Chemical Compounds Targeting the Eye and Their Use in the Treatment of Eye Diseases

Abstract

The present invention relates to a chemical compound C, which is a derivative of norbixin and has ocular activity, intended for use in the treatment of mammalian eye diseases, in particular in the context of alterations of the retinal pigment epithelium, more particularly in the context of age-related macular degeneration (AMD) and Stargardt's disease.

Description

Technical Field

[0001] The present invention relates to newly synthesized chemical compounds having directivity to the eye after oral administration. The present invention also relates to the field of therapeutic applications and to the use of said chemical compounds for the improvement of mammalian vision.

[0002] More specifically, the present invention relates to the use of compounds for the protection of cells of the retinal pigment epithelium (RPE), in particular for the treatment of age-related macular degeneration (AMD), Stargardt's disease and retinitis pigmentosa in mammals. The object of the present invention is to improve the vision of individuals suffering from these diseases or at least to stabilize the progression of these diseases.

Background Art

[0003] Age-related macular degeneration (AMD) is the most common cause of legal blindness in people over 60 years old, particularly in Europe and North America (Non-Patent Document 1). AMD affects the central part of the retina called the macula, resulting in severe visual impairment and irreversible loss of central vision.

[0004] The function of the macula is the origin of central vision and vision, and its high resolution is related to its high density in photoreceptors called cones, which are particularly involved in daytime vision and color perception. The initial stage of AMD is characterized by the appearance of deposits called drusen and the progressive loss of photoreceptors called rods, which are specialized for night vision and have little impact on daytime vision. However, the subject gradually observes changes in their vision, which is later diagnosed by an ophthalmologist as intermediate or age-related macular degeneration (AMD). In the later stages of AMD, there can be two forms: the exudative or neovascular (wet) form, which is characterized by the growth of choroidal neovascularization in the subretinal space, or geographic atrophy (dry form), which is characterized by the loss of retinal pigment epithelial (RPE) cells and photoreceptors, which are cells necessary for the visual cycle. The number of patients suffering from intermediate AMD or the dry form is much higher than the number of subjects suffering from wet-form AMD (Non-Patent Document 1). The later stages of AMD lead to irreversible damage to the macula, regardless of its form (wet or dry). The progression of exudative AMD (wet form) can lead to complete blindness in a few weeks, while the progression of dry AMD is generally slow.

[0005] Although there are multiple specific mechanisms involved in the development of AMD, oxidative stress and inflammation have been shown to be important factors contributing to its pathophysiology. The etiology of AMD includes hydrodynamic changes in Bruch's membrane caused by systemic accumulation of extracellular substances containing lipids, and aging of the RPE, whose activity is essential for photoreceptor survival. Aging, the first risk factor for AMD, causes dysfunction of RPE cells, metabolic dysfunction, and phagocytic dysfunction. Incomplete digestion of the outer segments of photoreceptors can lead to the formation of drusen, which reduces diffusion through Bruch's membrane. With age, the RPE accumulates increasing amounts of lipofuscin. Lipofuscin is composed of lipids and proteins, which are derived from phagolysosomes, lysosomes present in the RPE, and also directly from photoreceptors. Lipofuscin also contains N-retinyl-N-retinylidene ethanolamine (A2E), which is formed by the condensation of two retinaldehyde molecules and one ethanolamine molecule.

[0006] With age, an increase in the accumulation of A2E in the retinas of patients with AMD has been observed (Non-Patent Document 2). Under the action of blue light and in the presence of oxygen, A2E generates reactive species, which damage proteins, lipids, and DNA, thus causing considerable oxidative stress to aging RPE cells (Non-Patent Document 3). This damage inhibits the lysosomal activity of RPE cells, causes the accumulation of waste products, which in turn causes the death of RPE cells here and there, and subsequently causes the death of the associated photoreceptors.

[0007] Stargardt disease and retinitis pigmentosa are retinal degenerations of genetic origin that can be caused by a number of mutations or genetic polymorphisms. These two conditions can be considered equivalent to the dry form of AMD because, in the case of Stargardt disease, they are characterized by the progressive loss of RPE and photoreceptor cells associated with the progressive accumulation of A2E. Similar to the dry form of AMD, the degeneration of photoreceptors and RPE leads to the loss of night vision and a decrease in central vision in patients suffering from these two genetic conditions.

