• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Use of 3- (2-isothiocyanatoethyl) -5-methoxy-1H-indole for the treatment of degenerative diseases of the retina. The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the preventive or therapeutic treatment of retinal degenerative diseases. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2737709A1
    申请号:ES201830704
    申请日:2018-07-13
    公开日:2020-01-15
    发明作者:Martinez Rafael Leon；Blasco Laura Campello；Dziama Patrycja Michalska；Gil Agustina Noailles；Oksana Kutsyr；Sanchez Laura Fernandez；Flores Victoria Maneu；Zapata Pedro Lax；Garcia Antonio Garcia；Navarro Nicolás Cuenca
    申请人:Universidad de Alicante；Universidad Autonoma de Madrid；Fundacion para la Investigacion Biomedica del Hospital Universitario de la Princesa；
    IPC主号:
    专利说明:

    [0001]
    [0002] Use of 3- (2-isothiocyanatoethyl) -5-methoxy-1H-indole for the treatment of degenerative diseases of the retina
    [0003]
    [0004] Technical sector
    [0005]
    [0006] The invention falls within the scope of the pharmaceutical industry and, in particular, in the use of a compound of formula I in the treatment of those degenerative diseases of the retina that occur with destruction of the cellular structures present therein, preferably macular degeneration. associated with age (AMD), diabetic retinopathy (RD), retinitis pigmentosa (RP) and / or glaucoma. More preferably its use in the treatment of RP.
    [0007]
    [0008] State of the art
    [0009]
    [0010] The retina is a highly specialized and well structured neural tissue. Despite its peripheral location, this tissue is as extremely sensitive as the tissue structures of the Central Nervous System (CNS). The various degenerative diseases of the retina lead to cell death and impaired synaptic connectivity. The retinal changes underlying the different diseases modify the communication between the cells and, as a consequence, the retina undergoes a marked remodeling. These pathologies influence factors such as the increase in protein oxidation, as well as the failure of anti-oxidant defenses in the cells that make up the retina.
    [0011]
    [0012] Oxidative stress is recognized as one of the markers of aging. Several studies indicate that the activation of Nrf2-mediated pathways may increase survival in different models of neurodegenerative diseases (Leiser et al., 2010 , Mol Cell Biol, 30: 871-84, Lewis et al., 2010 , Integr Comp Biol, 50: 829-43). On the other hand, these routes are less active or deregulated during aging, in neurodegenerative processes and in age-related degenerative processes (Ungvari et al., 2011 , Am J Physiol Heart Circ Physiol, 301: H363-72). Inhibition or deregulation of these types of routes can obviously aggravate oxidative stress in these types of pathologies. In addition, signaling via Nrf2 can protect against inflammatory pathologies (Kim et al., 2010 , Mutat Res, 690: 12-23) and therefore, signaling deficiency via Nrf2, as occurs during aging, can increase the phenotype inflammatory.
    [0013] Regardless of their etiology, all retinal disorders have in common the fact that they have marked oxidative stress, inflammation and cell death due to apoptosis. Thus, oxidative stress has been shown to play a central role in retinal degeneration, with implications for the pathogenesis of AMD, DR, RP and glaucoma (Cuenca et al., 2014 , Prog Retin Eye Res, 43: 17- 75). The retina is one of the tissues most susceptible to damage by reactive oxygen species (from the English "reactive oxygen species" ROS). The photoreceptors, photosensitive cells of the retina, are exposed to light and are one of the largest consumers of oxygen in the CNS, mainly in the ellipsoid area, where there is a large accumulation of mitochondria. Oxidative stress is not only due to excessive ROS production; It can also be caused by a decrease in the activation of Nrf2 (“nuclear factor (erythroid-derived 2) -like 2”), as occurs in age-related macular degeneration (AMD) and RD (Sachdeva et al. ., 2014 , Exp Eye Res, 119: 111-4, Xu et al., 2014 , Diabetology, 57: 204-13). As a consequence, the route that involves the interaction of Nrf2 with ARE regulatory sequences (in English, “antioxidant response element”) is suggested as a possible therapeutic target for the prevention and treatment of this type of pathologies (Nakagami, 2016 , Oxid Med Cell Longev, 2016: 7469326) (Lambros et al., 2016 , Adv Exp Med Biol, 854: 67-72).
