Compounds and compositions for neurodegenerative diseases

Abstract

The present disclosure relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of neurodegenerative diseases.Furthermore, the present invention relates to the non-therapeutic use of said compound, preferably as a food or nutritional ingredient, for maintaining and / or improving neurological and / or brain function. [Formula 1] JPEG2025506271000012.jpg48102

Description

[Technical field]

[0001] The present disclosure relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of neurodegenerative diseases. It further relates to non-therapeutic uses of said compounds for maintaining and / or improving neuronal and / or brain function. [Background technology]

[0002] It is now comprehensively understood that as life expectancy increases, the world's population is ageing, accompanied by an acceleration over time and incidence of age-related diseases such as neurodegenerative diseases, nervous system dysfunctions and syndromes, ultimately leading to impaired mental and motor functions. A vast number of neurodegenerative diseases are known to affect the nervous system, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophies, multiple sclerosis, brain tumors and epilepsy. The crucial role of several factors such as misfolded protein aggregation, increased oxidative stress, lipid peroxidation, DNA damage, unregulated signaling and neuroinflammation have begun to emerge as relevant foci for developing new interventions to tackle disease progression. Current treatments only alleviate the physical complications and are unable to eradicate the pathology of this burden to society. These factors make the discovery of novel therapeutics to delay and prevent the onset of these diseases an urgent yet unmet need.

[0003] Neuroinflammation has emerged as one of the key processes involved in major neurodegenerative diseases, playing a detrimental role contributing to disease acceleration as well as being essential for recovery from some conditions. This process is controlled by microglial cells, the innate immune cells of the central nervous system (CNS). Microglia are generally accepted to play a major role in neurological and neurodegenerative diseases (for review see Prokop et al., Acta Neuropathol 126 (2013), 461-77), participating in the first line of defense against invading pathogens or other types of brain tissue damage and understood to be the "sentinels" of the CNS. Under transient injury, microglial cells activate to protect the surrounding microenvironment, perform immunoresolving, anti-inflammatory functions, and maintain normal function of the CNS by secreting trophic factors to support cell regeneration. Conversely, under pathological acute or chronic intense activation, which usually accompanies neurodegenerative diseases, stroke, and tumor invasion, microglial cells exhibit neurotoxicity and secrete large amounts of proinflammatory cytokines, such as TNF-α, IL-6, IL-10, IL-1β, or prostaglandins synthesized by COX-2, and reactive oxygen (ROS) and nitrogen (NOS) species, which can potentially impair neuronal activity and lead to impaired normal neurotransmitter function and irreversible tissue loss. The main signaling cascade behind the activation of microglial cells involves nuclear factor kappa B (NF-kB) through the mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, the transmembrane protein toll-like receptor 4 (TLR4) is also involved in the activation of NF-kB and the production of proinflammatory cytokines. The NF-kB transcription factor is one of the most important molecular mediators in inflammation and is also involved in tumor-promoting processes (Karin M, Greten FR. NF-kB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005 Oct; 5(10):749-59).

[0004] The identification of NF-kB and its inactivation by the regulatory protein IkB-α suggests that many of the proteins involved in its activation pathway and thus contributing to inflammation and cancer could be molecular targets for many drugs. Some of these agents have been discovered so far and some have been tested in the clinical literature (Karin M, Yamamoto Y, Wang QM. The IKK NF-kB system: a treasure trove for drug development. Nat Rev Drug Discov. 2004 Jan; 3(1):17-26). Thus, targeting microglial cells offers an interesting new avenue in the development of novel treatments for these diseases. Current approaches mainly aim to reduce microglial activation and the production of proinflammatory cytokines to avoid neuroinflammation-mediated neuronal damage (reviewed, for example, in Solito and Sastre, Front Pharmacol 3 (2012), and Wang et al., Ann. Transl. Med. 3 (2015): 136). Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2), which have been reported to interfere with the proper functioning of microglia (loss-of-function mutants), have been linked to a spectrum of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Nasu-Hakola disease (NHD, also known as polycystic lipomembranous skeletal dysplasia with sclerosing leukoencephalopathy, PLOSL) (reviewed in Yeh et al., Trends Mol. Med. 23 (2017), 512-533). TREM2 is expressed in microglia and promotes microglial survival, activation and the formation of a protective microglial barrier around amyloid plaques. Studies have shown that TREM2-mediated activity is closely involved in neurodegenerative diseases, thus providing a new therapeutic target.Specifically, in vitro and in vivo treatment of microglia and mouse hippocampus with transgenic soluble TREM2 (sTREM2) protein revealed a protective effect on microglial viability and a trigger for microglial activation (Zhong et al., J. Exp. Med. 214 (2017), 597-607). However, the application of recombinant protein-based drugs as shown in KR 2019-7029338 A, JP 2017-74982 A and WO20140330704A1 is highly inconvenient, cumbersome and expensive, as well as carrying the risk of causing undesirable immunogenic responses and insufficient exposure to protein therapeutics due to poor crossing of the blood-brain barrier (BBB), a dynamic interface that limits molecular exchange between blood and neural tissue, which has a key role in controlling the accessibility of nutrients and drugs to the brain.

[0005] Therefore, there remains a need for therapies that promote microglial survival and activation for the safe and tolerable treatment of neurological and neurodegenerative diseases that can overcome the above-mentioned drawbacks.

[0006] These objects are achieved by the present invention according to the embodiments characterized in the claims and further described below. During the past decades, several epidemiological studies have revealed that a polyphenol-rich diet consisting of fruits and vegetables has beneficial effects on humans and can prevent neurodegenerative diseases and cognitive decline. In fact, adherence to a Mediterranean diet rich in polyphenols is associated with a reduced incidence of neurodegenerative diseases. Olives and berries are the most promising fruits as a source of polyphenols with these health benefits. Hydroxytyrosol, oleuropein aglycone and other molecules with a polyphenolic structure are well known to be powerful antioxidants and anti-inflammatory agents. Oleuropein also exhibits coronary vasodilatory, hypoglycemic and anticholesterol activity and, like hydroxytyrosol, delays the oxidation of LDL (low density lipoprotein). Hydroxytyrosol has been shown to reduce gene expression in NOS and COX-2 cell lines, thus preventing the activation of the NF-kB transcription factor.

