmic condition (dry AMD or GA), such as by administration to the eye. In another embodiment, the use, treatment and/or prevention comprises contacting the vitreous and/or aqueous humour with an effective amount of a composition comprising a compound of the invention. Administration may be by an ocular route, such as topical, subconjunctival, sub-Tenon, intraocular, ocular implants, etcetera. Topical administration may comprise administration of one or a few drops of a composition comprising a compound of the invention to the eye. Delivery to areas within the eye, in situ can be accomplished by injection, cannula or other invasive device designed to introduce precisely metered amounts of a desired ophthalmic composition to a particular compartment or tissue within the eye (e.g. posterior chamber or retina). An intraocular injection may be into the vitreous (intravitreal), or under the conjunctiva (subconjunctival), or behind the eye (retrobulbar), into the sclera, or under the Capsule of Tenon (sub- Tenon). Other intraocular routes of administration and injection sites and forms are also contemplated and are within the scope of the invention. In a preferred embodiment, the treatment and/or prevention comprises administration of the compound by intravitreal injection. Preferably this is performed through self-sealing gauge needles or other any suitably calibrated delivery device. Injection into the eye may be through the pars plana via the self-sealing needle.

When administering the composition by intravitreal injection, the active agents should be concentrated to minimize the volume for injection. Preferably, the volume for injection is less than about 5 mL. Volumes such as this may require compensatory drainage of the vitreous fluid to prevent increases in intraocular pressure and leakage of the injected fluid through the opening formed by the delivery needle. More preferably, the volume injected is between about 10 and 200 mI_. Most preferably, the volume for injection is between 30 and 100 mί, in particular about 50 mI_. With regard to the preferred routes of administration, the pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof is also an ophthalmically acceptable salt, ophthalmically acceptable solvate, isomer or mixture thereof. In a preferred embodiment, the pharmaceutical composition comprises the compound and one or more opthalmically acceptable carriers. Interestingly, compounds of the invention were found to have a high aqueous solubility of over 100 mg/ml, while prior art compounds have single digit mg/ml or lower aqueous solubilities. In a preferred embodiment, a composition of the invention as disclosed herein is an aqueous solution comprising a compound of the invention. In another embodiment, the present invention provides a kit of parts comprising a container comprising a compound of the invention and another container comprising an aqueous buffer for dissolving the compound of the invention.

As will be understood to the skilled person, a composition as disclosed herein is preferably a sterile composition. In a particular embodiment, the present invention provides a sterile container comprising a compound or composition of the invention. In a further embodiment, the sterile container is a vial comprising a compound or composition of the invention. The vial may comprise the compound as a powder or as a solution, preferably an aqueous solution. In a more particular embodiment, the present invention provides a sterile vial comprising an aqueous solution of the compound of the invention. In an even more particular embodiment, a vial as described herein comprises a part that is designed to be pierceable by a syringe needle. In alternative embodiment, the present invention provides a kit comprising a vial with the compound of the invention in a powder form and a container comprising an aqueous solution, particularly an aqueous buffer solution. In another embodiment, the sterile container is a syringe prefilled with a pharmaceutical composition of the invention, particularly an aqueous solution comprising the compound of the invention. In yet another embodiment, the sterile container is a container comprising at least one tablet comprising a pharmaceutical composition of the invention. In particular a blister package or bottle comprising multiple tablets comprising a compound of the invention and one or more pharmaceutically acceptable carriers. In one particular embodiment, a vial as described comprises less than 5 mL, in particular less than 4 mL, more in particular less than 3 mL of a solution comprising the compound of the invention. One aspect of the present invention relates to a method for treating and/or preventing dry AMD or GA to a subject in need thereof, wherein said compound or pharmaceutical composition, as detailed above, is administered to the subject.

It is also understood that said composition can be administered in accordance with the gender, age, race, body condition of the subject in need thereof, which can be easily modified by those of ordinary skill in the art without undue burden. Optionally, said composition can be administered as frequently as necessary, preferably about once monthly. In a particular embodiment, the composition of the present invention is administered at least three times with a one-month interval.