    [0014]
    [0015] Degenerative diseases of the retina, such as glaucoma, RP or AMD, are also characterized by presenting a scenario of neuroinflammation and chronic activation of the microglia (Cuenca et al., 2014 , Prog Retin Eye Res, 43: 17-75) . Microglia cells have a protective effect on the damaged retina, but their excessive or prolonged activation produces chronic inflammation, with secretion of inflammatory cytokines that produce serious side effects that can trigger irreversible neuronal death (Polazzi et al., 2010 , Prog Neurobiol, 92: 293-315, Karlstetter et al., 2010 , Immunobiology, 215: 685 91). Thus, selective inhibition of microglia overactivation and preservation of its trophic and homeostatic functions may contribute to reducing the degeneration of photoreceptors, so that it could be a promising treatment for degenerative diseases.
    [0016]
    [0017] The proper development and functioning of the retina requires a balance between the processes of proliferation, differentiation and cell death. Certain genetic mutations, age and various environmental factors can trigger specific genetic mutations that induce apoptosis death in photoreceptors, contributing to the development of various diseases. The changes responsible for dystrophy in degenerative diseases of the retina, which cause structural and functional damage, can occur at any level of the signal transduction cascade or at any of the morphological components of these differentiated cells. The final result of cell death or survival seems to be the consequence of a complex balance between pro and antiapoptotic processes at various levels: extracellular, mitochondrial, nuclear and cytoplasmic. In the pathogenesis of several degenerative diseases, it seems that apoptosis is involved, in the case of photoreceptors in RP and AMD, or ganglion cells, photoreceptors and retinal pigment epithelium in diabetic patients (Cuenca et al., 2014 , Prog Retin Eye Res, 43: 17-75).
    [0018]
    [0019] Currently, the pharmacological treatment of degenerative diseases of the retina focuses on two main lines of action. First, the use of preventive strategies that attempt to counteract the underlying mechanisms of the disease, such as gene therapy. Secondly, try to avoid cell death by administering anti-apoptotic and anti-inflammatory compounds, as well as neurotrophic factors, which delay retinal cell death thus delaying the progression of the disease.
    [0020]
    [0021] The use of antiapoptotic compounds can prevent cell death in retinal diseases, which initially only affects certain cells such as photoreceptors and subsequently the rest of cells. In this sense, the administration of an antioxidant cocktail also proved beneficial in an animal model of RP. These cocktails included a-tocopherol, ascorbic acid, Mn (III) tetrakis (4-benzoic acid) porphyrin, and a-lipoic acid, and also antioxidants in a combination consisting of lutein, zeaxanthin, a-lipoic acid and L-glutathione ( GSH) (Komeima et al., 2007 , J Cell Physiol, 213: 809-15).
    [0022]
    [0023] Due to the great impact of the degenerative processes of the retina on the quality of life of patients, it is extremely interesting to find suitable pharmacological treatments. In patent documents EP2623494, JP20100221873 20100930, WO2010 / 016042, ES2331342, different options for treating retinal diseases based on one or more chemical compounds and / or natural products are proposed.
    [0024] The present invention focuses on the use of the 3- (2-isothiocyanatoethyl) -5-methoxy-1H-indole derivative as a therapeutic strategy to prevent, prevent or mitigate retinal degeneration in glaucoma, AMD or RP on the basis to its antioxidant and cytoprotective effect already described (Egea et al., 2015 , Br J Pharmacol, 172: 1807-21).
