Methods, compositions and kits for combination therapy

Abstract

To provide a method of treating an inflammatory neurological disease or condition that can result in destruction or degeneration of axons or myelin.SOLUTION: Provided is a combination comprising a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; and b) one or more drugs selected from the group consisting of I) a compound of a particular formula or a pharmaceutically or veterinarily acceptable salt thereof; ii) a sphingosine-1-phosphate receptor inhibitor (S1PR modulator); and iii) a signal transducer and activator of transcription 3 (STAT3) inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of European Patent Application No. 19382566.8 filed on July 3, 2019. Claim priority.

[0002] The present invention relates to the field of neurological disorders and methods for treating them using combination therapies. Regarding a particular approach. [Background technology]

[0003] As an inflammatory neurological disease or condition that can result in destruction or degeneration of axons or myelin , including but not limited to, multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, and Baro's disease , Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis (i.e., Hurst's disease), and myelitis. These include various central nervous system (CNS) diseases such as Schwarzburg's disease (i.e., acute MS). do.

[0004] MS occurs when the immune system attacks and damages the myelin protective sheath that surrounds axons and nerve fibers. MS is a degenerative autoimmune disease of the central nervous system (CNS) that results in significant disability. , characterized by multifocal inflammation, reactive gliosis, and oligodendrocyte and axonal loss. There are three clinical disease courses that individuals with MS typically experience: relapsing-remitting MS (RMS); There are three types of MS: RMS, secondary progressive MS (SPMS), and primary progressive MS (PPMS). MS is the most common disease process, affecting approximately 85% of MS patients, and is characterized by a deterioration of neurological function. These relapses are followed by partial or complete relapses. This is followed by a period of complete recovery, during which symptoms improve partially or completely and there is no progression of the disease. Although most individuals with RRMS will eventually progress to SPMS, This occurs after a period of relapse and remission, with or without relapse, when the disease becomes more steady. PPMS affects approximately 10% of MS patients and is characterized by distinct relapses. Or it is characterized by a steady deterioration of neurological function from the beginning without any remissions. The severity and course of the disease vary depending on the location of the myelin damage and the degree of demyelination.

[0005] NMO (also known as Devic's disease or Devic's syndrome) or NMO spectrum NMOSD occurs when immune system cells and antibodies attack astrocytes in the optic nerve, brain, and spinal cord. An autoimmune disorder of the CNS that mistakenly attacks and destroys cells, leading to secondary demyelination and axonal loss. Damage to the optic nerve can cause optic neuritis, which causes swelling and inflammation, resulting in pain. Spinal cord damage can cause weakness or paralysis in the legs or arms, loss of sensation, and vision loss. Both diseases have similar symptoms. However, NMO can be confused with MS because it can cause attacks of optic neuritis and myelitis. It is possible that this condition may have been a severe form of MS, and until recently it was thought to be a severe form of MS. However, recent studies suggest that NMO and MS are distinct diseases.

[0006] Optic neuritis is a demyelinating inflammation of the optic nerve that can be caused by many different conditions. Inflammation is often associated with MS and NMO. This can cause glaucoma, but is often caused by swelling and destruction of the myelin sheath that covers the optic nerve. Symptoms of optic neuritis include blurred vision, blurred colors, and pain when moving the eyes. These include loss of vision, blind spots, and contrast sensitivity. Summary of the Invention [Problem to be solved by the invention]

[0007] Currently, there is no cure for MS. The available treatments are for relapsing forms of MS, including RRMS. The study is aimed at the subset of patients with SPMS who have relapses, and at patients with SPMS who experience relapses. Most of the treatments approved by the U.S. Food and Drug Administration (FDA) reduce the frequency of recurrences. These treatments are immunomodulatory agents that slow the progression of MS. It has limited efficacy and inhibits immune system activation without exerting neuroprotective or regenerative effects. Furthermore, current treatments may result in adverse immune responses or severe opportunistic infections. It is associated with serious side effects such as

[0008] Currently, there is no cure for NMO. Intravenous high-dose corticosteroids and plasmapheresis to treat relapses are recommended. and rituximab, azathioprine, and mycophenolate for relapse prevention. These can cause serious side effects such as infections. The recurrence rate of NMO is 9 0%, and attacks are generally severe enough to require ongoing treatment to suppress the immune system. Therefore, in the art, it is believed that MS, NMO, optic neuritis, Baro's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis (i.e., Hurst's disease), and myelitis may result in destruction or degeneration of axons or myelin, such as St. Louis disease (acute MS), There is a need for more effective methods of treating inflammatory neurological diseases or conditions. [Means for solving the problem]

[0009] The present inventors have discovered that compounds of formula (I) (see below) have immunomodulatory and / or antioxidant activity. and one or more drugs having anti-inflammatory and / or anti-inflammatory activity. Inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin in Surprisingly, it has been found that compounds of formula (I) provide significant therapeutic activity in At least one or more additional drugs are considered and classified as subtherapeutic. The use of the above combination of compounds enhances the desired effect even when administered in amounts This combination significantly improved the therapeutic effect and reduced the associated side effects. What was even more surprising was that the subjects did not show any signs of axonal or myelin damage. These remarkable treatments for inflammatory neurological diseases or conditions that can result in destruction or degeneration The effect of activity is suboptimal or therapeutic doses of each compound when administered as a single active agent. The fact that this was achieved even at a dose below the amount of the compound of formula (I) Certain combinations with other specific compounds may provide benefits over each compound administered alone. In these diseases, the compound of formula (I) showed significantly improved results at sub-therapeutic doses. combination and one or more additional drugs administered at a dose lower than the dose expected to be active in chronic or advanced stages or stages of inflammatory neurological diseases or conditions. It was effective.

[0010] This unexpected improvement when the compounds are used in combination may be relevant for a wide range of inflammatory neurological disorders. The animal model used, namely experimental autoimmune encephalomyelitis (EAE) in mice, As a result, the present inventors have identified the compounds of formula (I) and their immunomodulatory and and / or one or more drugs with antioxidant and / or anti-inflammatory activity. When used in combination with other drugs, these incapacitating effects of neurological disease are reduced, resulting in clinical outcomes in EAE mice. This enhanced or improved effect was due to the fact that the oxidative stress was Stress, apoptosis, autophagy, synaptic pruning, energy metabolism Each drug activates different biological pathways, such as vasopressin, which can lead to cell damage. This is thought to be due to the convergence of efforts to prevent scalation.

[0011] Thus, a first aspect of the present invention provides: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) one or more drugs selected from the group consisting of: i) a compound of formula (IV), or a pharmaceutically or veterinarily acceptable salt thereof; ii) Sphingosine-1-phosphate receptor modulators (S1PR modulators) ); and iii) Signal Transducer and Activator of Transcription 3 (STAT3) Inhibitors The present invention relates to a combination comprising:

[0012] [ka] During the ceremony, R1 is substituted with halogen or trifluoromethyl, and further substituted with halogen, (C1-C 6) consisting of alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl or phenyl optionally substituted with one or two substituents selected from the group wherein R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl. and R3 is propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1- Methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl The alkyl group is selected from methyl, 2-methylpentyl, and 1-methylpentyl.

[0013] [ka] During the ceremony, R5 is selected from hydrogen (H) and (C1-C6) alkyl, and R6 is selected from H, (C1 —C6) alkyl and 2-(2,5-dioxopyrrolidin-1-yl)ethyl and when R5 is H, R6 is other than H;

[0014] The compounds of the present invention can be formulated into various types of compositions / kits. The second aspect of the Ming Dynasty is a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, i) an S1PR modulator, and iii) a STAT3 inhibitor. and one or more drugs that A single drug containing one or more pharmaceutically or veterinarily acceptable excipients or carriers. For pharmaceutical or veterinary compositions, The compound of formula (I) and the drug are as defined in the first aspect, and the amount of a) and and b) in combination are therapeutically effective.

[0015] A third aspect of the present invention is i) a predetermined amount of a compound of formula (I) or a pharmaceutical or veterinary equivalent thereof as defined above An acceptable salt may be formulated in combination with one or more pharmaceutically or veterinarily acceptable excipients or carriers. a first pharmaceutical or veterinary composition comprising: ii) a predetermined amount of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable derivative thereof one or more selected from the group consisting of a salt, an S1PR modulator, and a STAT3 inhibitor together with one or more pharmaceutically or veterinarily acceptable excipients or carriers. a pharmaceutical or veterinary composition; and iii) instructions for using i) and ii) in combination; and For a package or kit of parts comprising: The first and second compositions are separate compositions, and the first and second compositions are each a mixture of i) an amount of a compound of formula (I) and ii) the amounts of the one or more drugs are therapeutically effective in combination.

[0016] Furthermore, as mentioned above, the combination of the present invention may be used to treat axonal or myelin destruction or degeneration. It may be used in inflammatory neurological diseases or conditions that may result in

[0017] Thus, the fourth aspect of the present invention provides a method for treating axons and myelin-related disorders that result in destruction or degeneration of axons or myelin. a method for treating and / or preventing an inflammatory neurological disease or condition as defined above, The combined, single pharmaceutical or veterinary composition, or packaged or Mostly about kits of parts. [Brief explanation of the drawings]

[0018] [Figure 1A]In relation to Example 1, the daily clinical scores (CS) of Study EAE-C03 are shown, in which the effects of daily treatment with different doses of BN201 were compared with placebo. After 17 days of treatment, the clinical scores began to be significantly lower in the groups treated with BN201 (100 mg / kg) and BN201 (50 mg / kg) than in the pathological control group (**p≦0.01, *p≦0.05). [Figure 1B] In relation to Example 1, a daily clinical score (CS) study EAE-C05 is presented, in which the effects of daily treatment with different doses of BN201 and two active comparators (dimethyl fumarate DMF and fingolimod FTY720) were compared with placebo. After 5 days of treatment, clinical scores began to be significantly lower in the BN201 (100 mg / kg) and FTY720-treated groups than in the pathological control group (**p≦0.01, *p≦0.05). [Figure 1C] Daily clinical score (CS) study EAE-C06 was shown, testing five different concentrations of BN201 (12.5 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 150 mg / kg). Placebo, pathological control, and FTY720 (2 mg / kg) comparison groups were also included. All groups were dosed daily. Significant improvements in clinical scores were observed in animals receiving BN201 50 mg / kg, BN201 100 mg / kg, and FTY720 2 mg / kg across most observation / treatment days (days 2-30) (**p ≤ 0.01, *p ≤ 0.05). [Figure 2] Figure 1 is a plot of the daily clinical score (CS) for EAE mice treated with fingolimod (black diamonds), BN201 (white squares), the combination of fingolimod and BN201 (black circles), and placebo (white triangles), relating to Example 2. Arrows indicate the start date of treatment. The x-axis is the number of days after immunization of C57BL / 6 mice to develop an EAE phenotype. p<0.05 for the difference between the combination therapy (fingolimod 0.1 mg / kg + BN201 25 mg / kg) versus BN201 (25 mg / kg). [Figure 3]1 is a plot of the daily clinical score (CS) of EAE mice treated with dimethyl-fumarate (DMF) (black squares), BN201 (black diamonds), a combination of DMF and BN201 (black crosses), and placebo (triangles) relating to Example 3. The X-axis is the number of days post-immunization of C57BL / 6 mice until they developed an EAE phenotype. [Figure 4] 1 is a plot of the daily clinical score (CS) of EAE mice treated with the STAT3 inhibitors S31-201 (crosses), BN201 (triangles), the combination of S31-201 and BN201 (squares), and placebo (circles), relating to Example 4. Arrows indicate the start date of treatment. The X-axis is the number of days after immunization of C57BL / 6 mice until they developed an EAE phenotype. [Figure 5] 1 is a bar graph showing the viability of the human neuroblastoma cell line SH-SY5Y after oxidative stress conditions, relating to Example 6. The viability of cells treated with different assay concentrations (0.03 μM, 0.1 μM, 0.3 μM, 0.5 μM, 1 μM, 3 μM, 5 μM, 10 μM, 20 μM, 40 μM) of BN201 (first column), BN201-monomethyl fumarate (second column), or monomethyl fumarate (third column) in cell culture is shown compared to control (untreated human neuroblastoma cells). Figure 5 shows that cell viability as a percentage of control is increased after pretreatment with BN201-monomethylfumarate compared to BN201 or monomethylfumarate at the same test concentrations (*<0.00001 for BN201 alone, #p<0.05 or ##p<0.0001 for fumarate alone). DETAILED DESCRIPTION OF THE INVENTION

[0019] All terms used herein in this application are understood to be within the meaning of the art unless otherwise specified. Certain terms used in this application are to be understood in their ordinary and prevailing sense. The specific definitions are as follows, which are particularly important when explicitly stated: Unless a broader definition is provided, it shall be applied throughout the specification and claims. This is the intention.

[0020] Compounds of formula (I)

[0021] As described above, the present invention provides a) a compound of formula (I) or a pharmaceutical or veterinary derivative thereof as defined above: Acceptable salts, b) i) a compound of formula (IV) or a pharmaceutical or veterinary salt thereof; ii) an S1PR modulator, and iii) STAT3 inhibitors and one or more drugs selected from the group consisting of The present invention relates to a combination comprising:

[0022] [ka]

[0023] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (I), R1 is fluorophenyl phenyl, more specifically 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl phenyl, and even more particularly 2-fluorophenyl.

