Novel therapeutic methods for treating neurological diseases or conditions

Abstract

Novel therapeutic methods for the treatment of neurological diseases or conditions. The present invention relates to a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of a compound of formula (I) or any pharmaceutically or veterinarily acceptable salt thereof, for use in the treatment or prevention of a neurological disease or condition that leads to damage or degeneration of neurons, axons or myelin sheaths, wherein R1, R2 and R3 are as defined herein, where the treatment comprises a) a first period of time of 1 to 7 days, where a compound is administered to a subject in need thereof one or more times, and b) a second period of time equal to or longer than 13 days, where the compound is not administered, where the second period of time occurs after the first period of time and before the next administration of the compound.

Description

[0001] This application is a divisional application of patent application number 202080076585.9, entitled "A novel treatment method for treating neurological diseases or conditions". Technical Field

[0002] This invention relates to the pharmaceutical field. More specifically, this invention relates to the development of discontinuous treatment regimens for treating neurological diseases or conditions that result in the destruction or degeneration of neurons, axons, or myelin sheaths. Background Technology

[0003] Inflammatory neurological diseases or conditions that cause damage or degeneration of neurons, axons, or myelin sheaths can include, but are not limited to, various central nervous system (CNS) diseases, such as multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Balo's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis (i.e., Hurst's disease), and Marburg's disease (i.e., acute MS). Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), hereditary ataxia, or glaucoma. Optic neuropathy is a disease that damages the optic nerve, including optic neuritis, anterior ischemic optic neuropathy, Leber's disease, overt optic atrophy, or glaucoma, as well as toxic, traumatic, or tumor-related optic neuropathy.

[0004] MS is a degenerative autoimmune disease of the central nervous system (CNS) in which the immune system attacks and damages the myelin sheath protecting axons and nerve fibers, leading to significant disability. MS is characterized by demyelination, multifocal inflammation, reactive glial proliferation, and loss of oligodendrocytes and axons.

[0005] NMO (also known as Devic disease or Devic syndrome) or NMO spectrum disorder (NMOSD) is an autoimmune disease of the CNS in which immune system cells and antibodies mistakenly attack and destroy astrocytes in the optic nerve, brain, and spinal cord, leading to secondary demyelination and axonal loss. Damage to the optic nerve causes optic neuritis, which produces swelling and inflammation, resulting in pain and vision loss. Damage to the spinal cord can cause weakness or paralysis in the legs or arms, loss of sensation, and problems with bladder and bowel function. Because the two diseases have similar symptoms and can cause optic neuritis and myelitis, NMO can be confused with MS and was only recently considered a severe variant of MS. However, recent research has shown that NMO and MS are distinct diseases.

[0006] Optic neuritis is an inflammation of the optic nerve that causes demyelination. It can be caused by many different conditions, but it is commonly associated with MS and NMO. The inflammation can lead to vision loss or even blindness, usually due to swelling and destruction of the myelin sheath covering the optic nerve. Symptoms of optic neuritis include blurred vision, darkening of colors, pain when moving the eye, blind spots, and decreased contrast sensitivity.

[0007] Treatment of MS and other demyelinating diseases (including optic neuritis, myelitis, and neuromyelitis optica) involves three types of therapy: 1) Disease-modifying drugs (DMDs): designed to block the pathogenesis of the disease and alter the accumulation of disability; 2) Relapse treatment: designed to shorten the duration of relapse and reduce residual disability; 3) Symptomatic treatment: designed to improve symptoms caused by MS disability (such as pain, cramps, bladder symptoms, etc.).

[0008] For DMD in MS, all currently approved therapies are for chronic (long-term) use, requiring different administration regimens depending on the drug or method of administration: 1) Daily oral administration (fingolimod, simpomod, ozamod, dimethyl fumarate, and teriflunomide) (except for chemotherapy (mitoxantrone or cladribine), which is administered for only a few days), then continuing for several years; 2) Subcutaneous administration daily or every few days (interferon beta, glatiramer acetate); 3) Intravenous administration every few months (1-6-12) based on mechanism of action (MoA) (natezumab, rituximab, ozogizumab, alemtuzumab, dacrolimus, ofamumumab). These are all monoclonal antibodies (MABs) that work by depleting immune cell populations or inhibiting T cell migration. All of these drugs are immunomodulatory therapies, and none have definitively proven primary neuroprotective activity (secondary neuroprotection is a result of their immunomodulatory activity preventing inflammation by preventing damage to the central nervous system (CNS)). Some drugs (chemotherapy and monoclonal antibodies) are not used for long periods because their MoA far exceeds their exposure (e.g., by reducing specific immune cell populations that take months to recover from the bone marrow).

[0009] Regarding the treatment of relapse: There are currently no approved medications for treating relapse, but the standard of care (SoC) is intravenous methylprednisolone or oral high-dose prednisone (1 g / day for 3–5 days). Corticosteroid treatment exerts immunomodulatory activity to stop inflammation but has not shown neuroprotective effects. For this reason, the disability has not been altered.

[0010] Regarding symptomatic treatment, a variety of medications are available to improve MS symptoms. Almost all of these are oral medications administered long-term (daily) to prevent these symptoms. Several such medications (phenytoin, amiloride, aminopyridine, epigallocatechin gallate) and neuroprotective agents (for long-term use) have been explored, but none have been proven to alter the course of the disease (MS disability or relapse).

[0011] Therefore, there are currently no approved neuroprotective drugs for MS or as SoC. Current drugs are immunomodulatory (the claim of neuroprotection is due to secondary neuroprotective activity, i.e., less inflammation means less damage). Pulsating drugs involve corticosteroids or chemotherapy, and due to their MoA (MoA), their effects extend beyond the exposure.

[0012] In addition, current treatments are associated with significant side effects, such as adverse immune responses or serious opportunistic infections.

[0013] On the other hand, these diseases or conditions that cause damage or degeneration of neurons, axons, or myelin sheaths often follow a "hit-and-run" model, where the damage has a short duration (e.g., ischemia, inflammation, trauma), but the damage increases over weeks to months, increasing patient disability and reducing quality of life. For this reason, there is a need for treatments that provide prolonged and sustained efficacy.

[0014] WO2012028959 discloses neuroprotective peptides that have shown efficacy in preventing neuronal and axonal loss and protecting myelin sheaths in vitro and in animal models, which is associated with better clinical outcomes in models such as multiple sclerosis, optic neuritis, and glaucoma. However, the literature does not mention the in vivo effects of the compounds over time.

[0015] Therefore, there is a need in the art for novel methods that can treat these types of neurological diseases or conditions with prolonged and sustained efficacy while reducing side effects. Summary of the Invention

[0016] The inventors have discovered that when the neuroprotective peptides disclosed in WO2012028959 are administered for a short period (e.g., about 5 to 7 days) in an animal model of acute optic neuritis (AON) characterized by increased demyelination, increased axonal loss in the optic nerve, and a significant reduction in the number of retinal ganglion cells in the retina of the eye, they not only show the expected efficacy in the short term, but also exhibit remarkable efficacy in the long term (up to one month).