[0007] Despite accumulating evidence of beneficial effects, the fundamental mechanisms of action of polyphenols remain to be elucidated. Both indirect action via peripheral action and direct action in the brain have been suggested as possible mechanisms. Most in vitro mechanistic studies with polyphenols have used pure components and have not addressed their metabolism and bioavailability. In many cases, single molecules are less active relative to mixtures of compounds, suggesting synergistic interactions between compounds. The absorbed form is likely not the native food compound, but a plethora of circulating metabolites (e.g., sulfates, O-glucuronates, and / or methyl ether derivatives) resulting from extensive conjugation resulting from digestion, hepatic and colonic metabolism (Kroon PA et al, Am. J. Clin. Nutr. (2004), 80, 15-21). Furthermore, the ability of dietary polyphenolic compounds to directly affect the nervous system is related to the ability of the metabolites to cross the BBB. Indeed, evidence of BBB permeation from polyphenol metabolites, such as hydroxycinnamic acids, hydroxybenzenes, and benzoic acid derivatives, is growing in the literature (Gasperotti M. et al, ACS Chem. Neurosci. (2015), 6, (8), 1341-1352).

[0008] Several documents claiming nutritional and / or pharmaceutical compositions as antioxidants and neuroprotective agents have been reported in the patent literature, such as the teachings of WO2017160923A1, WO2013132376A1, WO199905391A1, and WO1999052524A1. Nevertheless, due to the use of non-psychotropic cannabinoid and / or flavonoid compounds and / or plant oil extracts, the bioavailability of important polyphenol metabolites across the BBB is low, and the reported effects do not necessarily relate to those that may occur in vivo. Moreover, the macrocyclic derivatives present in WO2013132376A1 can be expensive to prepare and purify.

[0009] The most important granted prior art reference is constituted by US9610256B2, which discloses the use of 2,5-dihydroxybenzenesulfonic acid to inhibit cancer cell proliferation. Surprisingly, the inventive concept that polyphenol metabolites can be directly used in nutritional and / or pharmaceutical compositions to prevent and treat neurodegenerative diseases has not been proposed before. These objectives are achieved by the present invention.

[0010] Identified patents and other publications, for example those described in such publications prior to the filing date, are expressly incorporated herein by reference for the purpose of describing and disclosing methodology that might be used in connection with the present invention.

[0011] These facts are disclosed to explain the technical problem addressed by the present disclosure. Summary of the Invention

[0012] One aspect of the present disclosure relates to a compound of formula (I) or (II) or a pharma- ceutically acceptable salt thereof for use in the prevention or treatment of a neurodegenerative disease.

[0013] Another aspect of the invention relates to the non-therapeutic use of said compounds for maintaining and / or improving neurological and / or brain function, preferably as a food or nutritional composition.

[0014] Another aspect of the present disclosure relates to the use of polyphenol and phenolic metabolite compounds for preventing and / or treating neuroinflammatory and / or neurodegenerative diseases.

[0015] Therefore, in one embodiment, the present invention refers to a compound of formula (I) or (II), or its pharma- ceutically acceptable salt, or a composition for preventing and / or treating neuroinflammation and / or neurodegenerative disease.Surprisingly, it has been found that the compound of formula (I) or (II) has anti-inflammatory activity, can penetrate the blood-brain barrier (BBB), and can treat or prevent neuroinflammation, and therefore can treat or prevent neurodegenerative disease.

[0016] Advantageously, the compound or composition of the present invention comprises a very different approach from that currently used in the nutritional supplement and / or pharmaceutical industry to prevent and / or treat neurodegenerative diseases.The compound or composition of the present invention can greatly expand the number and nature of low cytotoxicity active compounds accessible to the BBB, thus increasing the variety of treatments available, including but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, brain tumors, epilepsy.

[0017] An embodiment of the present disclosure relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of a neuroinflammatory or neurodegenerative disease, [ka] Where: [R], A, and B are each independently selected, [R]n represents one radical R when n is 1, or n radicals R attached to different positions of the base ring when n is greater than 1, where each R is H, OH, CH 3 , C.H. 2 OH, OCH 3 , O.C.H. 2 CH 3 , O.S.O. 3 H, O.S.O. 3 CH 3 , O.S.O. 3 CH 2 CH 3 , F, Cl, Br, and I; n is 1, 2, or 3; A is CH 2 , CH(OH), CH(CH 3 ), C.H. 2 CH 2 , CH(CH 3 )CH 2 , C.H. 2 CH(CH 3 ), CH(OH)CH 2 , C.H. 2 CH(OH), (Z)CH=CH, (E)CH=CH, C(=O)NHCH 2 is a spacer selected from the group consisting of m is 0 or 1, B is C(=O)OH, OSO 3 H, and At least one, two, or three radicals R are OH.

