Combination therapy methods, compositions and kits

Abstract

The present invention relates to a combination comprising: a) a compound # imgabs0 # of formula (I) wherein R1, R2 and R3 have specific meanings, or a pharmaceutically or veterinarily acceptable salt thereof; and (b) one or more drugs selected from the group consisting of i) a compound of formula (IV) # imgabs1 # or a pharmaceutically or veterinarily acceptable salt thereof wherein R5 and R6 have specific meanings, ii) a sphingosine-1-phosphate receptor inhibitor (S1PR modulators), and iii) a signaling and transcriptional activator 3 (STAT3) inhibitor. Specific combinations and single pharmaceutical compositions as well as multi-part kits are disclosed. These combinations, single pharmaceutical compositions, and multi-part kits are useful for treating and / or preventing inflammatory neurological diseases or conditions that can lead to axon or myelin disruption or degeneration in a subject in need thereof.

Description

[0001] Related Applications

[0002] This application is a divisional application of a Chinese patent application with application number 2020800485735, filing date July 2, 2020, and invention title "Combination Therapy Methods, Compositions, and Kits".

[0003] The above-mentioned Chinese patent application claims the benefit of European patent application EP19382566.8 filed on July 3, 2019. Technical Field

[0004] The present invention relates to the field of neurological diseases and to specific methods of treating neurological diseases using combination therapies. Background Art

[0005] Inflammatory neurological diseases or conditions that can cause axonal or myelin damage or degeneration can include, but are not limited to, various central nervous system (CNS) diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Baló disease, Schilder’s disease, transverse myelitis, acute hemorrhagic leukoencephalitis (i.e., Hurst’s disease), and Marburg disease (i.e., acute MS).

[0006] MS is a degenerative autoimmune disease of the central nervous system (CNS) in which the immune system attacks and damages the myelin protective sheath around axons and nerve fibers, resulting in severe disability. MS is characterized by demyelination, multifocal inflammation, reactive gliosis, and loss of oligodendrocytes and axons. People with MS typically experience three clinical courses: relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), and primary-progressive MS (PPMS). RRMS is the most common course, affecting approximately 85% of people with MS, and is characterized by well-defined episodes (i.e., relapses) that worsen neurological function. These relapses are followed by a partial or complete recovery period during which symptoms partially or completely improve and there is no disease progression. Most people with RRMS will eventually transition to SPMS, which means that after a period of relapses and remissions, the disease will begin to progress more steadily, with or without any relapses. PPMS affects approximately 10% of people with MS and is characterized by a continuous worsening of neurological function from the start, with no obvious relapses or remissions. The symptoms, severity, and course of MS will vary depending on the location of the damaged myelin and the degree of demyelination.

[0007] Neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, or neuromyelitis optica spectrum disorder (NMOSD), is an autoimmune disorder of the central nervous system (CNS) in which immune system cells and antibodies mistakenly attack and damage astrocytes in the optic nerves, brain, and spinal cord, thereby inducing secondary demyelination and axonal loss. Injury to the optic nerve results in optic neuritis, which produces swelling and inflammation that cause pain and vision loss. Injury to the spinal cord results in weakness or paralysis in the legs or arms, loss of sensation, and problems with bladder and bowel function. Because these two diseases have similar symptoms and can cause episodes of optic neuritis and myelitis, NMO can be confused with MS and until recently was considered a severe variant of MS. However, recent research has shown that NMO disease and MS are distinct diseases.

[0008] Optic neuritis is a demyelinating inflammation of the optic nerve that can be caused by a variety of different conditions but is often associated with MS and NMO. The inflammation can cause vision loss or even blindness, usually because of swelling and destruction of the myelin sheath that covers the optic nerve. Symptoms of optic neuritis include blurred vision, darkened colors, pain when moving the eyes, blind spots, and loss of contrast sensitivity.

[0009] There is currently no cure for MS. Available treatments are targeted at subsets of patients with relapsing forms of MS, which include relapsing-remitting MS (RRMS), and those with secondary progressive MS (SPMS) who experience relapses. Most of the treatments approved by the U.S. Food and Drug Administration (FDA) are immunomodulatory drugs that reduce the frequency of relapses and delay the progression of MS. However, these treatments are only partially effective and only target immune system activation, without exerting neuroprotective or regenerative effects. In addition, current therapies are associated with significant side effects, such as adverse immune reactions or severe opportunistic infections.

[0010] At present, there is also no cure for NMO. The standard of care for NMO includes intravenous high-dose corticosteroid treatment, plasmapheresis for treating relapses, and rituximab, azathioprine, and mycophenolate mofetil for preventing relapses, which may have severe side effects, including infections. The likelihood of NMO relapse is greater than 90%, and episodes are usually severe; therefore, continuous treatment to suppress the immune system is considered necessary. Accordingly, there is a need in the art for more effective methods of treating inflammatory neurological diseases or disorders that can cause axonal or myelin damage or degeneration, such as MS, NMO, optic neuritis, Baló disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis (i.e., Hurst's disease), and Marburg disease (acute MS). SUMMARY OF THE INVENTION

[0011] The inventors have found that a combination of a compound of formula (I) (see below) with one or more drugs having immunomodulatory activity and / or antioxidant action and / or anti-inflammatory activity provides significant therapeutic activity in inflammatory neurological diseases or conditions that can cause axonal or myelin damage or degeneration in a subject. Surprisingly, even when at least one of the compound of formula (I) or one or more additional drugs is administered at a dose considered and classified as sub-therapeutic, the combined use of the compounds enhances or improves the desired effect. The combination is considered to improve the therapeutic effect and also significantly reduce the associated side effects. The even more surprising fact is that these effects of significant therapeutic activity are achieved in inflammatory neurological diseases or conditions that can cause axonal or myelin damage or degeneration in a subject even at sub-optimal or sub-therapeutic doses of each compound when administered as a single active agent. Thus, a specific combination of a compound of formula (I) with other specific compounds exhibits significantly greater improvement at sub-therapeutic doses in these diseases than when each compound is administered alone. In addition, a combination of a compound of formula (I) and one or more additional drugs administered at a dose lower than expected to be active is effective in the chronic or progressive phase or stage of an inflammatory neurological disease or condition.