[0017] This is illustrated in the following example ( Figure 6-8Specifically, the results showed that short-term administration of peptide BN201 (i.e., ([N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N-(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl]glycamide) at a dose range of 10-70 mg / kg / day for 6 days, whether intraperitoneally (IP) or intravenously (IV), protected axons from damage. Short-term (7 days) administration of this peptide also demonstrated its effectiveness. Figure 5 ) injury and long-term (up to 28 days after injury, Figure 8 This damages both. In fact, this efficacy even increases at later time points. Furthermore, compared to the untreated group, BN201 treatment resulted in a short-term decrease in retinal ganglion cell and demyelinating scores. Figure 3-4 ) and long-term ( Figure 6-7 Both showed significant improvement.

[0018] From a clinical perspective, these results are crucial because, as mentioned above, the damage in these diseases can develop over weeks to months. Therefore, the prolonged and sustained efficacy shown by the neuroprotective peptides disclosed in WO2012028959 allows for discontinuous treatment regimens, which include short periods of efficacy with drug administration followed by long periods of efficacy without drug administration (the extension of which far exceeds the drug's half-life (8 hours)).

[0019] Compared to exposure to the same drug throughout the entire course of disability development, reduced drug exposure leads to fewer side effects, which improves safety and patient adherence to treatment regimens.

[0020] Furthermore, the discontinuous treatment regimen of this invention, which involves a prolonged period of no administration before the next dose, improves patient compliance, thereby enhancing adherence and treatment effectiveness. Typically, patients receive treatment during acute injury while hospitalized and benefit for an extended period afterward without requiring additional injections or administrations.

[0021] Phosphorylation events are very brief (10-30 minutes) and binding to the receptor extends use to less than a day because, in addition to the fact that target binding is not permanent and the dissociation constant can be very short, the receptor is also internalized and degraded.

[0022] It has been shown that BN201 activates the serum glucocorticoid (SGK) pathway, including phosphorylation of several of its targets, such as Foxo3 or NDRG1. This activation triggers trophic factor pathways, leading to changes in gene expression patterns over the following days. As observed in a Phase 1 trial in healthy volunteers, BN201 has a half-life of up to 8 hours in humans. Assuming active transport to the CNS, lack of drug accumulation, and rapid drug clearance are observed in the same Phase 1 trial, it is unlikely that BN201 exposure will be prolonged by more than one day after the last administration (day 6).

[0023] Unbound by theory, the unexpected results show that activation of the SGK pathway triggers changes that last for weeks, altering cellular phenotypes (far beyond drug-induced specific molecular events). This effect is likely mediated by the expression of multiple genes associated with the SGK pathway, which translate into proteins and produce this beneficial cellular phenotype in neurons, astrocytes, oligodendrocytes, and / or microglia.

[0024] Therefore, a first aspect of the present invention relates to a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof for the treatment or prevention of a neurological disease or condition resulting in the destruction or degeneration of neurons, axons, or myelin sheaths, or any stereoisomer or mixture of stereoisomers of said compound (I) or any pharmaceutically or veterinarily acceptable salt thereof.

[0025] (I) in: R1 is a phenyl group substituted with a halogen or trifluoromethyl group, and is further optionally substituted with one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkyl groups; or, R1 is pyrrolid-1-yl. R2 is 2-oxo-pyrrolidone-1-ylmethyl or aminosulfonylphenyl; and R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; The treatment mentioned above includes: a) During the first time period of 1 to 7 days, the compound was administered to subjects who required it once or multiple times, and b) A second time period equal to or longer than 13 days, during which the compound is not applied, wherein the second time period occurs after the first time period and before the next application of the compound.

[0026] Therefore, this aspect relates to the use of compounds of formula (I) as defined above, or derivatives thereof, in the preparation of medicaments for treating neurological diseases or conditions that cause damage or degeneration of neurons, axons, or myelin sheaths, wherein said treatment includes: a) During the first time period of 1 to 7 days, the compound was administered to subjects who required it once or multiple times, and b) A second time period equal to or longer than 13 days, during which the compound is not applied, wherein the second time period occurs after the first time period and before the next application of the compound.

[0027] Alternatively, this aspect can also be configured as a method for treating neurological diseases or conditions that cause damage or degeneration of neurons, axons, or myelin sheaths, said method comprising: a) A first time period of 1 to 7 days, during which the compound is administered once or multiple times to subjects in need (including mammals, particularly humans), and b) A second time period equal to or longer than 13 days, during which the compound is not applied, wherein the second time period occurs after the first time period and before the next application of the compound.

[0028] The compounds of the present invention can be formulated in a composition together with excipients or carriers. Therefore, a second aspect of the present invention relates to a pharmaceutical or veterinary composition for treating or preventing neurological diseases or conditions resulting in damage or degeneration of neurons, axons, or myelin sheaths, comprising a therapeutically effective amount of a compound of formula (I) or a derivative thereof as defined above, and one or more pharmaceutically or veterinarily acceptable excipients or carriers. The treatment mentioned above includes: a) During the first time period of 1 to 7 days, the compound was administered to subjects who required it once or multiple times, and b) A second time period equal to or longer than 13 days, during which the compound is not applied, wherein the second time period occurs after the first time period and before the next application of the compound. Attached Figure Description

[0029] Figure 1 The plasma drug concentrations in rats were assessed on day 7 after daily intraperitoneal (IP) administration of BN201 at different doses (10 mg / Kg, 25 mg / Kg and 70 mg / Kg) for 6 days.

[0030] Figure 2 The plasma drug concentrations in rats were assessed on day 7 after intravenous (IV) administration of BN201 at a dose of 25 mg / kg daily for 6 days.

[0031] Figure 3The number of retinal ganglion cells in an animal model of acute optic neuritis (AON) is shown on day 7 for the sham-operated group (healthy), the route (ill-sick, untreated) control group, and the pathological group treated daily with different doses (mpk=mg / Kg) of BN201 via intraperitoneal (IP) or intravenous (IV) administration. The p-value is 0.05; The p-value is 0.001.

[0032] Figure 4 The demyelination score (grades: 0-4) in AON was assessed on day 7 for the sham surgery group (healthy), the route (illness, untreated) control group, and the pathology group treated with BN201 intraperitoneally (IP) or intravenously (IV) daily at different doses (mpk=mg / Kg).

[0033] Figure 5 The axonal loss score (grades: 0-4) in AON assessed on day 7 is shown for the sham-operated group (healthy), the route (illness, untreated) control group, and the pathology group treated daily with different doses (mpk=mg / Kg) of BN201 intraperitoneally (IP) or intravenously (IV). The p-value is 0.05. The p-value is 0.001.