[0024] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (I), R1 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl and one or two substituents selected from the group consisting of halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and more preferably, one or two substituents selected from the group consisting of halogen, methyl, ethylene, methyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl fluoromethyl, further substituted with one or two substituents selected from the group consisting of It is phenyl.

[0025] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (I), R1 is chlorophenyl phenyl, more specifically 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl and even more specifically R1 is 2-chlorophenyl.

[0026] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (I), R1 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl and one or two substituents selected from the group consisting of halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and more preferably, one or two substituents selected from the group consisting of halogen, methyl, ethylene, methyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl chloromethyl, further substituted with one or two substituents selected from the group consisting of It is phenyl.

[0027] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R1 is bromophenyl , more particularly 2-bromophenyl, 3-bromophenyl or 4-bromophenyl, Even more specifically, it is 2-bromophenyl.

[0028] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (I), R1 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl and one or two substituents selected from the group consisting of halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and more preferably, one or two substituents selected from the group consisting of halogen, methyl, ethylene, methyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl bromo, further substituted with one or two substituents selected from the group consisting of bromomethyl; It is phenyl.

[0029] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R1 is iodophen nyl, more particularly 2-iodophenyl, 3-iodophenyl or 4-iodophenyl and even more particularly 2-iodophenyl.

[0030] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (I), R1 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl and one or two substituents selected from the group consisting of halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and more preferably, one or two substituents selected from the group consisting of halogen, methyl, ethylene, methyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl iodo which is further substituted with one or two substituents selected from the group consisting of iodomethyl It is phenyl.

[0031] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R is trifluoro Methylphenyl, more specifically 2-trifluoromethylphenyl, 3-trifluoromethylphenyl phenyl or 4-trifluoromethylphenyl, and more particularly 2-trifluoromethylphenyl It is fluoromethylphenyl.

[0032] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (I), R1 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl and one or two substituents selected from the group consisting of halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and more preferably, one or two substituents selected from the group consisting of halogen, methyl, ethylene, methyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl a trifluoromethyl group, further substituted with one or two substituents selected from the group consisting of It is fluorophenyl.

[0033] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R1 is pyrrolidine- It is 1-yl.

[0034] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R2 is 2-oxo- It is pyrrolidin-1-yl-methyl.

[0035] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R2 is sulfamoyl Phenyl, more specifically R2 is 2-sulfamoylphenyl, 3-sulfamoylphenyl phenyl, or 4-sulfamoylphenyl, and even more specifically 4-sulfamoylphenyl It is Venil.

[0036] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R3 is 2-methylpropyl. It's Ropil.

[0037] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R1 is 2-fluoro phenyl or pyrrolidin-1-yl, and R2 is 2-oxo-pyrrolidin-1-yl methyl or 4-sulfamoylphenyl.

[0038] In another embodiment, any of the various implementations described above or below throughout the description may be used. Compounds of formula (I) of the combination of the invention as described above in combination with one or more of the features of the form is selected from the group consisting of: [ka]

[0039] [N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N-(2-methylpropyl) [3-(2'-oxopyrrolidinyl)-propyl]glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl]glycine mido (known as G79 and also designated as BN201 in the examples below). Chemical formula:C 25 H 38 FN5O4;MW491.5987.

[0040] [N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N-(2-methylpropyl) [2-(4'-sulfamoyl-phenyl)ethyl]glycine Amide (G80, also known as BN119). Chemical formula: C 26 H 36 FN5O5S;M W549.658.

[0041] [N-(2-(1-pyrrolidinyl)ethyl)glycyl]-[N-(2-methylpropyl )glycyl]-N-[2-(4'-sulfamoyl-phenyl)ethyl]glycinamide (G81, also known as BN120). Chemical formula: C 24 H 40 N6OS;MW524. 6766.

[0042] Compounds of formula (I), in particular G79 (BN201), G80 (BN119) and G81 ( BN120) is a novel class of peptoid non-chiral peptides that function as agonists of trophic factors. Their synthesis and properties are described in European Patent No. 2611775. Detailed book “Agonists of neurotrophin receptors an and their use as medicines." Peptoy A notable feature of these compounds is that they contain amino acids that carry many of the secondary structural elements of peptides and proteins. One of these compounds, G79 (BN201), is in vitro Demonstrates neuroprotective effects in multiple models of neuronal injury in vitro and in vivo It has been shown that BN201 has other chemical names such as N-(2-amino-2 -oxoethyl)-2-(2-((4-fluorophenethyl)amino)-N-isobutyl Acetamido-N-(3-(2-oxopyrrolidin-1-yl)propyl)acetamide , and N-({carbamoylmethyl-[3-(2-oxo-pyrrolidin-1-yl)- Propyl]-carbamoyl}-methyl)-2-[2-(2-fluoro-phenyl)-ethyl hydroxylamino]-N-isobutyl-acetamide.

[0043] There is no limitation on the types of salts of the compounds of formula (I) that can be used, provided that they are not intended for therapeutic purposes. If used, it must be pharmaceutically or veterinarily acceptable. The term "veterinarily acceptable salt" refers to a compound that forms an alkali metal salt and is either a free acid or a free base. This includes salts commonly used to form addition salts of the compounds of formula (I). The preparation of pharmaceutical or veterinarily acceptable salts can be carried out by methods known in the art. For example, they can be prepared by conventional chemical methods to prepare compounds containing basic or acidic moieties. Generally, such salts can be prepared from the parent compound, for example, the compound of formula (I). The free acid or free base form of the compound is added to a stoichiometric amount of an appropriate pharmaceutically or veterinarily acceptable by reacting the compound with a base or acid in water or an organic solvent or a mixture thereof. The compounds of formula (I) and their respective salts are prepared by several physical methods. The properties may be different but are equivalent for the purposes of this invention.

[0044] The compounds of the present invention may be used in the form of either free solvates or solvates (eg, hydrates). The compound may be in crystalline form as a solvate, and both forms are intended to be within the scope of the present invention. This method is generally known in the art. Generally, pharmaceutical solvents such as water, ethanol, etc. Solvated forms with cosmetically or veterinarily acceptable solvents are not considered to be non-steroidal anti-inflammatory drugs for the purposes of the present invention. Equivalent to the solvated form.

[0045] In all embodiments of the present invention which refer to compounds of formula (I), their pharmaceutical or veterinary uses may also be Pharmaceutically acceptable salts are always intended, even if not specifically mentioned.

[0046] The compound of formula (I) (e.g., BN201) has been shown to be effective in mice at doses of 0.5 mg / kg to 20 mg / kg. It can be administered at a dose of 0.04 mg / kg to 16.26 mg / kg Human equivalent dose (HED) of [Early clinical trials of therapeutic agents in healthy adult volunteers] Industry guidance for estimating the maximum safe starting dose in clinical trials (FDA, CDER, 200 Therapeutic or optimal doses are calculated based on the HED calculated throughout this specification. , in particular, about 200 mg / kg or less, about 200 mg / kg, about 175 mg / kg or less, about 1 75mg / kg, about 150mg / kg or less, about 150mg / kg, about 125mg / kg or more Lower, about 125mg / kg, about 100mg / kg or less, about 100mg / kg, about 75mg / kg or less, about 75 mg / kg, about 60 mg / kg or less, about 60 mg / kg, about 55 mg / kg or less, approximately 55mg / kg, approximately 50mg / kg or less, approximately 50mg / kg, approximately 45mg / kg or less, about 45mg / kg, about 40mg / kg or less, about 40mg / kg, about 35mg / kg or less, about 35 mg / kg, about 30 mg / kg or less, or about 30 mg / kg. Subtherapeutic or suboptimal doses are particularly those between 0.5 mg / kg and 25 mg / kg. In certain embodiments, the suboptimal dose of a compound of formula (I) (e.g., BN201) is When combined with one or more drugs as defined above, 0mg / kg or less, approximately 20mg / kg, approximately 15mg / kg or less, approximately 15mg / kg, approximately 1 0mg / kg or less, approximately 10mg / kg, approximately 5mg / kg or less, approximately 5mg / kg, approximately 2.5 mg / kg or less, approximately 2.5 mg / kg, approximately 2.0 mg / kg or less, approximately 2.0 mg / kg, About 1.5mg / kg or less, about 1.5mg / kg, about 1.0mg / kg or less, about 1.0mg / kg, about 0.5 mg / kg or less, or about 0.5 mg / kg of a compound of formula (I) (e.g., In certain embodiments, the compound of formula (IV) or its pharmaceutical composition may be a commercially or veterinarily acceptable salt thereof, an SP1R inhibitor (e.g., fingolimod), and Suboptimal use in combination with one or more STAT3 inhibitors (e.g., S3I-201) The administration of a compound of formula (I) (e.g., BN201) in an amount of of a compound of formula (I) (e.g., BN201) at an optimal dose for the treatment of It results in reduced side effects compared to those associated with administration alone.

[0047] Compounds of formula (IV) and salts thereof

[0048] The compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof may be prepared by the reaction of fumaric acid with These compounds correspond to the following formula:

[0049] [ka] wherein R5 is selected from hydrogen (H) and (C1-C6) alkyl; R6 is H, (C 1-C6) alkyl and 2-(2,5-dioxopyrrolidin-1-yl)ethyl and when R5 is H, R6 is other than H.

[0050] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (IV), R6 and R5 are At least one of R6 and R5 is independently selected from hydrogen (H) and (C1-C6) alkyl. At least one is (C1-C6) alkyl.

[0051] (C1-C6) alkyl is methyl, ethyl, propyl, isopropyl, butyl, isopropyl Butyl and tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl The linear and branched alkyl groups are selected from the group consisting of hexyl, isohexyl and neohexyl. do.

[0052] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (IV), R5 and R6 may independently R5 is independently (C1-C4) alkyl, or R5 is (C1-C4) alkyl. and R6 is hydrogen (H). In more specific embodiments, one or more of R5 and R6 is When both are (C1-C4) alkyl, they are methyl, ethyl, propyl, and isopropyl. butyl, isobutyl, and tert-butyl (C1-C4) It is alkyl.

[0053] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (IV), R5 and R6 may independently and (C1-C4) alkyl, more specifically methyl, ethyl, propyl, ethyl The alkyl group is selected from the group consisting of isopropyl, butyl, isobutyl and tert-butyl.

[0054] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (IV), R5 and R6 are The same (C1-C4) alkyl, more specifically both are methyl (dimethyl fumarate). Further information on dimethyl fumarate is provided below.

[0055] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the above embodiment, in the compound of formula (IV), R5 is (C1-C4 ) alkyl, R6 is hydrogen (H), more specifically, R5 is ethyl, and R 6 is hydrogen (H) (monoethyl fumarate). In another more specific embodiment, R5 is methyl and R6 is hydrogen (H) (monomethyl fumarate).

[0056] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (IV), R6 is 2-(2,5 -dioxopyrrolidin-1-yl)ethyl, and R5 is (C1-C6)alkyl; More specifically, R5 is (C1-C4) alkyl, and even more specifically, R5 is R6 is 2-(2,5-dioxopyrrolidin-1-yl)ethyl, and R When 5 is methyl, the compound is also known as diroximel fumarate.

[0057] In yet another embodiment, the pharmaceutical or veterinary salt of the compound of formula (IV) is a Group I gold salt. More specifically, the salts of metals of the formula (I) are those of metals selected from the group consisting of metals of Groups VIII and VIII. V) is the sodium salt or iron(II) salt of the compound.

[0058] In addition to the compound of formula (IV), the inventors have also discovered that the compound of formula (IV) is a compound selected from the group consisting of Group I metals and Group VIII metals. Fumarates (HO2CCH=CHCO2H) of selected metals are also useful as compounds of formula (I). and optionally a sphingosine-1-phosphate receptor modulator (S1PR modulator) and signal transducer and activator of transcription 3 (STAT3) inhibitors. In certain embodiments, the salt is sodium fumarate and iron fumarate.

[0059] All specific embodiments of compounds of formula (IV) herein and the compounds thereof are The same embodiment also applies to the fumaric acid salts of these Group I and Group VIII metals.

[0060] Thus, also disclosed are combinations including: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof b) i) a compound of formula (IV) below, or a pharmaceutically or veterinarily acceptable salt thereof: ii) Sphingosine-1-phosphate receptor modulators (S1PR modulators) ), iii) signal transducer and activator of transcription 3 (STAT3) inhibitors, and iv) fumaric acid salts of metals selected from the group of Group I metals and Group VIII metals; One or more drugs selected from the group consisting of:

[0061] [ka] During the ceremony, R1 is substituted with halogen or trifluoromethyl, and further substituted with halogen, (C1-C 6) consisting of alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl or phenyl optionally substituted with one or two substituents selected from the group wherein R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl. the law of nature, R3 is propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1- Methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl methylpentyl, 2-methylpentyl, and 1-methylpentyl

[0062] [ka] wherein R5 is selected from hydrogen (H) and (C1-C6) alkyl; R6 is H, (C 1-C6) alkyl and 2-(2,5-dioxopyrrolidin-1-yl)ethyl and when R5 is H, R6 is other than H.

[0063] In particular, the combination comprises: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof and b) a fumaric acid salt of a metal selected from the group consisting of Group I metals and Group VIII metals. and salt.

[0064] The inventors have also discovered that fumaric acid or a compound of formula (IV) disclosed above, or a compound of formula ( IV) any pharmaceutically or veterinarily acceptable salt of any of the acids or compounds of formula (I) , in combination with other active ingredients, especially aspirin (i.e., acetylsalicylic acid) and a pharmaceutical formulation (i.e., capsule, pill, tablet) containing a combination of the compound of formula (I) and optionally a sphingosine-1-phosphate receptor modulator (S 1PR modulator) and signal transducer and activator of transcription 3 (STAT3) inhibitors I also realized that more than one can be used together.