    [0025]
    [0026] Detailed description of the invention
    [0027]
    [0028] The present invention relates to a compound of formula (I):
    [0029]
    [0030]
    [0031]
    [0032] 3- (2-Isothiocyanatoethyl) -5-methoxy-1H-indole
    [0033] as well as its pharmaceutically acceptable salts for use in the preventive or therapeutic treatment of retinal degenerative diseases.
    [0034]
    [0035] The term "pharmaceutically acceptable salts" used herein encompasses any salt formed from organic and inorganic acids, such as hydrochloric, sulfuric, aspartic, benzenesulfonic, citric, fumaric, glutamic, lactic, maleic, oxalic, pivotal, p-toluenesulfonic, tartaric and similar, or a metal salt, the metal being selected from sodium, potassium, lithium, calcium and the like, or ammonium salts, or a salt formed from from organic bases, such as 2-amino-1-butanol, choline, dibenzylmethylamine, diethanolamine, monoamine glycols, triisopropanolamine and the like, and salts with amino acids such as glycine and the like.
    [0036]
    [0037] The compound of the present invention is prepared according to known methods (Egea et al., 2015 , Br J Pharmacol, 172: 1807-21) being able to prepare soluble complexes with different excipients according to the literature (Michalska et al., 2017 , Carbohydr Polym, 157: 94-104).
    [0038] The compound of the present invention is conveniently administered formulated with suitable excipients by oral, injectable or intravenous route at daily doses between 0.01 and 100 mg, preferably between 0.01 and 50 mg.
    [0039]
    [0040] As the route of administration, the oral route is preferred. As oral presentations, tablets, capsules, dragees, gelatin capsules, granules, suppositories, drinking solutions and drops are chosen interchangeably for subsequent dilution in liquids. The active substance can be incorporated with excipients normally used in pharmaceutical compositions such as lactose, magnesium stearate, aqueous or non-aqueous vehicles, fatty substances of vegetable or animal origin, paraffin derivatives, glycols, dispersing agents, emulsion or soaking agents and preservatives.
    [0041]
    [0042] In a particular embodiment, compound I can be administered locally in the area where the treatment is needed. As an example of local administration, compound I can be administered in the form of eye drops, intraocular injection, an implant so that the implant can be constituted by a porous, non-porous, or gelatinous material including membranes such as sialistic membranes or fibers
    [0043]
    [0044] The invention also relates to a pharmaceutical composition comprising compound I, or its pharmaceutically acceptable salts, defined above, for use in the preventive or therapeutic treatment of retinal degenerative diseases.
    [0045]
    [0046] Degenerative disease can be retinitis pigmentosa, diabetic retinopathy, glaucoma or macular degeneration.
    [0047]
    [0048] The pharmaceutical composition can be administered in any of the ways mentioned above, and preferably, orally, rectally, subcutaneously, intramuscularly or intravascularly.
    [0049]
    [0050] Especially preferably, the pharmaceutical composition is prepared as a solution that can be used for local application in the eye.
    [0051] The method of administration can be selected from the group consisting of: eye drop solution, a solution suitable for intraocular injection, or a solution for intravitreal injection.
    [0052]
    [0053] In the pharmaceutical composition, the compound of formula (I) is present in an amount between 0.01 and 100 mg, preferably between 0.01 and 50 mg.
    [0054]
    [0055] An essential characteristic of the compound of the present invention is that it has a reducing effect of retinal degeneration associated with various degeneration models.
    [0056]
    [0057] Neither melatonin is a potent inducer of Nrf2 as the compound of the invention, nor is sulforaphane an effective antioxidant like our compound. Therefore the improvement is demonstrated with respect to each of the activities. The compound of the invention improves the antioxidant and inducing activity of Nrf2 of melatonin and sulforaphane respectively.