[0008] Among existing treatments, intravitreal injection of anti-VEGF (Vascular Endothelial Growth Factor) antibodies is known, which can partially block the formation of new blood vessels and thus provide a treatment option for the wet form of AMD. Currently, there is no treatment on the market for the dry form of AMD (AMD and geographic atrophy). Similarly, there are no available drugs for the treatment of Stargardt disease or retinitis pigmentosa. Among the frameworks of dry AMD, food supplements are formulated using common antioxidant compounds, namely minerals and vitamins with antioxidant properties, such as zinc, vitamins A, C, and E. Although these treatments are actually effective, they are limited to AMD. The AREDS nutritional supplement formulations 1 and 2 (Non-Patent Document 4) are regarded as treatment standards for the treatment of AMD in the United States, reducing the risk of progression of wet AMD by 25% over 5 years and reducing visual loss by 19%. Many products have proposed a common formulation base, namely zinc and vitamins C and E, to which various components such as lutein, resveratrol, and omega-3 fatty acids are added, but there is no convincing efficacy data regarding these additional components or the category of patients who can show a favorable response to these various molecules (Non-Patent Document 5).

[0009] Carotenoids (molecules derived only from dietary intake), some of which (lutein, zeaxanthin = xanthophyll) are naturally present in the macula, have been studied more specifically (Non-Patent Document 6), and it has been found that these compounds have strong antioxidant power and limit their toxic effects by absorbing blue light. Therefore, it is logical to test these compounds (alone or in combination) in the AREDS formulation. The results obtained were disappointing, and their supplementation was effective only in a subset of patients lacking these compounds (Non-Patent Document 7). Other xanthophylls have also been the subject of studies by oral supplementation alone or in combination with lutein and / or zeaxanthin (e.g., astaxanthin, Non-Patent Document 8). Diapocarotenoids (= carotenoids with both ends excised, IUPAC chemical nomenclature), particularly crocetin (= 8,8'-diapocarotene-8,8'-dioate) and its glycosides (crocine), have been tested in vitro and in vivo. Crocine has a photoprotective effect in vitro on primary cultures of bovine or primate photoreceptors (Non-Patent Document 9), and crocetin protects ganglion cells from oxidative stress (Non-Patent Document 10). Also, some of another apocarotenoid, bixin (= 6-methyl hydrogen [9Z]6,6'-diapocarotene-6,6'-dioate) or its derivatives, were used to conduct experiments in vitro on ganglion cells and in vivo by intravitreal injection to counteract the effects of endoplasmic reticulum stress (Non-Patent Document 11). The previously developed Urucum seed extract (Bixa orellana) fortified with bixin (Bixilia®) has shown a photoprotective effect on human skin exposed to UV (Patent Document 1; Non-Patent Document 12) and on RPE cells subjected to photooxidative stress (Patent Document 2; Non-Patent Document 13). Finally, norbixin (6,6'-diapocarotene-6,6'-dioate) and particularly its 9'-cis form can significantly reduce the cell death induced by blue light irradiation of RPE cells pretreated with N-retinyl-N-retinylidene ethanolamine (A2E) (Patent Document 3; Non-Patent Document 14, Non-Patent Document 15). Chronic oral treatment with 9'-cis norbixin in double KO mice (ABCA4- / - , RDH8 - / - ) can also reduce the accumulation of A2E in the retina (Non-Patent Document 15). Norbixin has good bioavailability, but its accumulation amount in the eye remains very low, so the protective activity of the retina is limited.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Summary of the Invention

Problems to be Solved by the Invention

[0012] The inventors have created innovative compounds by semi-synthesis. The inventors have also discovered that some of these compounds have a better pharmacokinetic profile and ocular targeting than norbixin. Furthermore, some of these compounds have a photo-protective activity of the retinal pigment epithelium (RPE) equal to or greater than that of norbixin.

Means for Solving the Problems

[0013] Accordingly, according to a first aspect, the present invention provides the following general formula (I):

[0014]

Chemical formula

[0015] A chemical compound having, wherein COR is a secondary or tertiary amide, and thus -R is: · -M; -NH-(CH 2 ) n -M and -NH-(CH 2 ) n -C(CH 3 )(CH 3 )-M, provided that -M is

[0016] a)

Chem.

[0017] b)

Chem.

[0018] c)

Chem.