[0065] All specific embodiments of the compounds of formula (IV) herein also include fumaric acid or or any pharmaceutically or veterinarily acceptable salt thereof with another compound of formula (IV): In combination with active ingredients, especially in combination with aspirin, it is also suitable for these pharmaceutical preparations. It is used.

[0066] Dimethyl fumarate

[0067] Dimethyl fumarate, the dimethyl ester of fumaric acid (i.e., Tecfidera (R) is approved in the United States and European Union for the treatment of adults with relapsing forms of MS. Dimethyl fumarate inhibits, among other pathways, nuclear factor (erythroid-derived 2) It exerts immunomodulatory and anti-inflammatory activities by activating the Nrf2-like pathway or GAPDH. It has been shown to have an oxidizing effect (see Tecfidera.com). However, the exact mechanism by which dimethyl fumarate combats relapsing MS remains unclear. Dimethyl fumarate has the following structure:

[0068] [ka]

[0069] Dimethyl fumarate is a compound that can produce immunomodulatory activity when administered alone. The approved dose of dimethyl fumarate is 1 mg twice daily for 1 week. 20 mg (equivalent to 1.7 mg / kg twice daily for a patient weighing 70 kg), then 1 day The dose is approximately 240 mg twice a day (equivalent to 3.4 mg / kg twice a day for a patient weighing 70 kg). In certain embodiments, fumarates (e.g., dimethyl fumarate) are used as described above. These doses, known as therapeutic or optimal doses, may be used to administer the compound of formula It may be administered in combination with a compound of formula (I) (e.g., BN201). Subtherapeutic doses of 120 mg or less twice daily for 1 week and approximately 240 mg twice daily thereafter The dose is less than about 120 mg twice daily or less than about 120 mg once daily. In certain of these embodiments, the administration of dimethyl fumarate is performed in an optimal dose of fumarate. This may result in reduced side effects compared to those associated with administration of dimethyl ester alone. In some embodiments, dimethyl fumarate is administered at a lower dose than would normally be administered alone. As a result, side effects of dimethyl fumarate treatment that can be reduced include anaphylaxis and and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia (i.e., lymphocyte Reduction in the number of stools), flushing (i.e., sensation of heat or itching and redness of the skin), gastrointestinal reactions ( i.e. abdominal pain, diarrhea and nausea), protein in the urine, elevated liver enzymes, rash or Any combination thereof may be included, but is not limited to these.

[0070] Dimethyl fumarate is a delayed-release preparation containing a combination of dimethyl fumarate and aspirin. It can also be used in the form of a preparation (capsules) (i.e., Vitalis Pharmaceuticals (VTS-72, a proprietary combination of acetaminophen and acetaminophen). This combination reduces the flushing caused by fumarate. It has been proposed for the treatment of patients with early-onset MS.

[0071] Monomethyl fumarate

[0072] Monomethyl fumarate, also known as fumaric acid monomethyl ester (i.e., B afiertam®) is a clinically isolated syndrome, relapsing-remitting type, in adults. Treatment of relapsing forms of multiple sclerosis (MS), including active secondary progressive disease The FDA-approved dose of monomethyl fumarate is 95 mg daily. Two doses (delayed-release capsules) orally for 7 days. After 7 days, the maintenance dose is 190 mg. Administer orally twice daily (administered as two 95 mg capsules).

[0073] Diroximel fumarate

[0074] Also known as 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate Diroximel fumarate (i.e., Vumerity®), a treatment for recurrent rheumatoid arthritis in adults, is Multiple sclerosis (MS) in its various forms, specifically active secondary progressive disease and clinically isolated Dimethyl fumarate is used in the treatment of relapsing-remitting MS as well as other conditions such as: It has the structure:

[0075] [ka]

[0076] The approved dose of diroximel fumarate is 231 mg orally twice daily for 7 days. After 7 days, the maintenance dose is 462 mg (administered as two 231 mg capsules) daily. Administer orally twice.

[0077] Those skilled in the art will be able to use their own specific knowledge and take into account the efficacy guidelines disclosed above. The dosage of a particular compound of formula (IV) can be calculated.

[0078] S1P receptor (SP1R) modulators

[0079] For purposes of this invention, an "S1P receptor modulator" includes an agent that reduces lymphocyte trafficking. These include compounds or agents that can modulate the extent of autoimmune attack. Lymphocyte trafficking can be indirectly monitored as lymphocytes in the blood using flow cytometry. Under S1PR modulators, lymphocyte trafficking is measured at baseline (SP1 lymphocyte reduction or response to ribozyme R modulators (before treatment with fingolimod) In certain embodiments, the increase is observed by the percentage of increase in the The S1PR modulator to be combined with the compound selected from (I) is fingolimo azanimod, siponimod, ozanimod, ponesimod and selalifimod. Ru. (Patrick Vermersch;''Sphingosine-1-pho sphate Receptor Modulators in Multiple S clerosis'';European Neurological Review- 2018;13(1):25-30)

[0080] Fingolimod is a structural analog of sphingosine, derived from myriocin. Golimod (Gilenya®, Novartis; also known as FTY720) has been shown to have immunomodulatory activity and has been shown to be effective in subjects with relapsing forms of MS. Approved in the US and European Union for reducing relapses and slowing disability progression Although the exact mechanism by which fingolimod reduces recurrence is unknown, fingolimod , reducing circulating lymphocytes by trapping them in the lymph nodes, thereby contributes to the autoimmune response and may prevent the immune system from attacking myelin (Gilenya Fingolimod has the following structure:

[0081] [ka]

[0082] In the case of SP1R modulators (e.g., fingolimod), the therapeutic or optimal dose is the dose that can produce immunomodulatory activity. The dosage in humans is 0.5 mg / day. Clinical trials have shown that it is administered at doses of 1.25 mg / day and 5 mg / day. A dose of 100 mg / day of fingolimod has been shown to be the most effective dose, but The side effects of fingolimod contraindicate its use at these doses. The standard therapeutic dose or optimal dose is 0.75 mg / day to 50 mg / day. The therapeutic dose is about 50 mg / day or less, about 50 mg / day, about 45 mg / day or less, about 45 mg / day or less g / day, about 40 mg / day or less, about 40 mg / day, about 35 mg / day or less, about 35 mg / day, Approx. 30mg / day or less, approx. 30mg / day, approx. 25mg / day or less, approx. 25mg / day, approx. 20m g / day or less, approximately 20 mg / day, approximately 15 mg / day or less, approximately 15 mg / day, approximately 10 mg / day or less Lower, about 10 mg / day, about 5 mg / day or less, about 5 mg / day, about 2.5 mg / day or less, about 2. 5mg / day, about 2.0mg / day or less, about 2.0mg / day, about 1.5mg / day or less, about 1. 5mg / day, approx. 1.25mg / day or less, approx. 1.25mg / day, approx. 1.0mg / day or less, approx. 1.0 mg / day, about 0.75 mg / day or less, or about 0.75 mg / day. The approved dose of fingolimod is 0.5 mg / day.

[0083] Those skilled in the art will be able to use their own specific knowledge and take into account the efficacy guidelines disclosed above. The dosage of a particular S1PR modulator can be calculated.

[0084] Subtherapeutic or suboptimal doses of fingolimod (an example of an S1PR modulator) In certain embodiments, fingolimod may be administered in a dose of 0.05 mg / day to 0.4 mg / day. is 0.4 mg / day or less, approximately 0.3 mg / day or less, approximately 0.3 mg / day, approximately 0.2 mg / day Below, approximately 0.2mg / day, approximately 0.1mg / day or less, approximately 0.1mg / day, approximately 0.05mg / These may be administered at suboptimal doses of 0.05 mg / day or less. In certain forms, administration of fingolimod is based on the single administration of fingolimod at the optimal dose. This may result in reduced side effects compared to side effects associated with sole administration. , as a result of administering fingolimod at a lower dose than would normally be administered alone Side effects of fingolimod treatment that may be reduced include, but are not limited to, headache flu, diarrhea, back pain, abnormal liver tests, cough, slow heart rate, risk of serious infections Increased risk of stroke, posterior reversible encephalopathy syndrome (PRES), macular edema, stroke, or hemorrhage Possible swelling and narrowing of blood vessels in the brain, respiratory problems, macular edema, bradycardia, shingles reactivation, blood clots phagocytosis, dysphagia ... syndrome, or any combination thereof.

[0085] Siponimod (FDA approved March 2019), marketed under the trademark Mayzent, , a selective sphingosine-1-phosphate receptor for oral administration used in multiple sclerosis (MS) It is a receptor modulator (S1P1 and S1P5) that is administered orally once daily. Siponimod is intended to block the migration of lymphocytes to sites of inflammation (e.g., in MS). It is considered very similar to fingolimod, but one of its main side effects is Lymphopenia, one of the conditions, is prevented.

[0086] [ka]

[0087] Ozanimod (RPC-1063) is a treatment for relapsing multiple sclerosis (RMS) and ulcerative colitis. is an investigational immunomodulator currently in Phase III clinical trials for the treatment of ulcerative colitis (UC). do.

[0088] [ka]

[0089] Ponesimod (INN, code name ACT-128800) is an anti-inflammatory drug for the treatment of multiple sclerosis (MS) and It is an experimental drug developed by Actelion to treat psoriasis and rheumatoid arthritis. do.

[0090] [ka]

[0091] Seralifim (CAS number 891859-12-4, or 1-[[6-[(2-methyl- [(4-(4-propylphenyl)methoxy]-1-methyl-3,4-dihydronaphthalene -2-yl]methyl]azetidine-3-carboxylic acid) is a sphingosine-1-phosphate ( S1P) receptors S1P1 and S1P5 interact with selalifimod. Delays disease onset and reduces lymphocytes in the spinal cord in a rat experimental model of EAE Inhibits invasion and prevents disease relapse in a non-obese diabetic mouse model of relapsing-remitting EAE Prevent.

[0092] [ka]

[0093] STAT3 inhibitors

[0094] For purposes of this invention, a "STAT3 inhibitor" is defined as a compound that inhibits the growth of STAT3 by pro-inflammatory cytokines. Compounds that can decrease the activity of STAT3 in inducing signal transduction STAT3 inhibition has been shown to reduce inflammatory cytokines in vitro and in vivo. This can be measured by suppressing the production of pSTAT in myelin-specific CD4 T cells. Dose-dependent suppression of IL-3 expression and IL-17 production in myelin-specific CD4 T cells It inhibits IL-6-induced IL-17 production.

[0095] The signal transducer and activator of transcription 3 gene (STAT3) regulates several pathways and cells It is a transcription factor involved in the formation of neurites and is involved in the protection of axons from axonal transection or axonal regeneration. It is also a sensor of axonal damage. At the immunological level, STAT3 acts on regulatory T cells. The anti-inflammatory response mediated by TH17 cells and the pro-inflammatory response mediated by TH17 cells It is a key mediator of both the IL-10 and IL-6 signaling pathways. Non-limiting examples of STAT3 inhibitors include (S,E)-3-(6-bromopyridinyl) N-(1-phenylethyl)-2-cyano-N-(2-phenyl-2-yl)acrylamide (STAT3 Inhibitor III, WP1066, CAS 857064-38-1), 4-((3-(Cal (4-hydroxy-1-naphthyl)sulfamoyl)benzoic acid Acid (STAT3 inhibitor IX Cpd188-CAS 823828-18-8), STA T3 inhibitor peptide (composition formula: C 38 H 63 N8O13 P or C 92 H 157 N 20 O 24 P or C 92 H 156 N 20 O 21 , SEQ ID NO: 1), 6-nitrobenzo[b]thio Phen-1,1-dioxide (STAT3 inhibitor V Stattic-CAS 1998 3-44-9), 2-hydroxy-4-[[[[(4-methylphenyl)sulfonyl]o [Oxy]acetyl]amino]-benzoic acid (STAT3 inhibitor VI S3I-201-CAS 501919-59-1), ethyl-1-(4-cyano-2,3,5,6-tetrafluoroethylene (fluorophenyl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3 -carboxylate (STAT3 inhibitor VII-CAS 1041438-68-9), 5,15-Diphenylporphyrin (STAT3 inhibitor VIII) 5,15-DPP-C AS 22112-89-6), PIAS3 (UniprotKB database accession Version 2 (V2) of the sequence of the application number Q9Y6X2, December 7, 2004, N-( 5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-2-phenyl Quinoline-4-carboxamide (STAT3 inhibitor XI STX-0119), STAT 3. Inhibitor XII SPI (SEQ ID NO: 2), N-(1',2-dihydroxy-1,2'-biphenyl) Naphthalen-4'-yl)-4-methoxybenzenesulfonamide, (CAS number: 43 2001-19-9, F1113-0789, STAT3 inhibitor XIII C188-9 ) are mentioned.

[0096] SEQ ID NO: 1 disclosed above is H-Pro-Tyr-(PO3H2)-Leu-Ly s-Thr-Lys-Ala-Ala-Val-Leu-Leu-Pro-Val-Le u-Leu-Ala-Ala-Pro-OH (also known as STAT3 inhibitor peptide) be.