[0034] Figure 6 The number of retinal ganglion cells (RGCs) in AONs assessed on days 7, 14, and 28 is shown for the sham-operated group (healthy), the route (illness, untreated) control group, and the pathology group treated daily with different doses (mpk = mg / kg) of BN201 via intraperitoneal (IP) or intravenous (IV). By day 28, the RGC count in the 25 mpk group was significantly higher than that in the placebo group (p < 0.05).

[0035] Figure 7 The demyelination score (grades: 0–4) in AON assessed on days 7, 14, and 28 is shown for the sham-operated group (healthy), the route (illness, untreated) control group, and the pathology group treated daily with different doses (mpk = mg / kg) of BN201 via intraperitoneal (IP) or intravenous (IV). By day 28, the demyelination score counts in the 10 mpk and 25 mpk groups were significantly lower than those in the placebo group (p<0.05).

[0036] Figure 8The axonal loss scores (grades: 0–4) in AON assessed on days 7, 14, and 28 are shown for the sham-operated group (healthy), the route (illness, untreated) control group, and the pathology group treated daily with different doses (mpk = mg / kg) of BN201 via intraperitoneal (IP) or intravenous (IV). By day 28, the axonal loss scores in the 10 mpk and 25 mpk groups were significantly lower than those in the placebo group (p < 0.05).

[0037] Figure 9 Histopathological images of the optic nerve stained with Luxol blue (LFB) in AON assessed on day 14 from the group 1-pathology group (disease- and untreated) and the group 1 pathology group treated with BN201 intraperitoneally (IP) for 6 days at 10 mg / Kg or 25 mg / Kg daily, to assess demyelination at different magnifications: 10X (left) and 20X (right).

[0038] Figure 10 Histopathological images of the optic nerve stained with Luxol blue (LFB) in AONs evaluated on day 28 from the group 1-pathology group (disease- and untreated) and the group 1 pathology group treated with BN201 intraperitoneally (IP) for 6 days at 10 mg / Kg or 25 mg / Kg daily, to assess demyelination at different magnifications: 10X (left) and 20X (right).

[0039] Figure 11 Histopathological images of the optic nerve stained with Bielschowsky's silver immersion staining (BSS) are shown in the AON pathology group assessed on day 14 from the group 1-pathology group (disease- and untreated) and the group 1 pathology group treated with BN201 intraperitoneally (IP) for 6 days at 10 mg / Kg or 25 mg / Kg daily, to assess axonal density at different magnifications: 10X (left) and 20X (right).

[0040] Figure 12 Histopathological images of the optic nerve stained with Bielschowsky's silver immersion staining (BSS) are shown in the AON pathology assessment at day 28 from the group 1-pathology group (disease- and untreated) and the group 1 pathology group treated with BN201 intraperitoneally (IP) for 6 days at 10 mg / Kg or 25 mg / Kg daily, to assess axonal density at different magnifications: 10X (left) and 20X (right). Detailed Implementation

[0041] Unless otherwise stated, all terms used in this application shall be understood in their ordinary meaning as known in the art. Other more specific definitions of certain terms used in this application are set forth below and are intended to be applied uniformly throughout the specification and claims, unless otherwise expressly stated that a broader definition is provided.

[0042] As used herein, the terms “about” or “approximately” refer to a range of values ​​within ±10% of a specified value. For example, the expression “about 10” or “approximately 10” includes ±10% of 10, that is, 9 to 11.

[0043] Compound of formula (I) As described above, the present invention relates to a novel treatment regimen comprising administering a compound of formula (I) or a derivative thereof as described herein.

[0044] For the purposes of this invention, the terminology (C1-C) n Alkyl groups refer to saturated branched or straight-chain hydrocarbon chains containing 1 to n carbon atoms and consisting only of single bonds. (C1-C2) n Non-limiting examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, etc.

[0045] Terminology (C1-C) n Alkoxy groups are those connected to the rest of the molecule or another group via an oxygen atom, as previously defined (C1-C2). n Alkyl group. (C1-C) n Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0046] The term halogenation (C1-C) n Alkyl groups refer to compounds in which some or all of their hydrogen atoms are substituted with fluorine, chlorine, bromine, and / or iodine, as previously defined (C1-C4). n alkyl. Halogenated (C1-C2) n Non-limiting examples of alkyl groups include chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc.

[0047] Halogen substituents refer to fluorine, chlorine, bromine, or iodine.

[0048] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is fluorophenyl, more particularly 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl, and even more particularly 2-fluorophenyl.

[0049] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a fluorophenyl further substituted with one or two substituents selected from halogens, (C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl; in particular, R1 is a fluorophenyl further substituted with one or two substituents selected from halogens, (C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkyl; even more particularly, R1 is a fluorophenyl further substituted with one or two substituents selected from halogens, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0050] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is chlorophenyl, more particularly 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl, and even more particularly, R1 is 2-chlorophenyl.

[0051] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a chlorophenyl further substituted with one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkyl; in particular, R1 is a chlorophenyl further substituted with one or two substituents selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy and halo(C1-C4)alkyl; even more particularly, R1 is a chlorophenyl further substituted with one or two substituents selected from halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0052] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is bromophenyl, more particularly 2-bromophenyl, 3-bromophenyl or 4-bromophenyl, more particularly 2-bromophenyl.

[0053] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a bromophenyl further substituted with one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkyl; in particular, R1 is a bromophenyl further substituted with one or two substituents selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy and halo(C1-C4)alkyl; even more particularly, R1 is a bromophenyl further substituted with one or two substituents selected from halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0054] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is iodophenyl, more particularly 2-iodophenyl, 3-iodophenyl or 4-iodophenyl, and even more particularly 2-iodophenyl.

[0055] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is an iodophenyl further substituted with one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkyl; in particular, R1 is an iodophenyl further substituted with one or two substituents selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy and halo(C1-C4)alkyl; more particularly, R1 is an iodophenyl further substituted with one or two substituents selected from halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0056] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is trifluoromethylphenyl, more particularly 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or 4-trifluoromethylphenyl, and even more particularly 2-trifluoromethylphenyl.

[0057] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a trifluoromethylphenyl further substituted with one or two substituents selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkyl; in particular, R1 is a trifluoromethylphenyl further substituted with one or two substituents selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy and halo(C1-C4)alkyl; more particularly, R1 is a trifluoromethylphenyl further substituted with one or two substituents selected from halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0058] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is pyrrolidine-1-yl.

[0059] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R2 is 2-oxo-pyrrolidine-1-yl-methyl.

[0060] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R2 is aminosulfonylphenyl, more particularly 2-aminosulfonylphenyl, 3-aminosulfonylphenyl or 4-aminosulfonylphenyl, and even more particularly 4-aminosulfonylethyl.

[0061] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R3 is 2-methylpropyl.

[0062] In another embodiment, optionally combined with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is 2-fluorophenyl or pyrrolidine-1-yl, and R2 is 2-oxo-pyrrolidine-1-ylmethyl or 4-aminosulfonylphenyl.