[0019] selected from, -R 1 is an oxygen atom, a sulfur atom, >CH 2 , >CH-O-(CH 2 ) n -CH 3 , >CH-(CH 2 ) n -O-(CH 2 ) n -CH 3 , >CH-(CH 2 ) n -OH, >CH-COOH, >C(OH)phenyl, or >NH group; -R 3 is a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -R 4 is a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -n is an integer from 0 to 6; ·-NH-(CH 2 ) n -W, provided that W is a hydrogen atom, or an -OH group, -O-(CH 2 ) n -CH 3 group, or

[0020] i)

Chemical formula

[0021] ii)

Chemical formula

[0022] iii)

Chemical formula

[0023] iv)

Chemical formula

[0024] v)

Chemical formula

[0025] is a group selected from -R 1 is an oxygen atom, a sulfur atom, >CH 2 , >CH-O-(CH 2 ) n -CH 3 , >CH-(CH 2 )n selected from -OH, >CH-COOH, >C(OH)phenyl, or >NH groups; -R 3 is a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -R 4 is a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -R 5 is -CH 3 , -OH, -O-(CH 2 ) n -CH 3 , -(CH 2 ) n -OH, or -COOH group; -n is an integer from 0 to 6; There is proposed a chemical compound selected from, and a pharmaceutically acceptable salt of said chemical compound.

[0026] The term "chemical compound" also means isomers, in particular stereoisomers, of said chemical compounds.

[0027] Within the framework of the present invention, "pharmaceutically acceptable" generally means safe, non-toxic, not biologically or otherwise undesirable, and useful for the preparation of pharmaceutical compositions that are acceptable for veterinary use and for human pharmaceuticals.

[0028] Within the framework of the present invention, the term "pharmaceutically acceptable salts of a compound" means salts that are pharmaceutically acceptable as defined herein and have the desired pharmacological activity of the parent compound. Such salts include the following: (1) An acid addition salt formed from mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or from organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, trimethylacetic acid, etc.; or (2) A salt formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0029] According to certain embodiments, the present invention relates to a chemical compound having the general formula (I) selected from the following chemical compounds: -1-[2-methoxyethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicos-2,4,6,8,10,12,14,16,18-nonenedioate; -1-[1,4-oxazineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicos-2,4,6,8,10,12,14,16,18-nonenedioate; -1-[piperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicos-2,4,6,8,10,12,14,16,18-nonenedioate; -1-[2-Hydroxyethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1[1,4-Oxazepam amide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-Thiomorpholine amide-(2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-Pyrrolidine amide-(2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-Morpholinopropanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(S)-3-Hydroxypyrrolidine amide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-Morpholinoethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(R)-3-Hydroxypyrrolidine amide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Hydroxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-Methyl-2-(4-morpholinyl)propylamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Hydroxymethylpiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(Z)-2,6-Dimethylmorpholineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Hydroxyphenylamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Benzyl-4-hydroxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Carboxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(E)-4-Hydroxycyclohexamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[3-Methoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Methoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-(2-Furyl)ethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-n-Propoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Ethylmethoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate.

[0030] According to a second aspect, the present invention relates to a composition comprising at least one chemical compound which is an object of the present invention.

[0031] According to certain embodiments of the present invention, the composition comprises at least one excipient. Examples of excipients are fillers, diluents, disintegrants, lubricants, preservatives, disintegrators, sweeteners, etc. According to certain examples, the at least one excipient is selected from oils, water and alcohols, and silicones.

[0032] According to certain embodiments of the present invention, the composition comprises a carrier in a form adapted for digestion, injection into the eye, or injection into the blood.

[0033] According to a third aspect, the present invention relates to a chemical compound having the general formula (I) as defined above, or a composition comprising at least one chemical compound having the general formula (I), for use as a medicament.

[0034] According to certain embodiments, the present invention relates to a chemical compound having the general formula (I) as defined above, or a composition comprising at least one chemical compound having the general formula (I), for use in the treatment and / or prevention of damage to the retina of a mammal caused by retinal degeneration.

[0035] According to certain embodiments, the present invention relates to a chemical compound having the general formula (I) as defined above, or a composition comprising at least one chemical compound having the general formula (I), for use in the photoprotection of cells of the retinal pigment epithelium of a mammal.

[0036] According to certain embodiments, the present invention relates to a chemical compound having the general formula (I) as defined above, or a composition comprising at least one chemical compound having the general formula (I), for use in the prevention of damage to the retina of a mammal caused by exposure to blue light having a wavelength of 435 nm to 490 nm corresponding to the blue band of the visible light spectrum.