[0097] SEQ ID NO: 2 disclosed above is H2N-FISKERERAILSTKPPGTFL LRFSESSK-CO3H (also known as STAT3 inhibitor XII SPI). In one embodiment, any one or more of the various embodiments described above or below may be used throughout the description. In combination with the above features, STAT3 inhibitors inhibit STAT3 activation and STAT3-dependent The target gene is S3I-201, an amidosalicylic acid compound that selectively inhibits transcription of the serotonin receptor. The chemical name of 3I-201 is 2-hydroxy-4-[[[[(4-methylphenyl) S3I-201 is a benzoic acid. It has the following structure:

[0098] [ka]

[0099] Therapeutic doses of STAT3 inhibitors (e.g., S3I-201) can inhibit immune responses when administered alone. A particular therapeutic or optimal dose is about 5 Therefore, the subtherapeutic dose is less than 5 mg / kg in mice. In particular, subtherapeutic doses are less than 0.1-5 mg / kg in mice (0 (equivalent to an HED of less than 0.01mg / kg to 0.4mg / kg).

[0100] Combination of the Invention

[0101] As described above, the present invention provides a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable derivative thereof, as defined above; Salt and b) as defined above; i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) an S1PR modulator, and iii) STAT3 inhibitors and one or more drugs selected from the group consisting of The present invention relates to a combination comprising:

[0102] In one embodiment, optionally, as described above or below throughout the description. In combination with one or more features of the various embodiments, the combination of the present invention may include: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable derivative thereof, as defined above; Salt and b) as defined above; i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) an S1PR modulator, and iii) STAT3 inhibitors and one or more drugs selected from the group consisting of The present invention relates to a combination comprising:

[0103] In another embodiment, optionally, any of the above or below described throughout the description. In combination with one or more features of the various embodiments, the combination of the present invention may include: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable derivative thereof, as defined above; Salt and b) as defined above; i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) an S1PR modulator, and iii) STAT3 inhibitors and one or more drugs selected from the group consisting of For combinations including The amount of a) and the amount of b) in combination are therapeutically effective.

[0104] In another embodiment, optionally, any of the above or below described throughout the description. In combination with one or more features of the various embodiments, the present invention provides a combination of: a) The amount of a) by itself is sub-therapeutic and the amounts of a) and b) in combination are therapeutic. It is effective above.

[0105] In another embodiment, optionally, any of the above or below described throughout the description. b) in combination with one or more features of the various embodiments, in the combination of the present invention; The amount of a) by itself is sub-therapeutic and the amounts of a) and b) in combination are therapeutic. It is effective above.

[0106] In another embodiment, optionally, any of the above or below described throughout the description. In combination with one or more features of the various embodiments, the present invention provides a combination of: a) The amount of a) and the amount of b) are sub-therapeutic amounts by themselves, and the amounts of a) and b) are sub-therapeutic amounts by themselves. In combination, they are therapeutically effective.

[0107] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, the combination of the present invention comprises a) a compound of the formula defined above Compounds of formula (I), specifically G79 (BN201), G80 (BN119) and G8 1 (BN120), and more specifically G79 (BN201). and b) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof: Specifically, the fumarate may be selected from dimethyl fumarate, monomethyl fumarate, and monoethyl fumarate. or It consists of them.

[0108] Specifically, compounds G79 (BN201), G80 (BN119) and G81 (BN12 0), more particularly G79 (BN201), Other salts which may be combined with the compounds of formula (I) include salts of fumaric acid, disodium fumarate, (sodium fumarate) and ferrous fumarate (iron(II) fumarate).

[0109] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more of the features of the present invention, the combination of the present invention is a) as defined above Compounds of formula (I), in particular G79 (BN201), G80 (BN119) and G 81 (BN120), and more specifically G79 (BN201). and b) specifically consisting of fingolimod, siponimod, and ozanimod. an S1PR modulator selected from the group, more particularly fingolimod; It comprises or consists of:

[0110] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more of the features of the present invention, the combination of the present invention is a) as defined above Compounds of formula (I), in particular G79 (BN201), G80 (BN119) and G 81 (BN120), and more specifically G79 (BN201). a) a compound; and b) a STAT3 inhibitor as defined herein, which is S3I-201; It comprises or consists of:

[0111] Other drugs to be combined with drugs (a) and (b)

[0112] In another specific embodiment of the first aspect, (a) a compound of formula (I) as defined above (such as i.e., all possible pharmaceutically or veterinarily acceptable salts thereof as set forth above) b) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, a sphingomyelin S1PR Modulators and Signal Transduction and one or more drugs selected from the group consisting of STAT3 inhibitors. In combinations containing other drugs for treating multiple sclerosis, In more specific embodiments, these drugs include interferon-beta, glatiramacetate, natalizumab, alentuzumab, teriflunomide, cladribine, oclizumab and and combinations thereof. The drugs include, among others, diroximel fumarate (ALKS8700), evobrutinib, off Atumumab, ublituximab, amiloride, fluoxetine, ibudilast, masitini , MD1003 (biotin), opicinumab (anti-LINGO-1, BIIB033), Riluzole, simvastatin, idebenone, temelimb (GNbAC1), nebilizumab (MEDI-551), naltrexone.

[0113] Pharmaceutical and veterinary compositions, packages or kits of parts

[0114] The present invention also provides a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, i) an S1PR modulator, and iii) a STAT3 inhibitor. and one or more drugs that a pharmaceutical composition comprising, together with one or more pharmaceutically or veterinarily acceptable excipients or carriers. for an article or veterinary composition or a package or kit of parts, The compounds of formula (I) and the drugs are as defined in the above aspects and related embodiments. It is.

[0115] The phrase "pharmaceutically or veterinarily acceptable excipient or carrier" means a pharmaceutical or veterinarily acceptable excipient or carrier. Refers to a veterinarily acceptable material, composition or vehicle. Each component is a pharmaceutical composition or Pharmaceutically or veterinarily acceptable in the sense of being compatible with the other ingredients of the veterinary composition. It must also be based on a reasonable benefit / risk ratio and not on excessive human and animal models without toxicity, irritation, allergic reaction, immunogenicity or other problems or complications. and be suitable for use involving contact with animal tissues or organs.

[0116] a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) a compound of formula (IV), or a pharmaceutically or veterinarily acceptable salt thereof, S1P and one or more drugs selected from the group consisting of R modulators, and STAT3 inhibitors. ,of, together with one or more pharmaceutically or veterinarily acceptable excipients or carriers, The compound of formula (I) and the drug are defined above, and the amount of a) and the amount of b) are combined. Together they are therapeutically effective, A single pharmaceutical or veterinary composition forms part of the present invention.

[0117] The term "therapeutically effective" as used herein throughout this specification means that, when administered, , preventing the onset of, or alleviating to some extent, one or more of the symptoms of the disease it is intended to address This refers to the amount of a compound or combination of compounds sufficient to This is to achieve the desired therapeutic effect in subjects being treated for MS, NMO and / or optic neuritis. The precise therapeutically effective amount is the amount of compound, combination of compounds, or composition that results in a therapeutically effective effect. The amount of the composition that will produce the most effective results in terms of therapeutic efficacy in a given subject. The specific dosage of the compounds of the present invention to achieve the above benefits will depend on the particular circumstances of each individual patient. In particular, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, The dosage and route of administration may vary depending on the above combination, composition or kit of Specific doses of the compounds of the present invention for therapeutic benefit when administered in parts are: It may vary with respect to the specific dose of the compound used as a single active agent.

[0118] Specific embodiments of the above combinations are provided in a single pharmaceutical or veterinary composition of the invention. It is also applicable as a specific embodiment of a composition, package or kit of parts.

[0119] Thus, in one embodiment, optionally, throughout all descriptions above or below A single medical device as defined above in combination with one or more features of the various embodiments described herein. In a pharmaceutical or veterinary composition, the amount of a) is by itself a sub-therapeutic amount. and the amounts of a) and b) in combination are therapeutically effective.

[0120] In another embodiment, any of the various components described above or below throughout the description may be used. A single pharmaceutical composition as defined above in combination with one or more features of the embodiments or In veterinary compositions, the amount of b) is by itself a sub-therapeutic amount, and The amounts of b) are therapeutically effective in combination.

[0121] In another embodiment, any of the various components described above or below throughout the description may be used. A single pharmaceutical composition as defined above in combination with one or more features of the embodiments or In veterinary compositions, the amount of a) and the amount of b) are by themselves sub-therapeutic amounts. and the amounts of a) and b) in combination are therapeutically effective.

[0122] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the embodiments, a single pharmaceutical composition or veterinary composition as defined above may be used. In a pharmaceutical composition, the amount of a) and the amount of b) are therapeutic amounts by themselves, and and b) in combination are therapeutically effective.

[0123] The terms "subtherapeutic" or "suboptimal amount" as used throughout this specification, and "Subtherapeutic dose" or "suboptimal dose" are all used interchangeably as synonyms. The term "suboptimal" refers to an amount / dose that is not therapeutically effective by itself. "Sub-therapeutic dose" or "sub-therapeutic dose" refers to a dose that, when used in single compound therapy, Health authorities have approved it as effective for certain target diseases, such as optic neuritis, NMO, and / or optic neuritis. the optimal (or therapeutic) dose (or dose range) approved for the compound in Therefore, the term "subtherapeutic" is used in embodiments or practice herein. Where it appears in the embodiments, it may be used by health authorities (i.e., the European Medicines Agency, the US Food and Drug Administration, etc. are recognized as effective when used as single-compound therapy for specific diseases. It is understood that the amount is less than or equal to the amount of a particular compound for which it is approved. The effective dose of BN201 (compound of formula I) in the If so, the suboptimal dose is 0.5mg / kg to 25mg / kg. The approved dose of acetaminophen (an SP1R inhibitor) is 0.5 mg / day in humans, and The most effective doses tested are 1.25 mg / day and 5 mg / day. SP1R inhibition Suboptimal doses of the agent (i.e., fingolimod) are less than 0.5 mg / day, 0.05 mg / day g / day to 0.4 mg / day. Similarly, the approved dose of dimethyl fumarate is For the first 24 hours, the dose is 120 mg twice daily, then approximately 240 mg twice daily. Suboptimal doses of dimethyl are less than about 120 mg twice daily for 1 week, and and then twice daily at a dose of less than about 240 mg. (I) and a compound of formula (IV) or a pharmaceutical or veterinary an S1PR modulator and a STAT3 inhibitor; The amount of one or more compounds administered in the combination, composition or kit of parts may vary. When used in combination, the effective amount is less than when used as the sole active agent.

[0124] The terms "dosage" and "dose" are used interchangeably herein.

[0125] In another particular embodiment, the present invention also optionally comprises any of the above or following throughout the description. In combination with one or more features of the various embodiments described below: i) a compound of formula (I) as defined above or a pharmaceutically or veterinarily acceptable derivative thereof A certain amount of the salt is mixed with one or more pharmaceutically or veterinarily acceptable excipients or carriers. a first pharmaceutical or veterinary composition comprising: ii) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, S1P and one or more drugs selected from the group consisting of R modulators and STAT3 inhibitors. the amount of the compound, together with one or more pharmaceutically or veterinarily acceptable excipients or carriers, 2. The pharmaceutical or veterinary composition of claim 2, iii) instructions for using i) and ii) in combination; The first and second compositions are separate compositions, and the amount of the compound of formula (I) in i) and ii) the amount of one or more drugs in a package or kit that is therapeutically effective in combination; Regarding to of parts.

[0126] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the embodiments, the kit-of-parts defined above may comprise a compound of formula The amounts of both the compound (I) and the one or more drugs (ii) are therapeutic amounts by themselves, and The amount of the combination of the compound of formula (I) in ii) and the one or more drugs in ii) is therapeutically effective. be.

[0127] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the embodiment, in a kit of parts as defined above, The amount of the compound of formula (I) in i) is a subtherapeutic amount by itself, and the amount of the compound of formula (I) in i) is a The combination of the amounts of the compound and the amount of the one or more drugs in ii) is therapeutically effective.

[0128] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in a kit of parts as defined above, ii) is a sub-therapeutic amount of one or more drugs by itself, and i) a compound of formula (I) and ii) the amount of the combination of one or more drugs is therapeutically effective.

[0129] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in the kit of parts defined above, i) The amount of the compound of formula (I) and the amount of the one or more drugs in ii) may not, by themselves, be a subtherapeutic amount. and the amount of the combination of i) the compound of formula (I) and ii) one or more drugs is It is therapeutically effective.

[0130] Throughout this specification, features may be optionally combined with one or more of the features of the various embodiments described above or below. Specific embodiments of this kit-of-parts taken together include a pharmaceutical or veterinary composition. a cartridge having a separate compartment containing one of i) and ii) and Instructions for use in conjunction with the product, in particular leaflets, data carriers (i.e. CDs, and instructions in a form selected from the group consisting of a QR code.

[0131] The choice of pharmaceutical or veterinary formulation will depend on the nature of the active compound and its route of administration. Any route of administration may be used, including oral, parenteral and topical administration.

[0132] For example, the pharmaceutical or veterinary composition may be formulated for oral administration, and may be administered in a solid form. or in liquid form may contain one or more physiologically compatible carriers or excipients. These preparations may contain conventional ingredients such as binders, fillers, lubricants, and acceptable wetting agents. It may contain minutes.

[0133] The pharmaceutical or veterinary composition may be administered in a conventional injectable solution such as water or a suitable alcohol. The compound may be formulated for parenteral administration by combining it with a suitable liquid carrier. Conventional pharmaceutical or veterinary excipients for injection, such as steroids and buffers, may be included in such compositions. These pharmaceutical or veterinary compositions may be administered intramuscularly, intraperitoneally, or intravenously. It can be done.