The dosage regimes or the amounts of said pharmaceutical composition, as described above, are believed to be suitable for human patients and are based on the known and presently understood pharmacology of the compounds, and the action of other similar entities in the human eye. It is understood that said pharmaceutical composition and said dosage regimes, as detailed above, are variable and can be individualized on the basis of the disease and the response of the subject in need thereof, based on the common knowledge of those of ordinary skill in the art. In another particular embodiment, method comprises administration of the compound or composition of the invention to the eye of a subject, such as by intravitreal injection. In particular, the method comprises intravitreal injection of a composition as described herein.

The present invention further provides the compounds and compositions described herein for use in the manufacture of a medicament for the prevention and/or treatment of dry AMD or GA as described herein.

EXAMPLES

EXAMPLE 1 - Synthesis of the compounds of the invention Compounds of the invention can be prepared according to the methods described in WO2011/119282 Al, WO2011/094285 Al, US2006/0052398 A1 and US2008/058348 Al, all of which are incorporated herein by reference. Exemplary synthesis methods for the synthesis of compounds according to Formula I are provided below. Synthesis of benzyl N-[{2S)-l-{tert-butoxy)-3-{{2,5-dimethyl-6-[4-(l,8-naphthyridin-2-yl)piperidin-l- yl]pyrimidin-4-yl}amino)-l-hydroxypropan-2-yl] carbamate

2-[l-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl]-l,8-naphthyridine and tert-butyl (2S)-3-amino- 2-{[(benzyloxy)carbonyl]amino}propanoate were prepared in accordance with the method described in US2008/0058348 Al, which is herewith incorporated by reference. Both molecules were coupled in a Buchwald-Hartwig amination reaction catalyzed by dichloro[l,l'-bis(diphenylphosphino) ferrocene] palladium(ll) dichloromethane complex (1:1), I, -ferrocenediyl-bis diphenylphosphine, phenylboronic acid, triethylamine and cesium fluoride in 2-methyltetrahydrofuran. The reaction mixture was filtered through celite and extracted with aqueous hydrochloric acid. The aqueous extract was neutralized with aqueous sodium acetate and extracted with dichloromethane which was washed with aqueous sodium bicarbonate and dried over sodium sulfate to give the crude product which was purified by column chromatography on silica using toluene/ethyl acetate as eluent. The chromatographed material was dissolved in ethyl acetate and further purified by crystallization as the (-)-dibenzoyl-L-tartaric acid salt. Using aqueous sodium bicarbonate the tartaric acid salt was removed to give the purified product.

Synthesis of tert-butyl (2S)-2-amino-3-{{2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoate Benzyl N-[(2S)-l-(tert-butoxy)-3-({2,5-dimethyl-6-[4-(l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4- yl}amino)-l-hydroxypropan-2-yl] carbamate was hydrogenated over palladium on activated carbon in 2- methyltetrahydrofuran. The catalyst was removed by filtration through celite. The solvent was evaporated off to give the desired product

Synthesis of tert-butyl {2S)-3-{{2,5-dimethyl-6-[4-{5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l- yl]pyrimidin-4-yl}amino)-2-{[(3-methoxy-3-oxopropoxy)carbonyl]amino} npropanoate

N,N-disuccinimidyl carbonate was reacted, in the presence of triethylamine, with methyl 3- hydroxypropanoate in dichloromethane to give methyl 2-({[(2,5-dioxopyrrolidin-l-yl)oxy] carbonyl}oxy)acetate. Tert-butyl (2S)-2-amino-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoate was added to give the desired product. The reaction mixture was washed with aqueous hydrochloric acid and aqueous sodium bicarbonate and then dried over sodium sulfate to give the crude product which was purified by column chromatography on silica using ethyl acetate/n-heptane/triethylamine as eluent.