[0037] According to certain embodiments, the present invention relates to a chemical compound having the general formula (I) as defined above, or a composition comprising at least one chemical compound having the general formula (I), for use in the treatment and / or prevention of eye diseases in a mammal.

[0038] According to certain embodiments, the present invention relates to a chemical compound having the general formula (I) as defined above, or a composition comprising at least one chemical compound having the general formula (I), for use in the treatment and / or prevention of retinopathy in a mammal.

[0039] According to one embodiment, the present invention relates to a chemical compound having the general formula (I), or a composition comprising at least one chemical compound having the general formula (I), for use in the treatment and / or prevention of age-related macular degeneration (AMD) in mammals. The chemical compound which is the object of the present invention can advantageously improve the vision of an individual suffering from this disease or at least stabilize the progression of the above-mentioned disease.

[0040] According to another embodiment, the present invention relates to a chemical compound having the general formula (I), or a composition comprising at least one chemical compound having the general formula (I), for use in the treatment and / or prevention of Stargardt's disease and retinitis pigmentosa in mammals. The chemical compound which is the object of the present invention can advantageously improve the vision of an individual suffering from this disease.

[0041] The present invention should be better understood by reading the following description, which is given by way of example and not limitation and with reference to the drawings.

Brief Description of the Drawings

[0042]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0043] The chemical compounds that are the object of the present invention do not exist in the chemical databases of carotenoids and apocarotenoids. These are synthesized according to a process that is industrially viable, i.e., involves a minimum number of synthetic steps and an optimal yield. These have a good pharmacokinetic profile and good ocular targeting compared to norbixin. Furthermore, some of these compounds have better photoprotective activity on the RPE than norbixin.

[0044] Description of Synthesis and General Structural Formula General formula (I):

Chemical formula

[0045] The chemical compounds having can be prepared by application or adaptation of any method that can already be described, that is known per se to those skilled in the art and / or within the scope of the art, or by application or adaptation of the methods described in the following procedure.

[0046] In the following description, various groups refer to the above definitions. That is: COR is a secondary or tertiary amide, and thus -R is: · -M; -NH-(CH 2 ) n -M and -NH-(CH 2 ) n -C(CH 3 )(CH 3 )-M, provided that -M is

[0047] a)

Chemical formula

[0048] b)

Chemical formula

[0049] c)

Chemical formula

[0050] selected from -R 1 is an oxygen atom, a sulfur atom, >CH 2 , >CH-O-(CH 2 ) n -CH 3 , >CH-(CH 2 ) n -O-(CH 2 ) n -CH 3 , >CH-(CH 2 ) n -OH, >CH-COOH, >C(OH)phenyl, or >NH group; -R 3 is a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -R 4 is a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -n is an integer from 0 to 6; ·-NH-(CH 2 ) n -W, provided that W is a hydrogen atom, or an -OH group, -O-(CH 2 ) n -CH 3 group, or

[0051] i)

Chem.

[0052] ii)

Chem.

[0053] iii) [Chemical formula]

[0054] iv) [Chemical formula]

[0055] v) [Chemical formula]

[0056] is a group selected from -R 1 is selected from an oxygen atom, a sulfur atom, >CH 2 , >CH-O-(CH 2 ) n -CH 3 , >CH-(CH 2 ) n -OH, >CH-COOH, >C(OH)phenyl, or >NH group; -R 3 is selected from a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -R 4 is selected from a hydrogen atom, C 1 -C 6 alkyl, -OH, or C 1 -C 6 -O-alkyl group; -R 5 is selected from -CH 3 , -OH, -O-(CH 2 ) n -CH 3 , -(CH 2 ) n -OH, or -COOH group; -n is an integer from 0 to 6.

[0057] Within the framework of the present invention, the term "C 1-C 6 The "alkyl group" means any linear or branched alkyl group having 1 to 6 carbon atoms, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl group. Advantageously, this is a methyl, ethyl, isopropyl or t-butyl group, especially a methyl or ethyl group, more particularly a methyl group.