[0012] This improved and unexpected effect in the case of combined use of the compounds has been shown in an animal model widely used for inflammatory neurological diseases (experimental autoimmune encephalomyelitis (EAE) in mice). According to the results, the present inventors have found that when used in combination, the compound of formula (I) and one or more drugs having immunomodulatory and / or antioxidant and / or anti-inflammatory activity are able to improve the clinical score of EAE mice in a manner that reduces those disabling effects of the neurological disease. This enhanced or improved effect is thought to be due to each drug activating different biological pathways that converge on preventing cascades leading to cell damage, such as oxidative stress, apoptosis, autophagy, synaptic pruning, energy metabolism balance, etc.

[0013] Accordingly, a first aspect of the present invention relates to a combination comprising:

[0014] a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof

[0015]

[0016] wherein:

[0017] R1 is phenyl substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halogen(C1-C6)alkyl; or alternatively R1 is pyrrolidin-1-yl;

[0018] R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and

[0019] R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; and

[0020] b) one or more drugs selected from the group consisting of:

[0021] a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof

[0022]

[0023] wherein R5 is selected from hydrogen (H) and (C1-C6) alkyl, R6 is selected from H, (C1-C6) alkyl, and 2-(2,5-dioxopyrrolidin-1-yl)ethyl, and wherein if R5 is H, then R6 is not H,

[0024] ii) a sphingosine-1-phosphate receptor modulator (S1PR modulator), and

[0025] iii) a signal transducer and activator of transcription 3 (STAT3) inhibitor.

[0026] The compounds of the present invention can be formulated into different types of compositions / multipart kits. Accordingly, a second aspect of the present invention relates to a single pharmaceutical or veterinary composition (i.e., a single pharmaceutical composition or a single veterinary composition) comprising:

[0027] a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; and

[0028] 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) an S1PR modulator, and iii) a STAT3 inhibitor;

[0029] and one or more pharmaceutically or veterinarily acceptable excipients or carriers; wherein the compound of formula (I) and the drugs are as defined in the first aspect, and wherein the amounts of a) and b) in combination are therapeutically effective.

[0030] A third aspect of the present invention relates to a multipart pack or kit comprising:

[0031] i) a first pharmaceutical or veterinary composition comprising an amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof as defined above, and one or more pharmaceutically or veterinarily acceptable excipients or carriers;

[0032] ii) A second pharmaceutical or veterinary composition comprising an amount of one or more agents selected from the group consisting of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator, and a STAT3 inhibitor, and one or more pharmaceutically or veterinarily acceptable excipients or carriers;

[0033] iii) Instructions for the combined use of i) and ii);

[0034] wherein the first composition and the second composition are separate compositions, and wherein the amount of the compound of formula (I) of i) and the amount of one or more agents of ii) in the combination are therapeutically effective.

[0035] In addition, as described above, the combinations of the present invention can be used in inflammatory neurological diseases or disorders that can lead to axonal or myelin damage or degeneration.

[0036] Accordingly, a fourth aspect of the present invention relates to a combination, single agent, or veterinary composition, multi-part pack, or kit as previously defined for the treatment and / or prevention of inflammatory neurological diseases or disorders that can lead to axonal or myelin damage or degeneration. Description of the Drawings

[0037] Figure 1(A) related to Example 1 shows the daily clinical score (CS) of EAE-C03, in which the effects of daily treatment with different doses of BN201 were compared with those of placebo. After 17 days of treatment, the clinical scores of the treatment groups with BN201 (100 mg / kg) and BN201 (50 mg / kg) began to be significantly lower than those of the pathological control group (**p≤0.01; *p≤0.05). Figure 1(B) related to Example 1 shows the daily clinical score (CS) of EAE-C05, 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 those of placebo. After 5 days of treatment, the clinical scores of the treatment groups with BN201 (100 mg / kg) and FTY720 began to be significantly lower than those of the pathological control group (**p≤0.01; *p≤0.05). Figure 1(C) shows the daily clinical score (CS) of EAE-C06, in which five different concentrations of BN201 (12.5 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg and 150 mg / kg) were tested. A sham-treatment group, a pathological control group and a comparator group of FTY720 (2 mg / kg) were also included in the experiment. All groups were administered daily. For almost all observation / treatment days (from day 2 to day 30), a significant improvement in the clinical (CS) scores of the animals was observed in BN201 50 mg / kg, BN201 100 mg / kg and FTY720 2 mg / kg (**p≤0.01; *p≤0.05).

[0038] Related to Example 2 Figure 2 is a graph of the daily clinical score (CS) of EAE mice treated with fingolimod (solid oblong / rhombus), BN201 (white square), a combination of fingolimod and BN201 (solid circle) and placebo (white triangle). The arrow indicates the day when treatment started. The X-axis is the number of days after immunization of C57BL / 6 mice to form the EAE phenotype. p<0.05 is the difference between the combination therapy (fingolimod 0.1 mg / kg + BN201 25 mg / kg) and BN201 (25 mg / kg).

[0039] Related to Example 3 Figure 3 is a graph of the daily clinical score (CS) of EAE mice treated with dimethyl fumarate (DMF) (solid square), BN201 (solid rhombus), a combination of DMF and BN201 (cross) and placebo (triangle). The X-axis is the number of days after immunization of C57BL / 6 mice to form the EAE phenotype.