[0018] In the present disclosure, formula (I) and formula (II) are equivalent, and formula (I) differs from formula (II) only by defining positions 1-6 of the aromatic ring. [ka]

[0019] Another aspect of the present disclosure relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of a neuroinflammatory or neurodegenerative disease, [ka] Where: [R], A, and B are each independently selected, [R]n represents one radical R when n is 1, or n radicals R attached to different positions of the base ring when n is greater than 1, where each R is H, OH, CH 3 , C.H. 2 OH, OCH 3 , O.C.H. 2 CH 3 , O.S.O. 3 H, O.S.O. 3CH 3 , O.S.O. 3 CH 2 CH 3 , F, Cl, Br, and I; n is 1, 2, or 3; A is CH 2 , CH(OH), CH(CH 3 ), C.H. 2 CH 2 , CH(CH 3 )CH 2 , C.H. 2 CH(CH 3 ), CH(OH)CH 2 , C.H. 2 CH(OH), (Z)CH=CH, (E)CH=CH, C(=O)NHCH 2 is a spacer selected from the group consisting of m is 0 or 1, B is C(=O)OH, OSO 3 H, and At least one, two, or three radicals R are OH; where B is C(=O)OH, R at position 5 is OSO 3 H and m=0.

[0020] In embodiments for better results, R is H, OH, OCH 3 , O.C.H. 2 CH 3 , O.S.O. 3 H, O.S.O. 3 CH 3 , O.S.O. 3 CH 2 CH 3 , F, Cl, Br, and I.

[0021] In an embodiment for better results, B is OSO 3 It's H.

[0022] In embodiments for better results, each R is H, OH, OCH 3 , O.S.O. 3H.

[0023] In an embodiment for better results, m is 0.

[0024] In an embodiment for better results, m is 1 and A is CH 2 , C.H. 2 CH 2 , CH(CH 3 )CH 2 , (Z)CH═CH or (E)CH═CH.

[0025] In an embodiment for better results, A is CH 2 CH 2 or (E) CH=CH.

[0026] In embodiments for better results, each R is OH, OCH 3 , O.S.O. 3 H, m is 0, and B is C(=O)OH, OSO 3 H, n is 1, 2 or 3, and at least one, two or three radicals R are OH.

[0027] In an embodiment for better results, at least one or two radicals R are OH.

[0028] In an embodiment for better results, R at positions 3 and 5 is OH.

[0029] In embodiments for better results, R at position 3 or 5 is OH.

[0030] In embodiments for better results, the compound is selected from the group consisting of 3-hydroxyphenyl hydrogen sulfate, 3,5-dihydroxyphenyl hydrogen sulfate, 3-hydroxy-4-methoxy-5-(sulfoxy)benzoic acid, or a salt thereof.

[0031] In embodiments for better results, the compound is 3,5-dihydroxyphenyl hydrogen sulfate, 3-hydroxyphenyl hydrogen sulfate, or a salt thereof.

[0032] In embodiments for better results, the compounds of the present disclosure can be used in any neurodegenerative disease that can be ameliorated or prevented by inhibiting the activation of the production of inflammatory cytokines, preferably the inflammatory cytokines are G-CSF, TNF-α, TGFβ1, IL-6, IL-10, IL-1β, IL-12, IL-18, IL23, CCL17, CCL22 and / or CXCL1.

[0033] In an embodiment for better results, the compounds of the present disclosure can be used in any neurodegenerative disease that is susceptible to be improved or prevented by inhibiting the activity of inflammatory transcription factors in brain immune innate immune cells. According to one embodiment, the brain immune innate immune cells are microglial cells. In another embodiment, the inflammatory transcription factor is NF-κB.

[0034] In embodiments for better outcomes, the compounds of the present disclosure may be used in neurodegenerative diseases that are susceptible to amelioration or prevention by decreasing the presence of TLR4 in the outer cell membrane.

[0035] In embodiments for better results, the compounds of the present disclosure may be used to prevent or treat Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, brain tumors or epilepsy.

[0036] Another aspect of the present disclosure relates to a composition for use in the prevention or treatment of neuroinflammatory or neurodegenerative diseases, comprising a therapeutically effective amount or a pharma- ceutically acceptable amount of at least one compound according to any of the above claims, and at least one pharma- ceutically acceptable vehicle and / or excipient and / or carrier. In one embodiment, the compound is 3,5-dihydroxyphenyl hydrogen sulfate or 3-hydroxyphenyl hydrogen sulfate, or a mixture thereof.

[0037] In embodiments for better results, the composition is in liquid, powder, dry or lyophilized form.

[0038] In an embodiment for better results, the composition includes at least another therapeutic agent as an active ingredient, preferably an anti-inflammatory agent.

[0039] In an embodiment for better results, the composition is in a solid form selected from a tablet, pill, hard capsule, powder or granules.In another embodiment, the composition is in a liquid form selected from a beverage, syrup, vial, drop or suspension.

[0040] Another aspect of the present disclosure relates to the use of any of the compounds or compositions described above as a medicament for maintaining and / or improving neurological and / or brain function. In a preferred embodiment, the compound is 3,5-dihydroxyphenyl hydrogen sulfate or 3-hydroxyphenyl hydrogen sulfate, or a mixture thereof.

[0041] In one embodiment, the compound or composition is used as a drug for reducing / decreasing neuroinflammation.In another embodiment, the compound or composition is used as a drug for maintaining and / or improving nerve and / or brain function.In one embodiment, the composition is a nutritional composition or a food composition.

[0042] The features and advantages of the present invention will become more apparent to those skilled in the art from the following detailed description of preferred embodiments of the invention, given as non-limiting examples with reference to the accompanying drawings, in which:

[0043] The following figures provide preferred embodiments to illustrate the disclosure and should not be considered as limiting the scope of the invention. [Brief description of the drawings]