[0058] Diagram A for the synthesis of the compound 1-[2-(2-furyl)ethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate (referred to as compound C21): Formation of amide (the first method)

[0059]

Chemical formula

[0060] Hydrolysis of methyl ester

Chemical formula

[0061] Diagram B for the synthesis of the compound 1-[(E)-4-hydroxycyclohexamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate (referred to as compound C19): Formation of amide (the second method)

[0062]

Chemical formula

[0063] DMF = dimethylformamide TEA = triethylamine DIA = diisopropylamine THF = Tetrahydrofuran CDI = Carbonyldiimidazole HBTU = (1H - Benzotriazol - 1 - yloxy)(dimethylamino) - N,N - dimethylmethaniminium hexafluorophosphate

Example

[0064] Equipment and Method The nuclear magnetic resonance (NMR) spectrum of protons ( 1 H) is performed on a Bruker Avance DPX500 device (500, 0.7 MHz). Chemical shifts (δ) are measured in parts per million (ppm). The spectrum is calibrated based on the chemical shift of the deuterated solvent used. Coupling constants (J) are expressed in Hertz (Hz), and multiplicities are represented as follows: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), doublet of triplets (td), quartet (q), multiplet (m). The mass spectrum (MS) is performed using an Agilent Technologies MSD spectrometer, model G1946A, and the sample is ionized by an "Atmospheric pressure chemical ionization (APCI)" source.

[0065] To illustrate an example of the present invention, the molecules shown in Table 1 were synthesized.

[0066]

Table 1

[0067] Example 1 (Diagram A) Preparation of Compound C21 Step 1 (Typical coupling method of an amine with carbonyldiimidazole (CDI)): Preparation of the methyl ester of C21 The chemical reaction was carried out under an argon atmosphere. During all steps of the reaction, as well as during the extraction and solvent removal steps, the reagents and products were protected from light with aluminum foil. The product was stored at 4 °C. Vixin (1 g; 2.54 mmol) was dissolved in 10 mL of dry dimethylformamide (DMF), and triethylamine (1.06 mL; 7.61 mmol) was added, followed by CDI (0.823 g; 5.07 mmol). After 2 hours, 2-aminoethylfuran (845 mg; 7.61 mmol) was added, and the reaction mixture was stirred at 20 °C for 18 hours. Hydrochloric acid (HCl, 1N; 20 mL) was added, and the resulting suspension was centrifuged. After removal of the supernatant, the pellet containing the methyl ester was resuspended twice in the presence of water. After centrifugation again, the pellet (1.24 g) was used directly in the hydrolysis step.

[0068] Step 2 (Typical procedure for hydrolysis): Conversion of the methyl ester of C21 to C21 The chemical reaction was carried out under an argon atmosphere and protected from light with aluminum foil. The product was stored at 4 °C. The methyl ester of C21 was dissolved in 15 mL of tetrahydrofuran (THF) and 13 mL of MeOH. Sodium hydroxide (NaOH, 1N; 15.3 mL) was added, and the reaction mixture was stirred at 20 °C for 20 hours. Hydrochloric acid (HCl; 1N; 16 mL) was added slowly. The resulting suspension was centrifuged, and the supernatant was removed. Subsequently, the pellet was resuspended and mixed twice with water, and centrifuged again to remove the supernatant. The resulting pellet containing water was transferred to a pear-shaped flask in the presence of water and acetonitrile and lyophilized to obtain 1.04 g of an orange to red powder.

[0069] Analysis of compound C21 LC-MS: m / z = 474.3 (MH + ) UV purity at 460 nm = 99%. NMR 1 H (500 MHz, DMSO-d 6 ) - δ 8.11 (t, 1H), 7.54 (s, 1H), 6.19 (d, 1H), 3.42 - 3.38 (m, 2H), 2.78 (t, 2H).

[0070] Preparation of Compound C19 Step 1 (Typical procedure for amine coupling using HBTU): Preparation of the methyl ester of C19 (The reaction using CDI is too slow for this compound and is only used for the preparation of the methyl ester of C19) The chemical reaction was carried out under an argon atmosphere. During all steps of the reaction, as well as during the extraction and solvent removal steps, the reagents and products were protected from light with aluminum foil. The product was stored at 4 °C. Vixin (1.17 g; 2.97 mmol) was dissolved in 20 mL of anhydrous DMF and diisopropylamine (1.23 mL; 7.42 mmol), followed by the addition of HBTU ((1H-benzotriazol-1-yloxy)-dimethylaminohexylfluorophosphate)-N,N’-dimethylmethaniminium; 1.69 g; 4.45 mmol). After 1 hour, trans-4-aminocyclohexanol (680 mg; 4.45 mmol) was added and the reaction mixture was stirred at 20 °C for 18 hours. 60 mL of water was added and the precipitate was filtered and washed twice with 60 mL of water to obtain 1.4 g of a purple solid compound, which was used as such in the hydrolysis step.