    [0058]
    [0059] The compound object of the present invention shows several clear and demonstrated advantages over melatonin and sulforaphane. First, the compound object of the invention has demonstrated a combination of biological activities with therapeutic effect that is not present in any of the precursor molecules. Compound I is a potent inducer of Nrf2 effect that does not possess melatonin, which demonstrates an advantage over melatonin. On the other hand, compound I has been shown to improve both activities with respect to the combination of precursor molecules in both activities, which indicates that it not only combines the activity of both molecules but also significantly improves them (Egea et al., 2015, Br J Pharmacol, 172: 1807-21). Finally, the most significant advantage demonstrated in compound I is that, in addition, it includes a drug-prodrug mechanism of action that does not possess any of the precursor molecules.
    [0060]
    [0061] Brief description of the figures
    [0062]
    [0063] Figure 1 shows the Effect of compound I on the viability of 661W cells exposed to sodium nitroprusside (SNP).
    [0064]
    [0065] Figure 2 shows Stimulus-response curves of scotopic ERGs from rd10 mice treated with vehicle (control) or 10 mg / Kg of compound I.
    [0066] Figure 3 shows Stimulus-response curves of scotopic ERGs from rd10 mice treated with vehicle (control) or 1 mg / Kg of compound I.
    [0067]
    [0068] Figure 4 shows the measured visual acuity expressed as spatial frequency in cycles / degree achieved by rd10 mice treated with vehicle (control), and by mice treated with compound I at 1 or 10 mg / kg of P16 to P30, intraperitoneally, twice daily.
    [0069]
    [0070] Figure 5 shows the contrast sensitivity measured at different spatial frequencies in cycles / degree achieved for rd10 mice treated with vehicle (control), as well as for mice treated with compound I at 10 mg / Kg from P16 to P30, intraperitoneally , twice daily.
    [0071]
    [0072] Embodiments of the invention
    [0073]
    [0074] The present invention is further illustrated by the following examples, which are not intended to be limiting in scope.
    [0075]
    [0076] The protective and reducing effects of retinal degeneration of the compound of formula (I) were studied in the 661W cell line, derived from photoreceptors (Example 1) and in an animal model of retinal degeneration (Example 2). In the first example, the 661W cell line was subjected to damage by the oxidizing agents nitroprusside sodium, measuring cell viability in the presence and absence of the compound. Cell viability was evaluated by measuring the reducing capacity of compound XTT. In the second example, the neuroprotective capacity of the compound was studied in vivo, in an autosomal recessive RP model, the mouse rd10. The compound of formula (I) was administered at 1 or 10 mg / kg, intraperitoneally, two daily doses for 3 or 7 days after ischemia or postnatal day P16 to P30 in rd10 mice.
    [0077]
    [0078] Example 1 : Cytoprotection against toxicity induced by sodium nitroprusside (300 uM) in the cell line derived from 661W photoreceptors.
    [0079]
    [0080] The 661W cell line was isolated from retinal tumors of transgenic mice expressing the SV40 T antigen under the control of the IRBP gene promoter (PBR-3). It is a cell line homogeneous that expresses several markers of cone-type photoreceptors: opsins, transducin and X-arrestine. There is a great deal of information available on the pathways that are activated in these cells in various apoptotic stimuli and have been used successfully as a tool in the research associated with retinal dystrophies.
    [0081]
    [0082] The 661W cell line was cultured in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% glutamine at 37 ° C in a humidified atmosphere at 5% CO 2 . Cellular survival was quantified by XTT reduction measure, performed spectrophotometrically according to the supplier's instructions.
    [0083]
    [0084] First, the ability of the compound of formula (I) to prevent cell death in the 661W line was studied. Cell cultures were incubated with different concentrations of compound (I) (0.1, 1 and 10 pM) for 1 h. After the pre-incubation period, the cells under treatment were exposed to toxic stimulation (300 pM sodium nitroprusside). After 24 h of incubation of the toxic stimulus, cell survival was measured by the XTT technique.