Synthesis of {2S)-3-{{2,5-dimethyl-6-[4-{5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l- yl]pyrimidin-4-yl}amino)-2-{[(3-methoxy-3-oxopropoxy)carbonyl]amino}propanoic acid trifluoro acetate

Tert-butyl (2S)-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin- 4-yl}amino)-2-{[(2-methoxy-2-oxoethoxy)carbonyl] amino} propanoate was dissolved in dichloromethane and treated with trifluoracetic acid. The reaction mixture was washed brine and the solvent evaporated off to give the desired product as a trifluoracetic acid salt. The resulting compound is further referred to as comparative compound A (cpd A).

Electron Spray (ES) low resolution MS m/z: 556 [ (M+l), 100%]

Synthesis of (2S)-2-{[(2-carboxyethoxy)carbonyl]amino}-3-{{2,5-dimethyl-6-[4-{5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoic acid

(2S)-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4- yl}amino)-2-{[(3-methoxy-3-oxopropoxy)carbonyl]amino}propanoic acid trifluoro acetate is dissolved in 2M aqueous hydrochloric acid. After completion of the reaction the solvent is lyophilized off the give the desired product. (2S)-2-{[(2-carboxyethoxy)carbonyl]amino}-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoic acid, is further referred to as compound 1 (cpdl).

Electron Spray (ES) low resolution MS m/z: 542 [ (M+l), 100%]

Synthesis of tert-butyl (2S)-2-({[2-{tert-butoxy)-2-oxoethoxy]carbonyl}amino)-3-{{2,5-dimethyl-6-[4- {5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoate

N,N-disuccinimidyl carbonate was reacted, in the presence of triethylamine, with tert-butyl 2- hydroxyacetate in dichloromethane to give tert-butyl 2-({[(2,5-dioxopyrrolidin-l-yl)oxy] carbonyl}oxy)acetate. Tert-butyl (2S)-2-amino-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoate was added. After completion of the reaction the reaction mixture was washed with aqueous hydrochloric acid and aqueous sodium bicarbonate and then dried over sodium sulfate to give the crude product. The crude product was purified by column chromatography on silica using ethyl acetate / n-heptane / triethylamine as eluent. Synthesis of (2S)-2-{[{carboxymethoxy)carbonyl]amino)-3-({2,5-dimethyl-6-[4-{5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoic acid dihydrochloride (THR-687) Tert-butyl (2S)-2-({[2-(tert-butoxy)-2-oxoethoxy]carbonyl}amino)-3-({2,5-dimethyl-6-[4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoate was hydrolyzed with aqueous hydrochloric acid. The reaction mixture is washed with n-heptane to give compound 2 (cpd2) upon evaporation.

^XH NMR (400 MHz, DMSO-d₆) d: 7.64 (d 1H), 6.71 (d 1H), 4.63 (d 1H), 4.46 (d 1H), 4.57 (dd 1H), 4.06 (dd 1H), 3.85 (dd 1H), 3.77 (m 2H), 3.53 (dd 2H), 3.27 (m, 2H), 3.01 (tt 1H), 2.84 (dd 2H), 2.58, (s 3H), 2.10 (dd, 2H), 2.07, (s 3H), 1.99 (t, 2H), 1.95 (td 2H)

Synthesis of tert-butyl {2S)-3-{{2,5-dimethyl-6-[4-{5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l- yl]pyrimidin-4-yl}amino)-2-({[(l-ethoxy-l-oxopropan-2-yl)oxy]carbonyl} amino)propanoate

N,N-disuccinimidyl carbonate was reacted, in the presence of triethylamine, with ethyl 2- hydroxypropanoate in dichloromethane to give ethyl 2-({[(2,5-dioxopyrrolidin-l- yl)oxy]carbonyl}oxy)propanoate. Tert-butyl (2S)-2-amino-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoate was added. After completion of the reaction the reaction mixture was washed with aqueous hydrochloric acid and aqueous sodium bicarbonate and then dried over sodium sulfate to give the crude product. The crude product was purified by column chromatography on silica using dichloromethane / methanol as eluent. Synthesis of (2S)-2-{[(l-carboxyethoxy)carbonyl]amino}-3-{{2,5-dimethyl-6-[4-{5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)piperidin-l-yl]pyrimidin-4-yl}amino)propanoic acid, dihydrochloride

Tert-butyl (2S)-3-({2,5-dimethyl-6-[4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)piperidin-l-yl]pyrimidin- 4-yl}amino)-2-({[(l-ethoxy-l-oxopropan-2-yl)oxy]carbonyl} amino)propanoate was hydrolyzed with aqueous hydrochloric acid. The reaction mixture is washed with n-heptane to give the product upon evaporation, further referred to as compound 3 (cpd3).