[0134] The pharmaceutical composition may be formulated for topical administration. Formulations include creams, lotions, These include gels, powders, solutions and patches, in which the compound is dispersed or dissolved in a suitable excipient. can be.

[0135] The pharmaceutical composition may be in any form, in particular in the form of tablets, for immediate or delayed release, Pellets, capsules, aqueous or oily solutions, suspensions, emulsions, or water before use or in a dry powder form suitable for reconstitution with another suitable liquid medium.

[0136] Suitable excipients and / or carriers, and their amounts, will depend on the type of formulation being prepared. and can be readily determined by one skilled in the art.

[0137] Treatment of inflammatory neurological diseases or conditions that result in destruction or degeneration of axons or myelin

[0138] a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) an S1PR modulator and iii) a STAT3 inhibitor. and one or more drugs, The compound of formula (I) and one or more drugs are as defined above and administered to a subject in need thereof. Inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin in combination, single pharmaceutical composition or veterinary composition for use in the treatment and / or prophylaxis of The pharmaceutical composition, package or kit-of-parts form part of the present invention.

[0139] This aspect also relates to inflammatory neurological diseases that can result in destruction or degeneration of axons or myelin. or may be translated into a method for treating and / or preventing a condition, said method being carried out by a person in need thereof. a mammalian subject, including a human subject, a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; iii) an S1PR modulator, and iv) a STAT3 inhibitor. one or more drugs; together with one or more pharmaceutically or veterinarily acceptable excipients or carriers, ) and the drug are as defined above, or Rui is, b) administering a package or kit-of-parts as defined in the above embodiments. Includes: (a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; (b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, i) an S1PR modulator and iii) a STAT3 inhibitor. and one or more drugs, wherein the compound of formula (I) and the drug are as defined above. As defined, an inflammatory neuropathic disorder that can result in destruction or degeneration of axons or myelin the combination for preparing a medicament for treating and / or preventing a disease or condition. The use of combinations also forms part of the present invention.

[0140] In certain embodiments, various of the above or below described throughout the description may optionally be used. In combination with one or more features of the embodiments, the medicament may comprise a single compound as defined in the above embodiments. or a package or veterinary composition as defined above. Includes kit of parts.

[0141] A single pharmaceutical or veterinary composition or a package or kit of parts In another specific embodiment of any of the above or below throughout the description, In combination with one or more features of the various embodiments described, the treatment may comprise: (a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; (b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, i) an S1PR modulator and iii) a STAT3 inhibitor. one or more drugs; and the compound of formula (I) and the drug are administered simultaneously, concurrently, separately, or sequentially. , as defined above.

[0142] In one embodiment, any of the various implementations described above or below throughout the entire description may be used. Combinations for use as described above in combination with one or more features of the form, single The pharmaceutical or veterinary composition, package or kit-of-parts may comprise: a) a compound of formula (I) as defined above or a pharmaceutically or veterinarily acceptable derivative thereof Salt and b) i) a compound of formula (IV) or a pharmaceutical or veterinary derivative thereof, as defined above; an acceptable salt, ii) an S1PR modulator, and iii) a STAT3 inhibitor. and a drug selected from the group:

[0143] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. Combinations, single compositions, and combinations for use as described above in combination with one or more features of the embodiments. The pharmaceutical or veterinary composition, package or kit of parts of a) a compound of formula (I) as defined above or a pharmaceutically or veterinarily acceptable derivative thereof Salt and b) i) a compound of formula (IV) or a pharmaceutical or veterinary derivative thereof, as defined above; an acceptable salt, ii) an S1PR modulator, and iii) a STAT3 inhibitor. and a drug selected from the group The amount of a) and the amount of b) in combination are therapeutically effective.

[0144] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. A single pharmaceutical composition for use as described above in combination with one or more of the features of the embodiments or in a veterinary composition, package or kit of parts, the amount of a) and b The amounts of a) and b) are both therapeutic amounts by themselves, and the amounts of a) and b) are therapeutic amounts in combination. It is therapeutically effective.

[0145] In another embodiment, any of the various compounds described above or below throughout the description may be used. Combinations for use as indicated above in combination with one or more features of the embodiments. in a single pharmaceutical or veterinary composition, package or kit of parts In this case, the amount of a) by itself is sub-therapeutic, and the amounts of a) and b) in combination are In combination, it is therapeutically effective.

[0146] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. Combinations, single compositions, and combinations for use as described above in combination with one or more features of the embodiments. b) in a pharmaceutical or veterinary composition, package or kit of parts of The amount of a) by itself is sub-therapeutic and the amounts of a) and b) in combination are therapeutically effective. It is effective.

[0147] In another embodiment, any of the various components described above or below throughout the description may be used. A single pharmaceutical composition as defined above in combination with one or more features of the embodiments or In a veterinary composition, package, or kit-of-parts, the amount of a) and the amount of b) is a sub-therapeutic amount by itself, and the amounts of a) and b) are therapeutically effective in combination. It is effective.

[0148] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. Combinations, single compositions, and combinations for use as described above in combination with one or more features of the embodiments. In a pharmaceutical or veterinary composition, package or kit of parts of the invention, comprising: a) Subtherapeutic doses are 0.5mg / kg to 25mg / kg (0.04mg / kg to 2mg / kg (corresponding to a human equivalent dose (HED) of 100 mg / kg).

[0149] In another embodiment, any of the various embodiments described above or below throughout the description may be used. Combinations, single compositions, and combinations for use as described above in combination with one or more features of the embodiments. b) in a pharmaceutical or veterinary composition, package or kit of parts of is a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, more particularly Specifically, dimethyl fumarate, and a sub-therapeutic amount of a compound of formula (IV) is 120 mg twice daily (1.7 mg / kg twice daily for a human patient weighing 70 kg) g), and then about 240 mg twice a day (corresponding to a human patient weighing 70 kg). (equivalent to 3.4 mg / kg twice daily)

[0150] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. Combinations, single compositions, and combinations for use as described above in combination with one or more features of the embodiments. b) in a pharmaceutical or veterinary composition, package or kit of parts of is an SP1R modulator, and the subtherapeutic dose in humans is 0.05 mg / day to 0.4 mg / day. More specifically, the amount is 0.05 mg / day to 0.1 mg / day. .

[0151] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. Combinations, single compositions, and combinations for use as described above in combination with one or more features of the embodiments. b) in a pharmaceutical or veterinary composition, package or kit of parts of is a STAT3 inhibitor, and subtherapeutic doses range from 0.1 to 5 mg / kg in mice. (corresponding to an HED of 0.01 mg / kg to 0.4 mg / kg).

[0152] In one embodiment, any of the various implementations described above or below throughout the entire description may be used. In combination with one or more features of the formulation, a single pharmaceutical composition or or veterinary composition, package or kit of parts is a) specifically G79(B N201), G80 (BN119) and G81 (BN120). a compound of formula (I) as defined above, more particularly a compound of formula G79 (BN201); and b) specifically dimethyl fumarate, monomethyl fumarate and monoethyl fumarate. and more particularly dimethyl fumarate, and a pharmaceutically or veterinarily acceptable salt of

[0153] Specifically, G79 (BN201), G80 (BN119) and G81 (BN120) and more particularly the compound G79 (BN201). Other salts that may be combined with the compounds of formula (I) are fumarates, disodium fumarate, (sodium fumarate) and iron fumarate (iron(Ii) fumarate), recognized that they were active in combination.

[0154] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. A single pharmaceutical composition for use as described above in combination with one or more of the features of the embodiments or the veterinary composition, package or kit of parts is a) specifically G79(B N201), G80 (BN119) and G81 (BN120). a compound of formula (I) as defined above, in particular the compound G79 (BN201), b) Specifically selected from the group consisting of fingolimod, siponimod and ozanimod, and an S1PR modulator, more specifically fingolimod, or It consists of:

[0155] In another embodiment, any of the various embodiments described above or below throughout the entire description may be used. A single pharmaceutical composition for use as described above in combination with one or more of the features of the embodiments or the veterinary composition, package or kit of parts is a) specifically G79(B N201), G80 (BN119) and G81 (BN120). a compound of formula (I) as defined above, more particularly the G79 (BN201) compound and b) a STAT3 inhibitor as defined herein, which is S3I-201; or consisting of them.

[0156] In another embodiment, any of the various embodiments described above or below throughout the description may be used. A single pharmaceutical composition for use as described above in combination with one or more of the features of the embodiments or the veterinary composition, package or kit-of-parts comprises: a) specifically compound G From the group consisting of 79 (BN201), G80 (BN119) and G81 (BN120) A compound of formula (I) as defined above is selected, more particularly G79 (BN201). and b) a STAT3 inhibitor as defined herein, specifically S3I-201. and, the amount of a) and the amount of b) in combination are therapeutically effective; Chronic inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin or in the advanced stages, specifically in multiple sclerosis (MS), optic neuritis (NMO), optic neuritis, Baro's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease, or a chronic or advanced stage of a disease or condition selected from the group consisting of any combination of It is used in.

[0157] Also, inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin. In a subject in need of treatment and / or prevention of together with one or more pharmaceutically or veterinarily acceptable excipients or carriers; i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) S1PR and iii) one or more selected from the group consisting of a STAT3 inhibitor. 1. For simultaneous, concurrent, separate or sequential administration in combination with a drug a compound of formula (I) together with one or more pharmaceutically or veterinarily acceptable excipients or carriers; or a pharmaceutically or veterinarily acceptable salt thereof also form part of the present invention. , the compound of formula (I) and the one or more drugs are as defined above.

[0158] Also, inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin. In a subject in need of treatment and / or prevention of a compound of the formula, together with one or more pharmaceutically or veterinarily acceptable excipients or carriers; (I) or a pharmaceutically or veterinarily acceptable salt thereof, Sometimes, one or more pharmaceutical or veterinary agents for administration in combination, separately, or sequentially. i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt, ii) an S1PR modulator, and iii ) one or more drugs selected from the group consisting of STAT3 inhibitors also form part of the present invention. , the compound of formula (I) and the drug are as defined above.

[0159] In another particular embodiment of the above combination, the combined and a single pharmaceutical or veterinary composition, or a package or kit of inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin Symptoms include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Baro's disease, and Schilder's disease. acute hemorrhagic leukoencephalitis, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease, or any combination thereof combinations thereof.

[0160] As used herein (see Examples below), "neuroprotection," "neuroprotective," The term "neuroprotective effect" also refers to the prevention of death or death of neural cells, including neurons and glia. or the ability to prevent or reduce damage to, or after damage to, e.g., the brain, central nervous system or Following injury resulting from or related to a pathological or injurious condition of the peripheral nervous system Rescue, revive, or resurrect nerve cells and their extensions, including axons, dendrites, and synapses This neuroprotective effect therefore refers to the ability of neurons to Neuroprotective effects include the ability to maintain or restore neuronal function. It stabilizes the function of neurons or helps normalize nerve cell function. It prevents the loss of vitality or function of neurons, which is the progressive deterioration of neurons that leads to cell death. It encompasses inhibition, which refers to the protection of neurons from any detectable stress. Neuroprotection involves the regeneration of neurons and myelin, i.e., the repopulation of neurons after disease or injury. Repopulation of the group is included.

[0161] The pharmaceutical compositions described herein can be administered to a subject in need thereof at least once a day up to once a month. It may be administered once or every few months.

[0162] A therapeutic amount or amounts of each of the compounds of formula (I) and one or more drugs disclosed above The following amounts may also be used in combination, in a single pharmaceutical or veterinary composition disclosed above: The dosage can be adjusted taking into consideration the body weight of the subject to be administered. Such amounts may be determined by considering the guidelines in the literature.

[0163] For purposes of this invention, the term "treatment" or variations of that term refers to treatment of a patient who is already suffering from a disease. Inflammatory neurological diseases or conditions that can result in destruction or degeneration of axons or myelin in affected patients The term "prophylaxis" means reducing, stabilizing, or inhibiting the progression of a condition or its symptoms. , as used herein, the prevention of the onset of clinically evident inflammatory neurological diseases or conditions such as those described above. Therefore, the present invention is used to refer to both the onset and delay of the onset of the disease. As used herein, the terms "treat," "treating," and "treatment" refer to the treatment of a disease. To cause complete or partial regression, eliminate or reduce the occurrence of symptoms associated with the above diseases , preventing or delaying the onset or risk of onset of the above diseases. reducing, preventing, delaying or reducing the rate and / or occurrence of recurrence; Preventing, delaying or reducing the time to progression of the disorder and providing a neuroprotective effect For example, treatment may refer to the treatment of a person who is in need thereof. It may refer to a reduction in the accumulation of damage in a subject. In certain embodiments, treatment also refers to neuroprotection. The term "immunomodulatory response" may refer to providing a therapeutic effect, an immunomodulatory response, or some combination thereof. .

[0164] The terms "patient" and "subject" are used interchangeably herein.

[0165] As used herein, the term "about" means 5% or less of a stated value or range of values. This means within 10%.

[0166] Salts of formula (II): Fumarate derivatives of compounds of formula (I)

[0167] The present invention also relates to salts of formula (II) which are fumarate derivatives of certain compounds of formula (I). death: [ka] wherein R1, R2 and R3 are as defined above for compounds of formula (I). and R4 is (C1-C6) alkyl.