[0040] Related to Example 4 Figure 4Graph of the daily clinical score (CS) of EAE mice treated with the STAT3 inhibitors S31-201 (cross), BN201 (triangle), the combination of S31-201 and BN201 (square), and placebo (circle). The arrow indicates the day of starting treatment. The X-axis is the number of days after immunization of C57BL / 6 mice to develop the EAE phenotype.

[0041] Related to Example 6 Figure 5 Is a bar graph showing the percentage viability of the human neuroblastoma cell line SH-SY5Y under oxidative stress conditions. The viability of cells treated with different assay concentrations of BN201 (first bar), BN201 - monomethyl fumarate (second bar), or monomethyl fumarate (third bar) in cell culture (0.03 μM, 0.1 μM, 0.3 μM, 0.5 μM, 1 μM, 3 μM, 5 μM, 10 μM, 20 μM, and 40 μM) is described in relation to the control (untreated human neuroblastoma cells). Figure 5 Shows that at the same test concentrations, cell viability (percentage relative to the control) increased after pretreatment with BN201 - monomethyl fumarate salt relative to BN201 or monomethyl fumarate (*p < 0.0001, relative to BN201 only; #p < 0.05 or ##p < 0.0001, relative to fumarate only). Detailed Description

[0042] Unless otherwise indicated, all terms used in this application as used herein shall be understood in their ordinary meaning as known in the art. Other more specific definitions of certain terms used in this application are set forth below and are intended to be applied uniformly throughout the specification and claims, unless a more expansive definition is provided by an expressly stated definition.

[0043] Compound of formula (I)

[0044] As described above, the present invention relates to a combination comprising:

[0045] A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof,

[0046]

[0047] As previously defined, and

[0048] 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) an S1PR modulator, and iii) a STAT3 inhibitor.

[0049] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a fluorophenyl group, more particularly 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl, and even more particularly 2-fluorophenyl.

[0050] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a fluorophenyl group which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halogen(C1-C6)alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy and halogen(C1-C4)alkyl; more preferably substituted by one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0051] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a chlorophenyl group, more particularly 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl, and even more particularly R1 is 2-chlorophenyl.

[0052] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a chlorophenyl group which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy and halogen(C1-C6)alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy and halogen(C1-C4)alkyl; more preferably substituted by one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0053] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a bromophenyl group, more particularly 2-bromophenyl, 3-bromophenyl or 4-bromophenyl, and even more particularly 2-bromophenyl.

[0054] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a bromophenyl group, which is further substituted with one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halogen(C1-C6) alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, and halogen(C1-C4) alkyl; more preferably one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0055] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is an iodophenyl group, more particularly 2-iodophenyl, 3-iodophenyl, or 4-iodophenyl, and even more particularly 2-iodophenyl.

[0056] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is an iodophenyl group, which is further substituted with one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halogen(C1-C6) alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, and halogen(C1-C4) alkyl; more preferably one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0057] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a trifluoromethylphenyl group, more particularly 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 4-trifluoromethylphenyl, and even more particularly 2-trifluoromethylphenyl.

[0058] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a trifluoromethylphenyl which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halogen(C1-C6)alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, and halogen(C1-C4)alkyl; more preferably one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0059] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is pyrrolidin-1-yl.

[0060] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R2 is 2-oxo-pyrrolidin-1-yl-methyl.

[0061] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R2 is a sulfamoylphenyl, more particularly 2-sulfamoylphenyl, 3-sulfamoylphenyl, or 4-sulfamoylphenyl, even more particularly 4-sulfamoylphenyl.

[0062] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R3 is 2-methylpropyl.

[0063] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is 2-fluorophenyl or pyrrolidin-1-yl, and R2 is 2-oxo-pyrrolidin-1-ylmethyl or 4-sulfamoylphenyl.

[0064] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the compound of formula (I) of the inventive combination as described above is selected from the group consisting of:

[0065]

[0066]

[0067] [N-(2-(2'-Fluorophenylethyl)glycyl]-[N-(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl]glycinamide (G79, also referred to as and labeled as BN201 in the following examples). Chemical formula: C 25 H 38 FN5O4; MW 491.5987.

[0068] [N-(2-(2'-Fluorophenylethyl)glycyl]-[N-(2-methylpropyl)glycyl]-N-[2-(4'-sulfamoylphenyl)ethyl]glycinamide (G80, also referred to as BN119). Chemical formula: C 26 H 36 FN5O5S; MW 549.658.

[0069] [N-(2-(1-Pyrrolidinyl)ethyl)glycyl]-[N-(2-methylpropyl)glycyl]-N-[2-(4'-sulfamoylphenyl)ethyl]glycinamide (G81, also referred to as BN120). Chemical formula: C 24 H 40 N6OS; MW 524.6766.

[0070] The compounds of formula (I), and in particular G79 (BN201), G80 (BN119) and G81 (BN120), are members of a new class of peptidomimetic achiral compounds which act as neurotrophic factor agonists. Their synthesis and properties are disclosed in European Patent 2611775 "Agonists of neurotrophin receptors and their use as medicaments". A notable feature of peptidomimetic compounds is that they lack the amide hydrogens responsible for many of the secondary structure elements of peptides and proteins. One of these compounds, G79 (BN201), has previously shown neuroprotective effects in several different in vitro and in vivo models of neuronal injury. Other chemical names for BN201 include N-(2-amino-2-oxoethyl)-2-(2-(4-fluorophenylethyl)amino)-N-isobutylacetamido-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)-ethylamino]-N-isobutylacetamide.