[0063] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the compound of formula (I) is selected from G79 ([N-(2-(2'-fluorophenyl)ethyl)-glycyl]-[N-(2-methylpropyl)-glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl]glycamide, BN201, chemical formula: C 25 H38 FN5O4; MW (molecular weight) 491.5987), G-80 ([N-(2-(2'-fluorophenyl)ethyl)-glycyl]-[N-(2-methyl-propyl)glycyl]-N-[2-(4'-aminosulfonyl-phenyl)ethyl]glycamide, BN119, chemical formula: C 26 H 36 FN5O5S; MW 549.658), and G81 ([N-(2-(1-pyrrolyl)ethyl)-glycyl]-[N-(2-methyl-propyl)glycyl]-N-[2-(4'-aminosulfonyl-phenyl)ethyl]glycamide, BN120, chemical formula: C 24 H 40 N6OS; MW524.6766):

[0064] Compounds of formula (I) can be prepared as disclosed in WO2012028959.

[0065] There are no restrictions on the types of salts of compounds of formula (I) that may be used, provided that they are pharmaceutically or veterinarily acceptable when used for therapeutic purposes. The term "pharmaceutically or veterinarily acceptable salt" includes salts commonly used to form alkali metal salts and salts commonly used to form addition salts of free acids or free bases. The preparation of pharmaceutically or veterinarily acceptable salts of compounds of formula (I) can be carried out by methods known in the art. For example, they can be prepared by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts are prepared, for example, by reacting the free acidic or basic form of a compound of formula (I) with a stoichiometric amount of a suitable pharmaceutically or veterinarily acceptable base or acid in water or an organic solvent, or in a mixture thereof. Compounds of formula (I) and their corresponding salts may differ in some physical properties, but they are equivalent for the purposes of this invention.

[0066] The compounds of this invention can be in crystalline form as free solvated compounds or solvates (e.g., hydrates), both of which are intended to be within the scope of this invention. Solvation methods are generally known in the art. Typically, for the purposes of this invention, a solvated form having a pharmaceutically, cosmetically, or veterinarily acceptable solvent, such as water, ethanol, etc., is equivalent to a non-solvated form.

[0067] Some compounds of the present invention may have chiral centers capable of producing a variety of stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of a single compound that differ only in the spatial orientation of their atoms. The term stereoisomer includes mirror-image isomers (enantiomers), mixtures of mirror-image isomers (racemic mixtures), geometric (cis / trans or cis / trans or E / Z) isomers, and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers). The present invention relates to each of these stereoisomers and mixtures thereof.

[0068] Diastereomers and enantiomers can be separated using conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved using conventional optical resolution techniques to obtain optically pure isomers. This resolution can be performed on any chiral synthetic intermediate or the compound of this invention. Optically pure isomers can also be obtained individually using enantiospecific synthesis.

[0069] In all embodiments involving a compound of formula (I), a pharmaceutically or veterinarily acceptable salt thereof, as well as a stereoisomer or mixture of stereoisomers of any compound of formula (I) or any pharmaceutically acceptable salt thereof, shall always be considered, unless otherwise specifically mentioned.

[0070] Drug and veterinary drug combinations Compounds of formula (I) may form part of a pharmaceutical or veterinary composition. A pharmaceutical or veterinary composition used in this invention comprises: a therapeutically effective amount of a compound of formula (I) as previously defined, or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof; together with one or more pharmaceutically or veterinarily acceptable excipients or carriers.

[0071] As used herein, the term "therapeuticly effective amount" refers to an amount of compound, when applied, sufficient to prevent the development of one or more symptoms of the treated disease or to alleviate, to some extent, one or more symptoms of the treated disease. The specific dosage of the compounds of this invention used to obtain therapeutic benefit can vary depending on the specific circumstances of the individual patient, including the patient's size, weight, age, and sex, the nature and stage of the disease, the invasiveness of the disease, and the route of administration.

[0072] The phrase "pharmaceutical or veterinary acceptable excipient or carrier" refers to a pharmaceutically or veterinary acceptable material, composition, or medium. Each component must be pharmaceutically or veterinary acceptable in the sense of compatibility with other components of a drug or veterinary drug composition. It must also be suitable for contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0073] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the pharmaceutical or veterinary composition is a solution of a compound of formula (I) as previously defined in saline (NaCl). More particularly, it is a 2 mg / mL or 5 mg / mL solution of a compound of formula (I) as previously defined in saline (NaCl).

[0074] Treatment plan As described above, the treatment regimen of the present invention includes administering a compound of formula (I) or a composition containing it, as previously defined, to a subject in need once or multiple times during a first time period of 1 to 7 days, and then discontinuing administration for a period of 13 days or longer.

[0075] For the purposes of this invention, the term "multiple times" means more than once.

[0076] In one embodiment, the term is optionally combined with one or more features of the various embodiments described above or below throughout the specification. The term "repeatedly" means from 2 to 42 times, and more particularly, means 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20, 21, 22, 24, 26, 27, 28, 30, 32, 34, 36, 38, 40, or 42 times.

[0077] The expressions "once a day," "once a day," and "once a day" are used interchangeably, meaning that only one dose of the drug is administered in a single day.

[0078] The treatment regimen of the present invention includes a first time period (when the drug is applied, i.e., the drug application period) and a second time period before the drug is applied again (when the drug is not applied, i.e., the drug-free period). Therefore, once the second time period without drug application has ended, the drug is applied at least once more. In one embodiment, optionally in combination with one or more features of the various embodiments described throughout the specification above or below, the treatment regimen of the present invention includes two or more, more particularly 2, 3, 4, 5, 6, 7, 8, 9, or 10 application periods, with corresponding drug-free periods in between.

[0079] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the treatment of the present invention is a cyclical treatment comprising repeating steps a) and b).

[0080] For the purposes of this invention, the term "treatment" refers to a neurological disease or condition that results in the destruction or degeneration of neurons, axons, or myelin sheaths, meaning that when a drug is used on a subject who exhibits or has exhibited symptoms or signs of a disease onset, it slows, stabilizes, or inhibits the progression of the disease / condition. The term "treatment" also includes those patients with a high risk of developing a full-blown disease or condition in the absence of a clinical history of the disease or condition, such as patients with radiologically isolated syndrome (RIS) showing brain damage on magnetic resonance imaging (MRI) or patients undergoing planned brain surgery, endarterectomy, or other endovascular procedures. For example, treatment can refer to reducing the accumulation of disability in a subject in need. In some embodiments, treatment can also refer to providing neuroprotection, an immunomodulatory response, or some combination thereof.

[0081] The term “prevention” may be used interchangeably with the term “preventive treatment”, referring to the prophylactic administration of a compound of formula (I) or a combination thereof to a subject, including the prevention of the onset, recurrence or spread of a disease or condition, or one or more symptoms thereof.