^XH NMR (400 MHz, D₂0) d: 7.5 (d 1H), 6.5 (d 1H), 4.5 (m 1H), 4.2 (m 1H), 3.9 (dd 1H), 33 3.1 (m 3H), 3.4 (t 2H), 3.1 (t 2H), 2.8 (m 1H), 2,7 (t 2H), 2.4 (s 3H), 1.9 (s 3H), 1.9-2.0 (m 3H), 1.7-1.9 (m 4H), 1.3 (d 3H). Accordingly, the following compounds of the invention according to Formula I have been made:

Other exemplary compounds according to the invention according to Formula I are:

Compound A (cpd A) is a compound according to Formula A, but not Formula I and was synthesized as described above:

Compound B (CpdB) is a compound according to Formula A, but not Formula I and was synthesized according to the procedures of US2008058348 Al:

Compound C (CpdC) is a compound according to Formula A, but not Formula I and was also synthesized according to the procedures of US2008058348 Al:

EXAMPLE 2 - Integrin antagonism

The principle of the competition ELISA assays used here was as follows: (1) the integrin receptor under investigation was coated to 96-well plates and the wells were blocked, (2) an integrin ligand (fibronectin) was then added to the relevant wells in the presence of increasing concentrations of a given integrin antagonist, (3) after a defined amount of time, the wells were washed and the bound ligand was detected with the help of a specific reagent. Quantitative analysis of the data was then performed to determine EC50 values, i.e. the concentration of the integrin antagonist that reduces ligand binding to the coated receptor by 50%.

Table 1: EC50 for the different integrins and human integrin antagonists.

+++: between 1 and lOnM; ++: between 10 and 25 nM; +: > 25nM The compound according to formula (I) inhibits interactions between integrins and their ligands. The compound according to formula (I) has been shown to antagonize several integrin receptors, including a_nb₃, a_nb₅ and a₅bi, with single-digit nanomolar affinity. Notably, compounds according to Formula I show a significantly reduced antagonism towards the platelet integrin ^ , which is involved in platelet aggregation. Fig. 1 sets forth the determined ratios of EC50 values for a_nb₃ over ai^b₃. As derivable from these results, compounds of Formula I show a much lower activity towards the platelet integrin compared to the a_nb₃ integrin. In contrast, compounds A and B as described in the prior art for the treatment of other diseases show a significantly higher activity towards the platelet integrin compared to the a_nb₃ integrin. Therefore, compounds of Formula I represent a subgroup of compounds that have an improved integrin antagonistic profile compared to other compounds of Formula A.

EXAMPLE 3 - Investigation of integrin inhibition in light-induced mouse model The induction of retinal degeneration by light exposure is widely used to study the mechanism of cell death in the retina. Moreover, excessive light irradiation of the eye is known to be described as a risk factor for AMD. The mouse light-induced model is therefore often used as a research tool to investigate dry AMD, since the blue light exposure will lead to oxidative stress, inducing apoptosis of the photoreceptors, infiltration of inflammatory cells, followed by RPE degeneration ( Nakamura et al. 2018, Nakamura et al. 2017, Kim et al. 2016, Geiger et al. 2015, Tenneson et al. 2013, Grimm et al. 2013.)

Methods for light induction

Animals- All experimental animal procedures were performed according the standards in the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research (ARVO) and the EC Directive 86/609/EEC for animal experiments. All experimental procedures were also approved by the Institutional Animal Care and Research Advisory Committee of the University of Leuven. Seven to nine weeks old male albino BALB/c mice (BALB/cAnNCrl) were purchased from Charles River (France) and used in this study. All animals were housed under controlled lighting conditions (12h:12h light/dark) and were acclimatized for 1 week before the experimental procedures were initiated. Exposure to light - After dark adaptation for 24h, non-anesthetized mice were exposed to 600 lux of blue light (Philips, TL-D Colored 36W Blue 1SL/25) for 2 hours and 20 minutes. After exposure to the blue light, the animals were kept in darkness for 24h, after which a 12-h light/dark cycle was resumed.