    [0085]
    [0086] Compound I was pre-incubated for 1 h and maintained during the toxic stimulus (sodium nitroprusside, NPS at 300 uM for 24 hours). Figure 1 shows the average value of the cell viability assay (XTT) in% with respect to the control, non-injured cells ± DS (n = 4, 8 wells in each condition). * p <0.05, paired t-test.
    [0087]
    [0088] The results are shown in Figure 1. Compound I increased neuronal survival statistically significantly at the concentration of 1 pM.
    [0089]
    [0090] Under these experimental conditions, after a toxic stimulation of sodium nitroprusside applied for 24 h, compound I at 1 pM increased the viability of the 661W cell line by 20%.
    [0091]
    [0092] Example 2 Rescue of visual responses in the animal model of pigmentary retinosis rd10
    [0093]
    [0094] Retinitis pigmentosa is considered a set of inherited diseases in which photoreceptors degenerate. In most forms of RP, initially the death of the stick-type photoreceptors, followed by the death of the cone-type photoreceptors. Patients with RP suffer a progressive loss of peripheral vision, which progresses to tunnel vision.
    [0095]
    [0096] Compound I can exert a protective effect and therefore be an effective agent for treating RP. The studies were proposed to study the efficacy of compound I as a treatment for retinitis pigmentosa.
    [0097]
    [0098] The rd10 murine strain is a model of autosomal recessive retinal degeneration, obtained due to a specific mutation in the Pde6b gene (cGMP phosphodiesterase 6B, cones receptor, beta polypeptide). It is a model in which degeneration appears late and shows a slower progression than other models, such as the rd1 strain, so that it is shown as a more suitable model for the therapy trial for RP. This model is also more accepted than the model of damage caused by acute light since photoreceptor cells in the rd10 mouse are lost over a period of weeks instead of days. The loss of photoreceptors in the rd10 model begins at approximately two weeks of life, with a peak of photoreceptor death at the P30 postnatal day.
    [0099]
    [0100] The doses studied were 1 mg / kg (D1) and 10 mg / kg (D2); administered intraperitoneally, twice a day, from the postnatal day P16 to P30, that is from the beginning to an advanced stage of the degenerative process.
    [0101]
    [0102] The study groups were:
    [0103]
    [0104] (1) C: control, rd10 mice injected with vehicle (PBS),
    [0105] (2) D1: rd10 mice treated with compound I, 1 mg / Kg,
    [0106] (3) D2: rd10 mice treated with compound I, 10 mg / Kg.
    [0107]
    [0108] Example 2.1 : measurement of the amplitude of the electroretingraphic response (ERG)
    [0109]
    [0110] The ability of the retina to respond to light can be assessed by recording the electrical potentials generated in the retina in response to light stimuli. The measurement is made through a recording electrode placed on the cornea of one or both eyes of the individual. The adaptation and maintenance of the individual in dark conditions allow get wider responses (scotopic waves). Once the responses have been digitized and processed, stimulus-response curves can be obtained, which relate the intensity of the stimulus to the amplitude of the recorded voltage waves. The amplitude of the “a” wave directly depends on the response of the photoreceptors, cones and rods. The amplitude of the "b" wave is proportional to the functionality of the cells of the internal retina.
    [0111]
    [0112] The stimulus-response curves of the ERG were analyzed in rd10 mice treated with vehicle (control) or treated with compound I at 1 and 10 mg / Kg. As detailed in Figure 2, the mean values of scotopic a and b waves were higher (20% and 28%, respectively) in rd10 mice treated with compound I at 10 mg / kg.
    [0113]
    [0114] Figure 2 shows stimulus-response curves of scotopic ERGs from rd10 mice treated with vehicle (control) or 10 mg / Kg of compound I. The graph shows the mean values ± SEM of waves a and b. ** p <0.05, *** p <0.001, MANOVA, using the Bonferroni post-hoc test.