[0044] [Figure 1] FIG. 1 shows the reduction in TNF-α release for phloroglucinol sulfate (3,5-dihydroxyphenyl hydrogen sulfate) and resorcinol sulfate (3-hydroxyphenyl hydrogen sulfate) after 2, 4 and 6 hours of preincubation followed by 24 hours of incubation with lipopolysaccharide. Compounds were tested at a concentration of 100 nM. Control: Basal levels of TNF-α after 2, 4 and 6 hours of preincubation with vehicle alone (phosphate buffered saline), i.e., buffer without phloroglucinol sulfate (3,5-dihydroxyphenyl hydrogen sulfate) and resorcinol sulfate (3-hydroxyphenyl hydrogen sulfate), followed by 24 hours of incubation with vehicle. [Diagram 2] Figure 2 shows the reduction of multiple cytokines including G-CSF, TNF-α, IL-6, IL-10, IL-1β, CCL17, IL-12p40, TGFβ1, CCL22, IL18, CXCL1 for phloroglucinol sulfate and resorcinol sulfate using 6 hours preincubation and 100 nM compound concentration followed by 24 hours of inflammation induction (inflammatory trigger) with lipopolysaccharide. Control: Basal levels of G-CSF, TNF-α, IL-6, IL-10, IL-1β, CCL17, IL-12p40, TGFβ1, CCL22, IL18, CXCL1 using 6 hours preincubation with vehicle alone (i.e., no phloroglucinol sulfate or resorcinol sulfate) followed by 24 hours incubation with vehicle. [Diagram 3] FIG. 3 shows reduction in multiple cytokines including TNF-α, CCL22, IL-10, IL-17, IL-1β, CXCL1, G-CSF, IL-6, IL-18, TGFβ1, IL23, IL-12p40, IL-12p70 for phloroglucinol sulfate and resorcinol sulfate using a 6 hour preincubation and compound concentration of 100 nM, followed by a 24 hour inflammatory stimulation with TNF-α 10 nM + IFNγ 1 nM. Control: Basal levels of TNF-α, CCL22, IL-10, CCL17, IL-1β, CXCL1, G-CSF, IL-6, IL-18, TGFβ1, IL23, IL-12p40, IL-12p70 using a 6-hour preincubation with vehicle alone (i.e., without phloroglucinol sulfate and resorcinol sulfate) followed by a 24-hour incubation with vehicle. [Figure 4] Figure 4 shows phloroglucinol-sulfate and resorcinol-sulfate treatment models: cells were subjected to an inflammatory trigger with lipopolysaccharide for 2 hours followed by compound incubation (100 nM) for 2, 4 and 6 hours. Control: Basal levels of TNF-α from cells pre-incubated with vehicle for 2 hours and then incubated with vehicle for 2, 4 and 6 hours. [Diagram 5] Figure 5 shows the protective effect of 24 h of metabolite pretreatment on (A) cell viability (metabolic capacity) and (B) ATP levels up to 24 h of MPP+, reducing damage caused by oxidative insults. Phloro‐Sulf: phloroglucinol sulfate, Resor‐Sulf: resorcinol sulfate. [Figure 6] Figure 6 shows the reduction of TLR4 in the outer cell membrane by compound incubation (100 nM) for up to 6 hours. Control: Basal levels of TLR4 in the outer cell membrane of cells incubated with vehicle for 6 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0046] Unless otherwise defined, scientific and technical terms used above and throughout the specification, such as, for example, "neurodegenerative," "neurological," "phenol," "polyphenol," "metabolite," "administration," "therapeutic," are intended to have the meanings commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0047] In this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an") and "at least one" can be used interchangeably herein. In some embodiments, the terms "a" or "an" mean "single". In other embodiments, the terms "a" or "an" include "two or more" or "multiple". Furthermore, as used herein, "and / or" is considered a specific disclosure of each of two particular features or components, with or without the other. Thus, the term "and / or" used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (single) and "B" (single).

[0048] The term "treatment" as used herein refers to both therapeutic treatment and prophylactic or preventative measures, where the purpose is to prevent or slow down an undesirable physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. Thus, patients in need of treatment include those who have already been diagnosed or are suspected of a disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reduction in the extent of a condition, disorder, or disease; a stable state of a condition, disorder, or disease; a delay in the onset or slowing down of the progression of a condition, disorder, or disease; an improvement or remission (whether partial or total) of a condition, disorder, or disease, whether detectable or undetectable; an improvement in at least one measurable physical parameter (not necessarily discernible by the patient); or an enhancement or improvement of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival in the absence of treatment.

[0049] The term "therapeutically effective amount" is meant to include an amount of a compound sufficient to prevent or alleviate to some extent the manifestation of one or more symptoms of the disorder, disease, or condition being treated when administered. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0050] The term "substantially pure" of an agent, compound, composition, or antibody, as used in the methods described herein, means that the agent, compound, composition, or antibody is purchased and / or prepared separated from components that normally accompany it.

[0051] The term "nutritional" as used herein refers to pharmaceutical grade and standardized nutrients, usually foods or food parts that provide health benefits. These can be categorized as dietary supplements, pre- and probiotics, polyunsaturated fatty acids, antioxidants, and other types of herbs and natural foods. Popular dietary supplements include ginseng, echinacea, green tea, glucosamine, omega-3, lutein, folic acid, and cod liver oil. Dietary supplements, being naturally occurring food parts, have fewer side effects and are less costly than man-made pharmaceuticals.

[0052] The terms "pharmaceutical pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutical acceptable" in the sense of being compatible with the other components of a pharmaceutical formulation (medicament) and suitable for use in contact with tissues or organs of humans and animals without undue toxicity, irritation, allergic reaction, immunogenicity, or other problems or complications, consistent with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004. The term "pharmaceutical composition" as used herein refers to a composition containing a compound described herein formulated with a pharma- ceutical acceptable excipient, which may be manufactured or sold with the approval of a government regulatory agency as part of a treatment regimen for the treatment of a disease in a mammal.