[0168] The preparation of salts of formula (II) can be carried out by methods known in the art, for example , which can be prepared by conventional chemical methods from the parent compound of formula (I) containing a basic moiety. Generally, such salts can be prepared by, for example, dissolving the salt in water or an organic solvent (e.g., methanol). in water and an organic solvent, The free acid forms of these compounds may be administered in stoichiometric amounts of the appropriate pharmaceutical or veterinary is prepared by reacting with a chemically acceptable acid: [ka] wherein R4 is as defined above.

[0169] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (II), R1 is a fluorophenyl nyl, more particularly 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl Phenyl, and even more particularly 2-fluorophenyl.

[0170] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (II), R1 is halogen , (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkoxy. one or two substituents selected from the group consisting of alkyl, preferably halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and one or two substituents selected from the group consisting of halogen, methyl, ethyl, and the like. propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoro fluoro, further substituted with one or two substituents selected from the group consisting of methyl; It is phenyl.

[0171] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more features of the present invention, in compounds of formula (II), R1 is chlorophenyl phenyl, more specifically 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl and even more specifically, R1 is 2-chlorophenyl.

[0172] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (II), R1 is halogen , (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkoxy. one or two substituents selected from the group consisting of alkyl, preferably halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and one or two substituents selected from the group consisting of halogen, methyl, ethyl, and the like. propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoro chlorofluorocarbons further substituted with one or two substituents selected from the group consisting of methyl; It is Venil.

[0173] In one embodiment, any of the various embodiments described above or below throughout the description may be used. In combination with one or more of the features of the present invention, in compounds of formula (I), R1 is bromophenyl , more particularly 2-bromophenyl, 3-bromophenyl or 4-bromophenyl, Even more specifically, it is 2-bromophenyl.

[0174] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (II), R1 is halogen , (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkoxy. one or two substituents selected from the group consisting of alkyl, preferably halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and one or two substituents selected from the group consisting of halogen, methyl, ethyl, and the like. propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoro methyl, It is Venil.

[0175] In one embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (II), R1 is iodo Phenyl, more specifically 2-iodophenyl, 3-iodophenyl or 4-iodophenyl phenyl, and even more particularly 2-iodophenyl.

[0176] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (II), R1 is halogen , (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkoxy. one or two substituents selected from the group consisting of alkyl, preferably halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and one or two substituents selected from the group consisting of halogen, methyl, ethyl, and the like. propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoro iodofluorene, further substituted with one or two substituents selected from the group consisting of methyl; It is Venil.

[0177] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the present invention, in compounds of formula (II), R1 is trifluoro Methylphenyl, more specifically 2-trifluoromethylphenyl, 3-trifluoromethylphenyl phenyl or 4-trifluoromethylphenyl, and more particularly 2-trifluoromethylphenyl It is fluoromethylphenyl.

[0178] In another embodiment, any of the various implementations described above or below throughout the description may be used. In combination with one or more features of the form, in compounds of formula (II), R1 is halogen , (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkoxy. one or two substituents selected from the group consisting of alkyl, preferably halogen, (C1 -C4) alkyl, (C1-C4) alkoxy and halo(C1-C4) alkyl and one or two substituents selected from the group consisting of halogen, methyl, ethyl, and the like. propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoro a triflate further substituted with one or two substituents selected from the group consisting of methyl; It is oromethylphenyl.

[0179] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the above embodiment, in the compound of formula (II), R1 is pyrrolidine- It is 1-yl.

[0180] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the above embodiment, in the compound of formula (II), R2 is 2-oxo- It is pyrrolidin-1-yl-methyl.

[0181] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the present invention, in compounds of formula (II), R2 is a sulfamoyl sulfamoylphenyl, more specifically 2-sulfamoylphenyl, 3-sulfamoylphenyl or 4-sulfamoylphenyl, even more specifically 4-sulfamoylphenyl It is.

[0182] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the above embodiment, in the compound of formula (II), R3 is 2-methylpropyl. It's Ropil.

[0183] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the above embodiment, in compounds of formula (II), R1 is 2-fluoro phenyl or pyrrolidin-1-yl, and R2 is 2-oxo-pyrrolidin-1-yl methyl or 4-sulfamoylphenyl.

[0184] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the present invention, the compound of formula (II) and therefore the compound of formula (III) In the compound, R4 is (C1-C4) alkyl, more preferably methyl, ethyl, Selected from the group consisting of propyl, isopropyl, butyl, isobutyl and tert-butyl It is selected.

[0185] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more features of the present invention, the compound of formula (II) and therefore the compound of formula (III) In the compound, R4 is methyl.

[0186] In another embodiment, any one of the various embodiments described above or below may be used throughout the description. In combination with the above features, the compound of formula (II) is as follows:

[0187] [ka]

[0188] A specific salt of formula (II), more specifically the fumarate salt of BN201 (referred to herein as BN 201-fumaric acid salt or compound of formula (IIa) (see Example 5), Its neuroprotective effect against BN201 or fumarate alone was evaluated (see Example 6 The results showed that both BN201 and fumarate inhibited the oxidative stress-induced However, BN201-Huma partially rescued neurons from death. The phosphate salts showed significantly higher levels of protection than either compound alone, demonstrating synergistic neuroprotective effects. This suggests the existence of a protective effect.

[0189] Therefore, all of these salts of formula (II) are useful for maintaining neuronal health. and / or as an active agent for rescuing damaged neurons in a pharmaceutical composition or It may be added to veterinary compositions.

[0190] Thus, the present invention also provides a method for administering a therapeutically effective amount of a compound of formula (II) to one or more pharmaceutical or a pharmaceutical or veterinary composition comprising the compound or compound of formula (I) together with a veterinarily acceptable excipient or carrier. Related to products.

[0191] The present invention also provides a method for treating inflammatory neurological disorders or conditions that can result in destruction or degeneration of axons or myelin. or a condition in a subject in need of such treatment and / or prevention. A salt of formula (II) or a pharmaceutical or veterinary composition containing same for use in the prevention of Related to products.

[0192] This aspect also relates to inflammatory neurological diseases that can result in destruction or degeneration of axons or myelin. or as a method for treating and / or preventing symptoms, said method being applicable to a person in need thereof. a therapeutically effective amount of a salt of formula (II), or a compound containing the same, administered to a mammalian subject, including a human subject, a pharmaceutical or veterinary composition comprising the compound of formula (I) or (II) in combination with one or more pharmaceutically or veterinarily acceptable excipients; This includes administering with a vehicle or carrier.

[0193] Treating inflammatory neurological diseases or conditions that can result in the destruction or degeneration of axons or myelin The use of a salt of formula (II) for preparing a medicament for the treatment and / or prevention of Forms part of the Ming.

[0194] In one embodiment, any of the various embodiments described above or below throughout the entire description may be used. In combination with one or more of the features of the present invention, a salt of formula (II) for the use disclosed above. or pharmaceutical or veterinary compositions, or kits of parts containing same, Myocardial infarction (MS), neuromyelitis optica (NMO), optic neuritis, Baro's disease, Schilder's disease, transverse myelopathy Myelitis dissecans, acute hemorrhagic leukoencephalitis, Marburg disease, or any combination thereof an inflammatory neuropathic agent that can result in destruction or degeneration of axons or myelin, selected from the group consisting of: Used for meridian disorders or symptoms.

[0195] In one embodiment, any of the various implementations described above or below throughout the entire description may be used. and a salt of formula (II), or a pharmaceutical or veterinary composition, in combination with one or more of the features of the present invention. The pharmaceutical composition is a salt of formula (IIa).

[0196] Throughout the specification and claims, the word "comprises" and variations of this word are used interchangeably. It is not intended to exclude any technical features, additives, ingredients or steps. Furthermore, the term "comprise" encompasses the case of "consisting of." These aspects and features will become apparent to those skilled in the art upon examination of this specification or may be readily apparent to those skilled in the art upon examination of this specification or upon practicing the invention. The following examples and figures are provided by way of illustration and are not intended to be limiting of the invention. Furthermore, the present invention is not intended to limit the scope of the invention to the specific All possible combinations of preferred embodiments are covered. [Example]

[0197] Example 1: Pharmaceutical efficacy of BN201 (an example of a compound of formula (I))

[0198] Three clinical trials support the medical benefits of BN201 in the treatment of MS and optic neuritis These studies were aimed at testing the neuroprotective effects of BN201. This was performed in a mouse model of experimental autoimmune encephalomyelitis (EAE), which exhibits neurodegeneration and demyelination. Myelin basic protein (MBP) or myelin proteolipid protein (PL Immune responses to P induce lesions located primarily in the spinal cord, but not in myelin oligodendrocytes. Immunization with myocyte glycoprotein (MOG) inhibits lesions located primarily in the optic nerve and spinal cord. In the literature, the EAE model has been shown to cause irreversible vision loss. Therefore, it is commonly used as a model for MS and optic neuritis (Kezuka et al. al,Analysis of the pathogenesis of exper imental autoimmune optic neuritis.J Biom ed Biotechnol.2011;2011:294046;Guo et al ,Decreased neural stem / progenitor cell p roliferation in mice with chronic / nonrem itting experimental autoimmune encephalo myelitis.Neurosignals.2010;18(1):1-8).

[0199] Study EAE-C03: Two different studies were conducted in comparison with placebo according to the following experimental design: The following concentrations of BN201 were tested by daily ip administration: - Placebo-treated animals affected by EAE (pathological control group); EAE-affected animals treated with BN201 at a dose of 50 mg / kg, and EAE-affected animals treated with BN201 at a dose of 100 mg / kg.

[0200] To test the therapeutic properties of the molecules, treatment was initiated during the chronic phase of the disease. Data are presented in Figure 1(A ) which shows the clinical scores (clinical scores of animals in each group) on the number of days after immunization for each group tested. The results are shown in the graph plotting the mean score (mean score) of the 50 or 100 mg / kg group. Both doses of BN201 significantly improved clinical scores compared to placebo after 17 days of treatment. This indicates that the amount of the ion exchange reaction has decreased.

[0201] The EAE animal model initially causes paralysis of the tail, followed by paralysis of the hind and forelimbs. The following scale is used to assign a clinical score to determine the progression of the disease: Severity was rated: 0 = normal, 0.5 = mildly lame tail, 1 = lame tail, 2 = mild lameness of hind limbs. 3 = total paraparesis, staggering gait; 3 = moderate paraparesis, voluntary movement still possible; 4 = severe degree paraparesis, almost complete hind limb paralysis, 5 = paraparesis or quadriplegia, 6 = outcome.

[0202] Therapeutic treatment was initiated on day 11 when 70% of the mice had a clinical score of 2 or higher. Ta.

[0203] EAE is a complex disease due to the variability in the incidence and severity of signs and symptoms among individuals. Therefore, any effect of the tested drugs may be related to the disease. After the onset of clinical symptoms, i.e., a few days after immunization, all behavior regarding clinical scores The threshold is set when a specific level (determined in the protocol) is exceeded in all animals. For a particular test compound or protocol, the observed parameters (e.g., clinical scores) a) for several days between tested groups (assay, control, etc.) and for several consecutive days within each group. If significance was maintained during this time, further significant data were considered to have been obtained.

[0204] According to this interpretation code for the results, and applicable to all other figures in this specification, However, Figure 1(A) shows significant and Conclusive data are marked with an asterisk (*). P values ​​for statistical significance are shown in each figure. This marked set of data should be defined in the footnotes or figure legends. The parameters remained stable over the course of several days, and the entire data set of the assayed groups was compared. were effectively different (between assay groups, e.g., placebo, vehicle, or sham animals). The parameters tested were compared (and there was a statistical difference at the test dose of the compound). The value corresponds to the data value (in this case, the clinical score).

[0205] A second experiment (study EAE-C05) was then performed using the same mouse model.

[0206] Study EAE-C05: Two groups, one treated with BN201 and one treated with placebo (pathological control group), were used. In addition to the dose level, the study design included two active comparators: dimethyl fumarate (DMF) ) and fingolimod (FTY720), and a placebo group (animals as a pathological group A group was introduced in which the mice were operated on but not injected with MOG. All groups received daily . - Placebo-controlled, non-diseased, placebo-treated animals (healthy control group); - EAE-affected placebo-treated animals (pathological control group); -EAE-affected animals treated orally with 15 mg / kg DMF; -EAE-affected animals treated with 2 mg / kg FTY720; -EAE-affected animals treated with 50 or 100 mg / kg BN201.

[0207] Clinical scores were assigned to assess disease severity using the following scale: 0 = normal; 0.5 = partial tail paralysis, 1 = complete tail paralysis, 1.5 = tail paralysis and righting Loss of reflexes, 2 = partial paralysis of hind limbs / paralysis of one limb, 2.5 = paralysis of one limb and the other 1 = partial loss of limb activity, 2 = bilateral hind limb paralysis, 3 = moribund, 4 = moribund, 5 = no outcome.

[0208] Each mouse was treated on day 12 or 13 when it began to show complete tail paralysis (score 1). Therapeutic treatment was initiated.

[0209] The data are shown in Figure 1(B), which shows the clinical scores per day from the start of treatment. The clinical scores (CS) of each group tested are plotted. The mean clinical scores for each day are shown.

[0210] A third experiment (Study EAE-C06) was then conducted to test the dose response of BN201. , performed using the same mouse model.

[0211] Study EAE-C06: Five different concentrations of BN201: 12.5 mg / kg, 25 mg / kg, 50mg / kg, 100mg / kg, and 150mg / kg. A physical control and FTY720 (2 mg / kg) comparison group were also included in the study. The drug was administered daily.