[0071] Step 2 (Typical procedure for hydrolysis): Conversion of the methyl ester of C19 to C19 The chemical reaction was carried out under argon and protected from light with aluminum foil. The product was stored at 4 °C. 1.4 g of the methyl ester of C21 was dissolved in 10 mL of tetrahydrofuran (THF) and 10 mL of MeOH (dark red solution). 5 equivalents of sodium hydroxide (NaOH, 10 N; 1.43 mL) were added and the reaction mixture was stirred at ambient temperature for 48 h. By HPLC-MS, a single peak and the absence of starting material were observed. Hydrochloric acid (HCl 12 N; 1.18 mL) was added. The resulting precipitate was diluted with 60 mL of water. The solution was centrifuged to remove the aqueous supernatant. Subsequently, a solid pellet was obtained, mixed with water (30 mL) and centrifuged again to remove the supernatant. This step was repeated 2 times until an orange solid paste (forming a suspension in the presence of water) was obtained. This solid paste was placed in 50 mL of water to obtain an orange suspension, which was frozen and freeze-dried directly to obtain an orange powder (1.02 g).

[0072] Analysis of Compound C19 LC-MS: m / z = 478.2 (MH + ) UV purity at 460 nm = 97.3%. NMR 1 H (500 MHz, DMSO-d 6 ) - δ 47.82 (s, 1H), 4.51 (m, 1H), 3.58 - 3.53 (m, 1H), 3.40 - 3.36 (m, 1H), 1.83 - 1.75 (m, 4H), 1.26 - 1.15 (m, 4H).

[0073] Cascade screening and characterization of the biological effects of norbixin-derived chemical compound (C) The development of the screening test was initiated from a literature study based on the characteristics of the pathology of dry AMD. At the pathophysiological level, this disease is characterized by the induction of progressive loss of vision following degeneration of photoreceptor and RPE cells. RPE cells play an important role in the survival and proper functioning of photoreceptors by supplying the nutrients necessary for photoreceptors, participating in the visual cycle, and removing fragments derived from this cycle that come from the outer segments of photoreceptors. It is important to screen the drug under development, preferably with respect to the ability to target the eye, while avoiding intraocular administration that subjects the patient to trauma and has a risk of local infection. To do this, a pharmacokinetic study of the norbixin-derived chemical compound (C), which is an object of the present invention, was carried out at plasma and intraocular levels, and a compound with an improved AUC (area under the curve) regarding the eye with respect to norbixin was selected.

[0074] In addition to better distribution in the target tissue, the selection of new compounds should also be based on good photoprotective activity that reduces the retinal degeneration observed between AMD and other degenerative diseases such as retinitis pigmentosa and Stargardt disease by limiting the loss of RPE cells. At the cellular level, for cultures of RPE cells derived from porcine retina, Non-Patent Document 15 shows that treatment with norbixin (BIO201) protects RPE cells from apoptosis after illumination in the presence of A2E (80% survival rate 24 hours after exposure). Using the same screening test according to the percentage of photoprotection, its modulation by the norbixin-derived chemical compound (C), which is an object of the present invention, was determined in comparison with the photoprotective effect of norbixin, and these modulations were characterized from a statistical point of view.

[0075] Protocol Pharmacokinetic study by oral administration of the molecule in mice Pharmacokinetic studies of the chemical compound (C) after oral administration were carried out using C57BL / 6 mice (Janvier, 53940, Le Genest-Saint-Isle, France). The chemical compound (C) derived from norbixin was administered at a dose of 50 mg / kg body weight. After administration, blood was collected from the tail at t = 0.25 h; 0.5 h; 1 h; 3 h; 6 h; 8 h. The blood samples were centrifuged to obtain plasma. Depending on the dose of the plasma sample, pharmacokinetic parameters, namely C max which corresponds to the maximum concentration observed after administration of the molecule, and T max which is the time required to reach the maximum concentration after administration of the molecule, and the determination of AUC, which is the area under the curve corresponding to plasma exposure, became possible (Figure 2).

[0076] In parallel, the chemical compound (C) derived from norbixin at multiple intraocular concentrations was dosed in the following manner (Figure 1): Both eyes of each mouse were placed in Precellys tubes and stored at -80 °C until dosing. Next, the eyes were homogenized using a bench-top homogenizer Fast-prep (Fischer Scientific, Hampton, USA) in a mixture of organic solvents, which was 500 μL of chloroform / methanol (1 / 1, v / v) in the first step and then 500 μL of chloroform / dichloromethane (1 / 1, v / v). The supernatant was collected at each step and transferred to a 2 mL 96-well plate.