Treatment with compounds of the invention - In the first set of experiments, cpd2 (100 mg/kg) or vehicle was administered intraperitoneally (IP) every day, starting at 1 day before the light induction until day 6 after the light induction. At 1 day before the light induction, cpd2 (50 pg) or vehicle was also administered intravitreally (IVT) in the right eye of the mice. In the second set of experiments, cpd 1 (120 pg/eye), cpd2 (50, 15 or 3.3 pg/eye), cpd 3 (63 pg/eye), cpdC (11 pg/eye), or respective vehicles were administered IVT in both eyes, 1 day prior the light induction. Isoflurane was used to induce general anesthesia and the eye was treated with a drop of Tropicol (tropicamide, 0.5%, w/v, Thea. Intravitreal injection (1 pL) was performed by using an analytic science syringe (SGE Analytic Science) and beveled glass micropipettes (80 pm diameter, Clunbury Scientific), controlled by the UMP3I Microsyringe Injector and Micro4 Controller (both from World Precision Instruments Inc., Hertfordshire, UK).

Methods for electroretinogram (ERG) measurements Electroretinography (ERG) was recorded on 4 days after blue light exposure, using the Celeris Rodent ERG system (Diagnosys). Mice were housed in a completely dark room for at least 12h, followed by anesthesia with a mixture of ketamine hydrochloride (Anesketin, lOOmg/kg, Dechra) and medetomidine (Domitor, lmg/mL, Orion Pharma) and the pupils were dilated with Tropicol (tropicamide, 0.5%, w/v, Thea). Next, mice were placed on a heated platform to maintain a constant body temperature during ERG recordings and eyes were hydrated with GenTeal eye drops (Thea). Scotopic a- and b-wave full field ERGs were recorded using 3mm bright full-field stimulator electrodes (light intensity range 0.01 cd.s/m² through 7.5 cd.s/m²) on both eyes simultaneously and by using Espion software (Diagnosys). If needed, a third ground, needle electrode was placed subcutaneously at the base of the mouse tail. All procedures were performed under dim red light. The a-wave amplitude was measured from baseline to the trough of the a-wave. The b-wave amplitude was measured from the trough of the a-wave to the peak of the b-wave.

Methods for OCT measurements

Spectral domain optical coherence tomography (SD-OCT) was applied to produce cross-sectional images of the retina, in order to measure the total retinal thickness at baseline and/or day 7 after blue light induction. Mice were anesthetized with a mixture of ketamine hydrochloride (Anesketin, lOOmg/kg, Dechra) and medetomidine (Domitor, lmg/mL, Orion Pharma). After application of Tropicol (tropicamide, 0.5%, w/v, Thea) and subsequently an-HyPro (An-vision), SD-OCT was performed on both eyes (OD & OS) using the Spectralis system of Heidelberg Engineering (Germany) at diopter 8.

EXAMPLE 4 -The effect of integrin inhibition (IP + IVT) in light-induced mouse model

For investigating the effect of compounds of the invention (via IP and IVT administration) on retinal degeneration, BALB/c mice were exposed to blue light (600 lux) for 2h and 20 minutes and divided in different groups: (1) cpd2 treated mice (n=4) and vehicle treated mice (n=4). One group of non-exposed mice were included as well as a control group (n=2). Cpd2 (100 mg/kg) or vehicle was administered IP from the day before the light induction until day 6, whereas cpd2 (50 pg/eye) or vehicle was also administered IVT in one eye at the day before the light induction. Measurements of visual function were performed at day 4 after light induction (by means of ERG). The a-wave represents photoreceptor function, whereas the b-wave reflects subsequent neuron function, such as bipolar cells and Muller cells. Total retinal thickness was evaluated at baseline and day 7 after light induction (by means of OCT).