[0053] Thus, in a first embodiment, the present invention provides a compound according to the present invention comprising at least a therapeutically effective amount of a compound of formula (II): [ka] or a salt thereof, Where: [R]n is one radical R if n is 1, or n radicals R if n is greater than 1, each of which is attached to a different position of the basic ring, and each R is selected from the group consisting of H, OH, OCH, 3 , O.C.H. 2 CH 3 , O.S.O. 3 H, O.S.O. 3 CH 3 , O.S.O. 3 CH 2 CH 3 , F, Cl, Br, I, preferably OH, OCH 3 , O.S.O. 3 H; when n is 0, 1, 2 or 3, A is CH 2 , CH(OH), CH(CH 3 ), C.H. 2 CH 2 , CH(CH 3 )CH 2 , C.H. 2 CH(CH 3 ), CH(OH)CH 2 , C.H. 2 CH(OH), (Z)CH=CH, (E)CH=CH, C(=O)NHCH 2 , preferably CH 2 CH 2 , (E) a spacer selected from the group consisting of CH=CH, and when m is 0, 1, 2 or 3, B is OH, C(=O)H, C(=O)OH, OCH 3 , C(=O)OCH 3 , C(=O)OCH 2 CH 3 , O.S.O. 3 H, O.S.O. 3 CH 3 , O.S.O. 3 CH 2 CH 3 is selected from the group consisting of:

[0054] Particularly preferred substituents of [R]n are OH, OCH 3 , O.S.O. 3H, n is preferably 1, 2 or 3, m is 0, and A is preferably CH 2 CH 2 , (E) CH=CH, B is selected from C(=O)OH, OSO 3 H, O.S.O. 3 CH 3 , O.S.O. 3 CH 2 CH 3 , preferably C(=O)OH, OSO 3 H. Many such compounds exhibit antioxidant and anti-inflammatory activity. Any of the compounds may be included in the compositions claimed according to the philosophy of the present invention, and some preferred compounds are 3,4,5-trihydroxybenzoic acid, 2-hydroxybenzoic acid, ethyl 3,4,5-trihydroxybenzoate, 3-(3-hydroxy-4-methoxyphenyl)propanoic acid, 3-hydroxy-3-(3-hydroxyphenyl)propanoic acid, 3-(4-hydroxy-3-methoxyphenyl)propanoic acid, 3-hydroxy-4-methoxy-5-(sulfoxy)benzoic acid, benzoic acid, (E)-3-(3,5-dimethoxy-4-hydroxyphenyl)-2-propenoic acid, 3-hydroxy Benzoic acid, 3,5-dihydroxy-4-methoxybenzoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid, 3,4-dihydroxy-5-methoxybenzoic acid, 3,4-dihydroxybenzoic acid, 3-methoxy-4-(sulfoxy)benzoic acid, (E)-3-phenylprop-2-enoic acid or salts thereof, most preferably 3,4,5-trihydroxybenzoic acid, 2-hydroxybenzoic acid, 3,5-dihydroxyphenyl hydrogensulfate (phloroglucinol-O-sulfate), 2,6-dihydroxyphenyl hydrogensulfate, 3-hydroxyphenyl hydrogensulfate (resorcinol-O-sulfate), and salts thereof.

[0055] In another embodiment, the compositions of the present invention are useful for treating neurodegenerative diseases (neurodegenerative disorders) by inhibiting the activation of the production of pro-inflammatory cytokines, including G-CSF, TNF-α, TGFβ1, IL-6, IL-10, IL-1β, IL-12, IL-18, IL23, CCL17, CCL22 and CXCL1, preferably TNF-α, IL-6, IL-1β.

[0056] In yet another embodiment, the compositions of the invention are useful for treating neurodegenerative diseases by promoting the inactivation of proinflammatory transcription factors, including NF-kB, through the regulatory protein IkB-α.

[0057] In yet another embodiment, the compositions of the present invention are useful for treating neurodegenerative diseases by decreasing the presence of TLR4 receptors in the outer cell membrane.

[0058] Neurodegenerative disorders may include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, brain cancer, epilepsy, and frontotemporal dementia.

[0059] In another embodiment, the composition of the present invention can be used to prepare a dietary supplement or food for preventing neurodegenerative diseases by oral administration, the formulation being liquid, powder, dry or lyophilized.

[0060] The composition can be formulated using liposome or proteinoid encapsulation. Liposomal encapsulation can be used, and liposomes can be derivatized with various polymers. In general, the formulation includes inactive ingredients to protect the composition in the stomach environment and release biologically active substances in the intestine. The nutritional composition of the present invention can optionally include other botanical and / or herbal extracts to maintain, restore and improve health benefits.

[0061] In yet another aspect, the compositions of the present invention can be used to prepare pharmaceutical formulations for treating neurodegenerative disorders by oral administration, said formulations being solid, e.g., tablets, pills, hard capsules, liquid, e.g., beverages, syrups, vials, drops, and other dosage forms according to the art.

[0062] A pharmaceutical formulation (pharmaceutical preparation) can include a pharma- ceutically acceptable vehicle and / or excipient and / or carrier. Excipients can include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Representative excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0063] Those skilled in the art will understand the inherent possibility of using the compositions of the present invention in therapeutic combination with other anti-inflammatory agents. In other embodiments, the anti-inflammatory agent can include pharmaceutical non-steroidal and steroidal ones. Representative examples of non-steroidal anti-inflammatory agents include oxicams (piroxicam, isoxicam, tenoxicam, sudoxicam, etc.), salicylates (aspirin, disalcid, benolylate, trilysate, safaprin, solprin, diflunisal, fendosal, etc.), acetic acid derivatives (diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, ketorolac, etc.), fenamates (mefenamic acid, meclofenamic acid, etc.), salicyclics (aspirin, disalcid, benolylate, trilysate, safaprin, solprin, diflunisal, fendosal, etc.), acetic acid derivatives (diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, ketorolac, etc.), fenamates (mefenamic acid, meclofenamic acid, etc.), salicyclics (aspirin, disalcid, benolylate, trilysate, safaprin, solprin, diflunisal, fendosal, etc.), salicyclics (aspirin, disalcid, benolysate, trilysate, trilysate, trilys Nonsteroidal anti-inflammatory agents include, but are not limited to, propionic acid derivatives (ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miloprofen, tioxaprofen, suprofen, aluminoprofen, tiaprofenic acid, etc.), pyrazoles (phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethasone, etc.). Mixtures of these nonsteroidal anti-inflammatory agents may also be used.