[0082] In this invention, the terms "patient" and "subject" are used interchangeably.

[0083] There are no limitations on the application regimen for step a) that can be used according to the invention, provided that the compound or composition of formula (I) as previously defined is applied once or more over a period of 1 to 7 days. Thus, the compound or composition of formula (I) as previously defined can be applied only once, or it can be applied more than once over a period of 1 to 7 days according to different application regimens. Non-limiting examples of such application regimens include every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), every 12 hours (Q12h), once a day, twice a day, three times a day, four times a day, every day, once every two days, every three days, etc.

[0084] In one implementation, optionally combined with one or more features of various implementations described above or below throughout the specification, the first time period of step a) is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, or 6 to 7 days.

[0085] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the compound or composition containing it, as previously defined, is applied multiple times during a first time period of 1, 2, 3, 4, 5, 6 or 7 days (more particularly, a time period of 6 or 7 days) in step a).

[0086] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in step a), the compound of formula (I) as previously defined, or a composition comprising it, is applied multiple times. More specifically, the compound is applied every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), every 12 hours (Q6h), once a day, twice a day, three times a day, four times a day, once a day, every two days, or every three days.

[0087] In a more specific implementation, it is applied daily, and more specifically, once daily, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h).

[0088] In another, more specific embodiment, it is applied every two or three days. Even more specifically, on the day of application, the compound of formula (I) or a composition containing it is applied once daily, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h).

[0089] In another embodiment, the compound or composition of formula (I) as previously defined is administered once daily for 6 or 7 days, optionally in combination with one or more features of the various embodiments described above or below throughout the specification.

[0090] As described above, the second period of non-application of the compound in step b) is equal to or longer than 13 days. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of non-application of the compound is from 13 days to one year (12 months).

[0091] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of time without compound application is 13 days to 3 months.

[0092] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of time during which the compound is not applied is 13 days to 1 month.

[0093] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of time during which the compound is not applied is equal to or longer than 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 37, 41, 44, 48, 51, 55, 58, 62, 69, 76, 83, 84, 85, 86, 87, 88, 89, or 90 days. More specifically, the second period of time is 21 or 22 days.

[0094] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of time during which the compound is not applied is 13 to 20 days, 13 to 21 days, 13 to 22 days, 13 to 23 days, 13 to 24 days, 13 to 25 days, 13 to 26 days, 13 to 27 days, 13 to 28 days, 13 to 29 days, 13 to 30 days, 13 to 34 days, 13 to 41 days, 13 to 48 days, 13 to 55 days, 13 to 62 days, 13 to 69 days, 13 to 76 days, 13 to 83 days, 13 to 84 days, 13 to 85 days, 13 to 86 days, 13 to 87 days, 13 to 88 days, 13 to 89 days, or 13 to 90 days.

[0095] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of time during which the compound is not applied is 13 to 358 days, 13 to 359 days, 13 to 360 days, 13 to 361 days, 13 to 362 days, 13 to 363 days, 13 to 364 days, or 13 to 365 days.

[0096] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the second period of time during which the compound is not applied is equal to 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, 15 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0097] In one embodiment, optionally combined with one or more features of the various embodiments described above or below throughout the specification, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is equal to or longer than 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 37, 41, 44, 48, 51, 55, 58, 62, 69, 76, 83, 84, 85, 86, 87, 88, 89, or 90 days, more specifically, the second time period is 21 or 22 days.

[0098] In one embodiment, optionally combined with one or more features of various embodiments described above or below throughout the specification, the first time period being 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound being 13 to 20 days, 13 to 21 days, 13 to 22 days, 13 to 23 days, 13 to 24 days, 13 to 25 days, 13 to 26 days, 13 to 27 days, or 13 to 28 days.

[0099] In one embodiment, optionally combined with one or more features of the various embodiments described above or below throughout the specification, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is equal to 13 days, meaning that the compound or composition thereof of formula (I) as previously defined will be applied every 2 weeks; or, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is equal to 20 days, meaning that the compound or composition thereof of formula (I) as previously defined will be applied every 3 ... The first time period is 2 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is equal to 27 days, which means that the compound or composition thereof of formula (I) as previously defined is applied every 4 weeks; or, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is equal to 34 days, which means that the compound or composition thereof of formula (I) as previously defined is applied every 5 weeks; or, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is equal to 41 days, which means that the compound or composition thereof of formula (I) as previously defined is applied every 6 weeks. In a more specific embodiment, the compound or composition is applied daily, more specifically, once daily, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h). In another, more specific embodiment, the compound or composition is applied every two or three days during the first time period. More specifically, on the day of application, it is applied daily, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h).

[0100] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is 27 to 30 days, which means that the compound or composition thereof as previously defined is applied once a month; or, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is 89 to 91 days, which means that the compound or composition thereof as previously defined is applied every 3 months; or, the first time period is 2 to 7 days, 3 to 7 days, 4 to 7 days, 5 to 7 days, 6 to 7 days, or 7 days, and the second time period without application of the compound is 364 to 365 days, which means that the compound or composition thereof as previously defined is applied once a year. In one more specific embodiment, the compound or composition is applied daily, more specifically, once daily, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h). In another more specific embodiment, the compound or composition is applied every two or three days during a first time period. More specifically, on the day of application, it is applied once daily, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h).

[0101] In another embodiment, the compound or composition of formula (I) as previously defined is administered intravenously, optionally in combination with one or more features of the various embodiments described above or below throughout the specification.

[0102] In another embodiment, the compound or composition of formula (I) as previously defined may be administered intraperitoneally, optionally in combination with one or more features of the various embodiments described above or below throughout the specification.

[0103] The compound of formula (I) can be administered to mice at doses from 0.5 mg / kg to 200 mg / kg according to the treatment regimen of the present invention, which correspond to a human equivalent dose (HED) from 0.04 mg / kg to 16.26 mg / kg [HED calculations throughout this description are based on industry guidance estimates of the maximum safe starting dose in initial clinical trials for treatment in healthy adult volunteers; FDA, CDER, July 2005].

[0104] Therefore, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the compound or composition of formula (I) as previously defined is administered in the human body once or alternatively daily at a dose equivalent to the dose in mice: 0.5 to 200 mg / Kg, more particularly 2 to 100 mg / Kg, even more particularly 5 to 75 mg / Kg, even more particularly 10 to 70 mg / Kg of the compound of formula (I).

[0105] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the compound or composition of formula (I) as previously defined is administered in humans only once or alternatively daily at a dose equivalent to the dose selected in mice from the following: about 200 mg / kg, about 175 mg / kg, about 150 mg / kg, about 125 mg / kg, about 100 mg / kg, about 75 mg / kg, about 70 mg / kg, about 60 mg / kg, about 55 mg / kg, about 50 mg / kg, about 45 mg / kg, about 40 mg / kg, about 35 mg / kg, about 30 mg / kg, about 25 mg / kg, about 20 mg / kg, about 15 mg / kg, about 10 mg / kg, about 5 mg / kg, about 2.5 mg / kg, about 2 mg / kg, about 1.5 mg / kg, about 1.0 mg / kg. Compounds of formula (I) at mg / Kg and about 0.5 mg / Kg. More specifically, compounds or compositions of formula (I) as previously defined are administered in humans at doses equivalent to those selected from those in mice: about 70 mg / Kg, about 25 mg / Kg and about 10 mg / Kg of compounds of formula (I).