[0071] There is no restriction on the type of salt of the compound of formula (I) that can be used, provided that these salts are pharmaceutically or veterinarily acceptable when used for therapeutic purposes. The term "pharmaceutically or veterinarily acceptable salts" includes salts commonly used to form alkali metal salts and addition salts of free acids or free bases. The preparation of pharmaceutically or veterinarily acceptable salts of the compound of formula (I) can be carried out by methods known in the art. For example, they can be prepared from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free acid or base form of the compound of formula (I) with a stoichiometric amount of a suitable pharmaceutically or veterinarily acceptable base or acid in water or an organic solvent or a mixture thereof. The compounds of formula (I) and their corresponding salts may differ in some physical properties, but for the purposes of the present invention, they are equivalent.

[0072] The compounds of the present invention can exist in crystalline forms as free solvated compounds or solvates (e.g., hydrates), and both forms are intended to be within the scope of the present invention. Solvation methods are generally known in the art. Generally, for the purposes of the present invention, the solvated forms with pharmaceutically, cosmetically or veterinarily acceptable solvents such as water, ethanol, etc. are equivalent to the unsolvated forms.

[0073] In all embodiments of the present invention relating to the compounds of formula (I), their pharmaceutically or veterinarily acceptable salts are always contemplated, even if they are not specifically mentioned.

[0074] Compounds of formula (I) (e.g., BN201) can be administered in mice at a dose of 0.5 mg / kg to 200 mg / kg, which corresponds to a human equivalent dose (HED) of 0.04 mg / kg to 16.26 mg / kg [The HED calculations in this specification are based on Guidance for Industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers; FDA, CDER, July 2005]. The therapeutic or optimal dose is in particular about 200 mg / kg or less, about 200 mg / kg, about 175 mg / kg or less, about 175 mg / kg, about 150 mg / kg or less, about 150 mg / kg, about 125 mg / kg or less, about 125 mg / kg, about 100 mg / kg or less, about 100 mg / kg, about 75 mg / kg or less, about 75 mg / kg, about 60 mg / kg or less, about 60 mg / kg, about 55 mg / kg or less, about 55 mg / kg, about 50 mg / kg or less, about 50 mg / kg, about 45 mg / kg or less, about 45 mg / kg, about 40 mg / kg or less, about 40 mg / kg, about 35 mg / kg or less, about 35 mg / kg, about 30 mg / kg or less or about 30 mg / kg. The sub-therapeutic or sub-optimal dose is in particular 0.5 mg / kg to 25 mg / kg. In certain embodiments, the sub-optimal dose of a compound of formula (I) (e.g., BN201) when combined with one or more drugs as defined above can be about 25 mg / kg or less, about 20 mg / kg or less, about 20 mg / kg, about 15 mg / kg or less, about 15 mg / kg, about 10 mg / kg or less, about 10 mg / kg, about 5 mg / kg or less, about 5 mg / kg, about 2.5 mg / kg or less, about 2.5 mg / kg, about 2.0 mg / kg or less, about 2.0 mg / kg, about 1.5 mg / kg or less, about 1.5 mg / kg, about 1.0 mg / kg or less, about 1.0 mg / kg, about 0.5 mg / kg or less or about 0.5 mg / kg of a compound of formula (I) (e.g., BN201).In certain embodiments, administering a compound of formula (I) (e.g., BN201) in combination with one or more of a sub-optimal dose of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an SP1R inhibitor (e.g., fingolimod), and a STAT3 inhibitor (e.g., S3I-201) results in a reduction in side effects (e.g., pain, seizures, ataxia, etc.) compared to administering the compound of formula (I) (e.g., BN201) alone at an optimal dose for treatment.

[0075] Compounds of formula (IV) and their salts

[0076] The compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof is a compound derived from fumaric acid. These compounds correspond to the following formula:

[0077]

[0078] wherein R5 is selected from hydrogen (H) and (C1-C6) alkyl, R6 is selected from H, (C1-C6) alkyl, and 2-(2,5-dioxopyrrolidin-1-yl)ethyl, and wherein if R5 is H, then R6 is not H.

[0079] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (IV), R6 and R5 are independently selected from hydrogen (H) and (C1-C6) alkyl, and wherein at least one of R6 and R5 is (C1-C6) alkyl.

[0080] (C1-C6) alkyl refers to straight-chain and branched-chain alkyls selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and neohexyl.

[0081] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (IV), R5 and R6 are independently (C1-C4) alkyl; or R5 is (C1-C4) alkyl and R6 is hydrogen (H); when one or both of R5 and R6 are (C1-C4) alkyl, in a more specific embodiment, it is (C1-C4) alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0082] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (IV), R5 and R6 are independently (C1-C4) alkyl; more specifically selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0083] In another specific embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (IV), R5 and R6 are the same (C1-C4) alkyl; more specifically, both are methyl (dimethyl fumarate). More information on dimethyl fumarate is given below.

[0084] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (IV), R5 is (C1-C4) alkyl and R6 is hydrogen (H); more specifically, R5 is ethyl and R6 is hydrogen (H) (monoethyl fumarate). In another more specific embodiment, R5 is methyl and R6 is hydrogen (H) (monomethyl fumarate).

[0085] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (IV), R6 is 2-(2,5-dioxopyrrolidin-1-yl)ethyl, and R5 is (C1-C6) alkyl, and more specifically, R5 is (C1-C4) alkyl, and even more specifically is methyl. When R6 is 2-(2,5-dioxopyrrolidin-1-yl)ethyl and R5 is methyl, the compound is also known as diroximel fumarate.

[0086] In another embodiment, the pharmaceutical or veterinary salt of the compound of formula (IV) is a salt of a metal selected from the group consisting of Group I metals and Group VIII metals. More specifically, it is the sodium salt or iron(II) salt of the compound of formula (IV).

[0087] The inventors have recognized that, in addition to the compounds of formula (IV), fumarates (HO2CCH=CHCO2H) of metals selected from the group consisting of Group I metals and Group VIII metals can also be used in combination with the compounds of formula (I) and optionally with any one of a sphingosine-1-phosphate receptor modulator (S1PR modulator) and a signal transducer and activator of transcription 3 (STAT3) inhibitor. In specific embodiments, these salts are selected from sodium fumarate and iron fumarate.