In the light-exposed mice treated with vehicle, both a- and b-wave amplitudes were decreased 4 days after exposure to light, compared to the control non-exposed mice. Animals treated with cpd2 showed improved a- and b-wave amplitudes, as compared to vehicle-treated mice (Figure 2). Separate analysis of the eyes who received an IVT injection showed an improvement in a- and b-wave amplitudes after cpd2 administration, as compared to vehicle (Figure 3). Uninjected eyes from the mice that were IP treated with cpd2 showed only very minor differences compared to the uninjected eyes of the vehicle-treated mice (Figure 4). These data indicate that the improved effect on visual function that is seen after cpd2 administration, seems to be mainly induced by the IVT administration, rather than the IP administration. Total retinal thickness was measured at baseline and/or at day 7 in the eyes who received an IVT injection. Analysis showed total retinal thickness was decreased in the light-exposed mice IVT treated with vehicle, as compared to the control non-exposed animals. Eyes treated with IVT injections of cpd2 showed a small increase in retinal thickness, as compared to vehicle-treated eyes (Figure 5). EXAMPLE 5 -The effect of integrin inhibition (IVT) in light-induced mouse model

For investigating the effect of compounds of the invention (via IVT administration) on retinal degeneration, BALB/c mice were exposed to blue light (600 lux) for 2h and 20 minutes and divided in different groups: (1) 120 pg/eye cpdl treated mice (n=4); (2) 50 pg/eye cpd2 treated mice (n=6); (3) 15 pg/eye cpd2 treated mice (n=6); (4) 3.3 pg/eye cpd2 treated mice (n=6); (5) 63 pg/eye cpd3 treated mice (n=4); (6) 11 pg/eye cpdC treated mice (n=6), as well as the different vehicles (n=6/group) Non-exposed mice were included as well as a control group (n=6). All compounds or vehicle were administered IVT in both eyes one the day before the light induction. Measurements of visual function were performed at day 4 after light induction (by means of ERG). The a-wave represents photoreceptor function, whereas the b-wave reflects subsequent neuron function, such as bipolar cells and Muller cells. Total retinal thickness was evaluated at day 7 after light induction (by means of OCT).

In the light-exposed eyes treated with vehicle, both a- and b-wave amplitudes were decreased 4 days after exposure to light, compared to the control non-exposed eyes. Eyes treated with 50 pg/eye of cpd2 or treated with llpg/eye of cpdC showed improved a- and b-wave amplitudes, as compared to the respective vehicle-treated eyes. The eyes treated with the lower doses of cpd2 (15 and 3.3 pg/eye) did not show any differences in a- and b-wave amplitudes, versus the vehicle-treated eyes (Figure 6). ERG measurements were not performed after administration of cpdl and cpd3. After day 4, 4 mice in total died, which can be explained by the sensitivity of the BALB/c mice to anesthesia. These mice belonged to different treatment groups or to the non-exposed control group of mice. In the remaining animals (n=4- 6/group), total retinal thickness was measured at day 7 and analysis showed that the total retinal thickness was decreased in the light-exposed mice treated with vehicle, as compared to the control non- exposed animals. Mice treated with 120 pg/eye of cpdl, 50 pg/eye of cpd2, 63 pg/eye of cpd3 or 11 pg/eye of cpdC showed an increase in retinal thickness, as compared to the respective vehicle-treated mice. The eyes treated with the other doses of cpd2 (15 and 3.3 pg/eye) did not show significant differences in retinal thickness, versus the vehicle-treated eyes (Figure 7).