[0106] In the treatment regimen of the present invention, administration of a compound or composition of formula (I) as previously defined for a short period of time can provide a certain area under the curve (AUC). 最终 ) and Cmax value.

[0107] The term "area under the curve (AUC)" 最终 "Cmax" refers to the area under the curve from the time of administration of a compound or composition of formula (I) as previously defined to the final measurable concentration within the first time period as described above. The maximum measurable plasma concentration of the drug administered is called "Cmax".

[0108] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined, sustained for the first time period as described above, can provide 1 hour. ng / mL to 100,000 h ng / mL, and more specifically 500 h ng / mL to 80,000 h ng / mL, or even more specifically 6,000 h ng / mL to 66,000 h Area under the curve (AUC) of ng / mL 最终 ).

[0109] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above can provide 6,000 h. ng / mL to 9,000 h Area under the curve (AUC) of ng / mL 最终 ).

[0110] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above can provide 12,000 h. ng / mL to 16,000 h Area under the curve (AUC) of ng / mL 最终 ).

[0111] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above can provide 60,000 h. ng / mL to 66,000 h Area under the curve (AUC) of ng / mL 最终 ).

[0112] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above can provide a Cmax value of 1 ng / mL to 100,000 ng / mL, more particularly 500 ng / mL to 80,000 ng / mL, and more particularly 3,000 ng / mL to 40,000 ng / mL.

[0113] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above is capable of providing a Cmax value of 3,000 ng / mL to 5,000 ng / mL.

[0114] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above is capable of providing a Cmax value of 6,000 ng / mL to 9,000 ng / mL.

[0115] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above can provide a Cmax value of 12,000 ng / mL to 16,000 ng / mL.

[0116] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, application of a compound or composition of formula (I) as previously defined for a first time period as described above is capable of providing a Cmax value of 30,000 ng / mL to 36,000 ng / mL.

[0117] Plasma concentrations AUC and Cmax can be determined using standard analytical methods well known in the art, such as automated or manual immunoassays, liquid chromatography, or liquid chromatography-mass spectrometry.

[0118] Neurological diseases or conditions This invention relates to a novel treatment regimen for treating neurological diseases or conditions that cause damage or degeneration of neurons, axons, or myelin sheaths, such as MS, NMO, transverse myelitis, recurrent optic neuritis, or systemic (rheumatic) diseases affecting the central nervous system. These neurological diseases include inflammatory diseases, non-inflammatory neurological diseases such as optic neuropathy, and neurodegenerative diseases.

[0119] Inflammatory diseases of the central nervous system are diseases triggered by activation of the immune system, characterized by the presence of inflammatory infiltrates or immune molecules that damage the central nervous system. This damage includes loss of neurons and axons, as well as loss of myelin sheaths and oligodendrocytes and their precursors. Non-limiting examples of inflammatory neurological diseases or conditions that lead to neuronal, axonal, or myelin sheath destruction or degeneration include demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Balo's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, and Marburg disease.

[0120] Optic neuropathy is a disease that causes damage, particularly to the optic nerve, resulting in visual impairment. Non-limiting examples of optic neuropathy include glaucoma, anterior ischemic optic neuropathy and optic neuritis, hereditary optic neuropathy such as Leber's disease and dominant optic atrophy, toxic optic neuropathy, traumatic optic neuropathy, and tumor-associated optic neuropathy.

[0121] Neurodegenerative diseases are characterized by progressive loss of neurons and axons, with low levels of reactive inflammation. This loss is caused by various toxic mechanisms, such as protein deposition and a lack of trophic factor support. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Lewy body disease, hereditary ataxia, and glaucoma.

[0122] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the neurological disease or condition resulting in the destruction or degeneration of neurons, axons, or myelin sheaths is selected from: demyelinating diseases, optic neuropathy, and neurodegenerative diseases. More particularly, it is selected from multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Balo's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease, glaucoma, anterior ischemic optic neuropathy, Leber's disease, overt optic atrophy, toxic optic neuropathy, traumatic optic neuropathy, tumor-associated optic neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body disease, and combinations thereof. Even more particularly, it is selected from multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, glaucoma, and combinations thereof.

[0123] Throughout the specification and claims, the word "comprising" and variations thereof are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprising" covers situations where it means "composed of." Other objects, advantages, and features of the invention will become apparent to those skilled in the art upon examination of the specification, or may be learned by practicing the invention. The following embodiments and figures are provided illustratively and are not intended to limit the invention. Moreover, the invention covers all possible combinations of the specific and preferred embodiments described herein.

[0124] Example Evaluation of multiple doses in a Sprague Dawley rat model of lysophosphatidylcholine-induced acute optic neuritis BN201 1. Research Objectives The study was conducted in two parts: Block 1 The aim was to determine the efficacy of BN201 in lysophosphatidylcholine-induced optic neuritis in SD rats at different doses (10 mg / Kg, 25 mg / Kg, 70 mg / Kg) via intraperitoneal administration and at 25 mg / Kg via intravenous administration (7-day study).

[0125] Block 2 The aim was to determine the efficacy of BN201 in a long-term visual model of lysophosphatidylcholine-induced neuritis in SD rats (14-day and 28-day studies).

[0126] 2. General Solution • Receive the animals (male Sprague Dawley rats, age: 12–13 weeks, weight range at the start of the study: 306.8–385.2 g) and allow the animals to acclimate for at least one week.

[0127] • Day 0: Application of lysophosphatidylcholine to the optic nerve • For Block 1, the test compound (BN201) was administered daily over 2 hours at different doses (10 mg / Kg, 25 mg / Kg, 70 mg / Kg) via intraperitoneal (IP) and intravenous (25 mg / Kg infusion) (day 0 to day 6 = 7 doses in total).

[0128] • On day 6, at predetermined time points (8-9 time points), blood samples of plasma are taken from block 1 for PK and tissue collection (eye and optic nerve) for histopathological evaluation.

[0129] • Determining BN201 levels in plasma by LC-MS / MS • Pharmacokinetic parameters of BN201 were determined using WinNonlin analysis. • For Block 2, administer the test compound once daily (IP@10 & 25 mg / Kg) (7 doses total from day 0 to day 6); tissue collections (eye and optic nerve collections at the end of the study) were performed on day 14 and day 28 for histopathological evaluation.