[0088] All specific embodiments of the compounds of formula (IV) in this specification and aspects included therein also apply to these fumarates of Group I metals and Group VIII metals.

[0089] Accordingly, a combination is also disclosed, which comprises:

[0090] a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof

[0091]

[0092] Wherein:

[0093] R1 is phenyl substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halogen(C1-C6)alkyl; or alternatively R1 is pyrrolidin-1-yl;

[0094] R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and

[0095] R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; and

[0096] b) one or more drugs selected from the group consisting of:

[0097] a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof

[0098]

[0099] wherein R5 is selected from hydrogen (H) and (C1-C6)alkyl, R6 is selected from H, (C1-C6)alkyl, and 2-(2,5-dioxopyrrolidin-1-yl)ethyl, and wherein if R5 is H, then R6 is not H,

[0100] ii) a sphingosine-1-phosphate receptor modulator (S1PR modulator),

[0101] iii) a signal transducer and activator of transcription 3 (STAT3) inhibitor, and

[0102] iv) a fumarate of a metal selected from the group consisting of Group I metals and Group VIII metals.

[0103] Specifically, the combination comprises: a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, and b) a fumarate of a metal selected from the group consisting of Group I metals and Group VIII metals.

[0104] The inventors also recognize that pharmaceutical formulations (i.e., capsules, pills, tablets) comprising fumaric acid or a compound of formula (IV) as disclosed above, or any pharmaceutically or veterinarily acceptable salt of any of said acids or compounds of formula (IV), in combination with other active ingredients, particularly in combination with aspirin (i.e., acetylsalicylic acid), can also be used together with any compound of formula (I) and optionally with one or more of a sphingosine-1-phosphate receptor modulator (S1PR modulator) and a signal transducer and activator of transcription 3 (STAT3) inhibitor.

[0105] All specific embodiments of the compounds of formula (IV) in this specification are also applicable to these pharmaceutical formulations, including combinations of fumaric acid or a compound of formula (IV) or any pharmaceutically or veterinarily acceptable salt thereof with other active ingredients, particularly in combination with aspirin.

[0106] Dimethyl fumarate

[0107] Dimethyl fumarate (i.e., ) is a dimethyl ester of fumaric acid and is approved in the United States and the European Union for the treatment of adults with relapsing MS. Among other pathways, dimethyl fumarate has been shown to have immunomodulatory activity and antioxidant effects by activating the nuclear factor (erythroid-derived 2)-like (Nrf2) pathway or GAPDH (see Tecfidera.com). However, the exact mechanism by which dimethyl fumarate counteracts relapsing MS is not clear. Dimethyl fumarate has the following structure:

[0108]

[0109] Dimethyl fumarate is generally used at a dose that can produce immunomodulatory activity when administered alone. The approved dosage of dimethyl fumarate is 120 mg twice daily for one week (equivalent to 1.7 mg / kg twice daily for a 70-kg patient), and then approximately 240 mg twice daily thereafter (equivalent to 3.4 mg / kg twice daily for a 70-kg patient). In certain embodiments, a fumarate ester (such as dimethyl fumarate) can be used at these dosages (referred to as the therapeutic dosage or optimal dose) as described above and in combination with a compound of formula (I) (such as BN201). A sub-therapeutic dose of dimethyl fumarate is less than 120 mg twice daily for one week, and thereafter less than approximately 240 mg twice daily, less than approximately 120 mg twice daily, or less than approximately 120 mg once daily. In certain of these embodiments, administration of dimethyl fumarate can result in a reduction in side effects compared to the side effects associated with administering dimethyl fumarate at the optimal dose used alone for treatment. In certain embodiments, side effects from treatment with dimethyl fumarate (which may be reduced due to administering dimethyl fumarate at a lower dosage than is typically administered alone) include, but are not limited to, allergic reactions and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia (i.e., a reduced lymphocyte count), flushing (i.e., a feeling of heat or itch and redness on the skin), gastrointestinal reactions (i.e., abdominal pain, diarrhea, and nausea), protein in the urine, elevated liver enzymes, rash, or some combination thereof.

[0110] Dimethyl fumarate can also be used in the form of a sustained-release formulation (capsule), including a combination of dimethyl fumarate and aspirin (i.e., VTS-72, a proprietary combination of Vitalis Pharma). This combination is proposed for the treatment of relapsing MS patients who have experienced a fumarate washout.

[0111] Monomethyl fumarate

[0112] Monomethyl fumarate (i.e., ) is also known as monomethyl fumarate and is indicated for the treatment of relapsing multiple sclerosis (MS), including clinically isolated syndromes, relapsing-remitting disease, and active secondary progressive disease in adults. The dosage of monomethyl fumarate approved by the FDA is 95 mg twice daily (sustained-release capsules), orally, for 7 days. The maintenance dose after 7 days is 190 mg twice daily (administered as two 95-mg capsules), orally.

[0113] Deoxysapogenin fumarate

[0114] Diroximel fumarate (i.e., ) Also known as 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate, is indicated for the treatment of relapsing multiple sclerosis (MS) in adults; particularly active secondary progressive disease and clinically isolated syndromes, as well as relapsing-remitting MS. Dimethyl fumarate has the following structure:

[0115]

[0116] The approved dose of dimethyl fumarate is 231 mg twice daily, orally, for 7 days. The maintenance dose after 7 days is 462 mg twice daily (administered as two 231 mg capsules), orally.

[0117] Those skilled in the art can use their own specific knowledge and take into account the guidance of the effects disclosed above to calculate the dose of a specific compound of formula (IV).