Claims

1. A compound according to formula (A), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof,

wherein:

G is selected from the group consisting of (B-a) to (B-e) :

each of R' and R", independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci-io alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ORu and NR₁₁R₁₂, wherein each of Ru and R₁₂, independently from each other and at each occurrence, are selected from hydrogen or Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; nl and n2 are integers in the range from 0 to 4, preferably nl and n2 are integers in the range from 0 to 2; each of R'", independently from each other and at each occurrence is selected from the group consisting of hydrogen, Ci-₁₀ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, ORu and NRuRu, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents selected from halo, Ci-e alkyl or OCi-e- alkyl, and wherein each of Ru and Ru, independently from each other and at each occurrence, are selected from hydrogen or Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; n3 is an integer in the range from 0 to 4, preferably n3 is an integer in the range from 0 to 2;

R3 is independently selected from the group consisting of hydrogen, Ci-e alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, COR31, COOR₃₂, S0₂R₃₃ and CON(R₃₄)₂, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl are optionally substituted with one or more substituents selected from halo,

alkyl, C_2. alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, 0C(RU)₂0, N(Ru)₂and ORu; and wherein said R31, R3₂, R33 and R3₄, independently from each other and at each occurrence, are selected from the group consisting of hydrogen, Ci_₆ alkyl, heterocyclyl, aryl and aralkyl, wherein said alkyl, heterocyclyl, aryl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu and S0₂Ri and wherein each of Ru, independently from each other and at each occurrence is hydrogen or Ci_ alkyl, for use in the treatment and/or the prevention of dry age-related macular degeneration (AMD) or geographic atrophy (GA).

2. The compound for use according to claim 1, wherein said compound is chosen among those of formula (A-l):

wherein: each of Ri and R₂ are independently selected from the group consisting of hydrogen and Ci_ alkyl; R₄ is ORu wherein each of Ru is selected from hydrogen or Ci_₆ alkyl R₃ is as defined as in claim 1.

3. The compound for use according to claim 1 or 2, wherein said compound is of formula (A-l-1)

(Formula A-l-1) wherein: - is Ci-₆ alkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, ORu, N(Ru)₂, COORu and S0₂Ri; and wherein each of Ru, independently from each other and at each occurrence is selected from the group consisting of hydrogen and Ci_ alkyl.

Ri, R₂, and R₄ are as defined as in claim 2.

4. The compound for use according to any one of the previous claims, wherein said compound is of formula

(I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, isomer or mixture thereof,

wherein Ri and R₂ are independently selected from the group consisting of hydrogen, methyl and ethyl; and

Aik is Ci^alkylene for use in the treatment and/or the prevention of dry age-related macular degeneration (AMD) or geographic atrophy (GA).

5. The compound for use according to any one of the previous claims, wherein either Ri and R₂ are both methyl, or Ri is hydrogen and R₂ is ethyl.

6. The compound for use according to any one of the previous claims, wherein both Ri and R₂ are methyl.

7. The compound for use according to any one of claim 4, wherein Aik is a Ci or C₂ alkylene and both Ri and R₂ are methyl.

8. The compound for use according to any one of the previous claims, wherein the compound is selected from the group consisting of:

9. The compound for use according to any one of previous claims, wherein the compound is a compound according to Formula II, Formula II wherein Ri, R₂ and Aik are as defined in claim 4.

10. The compound for use according to claim 9, wherein the compound is selected from the group consisting of:

11 A pharmaceutical composition for use in the treatment and/or the prevention of dry AMD or GA, wherein the composition comprises a compound as defined in any one of claims 1 to 10, and one or more pharmaceutically acceptable carriers.

12. The pharmaceutical composition for use according to claim 11, wherein the composition further comprises an aqueous buffer wherein the compound and/or the one or more pharmaceutically acceptable carriers has been dissolved.

13. The compound for use according to any one of claims 1 to 10 or the pharmaceutical composition for use according to any one of claims 11 or 12, wherein the treatment and/or prevention comprises administration of the compound by intravitreal injection.

14. The compound for use according to any one of claims 1 to 10 or the pharmaceutical composition for use according to any one of claims 11 or 12, wherein the treatment is a monotherapy treatment with the compound as defined in any one of claims 1 to 10 or the composition as defined in any one of claims 11 or 12.

15. A method for the treatment and/or prevention of dry AMD or GA in a subject in need thereof, the method comprising administration of a compound as defined in any one of claims 1 to 10 or of a composition as defined in claim 11 or 12 to the subject.