[0130] 3. Animal conditioning Animals were kept in a controlled environment with a temperature of 22±3℃, humidity of 50±20%, a 12-hour light / dark cycle, and 15-20 fresh air changes per hour. Animals were housed in groups (3 animals per cage) in individual ventilated cages (IVCs) using autoclaved corn cobs as bedding. They were fed freely with certified irradiated laboratory rodent feed.

[0131] 4. Study and implement the plan The animals were divided into different groups according to the following scheme:

[0132] 5. Experimental Group Group 1: 7-day treatment group

[0133] Double-cannulated (jugular vein and femur) rats were used in the IV infusion group. Jugular vein cannulation was used in groups 2, 3, 4, and 5. mouse.

[0134] Blood was drawn via a jugular vein cannula.

[0135] IV infusion - administered over 2 hours using an infusion pump (via the femoral vein). Block 1: 7-day treatment group

[0136] Induction procedure: 0.8 μL of 1% lysophosphatidylcholine (containing 0.02% Evans blue) 6. Preparation of the Experimental Project Dissolve BN201 in physiological solution (0.9% NaCl) at room temperature. Prepare a stock solution with a concentration of 100 mg / mL, aliquot it, and store it at 20°C. Thaw the solution on the day of the experiment and take out a sufficient amount for further dilution. Prepare a 5 mg / mL working solution for groups 3 to 5 by diluting the stock solution with physiological saline. For IV infusion, prepare 2 mg / mL daily (days 0 to 6).

[0137] 7. Disease induction procedure Anesthetize the animals; disinfect the shaved skin with 75% ethanol. Make a 1 cm incision in the skin above the orbit. Remove the lacrimal gland and extraocular muscles, exposing the optic nerve 3 mm under a surgical microscope. Longitudinally open the dura mater and arachnoid material around the optic nerve. Place a small amount of dye on the dura mater to indicate the microinjection site. This is done to identify focal histological lesions. Perform microinjection using a glass micropipette attached to a Hamilton syringe. Insert the pipette as shallowly as possible into the optic nerve, 2 mm posterior to the eyeball, and then slowly inject 0.8 μL of 1% lysophosphatidylcholine (containing 0.02% Evans blue) into the nerve over approximately 30 seconds. Inject sham control rats (disease-free animals) with 0.02% Evans blue (without lysophosphatidylcholine) in 0.8 μL of physiological saline. Suture the skin incision after injection and administer an antibiotic solution to prevent infection.

[0138] 8. Treatment Procedure • Group 1 and Group 2 served as the sham control group and the pathological control group, respectively, and were administered only physiological saline. • The test compound was delivered once per group via IP or IV infusion at different doses (as described above). The first dose was given 1 hour after the lysophosphatidylcholine injection, repeated once daily until the end of the experiment. • On day 6, blood samples were collected at different time points after administration for drug concentration measurement: • Groups 3-5 (IP group): Before administration, at 0.25, 0.5, 1, 4, 8 h, 12 h, and 24 h (8 time points) • Group 6 (IV infusion group): Before administration, and then at the following times after infusion: 0 h (end of infusion), 0.25 h, 0.5 h, 1 h, 4 h, 8 h, 12 h and 24 h (9 time points). • In K2EDTA blood collection tubes, approximately 200 μL of blood was collected from the jugular vein at each time point and stored at 4°C until plasma separation was performed within 30 minutes. After plasma separation, all plasma samples were divided into two aliquots and stored at -80°C until all time points were completed. Additionally, one aliquot of the plasma sample was submitted together to DMG / KG for drug concentration analysis.

[0139] 9. Observation and reading 9.1 Weight Take weight measurements every morning from day 0 to day 7. Regularly observe all animals for clinical signs.

[0140] 9.2 Histopathology • Euthanize the animals with CO2 on day 7 and perfuse them with saline and 4% paraformaldehyde via the heart. Remove the optic nerve (from the eyeball to the optic chiasm) and the eyes, and fix them overnight in 1% paraformaldehyde. Collect all the animals' eyes in Davidson's fixative.

[0141] • All tissues were processed in an automated tissue processor and embedded in paraffin. Transverse sections, 5 μm thick, were prepared at the injection sites (dye locations) using a microtome under a rotating microscope.

[0142] • Obtain serial sections (4–6 sections) of each optic nerve. Stain the slides with H&E, LFB, and Bielschowsky silver immersion staining (BSS) to assess inflammation, demyelination, and axonal pathology of the optic nerve. Stain retinal (eye) sections with H&E for retinal ganglion cell (RGC) counting.

[0143] 10. Scoring Criteria • Measure the demyelinated area (in Luxol solid blue stained sections) and score the observation using the following criteria: 0.5 micro-volume perivascular or subpial demyelination 1. Obvious perivascular or subpial demyelination 2. Confluent perivascular or subpial demyelination 3. Extensive confluent demyelination (half of the spinal cord) 4. Extensive demyelination • An observational rating scale of 0 to 4 is used to assess the severity of axonal loss (in silver-stained sections), as shown below: 0 Normal staining of axons under silver immersion 0.5 microvascular or subpiaural axonal loss 1. Obvious perivascular or subpiaural axonal loss 2. Axonal loss around confluence vessels or subpia mater 3. Abundant confluent axonal loss 4. Extensive axonal absence • Scoring criteria used to assess inflammation (in H&E slides): 0 Normal: No infiltration 0.5 micro-volume perivascular or subpiaural infiltration 1. Obvious perivascular or subpiaural infiltration 2. Perivascular or subpiacular infiltration 3 Large-scale confluence infiltration 4. Extensive infiltration Representative photographs (10X and 20X) were taken using a Leica DFC425C camera with a Nikon Eclipse 80i microscope.

[0144] Retinal ganglion cells (RGCs) were counted in H&E-stained sections of the eyes (6 high-power fields [40x] per animal) to compare ganglion cell density between treatment groups.

[0145] 11. Bioanalytical Procedures 11.1 Sample Preparation The study samples were processed using cold acetonitrile via protein precipitation. Briefly, 10 μL of plasma was mixed with 200 μL of acetonitrile containing 100 ng / mL verapamil as an internal standard. The contents were vortexed to ensure mixing, and the precipitated proteins were removed by centrifugation at 4000 rpm for 15 minutes at 4°C. The supernatant was collected and submitted for bioanalysis.

[0146] 11.2 Analysis Parameters Chromatographic conditions

[0147] gradient condition

[0148] 12. Results 12.1 Weight (Blocks 1 and 2) When compared by t-test at various study days throughout the life-cycle, there was no significant change in rat body weight between the sham control group and the pathway control group. Treatment with BN201 did not significantly alter body weight compared to the pathological control group.

[0149] 12.2 Pharmacokinetic Parameters (Block 1) Pharmacokinetic parameters for the IP and IV groups are shown in Tables 1 and 2 below. Figure 1 and 2 middle.

[0150]

[0151]

[0152] 12.3 Histopathological evaluation 12.3.1 Retinal ganglion cell count (RGC) The RCG count results for the eye (6x magnification) are shown below. Figure 3 (Block 1) and Figure 6 In (Block 2).