[0118] S1P receptor (SP1R) modulator

[0119] For the purposes of the present invention, an "S1P receptor modulator" includes a compound or agent capable of reducing lymphocyte trafficking and modulating the degree of autoimmune attack. Lymphocyte trafficking is measured indirectly as lymphocytes in the blood using flow cytometry. Lymphocyte trafficking is to be considered under an S1PR modulator by observing the percentage decrease or increase of lymphocytes relative to the baseline (before treatment with an SP1R modulator, i.e., fingolimod). In a specific embodiment, the S1PR modulator to be combined with a compound of formula (I) as defined above is selected from the group consisting of fingolimod, siponimod, ozanimod, ponesimod, and ceralifimod. (Patrick Vermersch; "Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis"; European Neurological Review - 2018; 13(1):25–30).

[0120] Fingolimod is a sphingosine structural analogue derived from myriocin. Fingolimod ( Novartis (also known as FTY720) has been shown to have immunomodulatory activity and is approved in the United States and the European Union for reducing relapses and delaying disability progression in subjects with relapsing MS. Although the exact mechanism by which fingolimod reduces relapses is not known, it is thought that fingolimod reduces circulating lymphocytes by sequestering them in lymph nodes, which prevents them from participating in autoimmune responses and attacking myelin (see Gilenya.com). Fingolimod has the following structure:

[0121]

[0122] For S1PR modulators (such as fingolimod), the therapeutic or optimal dose is those doses that are capable of producing immunomodulatory activity. For humans, the approved dose of fingolimod is 0.5 mg / day. In clinical trials, doses of 1.25 mg / day and 5 mg / day of fingolimod were shown to be the most effective; however, the side effects of fingolimod prevented its use at these doses. The specific therapeutic or optimal dose of fingolimod is from 0.75 mg / day to 50 mg / day. More specifically, the therapeutic dose is about 50 mg / day or less, about 50 mg / day, about 45 mg / day or less, about 45 mg / day, about 40 mg / day or less, about 40 mg / day, about 35 mg / day or less, about 35 mg / day, about 30 mg / day or less, about 30 mg / day, about 25 mg / day or less, about 25 mg / day, about 20 mg / day or less, about 20 mg / day, about 15 mg / day or less, about 15 mg / day, about 10 mg / day or less, about 10 mg / day, about 5 mg / day or less, about 5 mg / day, about 2.5 mg / day or less, about 2.5 mg / day, about 2.0 mg / day or less, about 2.0 mg / day, about 1.5 mg / day or less, about 1.5 mg / day, about 1.25 mg / day or less, about 1.25 mg / day, about 1.0 mg / day or less, about 1.0 mg / day, about 0.75 mg / day or less or about 0.75 mg / day. As previously mentioned, the approved dose of fingolimod is 0.5 mg / day.

[0123] Those skilled in the art are able to use their own specific knowledge and take into account the guidance on the effects disclosed above to calculate the dose of a specific S1PR modulator.

[0124] Sub-therapeutic or sub-optimal doses of fingolimod (an example of an S1PR modulator) can be from 0.05 mg / day to 0.4 mg / day. In certain embodiments, fingolimod can be administered at a sub-optimal dosage of 0.4 mg / day or less, about 0.3 mg / day or less, about 0.3 mg / day, about 0.2 mg / day or less, about 0.2 mg / day, about 0.1 mg / day or less, about 0.1 mg / day, about 0.05 mg / day or less, or about 0.05 mg / day. In certain of these embodiments, administration of fingolimod can result in a reduction in side effects compared to those associated with administering fingolimod at the optimal dose used alone for treatment. In certain embodiments, side effects from treatment with fingolimod (which may be reduced due to administering fingolimod at a lower dosage than typically administered alone) include, but are not limited to, headache, flu, diarrhea, back pain, abnormal liver function, cough, slow heart rate, increased risk of serious infection, posterior reversible encephalopathy syndrome (PRES), macular edema, swelling and narrowing of blood vessels in the brain that can lead to stroke or bleeding, breathing problems, macular edema, bradycardia, herpes zoster reactivation, hemophagocytic syndrome, or some combination thereof.

[0125] Siponimod is marketed under the trade name Mayzent (FDA approved in March 2019) and is an oral selective sphingosine-1-phosphate receptor modulator (S1P1 and S1P5) for multiple sclerosis (MS). It is intended for once-daily oral administration. Siponimod inhibits the migration of lymphocytes to sites of inflammation (e.g., in MS). It may be very similar to fingolimod but prevents lymphopenia, which is one of its major side effects.

[0126]

[0127] Ozanimod (RPC-1063) is an investigational immunomodulatory drug that is currently in Phase III clinical trials for the treatment of relapsing multiple sclerosis (RMS) and ulcerative colitis (UC).

[0128]

[0129] Ponimod (INN, code name ACT-128800) is an experimental drug for the treatment of multiple sclerosis (MS) and psoriasis. Actelion is developing it.

[0130]

[0131] Selinexor (CAS No. 891859-12-4, or 1-[[6-[(2-methoxy-4-propylphenyl)methoxy]-1-methyl-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid) interacts with the sphingosine-1-phosphate (S1P) receptors S1P1 and S1P5. Selinexor delays disease onset and inhibits lymphocyte infiltration in the spinal cord in a rat model of experimental autoimmune encephalomyelitis (EAE), and prevents disease recurrence in a non-obese diabetic mouse model of relapsing-remitting EAE.

[0132]

[0133] STAT3 inhibitor

[0134] For the purposes of the present invention, a "STAT3 inhibitor" includes a compound or agent capable of reducing the activity of STAT3 in inducing signal transduction by pro-inflammatory cytokines. STAT3 inhibition can be measured by inhibiting the production of inflammatory cytokines in vitro and in vivo. Inhibiting pSTAT3 expression and IL-17 production in myelin-specific CD4 T cells in a dose-dependent manner inhibits IL-6-induced IL-17 production in myelin-specific CD4 T cells.