    [0115]
    [0116] On the other hand, no differences were observed between animals treated with 1 mg / kg of compound I and vehicle treated mice. Figure 3 shows the stimulatory response curves of the scotopic ERGs of rd10 mice treated with vehicle (control) or 1 mg / Kg of compound I. The graph shows the mean values ± SEM of waves a and b.
    [0117]
    [0118] Therefore, in our experimental conditions, rd10 mice injected with compound I at a dose of 10 mg / Kg of P16 to P30, twice daily, showed stimulus-response curves of greater amplitude than rd10 mice injected with vehicle (PBS), this difference being statistically significant, indicating an improvement in the functional response of the retina.
    [0119]
    [0120] Example 2.2: Measurement of visual acuity in the rd10 model treated with compound I.
    [0121]
    [0122] Visual acuity gives a measure of the functional activity of the retina. The visual acuity analysis in treated and untreated rd10 mice was performed using the optomotor test. In this test, the animals, located inside a box with projection panels on all four walls, are exposed to moving images of vertical bars that rotate in one direction or another. The experimenter analyzes the visual response of the animals to the changes of direction of the bars. The thickness of the bars is progressively reduced. The minimum thickness of the bars to which the animal is able to respond determines a measure of visual acuity.
    [0123]
    [0124] This test showed that visual acuity increased by 14.0% in mice treated with compound I at 1 mg / kg compared to vehicle-treated (control) rd10 mice, although the difference was not significant. With a dose of 10 mg / kg, visual acuity increased significantly by 35.6% compared to rd10 mice treated with vehicle. Figure 4 shows the visual acuity measured expressed as spatial frequency in cycles / degree achieved by rd10 mice treated with vehicle (control), and by mice treated with compound I at 1 or 10 mg / Kg of P16 to P30, intraperitoneally, twice daily. Data represent mean values ± SEM. * p <0.05, MANOVA, using the Bonferroni post-hoc test.
    [0125]
    [0126] Regarding contrast sensitivity, compared to vehicle-treated rd10 mice, in animals treated with compound I at 10 mg / Kg the contrast sensitivity increased between 11% and 115%, depending on the spatial frequency of the stimulus (Figure 5). No significant differences in contrast sensitivity were found between rd10 mice treated with compound I at 1 mg / kg compared to control rd10 mice. Figure 5 shows the contrast sensitivity measured at different spatial frequencies in cycles / degree reached for rd10 mice treated with vehicle (control), as well as for mice treated with compound I at 10 mg / Kg from P16 to P30, intraperitoneally , twice daily. Data represent mean values ± SEM. * p <0.001, MANOVA, Bonferroni post hoc test.
    [0127]
    [0128] In the rd10 mouse model, a mouse model of pigmentary retinosis, compound I rescued visual responses to rd10 vehicle-treated mice when administered at a dose of 10 mg / Kg twice daily intraperitoneally, from P16 to P30. Compound I preserved the scotopic ERG amplitudes of the a and b waves (with values 20% and 28% respectively higher than those obtained in rd10 mice treated with vehicle). It also increased visual acuity in animals treated with the compound up to 35.60% and increased its contrast sensitivity from 11% to 115% depending on spatial frequency.
    [0129] Bibliography.