[0077] For the quantification of chemical compound C, a calibration curve was prepared using eight standard solutions (5 - 5,000 ng / mL) in the same organic solvent mixture and transferred to a 2 mL 96-well plate (100 μL).

[0078] The supernatant and the standard solutions were volatilized without heating in an EZ2 (Genevac, Ipswich, UK), taken up in 100 μL of DMSO / methanol (20:80, v / v), and then transferred to a 200 μL 96-well plate.

[0079] LC-MS / MS analysis was performed using an HPLC 1200 Infinity chain (Agilent Technologies, Santa Clara, USA), a UV detector, and a mass spectrometer QQQ6420 (Agilent Technologies, Santa Clara, USA). The injection volume was 5 μL. Chemical compound C was eluted on a reverse-phase column C18 (2.1 × 50 mm, particle 3 μm; Ace-C18-Excel, AIT) using a gradient of acetonitrile and water (containing 0.1% formic acid) and a flow rate of 0.3 mL / min. The gradient conditions can vary depending on the chemical compound C being analyzed. The UV detector performed the analysis at 460 nm, and the mass spectrometer performed the analysis in the MRM-Positive mode.

[0080] Photoprotection of RPE cells In vitro tests of photoprotection of RPE cells illuminated in the presence of A2E by various chemical compounds C Using the in vitro tests aimed at studying the photoprotective effect of norbixin described above, the photoprotective effect of various chemical compounds (C) derived from norbixin on RPE cells illuminated with blue light in the presence of A2E was quantified (Figure 3). The photoprotective effect of the above molecules was evaluated in a cellular model of phototoxicity induced by treatment with A2E and subsequent illumination with blue light. The term "blue radiation" means radiation corresponding to the blue band of the visible light spectrum, i.e., radiation with a wavelength of 435 - 490 nm. This model uses primary cultures of porcine RPE. Cell viability is quantified by a cell viability assay. At -48 h, the compound under test (a 5 mM solution in DMSO) is added to a concentration of 1 - 20 μM, followed by addition of A2E at -19 h (final concentration 30 μM), and the cells are illuminated (time point: 0 h). Cell viability is measured 24 h later. Image acquisition and its processing are carried out using a fluorescence microscope controlled by Metamorph software and a dedicated quantification program. The experiments are carried out on quadruplicate 96-well microplates, and the experiments are reproduced at least 4 times. The results are presented in the form of a ratio representing the number of viable cells in the wells treated with the molecule under test divided by the number of viable cells in the control wells (treated with a dilution medium without A2E). This test was previously able to reveal the photoprotective activity of norbixin (Non-Patent Document 15).

[0081] Results Pharmacokinetic study of chemical compound C in mice Table 2 discloses the pharmacokinetic results of chemical compound C after p.o. administration of 50 mg / kg of 20% D-α-tocopheryl polyethylene glycol 1000 succinate (VitE-TPGS) in sodium bicarbonate buffer (0.1 M).

[0082]

Table 2

[0083] Table 3 corresponds to the percentage of photoprotection of RPE cells by chemical compound C in vitro and shows the percentage of RPE cells surviving after illumination in the presence of N-retinyl-N-retinylidene ethanolamine (A2E) and various chemical compounds C derived from norbixin (tested at 5, 10 or 20 μM) or in the presence of norbixin at the same concentration.

[0084]