[0135] Signal transducer and activator of transcription 3 gene (STAT3) is a transcription factor that is involved in several pathways and cell types, including serving as a sensor for axonal damage to prevent axonal transection or synaptic recycling. At the immunological level, STAT3 is a key mediator of the IL-10 and IL-6 signal transduction pathways, being involved in both the anti-inflammatory response mediated by regulatory T cells and the pro-inflammatory response mediated by Th17 cells. Non-limiting examples of STAT3 inhibitors include (S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide (STAT3 inhibitor III, WP1066, CAS 857064-38-1), 4-((3-(carboxymethylsulfonyl)-4-hydroxy-1-naphthyl)sulfamoyl)benzoic acid (STAT3 inhibitor IX Cpd188 - CAS 823828-18-8), STAT3 inhibitor peptide (linear molecular formula: C 38 H 63 N8O 13 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]thiophene-1,1-dioxide (STAT3 inhibitor V Stattic - CAS 19983 - 44 - 9), 2-hydroxy-4-[[[[(4-methylphenyl)sulfonyl]oxy]acetyl]amino]-benzoic acid (STAT3 inhibitor VI S3I - 201 - CAS 501919 - 59 - 1), ethyl 1-(4-cyano-2,3,5,6-tetrafluorophenyl)-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 - CAS 22112 - 89 - 6), PIAS3 (UniprotKB database accession number Q9Y6X2, version 2 of the sequence as of December 7, 2004, -v2), N-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-2-phenylquinoline-4-carboxamide (STAT3 inhibitor XI STX - 0119), STAT3 inhibitor XII SPI (SEQ ID NO: 2), N-(1′,2-dihydroxy-1,2′-binaphthalen-4′-yl)-4-methoxybenzenesulfonamide (CAS number: 432001 - 19 - 9, F1113 - 0789, STAT3 inhibitor XIII C188 - 9).

[0136] The above-disclosed SEQ ID NO: 1 is: H-Pro-Tyr-(PO3H2)-Leu-Lys-Thr-Lys-Ala-Ala-Val-Leu-Leu-Pro-Val-Leu-Leu-Ala-Ala-Pro-OH (also known as STAT3 inhibitor peptide).

[0137] The above-disclosed SEQ ID NO: 2 is H2N-FISKERERAILSTKPPGTFLLRFSESSK-CO2H (also known as STAT3 inhibitor XII SPI).

[0138] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the STAT3 inhibitor is S3I - 201, which is an aminosalicylic acid compound that selectively inhibits STAT3 activation and STAT3-dependent transcription. The chemical name of S3I - 201 is as shown above: 2-hydroxy-4-[[[[(4-methylphenyl)sulfonyl]oxy]acetyl]amino]-benzoic acid. S3I - 201 has the following structure:

[0139]

[0140] The therapeutic doses of STAT3 inhibitors (such as S3I-201) are those doses that are capable of producing immunomodulatory activity when administered alone. A specific therapeutic dose or optimal dose is about 5 mg / kg. Thus, sub-therapeutic doses in mice are below 5 mg / kg. Specifically, sub-therapeutic doses in mice are from 0.1 to below 5 mg / kg (which corresponds to a HED of 0.01 mg / kg to below 0.4 mg / kg).

[0141] The combination of the present invention

[0142] As described above, the present invention relates to a combination comprising:

[0143] a) a compound of formula (I) as previously defined or a pharmaceutically or veterinarily acceptable salt thereof, and

[0144] 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) an S1PR modulator, and iii) a STAT3 inhibitor, as previously defined.

[0145] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination of the present invention comprises:

[0146] a) a compound of formula (I) as previously defined or a pharmaceutically or veterinarily acceptable salt thereof, and

[0147] b) a drug selected from the group consisting of: i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor, as previously defined.

[0148] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination of the present invention comprises:

[0149] a) a compound of formula (I) as previously defined or a pharmaceutically or veterinarily acceptable salt thereof, and

[0150] 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) an S1PR modulator, and iii) a STAT3 inhibitor, as previously defined,

[0151] wherein the amounts of a) and b) of the combination are therapeutically effective.

[0152] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination of the present invention, the amount of a) alone is a sub-therapeutic amount; and the combined amount of a) and b) is therapeutically effective.

[0153] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination of the present invention, the amount of b) alone is a sub-therapeutic amount; and the combined amount of a) and b) is therapeutically effective.

[0154] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination of the present invention, the amounts of a) and b) alone are sub-therapeutic amounts; and the combined amount of a) and b) is therapeutically effective.

[0155] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination of the present invention comprises or consists of: a) a compound of formula (I) as previously defined, which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically is G79 (BN201); and b) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, more specifically, the compound of formula (IV) is selected from dimethyl fumarate, monomethyl fumarate, and monoethyl fumarate, and even more specifically is dimethyl fumarate.

[0156] Other salts in combination with the compound of formula (I) as previously defined (which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically is G79 (BN201)) are disodium fumarate (sodium fumarate) and iron fumarate (iron(II) fumarate).

[0157] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination of the present invention comprises or consists of: a) a compound of formula (I) as previously defined, which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically is G79 (BN201); and b) an S1PR modulator, which is specifically selected from the group consisting of fingolimod, siponimod, and ozanimod, and even more specifically is fingolimod.

[0158] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination of the present invention comprises the following or consists of the following: a) a compound of formula (I) as previously defined, which is specifically selected from the group consisting of compounds G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically is G79 (BN201); and b) a STAT3 inhibitor as defined herein, which is S3I-201.