    [0130]
    [0131] Cuenca N, Fernandez-Sanchez L, Campello L, Maneu V, De la Villa P, et al. 2014. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 43: 17-75
    [0132] Egea J, Buendia I, Stop E, Navarro E, Rada P, et al. 2015. Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a 'drug-prodrug' mechanism of action. Br J Pharmacol 172: 1807-21
    [0133] Karlstetter M, Ebert S, Langmann T. 2010. Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology 215: 685-91
    [0134] Kim J, Cha YN, Surh YJ. 2010. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res 690: 12-23
    [0135] Komeima K, Rogers BS, Campochiaro PA. 2007. Antioxidants slow photoreceptor cell death in mouse models of retinitis pigmentosa. J Cell Physiol 213: 809-15
    [0136] Lambros ML, Plafker SM. 2016. Oxidative Stress and the Nrf2 Anti-Oxidant Transcription Factor in Age-Related Macular Degeneration. Adv Exp Med Biol 854: 67-72 Leiser SF, Miller RA. 2010. Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice. Mol Cell Biol 30: 871-84
    [0137] Lewis KN, Mele J, Hayes JD, Buffenstein R. 2010. Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integr Comp Biol 50: 829-43
    [0138] Michalska P, Wojnicz A, Ruiz-Nuno A, April S, Buendia I, Leon R. 2017. Inclusion complex of ITH12674 with 2-hydroxypropyl-beta-cyclodextrin: Preparation, physical characterization and pharmacological effect. Carbohydr Polym 157: 94-104
    [0139] Nakagami Y. 2016. Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases. Oxid Med Cell Longev 2016: 7469326
    [0140] Polazzi E, Monti B. 2010. Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog Neurobiol 92: 293-315
    [0141] Sachdeva MM, Cano M, Handa JT. 2014. Nrf2 signaling is impaired in the aging RPE given an oxidative insult. Exp Eye Res 119: 111-4
    [0142] Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, et al. 2011. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301: H363-72
    [0143] Xu Z, Wei Y, Gong J, Cho H, Park JK, et al. 2014. NRF2 plays a protective role in diabetic retinopathy in mice. Diabetology 57: 204-13
    权利要求:
    Claims (11)
    [1]
    1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the preventive or therapeutic treatment of retinal degenerative diseases.

    [2]
    2. A compound according to claim 1, wherein the degenerative disease is retinitis pigmentosa, diabetic retinopathy, glaucoma or macular degeneration.
    [3]
    3. A compound according to claim 1, wherein the pharmaceutically acceptable salt is an organic acid salt, an inorganic acid salt, a salt formed from organic bases, and a salt with amino acids.
    [4]
    4. A compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt selected from a salt of hydrochloric, sulfuric, aspartic, benzenesulfonic, citric, fumaric, glutamic, lactic, maleic, oxalic, pivotal, p-toluenesulfonic acid , tartaric, and the like, a salt formed from 2-amino-1-butanol, a salt formed from choline, a salt formed from dibenzylmethylamine, a salt formed from diethanolamine, a salt formed from monoamine glycols, a salt formed from triisopropanolamine, and a salt formed from glycine.
    [5]
    5. A compound according to one of claims 1 to 4, for use in a dose of 0.01 to 100 mg, preferably 0.01 to 50 mg.
    [6]
    6. A pharmaceutical composition comprising the compound I defined in one of claims 1 to 5, for use in the preventive or therapeutic treatment of retinal degenerative diseases.
    [7]
    7. A pharmaceutical composition according to claim 6, wherein the degenerative disease is retinitis pigmentosa, diabetic retinopathy, glaucoma or macular degeneration.
    [8]
    8. A pharmaceutical composition according to claim 6 or 7, for administration orally, rectally, subcutaneously, intramuscularly or intravascularly.
    [9]
    9. A pharmaceutical composition according to one of claims 6 to 8, as a solution that can be used for local application in the eye.
    [10]
    10. A pharmaceutical composition according to claim 9, in a form selected from the group consisting of: eye drop solution, a solution suitable for intraocular injection, or a solution for intravitreal injection.
    [11]
    11. A pharmaceutical composition according to one of claims 6 to 10, wherein the compound of formula (I) is present in an amount comprised between 0.01 and 100 mg, preferably between 0.01 to 50 mg.