Table 3

Claims

1. A chemical compound having the following general formula (I): 【Chemical 1】 wherein COR is a secondary or tertiary amide, and thus -R is: ・-M; -NH-(CH ２ ) ｎ -M and -NH-(CH ２ ) ｎ -C(CH ３ )(CH ３ )-M, provided that -M is a) [Chemical 2] b) [Chemical Formula 3] c) 【Chemical Formula 4】 selected from -R １ is selected from an oxygen atom, a sulfur atom, >CH ２ , >CH-O-(CH ２ ), ｎ -CH ３ , >CH-(CH ２ ), ｎ -O-(CH ２ ), ｎ -CH ３ , >CH-(CH ２ ), ｎ -OH, >CH-COOH, >C(OH)phenyl, or >NH group; -R ３ is a hydrogen atom, C １ -C ６ -alkyl, -OH, or C １ -C ６ -O-alkyl group; -R ４ is a hydrogen atom, C １ -C ６ -alkyl, -OH, or C １ -C ６ -O-alkyl group; - n is an integer from 0 to 6; ・-NH-(CH ２ ) ｎ -W, provided that W is a hydrogen atom, or an -OH group, -O-(CH ２ ) ｎ -CH ３ group, or i） 【Chemical Formula 5】 ii) 【Chemical Formula 6】 iii) [Chemical Formula 7] iv) 【Chemical 8】 v） 【Chemical Formula 9】 a group selected from -R １ is selected from an oxygen atom, a sulfur atom, >CH ２ , >CH-O-(CH ２ ) ｎ -CH ３ , >CH-(CH ２ ) ｎ -OH, >CH-COOH, >C(OH)phenyl, or >NH group; -R ３ is a hydrogen atom, C １ -C ６ -alkyl, -OH, or C １ -C ６ -O-alkyl group; -R ４ is a hydrogen atom, C １ -C ６ -alkyl, -OH, or C １ -C ６ -O-alkyl group; -R ５ is selected from -CH ３ , -OH, -O-(CH ２ ), ｎ -CH ３ , -(CH ２ ), ｎ -OH, or -COOH group; - n is an integer from 0 to 6; A chemical compound selected from the above.

2. The following chemical compounds: - 1-[2 - Methoxyethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1-[1,4 - Oxazineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1-[Piperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1-[2 - Hydroxyethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1[1,4 - Oxazepaneamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1 - Thiomorpholineamide-(2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1 - Pyrrolidineamide-(2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; - 1-[2 - Morpholinopropanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17 - Tetramethylicos - 2,4,6,8,10,12,14,16,18 - nonaenedioate; -1-[(S)-3-Hydroxypyrrolidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-Morpholinoethaneamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(R)-3-Hydroxypyrrolidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Hydroxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-Methyl-2-(4-morpholinyl)propylamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Hydroxymethylpiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(Z)-2,6-Dimethylmorpholineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Hydroxyphenylamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Benzyl-4-hydroxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Carboxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[(E)-4-Hydroxycyclohexamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[3-Methoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Methoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[2-(2-Furyl)ethanamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-n-Propoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate; -1-[4-Ethylmethoxypiperidineamide](2E,4E,6E,8E,10E,12E,14E,16Z,18E)-4,8,13,17-tetramethylicosa-2,4,6,8,10,12,14,16,18-nonaenedioate The chemical compound according to claim 1, selected from:

3. A pharmaceutical composition comprising at least one chemical compound according to claim 1 or 2.

4. The pharmaceutical composition according to claim 3, comprising at least one excipient.

5. The pharmaceutical composition according to claim 3 or 4, comprising a carrier in a form adapted for digestion, injection into the eye, or injection into the blood.

6. The chemical compound having the general formula (I) according to claim 1 or 2, for use as a medicament.

7. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the photoprotection of cells of the mammalian retinal pigment epithelium.

8. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the treatment and / or prevention of damage to the mammalian retina caused by exposure to blue light having a wavelength of 435 nm to 490 nm corresponding to the blue band of the visible light spectrum.

9. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the treatment and / or prevention of damage to the mammalian retina caused by retinal degeneration.

10. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the treatment and / or prevention of mammalian eye diseases.

11. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the treatment and / or prevention of mammalian retinopathy.

12. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the treatment and / or prevention of age-related macular degeneration (AMD) in mammals.

13. A chemical compound having the general formula (I) according to claim 1 or 2 for use in the treatment and / or prevention of Stargardt's disease and retinitis pigmentosa in mammals.

14. A pharmaceutical composition according to any one of claims 3 to 5 for use in the photoprotection of cells of the mammalian retinal pigment epithelium.

15. A pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment and / or prevention of damage to the mammalian retina caused by exposure to blue light having a wavelength of 435 nm to 490 nm corresponding to the blue band of the visible light spectrum.

16. A pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment and / or prevention of damage to the mammalian retina caused by retinal degeneration.

17. A pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment and / or prevention of mammalian eye diseases.

18. A pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment and / or prevention of mammalian retinopathy.

19. A pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment and / or prevention of age-related macular degeneration (AMD) in mammals. The pharmaceutical composition according to any one of claims 3 to 5 for use in the treatment and / or prevention of mammalian Stargardt's disease and retinitis pigmentosa.

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