[0212] A clinical score was assigned to assess disease severity using the following scale: 0 = normal, 0.5 = partial tail paralysis, 1 = complete tail paralysis, 1.5 = tail paralysis 1 = loss of righting reflex, 2 = partial paralysis of hind limbs / paralysis of one limb, 2.5 = paralysis of one limb 1 = paralysis and partial loss of activity in the other limb, 2 = bilateral hind limb paralysis, 3 = moribund, 4 = moribund, 5 = no outcome.

[0213] Therapeutic treatment was discontinued on day 12 when each mouse began to show complete tail paralysis (score 1). It has started.

[0214] The data are shown in Figure 1(C), where the clinical scores for each group tested were plotted on each day after disease onset. The results showed that BN was significantly higher on almost all observation / treatment days (days 2 to 30). 201 50mg / kg, BN201 100mg / kg and FTY 720 2mg 1 / kg animals show a significant improvement in clinical scores (Table 1).

[0215] [Table 1]

[0216] Example 2: Combination of BN201 and Fingolimod vs. BN201 or Fingolimod Comparison with golimod alone

[0217] The effect on the clinical progression of EAE in 8- to 12-week-old female C57BL / 6 mice was evaluated. Mice were treated once daily, six days a week, with suboptimal doses: - Placebo-controlled, non-diseased, placebo-treated animals (healthy control group); - EAE-affected placebo-treated animals (pathological control group); EAE-affected animals treated with 0.1 mg / kg FTY720, EAE-affected animals treated with 25 mg / kg BN201, or - EAE-affected animals treated with these combinations

[0218] A combination of BN201 and fingolimod was administered to 8-12 week old female C57BL / 6 mice. We evaluated its effect on the clinical progression of EAE in EAE animal models. , characterized by initial paralysis of the tail followed by paralysis of the hind limbs and further progression to paralysis of the forelimbs Let's say.

[0219] Clinical scores were assigned to assess disease severity using the following scale: 0 = normal; , 0.5 = mild lameness of tail, 1 = lameness of tail, 2 = mild paraparesis of hind legs, unsteady gait, 3 = severe lameness of tail, 1 = severe ... 4 = moderate paraparesis, voluntary movement still possible; 5 = severe paraparesis, almost complete hind limb paralysis, 5 = paraparesis or tetraparesis, 6 = outcome.

[0220] Acclimation, distribution of mice based on weight, and immunization were performed as in Example 1.

[0221] Starting on day 15, when 70% of the animals had a clinical score of 1 or greater, mice were treated with 100 mg / kg of IV HCl once daily. , fingolimod, BN201, or their combination at suboptimal doses for 6 days per week. (0.1 mg / kg for fingolimod and 25 mg / kg for BN201) g) was administered.

[0222] The results are summarized in Figure 2. Mice treated with a combination of BN201 and fingolimod On average, mice treated with either compound alone had 1.5 times more inflammatory bowel disease from day 30 to day 35 than mice treated with either compound alone. The results showed a significant improvement in daily clinical scores (p≦0.05). The effect of the compound is greater than the sum of the effects of the compound and is much lower than the therapeutic dose of each compound administered alone. This suggests that even at different doses, they are effective when administered together.

[0223] Example 3: Combination of BN201 and Dimethyl Fumarate (DMF) vs. BN201 or comparison with DMF alone

[0224] An animal model of MS similar to that in Example 2 (i.e., C57B immunized with MOG35-55) was used. Effect on EAE in L6 mice).

[0225] Starting on day 15, mice were administered: - dimethyl fumarate (DMF) (group A, 10 mice), -BN201 (Group B, 10 mice) - their combination (Group C, 10 mice)

[0226] Once daily, 6 days a week, at suboptimal doses (10 mg / kg for DMF, BN20 25 mg / kg for 1).

[0227] DMF was administered orally via a rigid cannula in saline vehicle at a volume of 10 mL / kg. BN201 was administered intraperitoneally in a saline vehicle at a volume of 5 mL / kg. Control mice received vehicle only, both orally and by ip injection. (Group D, 10 mice) or not at all (Group E, 2 mice).

[0228] The aim of this study was to evaluate the effect of BN201 (25 mg / kg) on ​​the progression of chronic EAE in mice. g) and a suboptimal dose of dimethyl fumarate (DMF) (10 mg / kg) in combination therapy. We aimed to evaluate the efficacy and safety of

[0229] During the one-week acclimation period starting on day -7, mice were stratified into different experimental groups based on their weight. On day 0, mice were given 5 doses of incomplete Freund's adjuvant (IFA) 0 μg of Mycobacterium tuberculosis (H37Ra strain; Di 150 μg of MOG peptide 35-5 emulsified with PEG-400 (FCO, Detroit, MI) Mice were immunized subcutaneously in both hind leg pads with pertussis toxin (Spichem, Firenze). Sigma (500 ng) was injected intraperitoneally (ip) at the time of immunization and again 2 days later. Clinical scores were assigned to assess disease severity using the following scale: 0 = Normal, 0.5 = mild lameness, 1 = lameness, 2 = mild paralysis of hind legs, unsteady gait, 3 = Moderate paraparesis, voluntary movement still possible; 4 = paraplegia or tetraparesis; 5 = 6 = moribund, 7 = failure. By day 14, 70% of mice had a clinical score of 1 or higher. .

[0230] Starting on day 15, mice were treated with dimethyl fumarate (DMF) (Group A, 10 mice) 10 mice), BN201 (Group B, 10 mice), or a combination thereof (Group C, 10 mice) mice) once daily, 6 days a week, at a suboptimal dose (10 mg / kg for DMF). DMF was administered at a dose of 10 mL / kg of body weight. The subjects were administered orally via a rigid cannula in a saline vehicle at 5 ml Control mice were administered intraperitoneally in saline vehicle at a volume of 1 L / kg. Both oral and ip injections received either vehicle alone (Group D, 10 mice) or Animals were weighed and weighed by a blinded observer. Mice were examined for clinical signs of disease 6 days a week. On day 30, mice were anesthetized and given 0.1 mL of The mice were perfused intracardially with 4% paraformaldehyde in phosphate buffer (pH 7.6). , spinal cords and brains were dissected and fixed until use.

[0231] As shown in Figure 3, animals treated with suboptimal doses of either BN201 or DMF The mice treated with suboptimal doses suffered from EAE similar to that of placebo-treated mice. The combination of DMF and BN201 significantly delayed disease progression from days 34 to 38. (See Figure 3. Values ​​marked with an asterisk (*) indicate p<0.05.) In summary, the combination therapy of BN201 and DMF showed synergistic effects to improve the course of EAE. Show the results.

[0232] Example 4: Combination of BN201 and STAT3 inhibitors versus BN201 or STAT3 Comparison of inhibitors alone

[0233] An animal model of multiple sclerosis (i.e., C57BL6 mice immunized with MOG35-55) Effect during the chronic phase of the disease in EAE

[0234] Optimal dose of BN201 (50 mg / kg) and its effects on the progression of chronic EAE in mice Efficacy and safety of combination therapy with acetaminophen and S31-201 (5 mg / kg).

[0235] The chronic phase of the disease was allowed to begin (by day 34) and mice were administered: -STAT3 inhibitor S31-201 (Group A, 7 mice), -BN201 (Group B, 6 mice), or - their combination (Group C, 6 mice)

[0236] Once daily, 6 days a week, at the optimal dose (5 mg / kg for S31-201, 5 mg / kg for BN2 50mg / kg for 01).

[0237] S31-201 and BN201 were administered intraperitoneally in a saline vehicle at a volume of 5 mL / kg. Control mice received vehicle alone, both orally and by i.p. injection. (Group D, 6 mice) or not at all (Group E, 2 mice). Mice were treated from day 34 (chronic EAE stage) until the end of the experiment on day 54.

[0238] The combination of BN201 and the STAT3 inhibitor S31-201 was tested in animals with multiple sclerosis. Model (i.e., EAE in C57BL6 mice immunized with MOG35-55) The aim of the study was to evaluate its efficacy during the chronic phase of the disease in mice. BN201 (50 mg / kg) and S 31-201 (5 m We aimed to evaluate the efficacy and safety of combination therapy using an optimal dose of 100 mg / kg.

[0239] During the one-week acclimation period starting on day -7, mice were stratified into different experimental groups based on their weight. On day 0, mice were given 5 doses of incomplete Freund's adjuvant (IFA) 0 μg of Mycobacterium tuberculosis (H37Ra strain; Di 150 μg of MOG peptide 35-5 emulsified with PEG-400 (FCO, Detroit, MI) Mice were immunized subcutaneously in both hind leg pads with pertussis toxin (Spichem, Firenze). Sigma (500 ng) was injected intraperitoneally (ip) at the time of immunization and again 2 days later. Clinical scores were assigned to assess disease severity using the following scale: 0 = Normal, 0.5 = mild lameness, 1 = lameness, 2 = mild paralysis of hind legs, unsteady gait, 3 = Moderate paraparesis, voluntary movement still possible; 4 = paraplegia or tetraparesis; 5 = 6 = moribund, 7 = failure. By day 17, 70% of mice had a clinical score of 1 or higher. .

[0240] Starting on day 34, mice were treated with the STAT3 inhibitor S 31-201 (Group A, 7 mice) mice, Sigma), BN201 (Group B, 6 mice), or their combination (Group C, 6 mice) C, 6 mice) once daily, 6 days a week, at the optimal dose (5 for S31-201). S31-201 and BN201 were administered at 50 mg / kg. BN201 was administered by intraperitoneal injection in a saline vehicle at a volume of 5 mL / kg. Control mice received only vehicle, both orally and ip infusion (Group D, 6 Mice were either treated with steroids (group A, 2 mice) or not treated at all (group E, 2 mice). The mice were treated from the EAE stage until the end of the experiment on day 54. At the start of treatment, the groups were assigned to mice with different levels of EAE severity. (e.g., the BN201 alone group may experience more severe disease from the start of treatment than placebo. Therefore, comparisons between groups were based on the change in EAE scores after treatment initiation. The animals were weighed and examined by blinded observers for clinical signs of disease 6 days per week. On the day 1, mice were anesthetized and lysed with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.6). The mice were intracardially perfused with HCl. The eyes, optic nerves, spinal cord, and brain were dissected and fixed until use.

[0241] As shown in Figure 4, the optimal dose of BN201 or the optimal dose of S31-201 alone , treatment at the chronic stage of the disease (i.e., day 34, see arrow) is ineffective at this stage of the disease. However, the optimal use of the combination of BN201 and S31-201 Treatment with these doses significantly improved the course of EAE during the chronic phase of the disease. Scores were significantly lower with the combination therapy compared with the other treatments. Combination therapy with the 3 inhibitor S31-201 significantly improved survival in mice with late chronic EAE. The magnitude of the effect was greater than the sum of the effects of each drug alone, so this This suggests the existence of synergistic activity between the two drugs.

[0242] Example 5: Preparation of BN201-monomethyl fumarate

[0243] For the preparation of BN201-monomethyl fumarate, 100 mg of AM-G79_03 (BN201) (1 equivalent) and 26 mg of monomethyl fumarate (1 equivalent) were dissolved in methanol. The mixture was stirred for 1 hour, then concentrated in vacuo. The residue obtained was 1 The product was analyzed by H-NMR.

[0244] 1 The H-NMR data clearly confirmed that the compound of formula (IIa) was obtained: Ta: [ka]

[0245] Example 6: BN201-monomethyl fumarate and BN201 or monomethyl fumarate Comparison with single

[0246] The purpose of this study was to evaluate the efficacy of BN201-monomethyl fumarate in neuroprotection assays. It was decided to test the possibility of a synergistic effect. Therefore, the BN obtained as shown in Example 5 201-Fumaric acid monomethyl salt was treated with MTT (3-(4,5-dimethylthiazol-2-yl)- (I)-2,5-diphenyltetrazolium bromide) oxidation using a cell proliferation assay Stress (i.e., hydrogen peroxide (H2O2))-induced death in human neuroblastoma Its ability to protect the cell line SH-SY5Y was tested.

[0247] SH-SY5Y cells were cultured in 50% Eagle's minimum essential medium (EMEM), 50% Ham's F12 Nutrient mixture, 10% fetal bovine serum (FBS), 2 mM L-Glu and 1% penicillin / All cell cultures were maintained in a humidified atmosphere at 5% CO2 and 37°C. SH-SY5Y cells were maintained in an incubator. BN201 monomethyl fumarate (n=5, concentration: 0.0 3μM, 0.1μM, 0.3μM, 0.5μM, 1μM, 3μM, 5μM, 10μM, 2 Preincubated with HO (15 μM, 40 μM) for 1 hour, then Stress was induced by adding sodium pyruvate (10 mM). Incubation with H2O2 for 30 min was used as a positive control. Afterwards, the medium was replaced and thiazolyl blue tetrazolium bromide (MTT; Sigma-Aldrich) was added. Rich (stock concentration 10 mg / ml) was added to each well at a final concentration of 0.5 mg / ml After 2 hours of incubation with MTT, the cell culture medium was removed and the cells were incubated in a pure medium. The cells were resuspended in dimethyl sulfoxide (DMSO) and the absorbance was measured at 570 nm. Cell viability was determined by the following method. Each experiment was performed in quintuplicate.

[0248] Results are presented as a percentage of cell viability compared to the control, where the same concentration was used alone. Compared with BN201 or fumarate tested separately, BN201-monomethyl fumarate The data are shown in Figure 5, demonstrating that the ATP content increases after pretreatment with salt.