    类似技术:
    公开号 | 公开日 | 专利标题
    ES2733954T3|2019-12-03|Composition comprising torasemide and baclofen to treat neurological disorders
    Ferrucci et al.2010|A systematic study of brainstem motor nuclei in a mouse model of ALS, the effects of lithium
    ES2586843T3|2016-10-19|Treatment of disorders related to BDNF using laquinimod
    Biswal et al.2015|Systemic treatment with a 5HT1a agonist induces anti-oxidant protection and preserves the retina from mitochondrial oxidative stress
    JP6666899B2|2020-03-18|ANG- | derivative oligopeptides and methods for using and making them
    Karimi et al.2017|The protective effect of hydrogen sulfide | on traumatic brain injury | induced memory deficits in rats
    US20120135084A1|2012-05-31|Use of Deuterium Oxide for Treating Viral Diseases of the Eye
    EP2964026A1|2016-01-13|Hdac inhibitors for treating traumatic brain injury
    Wang et al.2019|Protective effects of ACY-1215 against chemotherapy-related cognitive impairment and brain damage in mice
    Huang et al.2018|Asiatic acid prevents retinal ganglion cell apoptosis in a rat model of glaucoma
    ES2750839T3|2020-03-27|Pharmaceutical composition for the prevention, treatment or delay of Alzheimer&#39;s disease or dementia containing G 19 protein-coupled receptor agent as an active ingredient
    ES2737709B2|2020-06-17|Use of 3- | -5-methoxy-1H-indole for the treatment of degenerative diseases of the retina
    Smith et al.2019|Effects of nicotinamide on spatial memory and inflammation after juvenile traumatic brain injury
    Ahmed et al.2016|Repurposing an orally available drug for the treatment of geographic atrophy
    EP3765082A1|2021-01-20|Uses, compositions and methods
    ES2729208T3|2019-10-30|Baclofen and acamprosate-based therapy of macular degeneration disorders
    Demeter et al.2013|Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study
    WO2015060746A1|2015-04-30|Combination for treating and/or preventing manifestations of psychiatric, cognitive, behavioral and neurological disorders in the case of organic diseases of the central nervous system having various origins
    US8778884B2|2014-07-15|Glioprotectant peptide for use in the treatment of amyotrophic lateral sclerosis | and methods related thereto
    ES2804541T3|2021-02-08|Compound for use in the prevention and treatment of neurodegenerative diseases
    Mahmoudi et al.2019|Curcumin protects purkinje neurons, ameliorates motor function and reduces cerebellar atrophy in rat model of cerebellar ataxia induced by 3-AP
    ES2848828T3|2021-08-12|Withania extract for the treatment of amyloid-related diseases
    Geva et al.2021|Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma
    TW201035081A|2010-10-01|Novel pharmaceutical composition for treatment of schizophrenia
    ES2277567B1|2008-06-01|COMPOUNDS WITH NEUROPROTECTOR PROPERTIES.
    同族专利:
    公开号 | 公开日
    WO2020012052A1|2020-01-16|
    ES2737709B2|2020-06-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ES2526979A1|2013-07-17|2015-01-19|Fundación Para La Investigación Biomédica Del Hospital Universitario De La Princesa|Use of 3- -5-methoxy-1H-indole for the treatment of neurodegenerative diseases |
    法律状态:
    2020-01-15| BA2A| Patent application published|Ref document number: 2737709 Country of ref document: ES Kind code of ref document: A1 Effective date: 20200115 |
    2020-06-17| FG2A| Definitive protection|Ref document number: 2737709 Country of ref document: ES Kind code of ref document: B2 Effective date: 20200617 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201830704A|ES2737709B2|2018-07-13|2018-07-13|Use of 3--5-methoxy-1H-indole for the treatment of degenerative diseases of the retina|ES201830704A| ES2737709B2|2018-07-13|2018-07-13|Use of 3--5-methoxy-1H-indole for the treatment of degenerative diseases of the retina|
    PCT/ES2019/070485| WO2020012052A1|2018-07-13|2019-07-11|Use of 3--5-methoxy-1h-indole for the treatment of degenerative retinal diseases|
    [返回顶部]