[0064] Representative examples of steroidal anti-inflammatory agents include corticosteroids, such as hydrocortisone, hydroxytriamcinolone, α-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, deoxymethasone, deoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone a These include, but are not limited to, cetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolon, fludrocortisone, diflurozone diacetate, fluradrenolon acetonide, medrysone, amcinafide, amcinafide, balance of betamethasone and its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clesinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof.

[0065] The embodiments of the present invention are illustrated by the following examples, which should not be construed as limiting the scope of the present invention in any manner. On the contrary, it should be clearly understood that resort must be various other embodiments, modifications, and their equivalents that may suggest themselves to those skilled in the art after reading the description herein, without departing from the spirit of the present invention. In the tests described in the following examples, conventional procedures of medicinal chemistry and pharmacology were followed unless otherwise indicated. Some of the procedures are described below for the purpose of illustrating the effectiveness of the compositions of the present invention.

[0066] Working Example Materials and Methods: Solvents and chemicals were purchased and used substantially pure without further purification. Phenolic metabolites were purchased and used substantially pure without further purification and / or synthesis according to well-established chemical pathways known to those skilled in the art. Synthetic compounds were obtained as sodium salts and first dissolved in DMSO before dilution to final concentrations in the specific cell culture media.

[0067] CAS number: 72630-02-5 and the following structure: [ka] The better identified 3,5-dihydroxyphenyl hydrogen sulfate (phloroglucinol sulfate) was obtained from an in-house chemical synthesis.

[0068] Synthesis and characterization of 3,5-dihydroxyphenyl hydrogen sulfate. Phenol (phloroglucinol) and sulfur trioxide-pyridine were dissolved in anhydrous pyridine and stirred constantly at 65°C for 24 hours. The reaction was quenched by the addition of water. The solvent was removed under reduced pressure and the residue was dissolved in water. Unreacted starting material was separated with ethyl acetate and the product was purified on sodium loaded Dowex 50W-X8 ion exchange resin. The final residue was dried under reduced pressure and 1 H and 13 It was characterized by C NMR.

[0069] 3-Hydroxyphenyl hydrogen sulfate (resorcinol sulfate), better identified by the following structure, was obtained from in-house chemical synthesis. [ka]

[0070] Synthesis and characterization of 3-hydroxyphenyl hydrogen sulfate. Phenol (resorcinol) and sulfur trioxide-pyridine were dissolved in anhydrous pyridine and stirred constantly at 65° C. for 24 hours. The reaction was quenched by the addition of water. The solvent was removed under reduced pressure and the residue was dissolved in water. Unreacted starting material was separated with ethyl acetate and the product was purified on sodium-loaded Dowex 50W-X8 ion exchange resin. The final residue was dried under reduced pressure and 1 H and 13 It was characterized by C NMR.

[0071] The "N9" mouse microglial cell line was cultured in Eagle Minimum Essential Media (EMEM) supplemented with 10% (v / v) FBS, 200 nM L-glutamine, and 1% (v / v) NEAA at 37°C and 5% (v / v) CO. 2 The cells were maintained at 4°C for 24 hours. Experiments were performed in 24-well plates. Compounds were incubated in the cells for the indicated times (2, 4 or 6 hours) before addition of the indicated inflammatory stimuli (lipopolysaccharide (LPS) or TNFα:IFNγ).

[0072] LUHMES cells (a human dopaminergic cell line) were cultured in 5% (v / v) CO 2 The cells were cultured in Advanced DMEM-F12 (Dulbecco's Minimal Essential Media) at 37°C. Experiments were performed in 24-well plates. Compounds were incubated for 24 hours before the Parkinson's inducing toxin MPP+ was added to the cells.

[0073] A variety of immunoassay (immunoquantification) protocols for measuring the amount or activity of protein are known in the art. Examples of immunoquantification include, but are not limited to, radioimmunoassay, radioimmunoprecipitation, immunoprecipitation, fluorescence-activated cell sorting (FACS), ELISA (enzyme-linked immunosorbent assay), which are described in the literature (Enzyme Immunoassay, ET Maggio, ed., CRC Press, Boca Raton, Fla., 1980; Gaastra W., Enzyme-linked immunosorbent assay (ELISA), in Methods of Molecular Biology, Vol. 1, Walker JM ed., Humana Press, NJ, 1984).

[0074] The performance of the compounds to reach the brain was evaluated using an in silico approach. 3D structures were created in ChembioDraw (v.14.0, PerkinElmer, Waltham, MA, USA). These structures were first imported as mol files into the Maestro software package (version 2018-4, Schrodinger, New York, NY, USA). The structures were then processed with LigPrep (version 2018-4, Schrodinger) using the OPLS force field. We defined pH 7.4 ± 2.8 as the biologically relevant target pH using Epik (version 2018-4, Schrodinger). For each molecule, a set of molecular descriptors was created using QikProp (version 2018-4, Schrodinger). These molecular descriptors are relevant to predict drug-like molecules and molecules with the ability to reach the brain.

[0075] Example 1: Reduction of LPS-induced TNF-α production by phenolic metabolites in microglial cells. The experiments were performed in vitro using the N9 mouse microglial cell line. The phenolic metabolites or their derived metabolites were preincubated with microglial cells in cell culture medium at 5 micromolar for 6 hours. The cells were then washed and incubated with lipopolysaccharide for 24 hours. At the end of this period, the cell culture medium was harvested and analyzed for the presence of TNF-α using ELISA, with the results shown in Table 1.