[0153] RGC (Block 1) Compared with the sham control group (94±3.6), the pathological control group showed significantly lower RGC counts (73.6±2.2) in 6 random high-power fields. Treatment with BN201 showed a trend toward increasing RGC counts. Compared with the pathological control, the IV infusion group (25 mg / Kg) showed a statistically significant improvement in RGC counts. The BN201@25 and 70 mg / Kg IP groups also showed improvements in RGC counts, with protection against retinal ganglion cell loss at 48% and 69%, respectively.

[0154] RGC (Block 2) The pathological control groups (14-day and 28-day groups) showed significantly reduced RGC counts in 6 random high-power fields. Treatment with BN201 showed improvement on day 28 (25 mg / Kg group).

[0155] 12.3.2 Demyelination (in Luxol blue-stained optic nerve sections) Demyelination score results showed Figure 4 (Block 1) and Figure 7 In (Block 2). Separately in Figure 9 and Figure 10 Histopathological images of the optic nerve stained with LFB, evaluated on days 14 and 28, are shown to assess demyelination.

[0156] Demyelination (Block 1) The pathological control group showed a mean demyelination score of 1.6 ± 0.4. Treatment with BN201@10 mg / Kg, 25 mg / Kg, and 70 mg / Kg intravenous infusion (IP) showed a trend toward a decrease in the demyelination score, with protection rates of 13%, 15%, and 44%, respectively. The 25 mg / Kg IV infusion group showed 22% protection against demyelination.

[0157] Demyelination (block 2) Moderate demyelination was observed in the pathological control group at 14 and 28 days.

[0158] 12.3.3 Axonal loss (in BSS-stained sections of the optic nerve) Axonal loss score (silver-impregnated slices, grade: 0-4) is shown in Figure 5 (For block 1) and Figure 8 (For block 2) In respectively Figure 11 and Figure 12 Histopathological images of the optic nerve stained with BSS, evaluated on days 14 and 28, are shown to assess axonal density.

[0159] Axonal loss (block 1) The pathological control group showed a significant increase in axonal loss scores (2.4 ± 0.3) (observed in BSS-stained optic nerve sections). Treatment with BN201@10 mg / Kg, 25 mg / Kg, and 70 mg / Kg intravenous infusions (IP) showed score reductions (36-39% protection). IV infusion resulted in significant protection against axonal loss (62%).

[0160] Axonal loss (block 2) Progressive axonal loss was observed on days 14 and 28 in the pathological control group (scores of 1.9 and 2.2 on days 14 and 28, respectively). BN201@10 mg / Kg and 25 mg / Kg showed a significant reduction in axonal loss on day 28.

[0161] 13. Conclusion Significant induction of optic neuritis and retinal ganglion cell loss was observed in the pathological control group (days 7 (block 1), 14, and 28 (block 2)). Optic neuritis is characterized by increased inflammatory cell infiltration in the optic nerve (as observed in H&E staining), demyelination (LFB staining), and axonal loss (BSS staining), as well as a significant reduction in retinal ganglion cell count in the retina of the eye in the pathological control group. BN201 treatment resulted in significant improvement in retinal ganglion cell count and reduction in inflammation, axonal loss, and demyelination. Daily IV administration of BN201 at 25 mg / kg (2 h infusion) resulted in superior protection against optic neuritis compared to intraperitoneal administration of BN201 at 10 mg / kg, 25 mg / kg, and 70 mg / kg.

[0162] Citation List - WO2012028959 - Industry Guidelines - Estimating the maximum safe starting dose in initial clinical trials for treatment in healthy adult volunteers (FDA, CDER, July 2005).

Claims

1. A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of said compound of formula (I) or of any pharmaceutically or veterinarily acceptable salt thereof, for use in the treatment or prevention of a neurological disease or condition causing damage or degeneration of neurons, axons or myelin, (I) wherein: R1 is phenyl substituted with halogen or trifluoromethyl and further optionally substituted with one or two substituents selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy and halo(Ci-C6)alkyl; or, R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfonamidephenyl; and R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl and 1-methylpentyl; wherein the treatment comprises: a) a first period of 1 to 7 days, wherein the compound is administered one or more times to a subject in need thereof, and b) a second period of equal to or longer than 13 days, wherein the compound is not administered, wherein the second period occurs after the first period and before the next administration of the compound.

2. The compound for use according to claim 1, wherein in the compound of formula (I) R3 is 2-methylpropyl and R1 and R2 are as defined in claim 1.

3. The compound for use according to claim 2, wherein the compound of formula (I) is selected from: 。 4. The compound for use according to any one of claims 1 to 3, wherein the first period of step a) is from 3 to 7 days.

5. The compound for use according to any one of claims 1 to 4, wherein the first period is 7 days.

6. The compound for use according to any one of claims 1 to 5, wherein in step a) the compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of said compound of formula (I) or of any pharmaceutically or veterinarily acceptable salt thereof, is administered every 3 hours, every 4 hours, every 6 hours, every 8 hours, every 12 hours, once a day, twice a day, three times a day, four times a day, every day, every two days or every three days.

7. The compound for use according to claim 6, wherein in step a) the compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of said compound of formula (I) or of any pharmaceutically or veterinarily acceptable salt thereof, is administered once a day.

8. The compound for use according to any one of claims 1 to 7, wherein the second period is from 13 days to 89 days.

9. The compound for use according to claim 8, wherein the second period is 21 days.

10. The compound for use according to any one of claims 1-9, wherein the compound of Formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of the compound of Formula (I) or of any pharmaceutically or veterinarily acceptable salt thereof, is administered intravenously.

11. The compound for use according to any one of claims 1-9, wherein the compound of Formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of the compound of Formula (I) or of any pharmaceutically or veterinarily acceptable salt thereof, is administered intraperitoneally.

12. The compound for use according to any one of claims 1-11, wherein the compound of Formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of the compound of Formula (I) or of any pharmaceutically or veterinarily acceptable salt thereof, is administered to a subject in need thereof at a dose equivalent to 5-75 mg / Kg per day.

13. The compound for use according to any one of claims 1-12, wherein the disease or condition is selected from the group consisting of multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Balo disease, Schilder disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease, glaucoma, anterior ischemic optic neuropathy, optic neuritis, Leber disease, dominant optic atrophy, toxic optic neuropathy, traumatic optic neuropathy, tumor-related optic neuropathy, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body disease, hereditary ataxias, and glaucoma.

14. The compound for use according to claim 13, wherein the disease or condition is selected from the group consisting of multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, anterior ischemic optic neuropathy, and glaucoma.

15. A pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1-3, and one or more pharmaceutically or veterinarily acceptable excipients or carriers, for use in the treatment or prevention of a neurological disease or condition causing destruction or degeneration of neurons, axons, or myelin, wherein the treatment is as defined in any one of claims 1-14.

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