[0249] Both BN201 and fumarate protect neurons from oxidative stress-induced death. partially rescues the oxidative stress and reduces the effectiveness of similar well-known antioxidants such as sodium pyruvate. On the other hand, BN201-monomethyl fumarate showed significantly higher activity than either compound alone. showed a high level of neuroprotection, indicating that BN201-monomethyl fumarate exerted a synergistic effect These results suggest that α-glucan-1-phosphate dehydrogenase (G1) exerts a neuroprotective effect.

[0250] Further aspects / embodiments of the present invention are set out in the following form:

[0251] Form 1 A combination of: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b): (i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof (ii) sphingosine-1-phosphate receptor inhibitors (S1PR modulators), and Beauty (iii) Signal Transducer and Activator of Transcription 3 (STAT3) Inhibitors and one or more drugs selected from the group consisting of combinations, including [ka] During the ceremony, R1 is substituted with halogen or trifluoromethyl, and further substituted with halogen, (C1-C 6) consisting of alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl or phenyl optionally substituted with one or two substituents selected from the group wherein R1 is pyrrolidin-1-yl and R2 is 2-oxo-pyrrolidin-1-ylmethyl R3 is propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4 -methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl Selected from the list; [ka] wherein R6 and R5 are independently selected from hydrogen (H) and (C1-C6) alkyl. (will be done).

[0252] Form 2 A compound of formula (I) and a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof a drug selected from the group consisting of a salt thereof, an S1PR modulator, and a STAT3 inhibitor 2. The combination of claim 1, comprising:

[0253] Form 3 In the compound of formula (I), R3 is 2-methylpropyl and R1 and R2 are as claimed 3. The combination according to any one of aspects 1 to 2, as defined in item 1.

[0254] Form 4 The compound of formula (I) [ka] 4. The combination according to claim 3, selected from the group consisting of:

[0255] Form 5 The compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof is The group consisting of methyl, monoethyl fumarate, sodium fumarate, and iron(II) fumarate 5. The combination of any one of aspects 1 to 4, wherein the combination is selected from:

[0256] form 6 S1PR modulators include fingolimod, siponimod, ozazimod, ponesimod, and and selalifimod, .

[0257] Form 7 STAT3 inhibitors include 2-hydroxy 4-[[[[(4-methylphenyl)sulfonyl ]oxy]acetyl]amino]-benzoic acid, (S,E)-3-(6-bromopyridine-2 -yl)-2-cyano-N-(1-phenylethyl)acrylamide, 4-((3-( (carboxymethylsulfanyl)-4-hydroxy-1-naphthyl)sulfamoyl)benzo carboxylic acid, STAT3 inhibitor peptide of SEQ ID NO: 1, 6-nitrobenzo[b]thiophene-1 ,1-dioxide, ethyl-1-(4-cyano-2,3,5,6-tetrafluorophenyl) (Iron)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carbo xylate, 5,15-diphenylporphyrin, PIAS3 protein, N-(5-( Furan-2-yl)-1,3,4-oxadiazol-2-yl)-2-phenylquinolin 4-carboxamide, STAT3 inhibitor XII SPI of SEQ ID NO: 2, and N-( 1'2-Dihydroxy-1,2'binaphthalen-4'-yl)-4-methoxybenzenes 7. The combination according to any of the preceding claims, wherein the compound is selected from the group consisting of sulfonamides.

[0258] Form 8 A combination according to any one of aspects 1 to 7, selected from: The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N -(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-pro Pyr]glycinamide and dimethyl fumarate, or The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N -(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-pro Pill] glycinamide and fingolimod, or The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N -(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-pro 2-hydroxy-4-[[[(4-methylphenyl)sulfonyl]glycinamide [Alkyl]oxy]acetyl]amino]benzoic acid.

[0259] Form 9 a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) as defined above; i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) an S1PR modulator, and iii) STAT3 inhibitors and one or more drugs selected from the group consisting of wherein the amount of a) and the amount of b) are therapeutically effective in combination. The combination described above.

[0260] Form 10 The amount of a) by itself is sub-therapeutic and the amounts of a) and b) in combination 10. A combination according to any of aspects 1 to 9, which is therapeutically effective.

[0261] Form 11 The amount of b) by itself is sub-therapeutic and the amounts of a) and b) in combination 10. A combination according to any of aspects 1 to 9, which is therapeutically effective.

[0262] Form 12 The amount of a) and the amount of b) are subtherapeutic amounts by themselves, and the amounts of a) and b) 10. The combination according to any one of aspects 1 to 9, which is therapeutically effective in combination.

[0263] Form 13 A therapeutically effective amount of: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; [ka] b) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, S1PR one or more drugs selected from the group consisting of STAT3 modulators and STAT3 inhibitors; [ka] together with one or more pharmaceutically or veterinarily acceptable excipients or carriers, The compound of formula (I) and one or more drugs are as defined in any of Forms 1 to 9. wherein the amount of a) and the amount of b) are combined therapeutically effective. or a veterinary composition.

[0264] Form 14 i) a predetermined amount of a compound of formula (I) as defined in Forms 1 to 9 or a pharmaceutical or A veterinarily acceptable salt may be combined with one or more pharmaceutically or veterinarily acceptable excipients or a first pharmaceutical or veterinary composition comprising, in combination with a carrier; ii) a predetermined amount of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable derivative thereof one or more selected from the group consisting of a salt, an S1PR modulator, and a STAT3 inhibitor together with one or more pharmaceutically or veterinarily acceptable excipients or carriers. a pharmaceutical or veterinary composition; and Including, The first and second compositions are separate compositions, and the amount of the compound of formula (I) in i) and ii) the amount of one or more drugs in a package or kit that is therapeutically effective in combination; Toofparts.

[0265] Form 15 Treatment of inflammatory neurological diseases or conditions that may result in destruction or degeneration of axons or myelin for use in the treatment and / or prevention in a subject in need thereof. A combination as defined in any of claims 1 to 12, a single product as defined in claim 13, A pharmaceutical or veterinary composition, or a package or capsule as defined in Form 14. Kit of parts.

[0266] References Patent documents -EP Patent No. 2611775 Non-patent literature -Patrick Vermersch et al.,''Sphingosine- 1-phosphate Receptor Modulators in Multi ple Sclerosis'';European Neurological Re view-2018;13(1):25-30 -Guidance for Industry estimating the ma ximum safe starting dose in initial clin ical trials for therapeutics in adult he althy volunteers;FDA,CDER,July 2005 -Kezuka et al,Analysis of the pathogenes is of experimental autoimmune optic neur itis.J Biomed Biotechnol.2011;2011:29404 6. -Guo et al,2009;Guo J,Li H,Yu C,Liu F,Me ng Y,Gong W,Yang H,Shen X,Ju G,Li Z,Wang J.Decreased neural stem / progenitor cell proliferation in mice with chronic / nonr emitting experimental autoimmune encepha lomyelitis.Neurosignals.2010;18(1):1-8

Claims

1. a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; and b) i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) sphingosine-1-phosphate receptor inhibitors (S1PR modulators); and iii) Signal Transducer and Activator of Transcription 3 (STAT3) inhibitors; one or more drugs selected from the group consisting of Including, combinations. 【Chemistry 1】 During the ceremony, R １ is substituted with halogen or trifluoromethyl, and further substituted with halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and halo (C １ -C ６ ) consisting of alkyl phenyl optionally substituted with one or two substituents selected from the group , R １ is pyrrolidin-1-yl, R ２ is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl and R ３ is propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1- Methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl The alkyl group is selected from methyl, 2-methylpentyl, and 1-methylpentyl. 【Chemistry 2】 During the ceremony, R ５ is hydrogen (H) and (C １ -C ６ ) alkyl, R ６ is H, (C １ -C ６ ) alkyl and 2-(2,5-dioxopyrrolidin-1-yl)ethyl , R ５ is H, then R ６ is other than H.

2. A compound of formula (I) and a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof a drug selected from the group consisting of a salt thereof, an S1PR modulator, and a STAT3 inhibitor The combination of claim 1 comprising:

3. In the compound of formula (I), R ３ is 2-methylpropyl, and R １ and R ２ but 3. The combination according to any one of claims 1 to 2, as defined in claim 1.

4. The compound of formula (I) 【Transformation 3】 4. The combination of claim 3, selected from the group consisting of:

5. In the compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, R ６ and R ５ are independently hydrogen (H) and (C １ -C ６ ) alkyl, R ６ and R ５ At least one of (C １ -C ６ ) alkyl The combination according to any one of claims 1 to 4.

6. The compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof is 6. The method according to claim 1, wherein the carboxylic acid is selected from the group consisting of dimethyl fumarate and monoethyl fumarate. The combination according to any one of claims 1 to 4.

7. In the compound of formula (IV), R ６ 2-(2,5-dioxopyrrolidine-1-yl) R is ethyl; ５ A combination according to any one of claims 1 to 4, wherein is methyl. 。

8. S1PR modulators include fingolimod, siponimod, ozazimod, ponesimod, and 8. The method according to claim 1, wherein the compound is selected from the group consisting of cefotaxime, ... combination.

9. STAT3 inhibitors include 2-hydroxy 4-[[[[(4-methylphenyl)sulfonyl ]oxy]acetyl]amino]-benzoic acid, (S,E)-3-(6-bromopyridine-2 -yl)-2-cyano-N-(1-phenylethyl)acrylamide, 4-((3-( (carboxymethylsulfanyl)-4-hydroxy-1-naphthyl)sulfamoyl)benzo carboxylic acid, STAT3 inhibitor peptide of SEQ ID NO: 1, 6-nitrobenzo[b]thiophene-1 ,1-dioxide, ethyl-1-(4-cyano-2,3,5,6-tetrafluorophenyl) (Iron)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carbo xylate, 5,15-diphenylporphyrin, PIAS3 protein, N-(5-( Furan-2-yl)-1,3,4-oxadiazol-2-yl)-2-phenylquinolin STAT3 inhibitor XII SPI of SEQ ID NO: 2, and N-( 1'2-dihydroxy-1,2'binaphthalen-4'-yl)-4-methoxybenzenes 9. The combination according to claim 1, wherein the amide is selected from the group consisting of sulfonamides. 。

10. A combination according to any one of claims 1 to 9 selected from: The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]- [N-(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)- propyl]glycinamide and dimethyl fumarate, or The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]- [N-(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)- propyl]glycinamide and fingolimod, or The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]- [N-(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)- propyl]glycinamide and 2-hydroxy-4-[[[(4-methylphenyl)sulfonyl] [phenyl]oxy]acetyl]amino]-benzoic acid.

11. a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; b) as defined above i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof; ii) S1PR modulators and iii) STAT3 inhibitors one or more drugs selected from the group consisting of Including, 11. The method of claim 1, wherein the amount of a) and the amount of b) are therapeutically effective in combination. The combination according to any one of claims 1 to 4.

12. The amount of a) by itself is sub-therapeutic and the amounts of a) and b) in combination Therapeutic and subtherapeutic effective amounts are defined for a particular compound and for a particular disease.

12. The combination according to any one of claims 1 to 11, wherein the combination is administered in a sub-therapeutic amount.

13. The amount of b) by itself is sub-therapeutic and the amounts of a) and b) in combination Therapeutically effective, defined as an amount of a specific compound that is below the therapeutically effective amount for a specific disease 12. The combination according to any one of claims 1 to 11, wherein the combination is administered in a sub-therapeutic amount.

14. The amount of a) and the amount of b) are subtherapeutic amounts by themselves, and the amounts of a) and b) However, certain compounds are therapeutically effective in combination and are below the therapeutically effective amount for a particular disease.

12. The compound according to claim 1, wherein the compound is a sub-therapeutic amount, which is defined as an amount of the compound. The combination of the above.

15. a therapeutically effective amount of: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; 【Chemistry 4】 b) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, S1PR one or more drugs selected from the group consisting of STAT3 modulators and STAT3 inhibitors; 【Transformation 5】 together with one or more pharmaceutically or veterinarily acceptable excipients or carriers, The compound of formula (I) and one or more drugs are as defined in any of claims 1 to 11. wherein the amount of a) and the amount of b) are in combination therapeutically effective in a single therapeutic agent. Pharmaceutical or veterinary compositions.

16. i) a predetermined amount of a compound of formula (I) as defined in any one of claims 1 to 11 or A pharmaceutically or veterinarily acceptable salt may be combined with one or more pharmaceutically or veterinarily acceptable salts. a first pharmaceutical or veterinary composition comprising the compound of formula (I) together with an excipient or carrier selected from the group consisting of: ii) a predetermined amount of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable derivative thereof one or more selected from the group consisting of a salt, an S1PR modulator, and a STAT3 inhibitor together with one or more pharmaceutically or veterinarily acceptable excipients or carriers. a pharmaceutical or veterinary composition; and iii) instructions for using i) and ii) in combination; and Including, the first and second compositions are separate compositions, and i) the amount of the compound of formula (I) and ii) the amount of one or more drugs in a package or kit that is therapeutically effective in combination Toofparts.

17. Treatment of inflammatory neurological diseases or conditions that may result in destruction or degeneration of axons or myelin and / or for use in the treatment and / or prevention in a subject in need thereof. a combination as defined in any one of claims 1 to 14, a single compound as defined in claim 15, or a package or veterinary composition as defined in claim 16. is a kit of parts.

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