[0076] [Table 1]

[0077] As seen in Table 1, several compounds were tested for their ability to attenuate TNFα release in microglial cells after 24 hours of lipopolysaccharide injury following 6 hours of preincubation at 5 micromolar. Phloroglucinol-sulfate and resorcinol-sulfate were selected based on their ability to attenuate TNFα release at low concentrations, i.e., concentrations below 100 nanomolar (data not shown).

[0078] Synthesis and characterization of compounds in Table 1: [ka] Phenol and sulfur trioxide-pyridine were dissolved in anhydrous pyridine and stirred constantly at 65°C for 24 hours. The reaction was quenched by the addition of water. The solvent was removed under reduced pressure and the residue was dissolved in water. Unreacted starting material was separated with ethyl acetate and the product was purified on sodium charged Dowex 50W-X8 ion exchange resin. The final residue was dried under reduced pressure and 1 H and 13 It was characterized by C nuclear magnetic resonance.

[0079] In one embodiment, the compounds resorcinol-sulfate and phloroglucinol-sulfate were pre-incubated with cells in cell culture medium at 100 nanomolar for 2, 4, and 6 hours. The cells were then washed and incubated with lipopolysaccharide for 24 hours. At the end of this period, the cell culture medium was harvested and analyzed for the presence of TNF-α using ELISA, showing results substantially as shown in Figure 1.

[0080] Example 2: Reduction of LPS-induced multiple cytokine production by phenolic metabolites in microglial cells The experiments were performed in vitro using the N9 mouse microglial cell line. The phenolic metabolites were pre-incubated in the cell culture medium at the indicated concentrations for 6 hours. The cells were then washed and incubated with lipopolysaccharide for 24 hours. At the end of this period, the cell culture medium was collected and analyzed for the presence of various cytokines using flow cytometry (LEGENDplex™ Mouse Macrophage / Microglia Panel), with results substantially as shown in Figure 2.

[0081] Example 3: Reduction of TNF-α- and IFN-γ-induced multiple cytokine production by phenolic metabolites in microglial cells The experiments were performed in vitro using the N9 mouse microglia cell line. The phenolic metabolites were pre-incubated in regular cell culture medium at the indicated concentrations for 6 hours. The cells were then washed and incubated with TNF-α 10 nM + IFNγ 1 nM for 24 hours. At the end of this period, the cell culture medium was collected and analyzed for the presence of various cytokines using flow cytometry (LEGENDplex™ Mouse Macrophage / Microglia Panel), with results substantially as shown in Figure 3.

[0082] Example 4: Therapeutic model for reducing LPS-induced TNF-α production by phenolic metabolites in microglial cells Experiments were performed in vitro using the N9 mouse microglial cell line. Cells were incubated with 300 ng / mL lipopolysaccharide. After 2 hours, phenolic metabolites were added to the cell culture medium at concentrations substantially as shown in Figure 4. Cell culture medium was harvested after 2, 4 and 6 hours and analyzed for the presence of TNF-α by ELISA.

[0083] Example 5: Effect of phenolic metabolites on cell viability and ATP concentration Using the human dopaminergic cell line "LUHMES", 2 Experiments were performed in vitro at 37 °C. Phenol metabolites were incubated at 5 μM for 24 h. After this period, cells were washed and incubated (or not) with MPP+ (1-phenyl-4-methylpyridinium ion) for 24 h to produce oxidative damage, mimicking the dopaminergic pathology found in some neurodegenerative diseases, namely Parkinson's disease brain. The cell medium was then replaced with fresh medium containing cell metabolic dyes: resazurin for 2 h or luciferase for 30 min. Color development was measured by fluorescence and luminescence, respectively, in a Synergy (Biotek) plate reader, with results substantially as shown in Figure 5.

[0084] Example 6: Reduction of TLR4 in the outer cell membrane The experiments were performed in vitro using the N9 mouse microglial cell line. Polyphenols and phenolic metabolites were pre-incubated for 6 h in regular cell culture medium. Afterwards, cells were washed and incubated with TLR4-PE antibody for 30 min. Afterwards, cells were washed and the amount of TLR4 in the cell membrane was measured by flow cytometry. The results are presented as a percentage of TLR4 relative to the control, as substantially shown in Figure 6.

[0085] Example 7: Brain Penetration Experiments were performed in silico using the Maestro software package (version 2018-4, Schrodinger, New York, NY, USA). For each molecule, a set of molecular descriptors was created using QikProp (version 2022-1, Schrodinger). These molecular descriptors are relevant to predict drug-like molecules and molecules with the ability to reach the brain. The overall performance of the molecules to reach the brain is reflected from the predicted partition coefficient between the brain and blood (logBrain / Blood) and from the Qikprop predicted permeability (nm / s) through the CACO cell line (QPPCACO) and the MDCK cell line (QPPMDCK). The compounds showed logBrain / blood in the range of recommended values ​​supported by Qikprop (-3.0 to 1.2), while the QPPCACO and QPPMDCK values ​​were above 0 nm / s (Table 2), indicating that these compounds could reach the brain.

[0086] [Table 2]

[0087] Whenever used in this document, the term "comprising" is intended to indicate the presence of stated features, integers, steps or components, but does not exclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0088] The present disclosure is not limited to the described embodiments, and those skilled in the art foresee many possibilities for its modification. The above-described embodiments can be combined.

[0089] When ranges are specified, the upper and lower limits of the range are inclusive. Unless otherwise indicated or clear from the context and / or the understanding of a technical expert, it should be understood that values ​​expressed as ranges can assume any particular value within the ranges set forth in the various achievements of the present invention, up to one-tenth of the value of the lower limit of the interval, unless the context clearly indicates the contrary. Also, unless otherwise indicated or clear from the context and / or the understanding of a technical expert, values ​​expressed as ranges can assume any subranges within the specified range, with the limits of the subranges being expressed to the same precision as one-tenth of the unit of the lower limit of the range.

[0090] The following dependent claims further describe particular embodiments of the present disclosure.

Claims

1. 1. A compound of formula (I): 【Chemistry 1】 A compound of the formula [R], A, and B are each independently selected; [R]n represents one radical R when n is 1, or n radicals R attached to different positions of the base ring when n is greater than 1, where each R is selected from the group consisting of OH, CH 3 , C.H. 2 OH, OCH 3 , OCH 2 CH 3 , OSO 3 H, OSO 3 CH 3 , OSO 3 CH 2 CH 3 , F, Cl, Br, and I; n is 1, 2, or 3; A is CH 2 , CH(OH), CH(CH 3 ), C.H. 2 CH 2 , CH(CH 3 ) CH 2 , C.H. 2 CH (CH 3 ), CH(OH)CH 2 , C.H. 2 CH(OH), (Z)CH=CH, (E)CH=CH, C(=O)NHCH 2 is a spacer selected from the group consisting of m is 0 or 1, B is C(=O)OH, OSO 3 H, and at least one, two, or three radicals R are OH; where, when B is C(=O)OH, R at position 5 is OSO 3 H and m=0; The compound, or a pharmaceutically acceptable salt thereof.

2. R is OH, OCH 3 , OCH 2 CH 3 , OSO 3 H, OSO 3 CH 3 , OSO 3 CH 2 CH 3 2. The compound for use according to claim 1, wherein each of the compounds is independently selected from the group consisting of F, Cl, Br, and I.

3. B is OSO 3 2. The compound for use according to claim 1, wherein H.

4. Each R is OH, OCH 3 , OSO 3 10. The compound for use according to claim 1, wherein each compound is independently selected from the group consisting of H.

5. 2. The compound for use according to claim 1, wherein m is 0.

6. m is 1 and A is CH 2 , C.H. 2 CH 2 , CH(CH 3 ) CH 2 2. The compound for use according to claim 1, wherein the compound is selected from the group consisting of (Z)CH=CH or (E)CH=CH.

7. A is CH 2 CH 2 or (E) CH=CH.

8. Each R is independently OH, OCH 3 , OSO 3 H, m is 0, B is C(=O)OH, OSO 3 H, n is 1, 2, or 3, and At least one, two or three of the radicals R are OH; 2. A compound for use according to claim 1.

9. 2. The compound for use according to claim 1, wherein at least one or two of the radicals R are OH.

10. 2. The compound for use according to claim 1, wherein R in positions 3 and 5 is OH.

11. 2. The compound for use according to claim 1, wherein R at position 3 or position 5 is OH.

12. 2. The compound for use according to claim 1, wherein the compound is selected from the group consisting of 3-hydroxyphenyl hydrogen sulfate, 3,5-dihydroxyphenyl hydrogen sulfate, 3-hydroxy-4-methoxy-5-(sulfoxy)benzoic acid, or salts thereof.

13. 2. The compound for use according to claim 1, wherein the compound is 3,5-dihydroxyphenyl hydrogen sulfate or 3-hydroxyphenyl hydrogen sulfate, or a salt thereof.

14. 2. A compound for use according to claim 1 for use in neurodegenerative diseases which can be ameliorated or prevented by inhibiting the activation of the production of inflammatory cytokines, preferably wherein the inflammatory cytokines are G-CSF, TNF-α, TGFβ1, IL-6, IL-10, IL-1β, IL-12, IL-18, IL23, CCL17, CCL22 and / or CXCL1.

15. 10. A compound for use according to claim 1 for use in a neurodegenerative disease that can be ameliorated or prevented by inhibiting the activation of inflammatory transcription factors in immune innate cells of the brain.

16. 16. The compound for use according to claim 15, wherein said brain immune innate cells are microglial cells.

17. 15. The compound for use according to claim 14, wherein the inflammatory transcription factor is NF-κB.

18. 2. A compound for use according to claim 1 for use in a neurodegenerative disease that can be ameliorated or prevented by reducing the presence of TLR4 in the outer cell membrane.

19. 10. The compound for use according to claim 1 for use in the prevention or treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, brain tumors, or epilepsy.

20. A composition for use in the prevention or treatment of neuroinflammatory or neurodegenerative diseases, comprising a therapeutically effective amount of at least one compound according to claim 1 and at least one pharmaceutically acceptable vehicle and / or excipient and / or carrier.

21. 21. The composition for use according to claim 20, wherein the compound is 3,5-dihydroxyphenyl hydrogen sulfate or 3-hydroxyphenyl hydrogen sulfate, or a mixture thereof.

22. 22. The composition of claim 21, wherein the composition is in liquid, powder, dry, or lyophilized form.

23. 21. The composition of claim 20, comprising as an active ingredient at least one further therapeutic agent, preferably an anti-inflammatory agent.

24. 21. The composition of claim 20, wherein the composition is in a solid form selected from a tablet, a pill, a hard capsule, a powder, or a granule.

25. 21. The composition of claim 20, wherein the composition is in a liquid form selected from a beverage, a syrup, a vial, drops, or a suspension.

26. Use of a compound or composition according to any one of claims 1 to 25 as a drug for maintaining and / or improving nerve and / or brain function.

27. 27. The use according to claim 26, wherein the compound of formula (I) is 3,5-dihydroxyphenyl hydrogen sulfate or 3-hydroxyphenyl hydrogen sulfate, or a mixture thereof.

28. 27. The use according to claim 26 as a medicament for reducing / decreasing neuroinflammation.

29. 27. Use according to claim 26 as a drug for maintaining and / or improving nerve and / or brain function.

30. 27. The use according to claim 26, wherein the composition is a nutritional supplement or a food composition.

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