[0159] Other drugs in simultaneous combination with (a) and (b)

[0160] In other specific embodiments of the first aspect, other drugs for the treatment of multiple sclerosis are included in the combination, and the combination comprises: (a) a compound of formula (I) as defined above (i.e., including all its possible pharmaceutically or veterinarily acceptable salts as previously described); and b) one or more drugs selected from the group consisting of a compound of formula (IV) or its pharmaceutically or veterinarily acceptable salt, a sphingosine-1-phosphate receptor modulator (S1PR modulator), and a signal transducer and activator of transcription 3 (STAT3) inhibitor. In more specific embodiments, these drugs include drugs selected from interferon-β, glatiramer acetate, natalizumab, alemtuzumab, teriflunomide, cladribine, ocrelizumab, and combinations thereof. Other drugs that can be combined are selected from diroximel fumarate (ALKS 8700), evobrutinib, ofatumumab, ublituximab, amiloride, fluoxetine, ibudilast, masitinib, MD1003 (biotin), opicinumab (anti-LINGO-1, BIIB033), riluzole, simvastatin, idebenone, temelimab (GNbAC1), inebilizumab (MEDI-551), naltrexone, etc.

[0161] Pharmaceutical and veterinary compositions, multi-part packs or kits

[0162] The present invention also relates to pharmaceutical and veterinary compositions or multi-part packs or kits, which comprise: a) a compound of formula (I) or its pharmaceutically or veterinarily acceptable salt; and b) one or more drugs selected from the group consisting of: i) a compound of formula (IV) or its pharmaceutically or veterinarily acceptable salt, ii) an S1PR modulator, and iii) a STAT3 inhibitor;

[0163] and one or more pharmaceutically or veterinarily acceptable excipients or carriers; wherein the compound of formula (I) and the drugs are as defined above in any aspect and related specific embodiments.

[0164] The expression "pharmaceutically or veterinarily acceptable excipient or carrier" refers to a pharmaceutically or veterinarily acceptable material, composition or vehicle. Each component must be pharmaceutically and veterinarily acceptable in the sense that it is compatible with the other ingredients of the pharmaceutical or veterinary composition. They must also be suitable for use in contact with the tissues or organs of humans and animals without producing excessive toxicity, irritation, allergic reactions, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0165] A single pharmaceutical or veterinary composition forms part of the present invention and comprises:

[0166] a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof; and

[0167] b) one or more drugs selected from the group consisting of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator and a STAT3 inhibitor;

[0168] and one or more pharmaceutically or veterinarily acceptable excipients or carriers; wherein the compound of formula (I) and the drugs are as defined previously, and wherein the amounts of a) and b) in combination are therapeutically effective.

[0169] As used herein in the present specification, the expression "therapeutically effective" means an amount of a compound or combination of compounds which, when administered, is sufficient to prevent the development of the disease to be addressed or to alleviate to some extent one or more of its symptoms. In this particular description, the amount of the compound, combination of compounds or composition produces the desired therapeutic effect in a subject, such as in the treatment of MS, NMO and / or optic neuritis. The precise therapeutically effective amount is the amount of the composition that will produce the most effective result in terms of therapeutic effect in a given subject. The specific dose of the compounds of the present invention that achieves a therapeutic benefit may vary depending on the specific circumstances of the individual patient, said specific circumstances including in particular the patient's body size, weight, age and gender, the nature and stage of the disease, the aggressiveness of the disease and the route of administration, etc. When administered as the combination, composition or multi-part kit, the specific dose of the compounds of the present invention that achieves a therapeutic benefit may vary depending on the specific dose of the compound used as the single active agent.

[0170] Those specific embodiments of the above combinations are also applicable to specific embodiments of the single pharmaceutical or veterinary composition, multi-part pack or kit of the present invention.

[0171] Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the single pharmaceutical or veterinary composition as defined above, the amount of a) alone is sub-therapeutic; and the amounts of a) and b) in combination are therapeutically effective.

[0172] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in a single pharmaceutical or veterinary composition as defined above, the amount of b) alone is sub-therapeutic; and the combined amounts of a) and b) are therapeutically effective.

[0173] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in a single pharmaceutical or veterinary composition as defined above, the amounts of a) alone and b) alone are sub-therapeutic; and the combined amounts of a) and b) are therapeutically effective.

[0174] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in a single pharmaceutical or veterinary composition as defined above, the amounts of both a) alone and b) alone are therapeutic; and the combined amounts of a) and b) are therapeutically effective.

[0175] As used in this specification, the terms "sub-therapeutic amount" or "sub-optimal amount", and "sub-therapeutic dose" or "sub-optimal dose", all of which terms may be used interchangeably as synonyms, are amounts / doses that are individually non-therapeutically effective. Thus, a "sub-optimal dose" or "sub-therapeutic dose" means a dose that is lower than the optimal (or therapeutic) dose (or dose range) which, when used in a single compound therapy for a particular disease (such as MS, NMO disease, and / or optic neuritis), is approved by the health authorities as being effective for that compound. Thus, when the term "sub-therapeutic amount" appears in an aspect or embodiment of this specification, it should be understood as an amount of a particular compound that is lower than the therapeutic amount approved by the health authorities (i.e., the European Medicines Agency of the European Union, the US Food and Drug Administration, etc.) as being effective when used in a single compound therapy for a particular disease. For example, if the effective dose of BN201 (a compound of formula I) in a single compound therapy ranges from above 25 mg / kg to 200 mg / kg, then the sub-optimal dose is from 0.5 mg / kg to 25 mg / kg. The approved dose of fingolimod (an S1PR inhibitor) in humans is 0.5 mg / day, which is the most effective dose based on clinical trials at 1.25 mg / day and 5 mg / day. The sub-optimal doses of S1PR inhibitors (i.e., fingolimod) are those doses that are lower than 0.5 mg / day, ranging from 0.05 mg / day to 0.4 mg / day. Similarly, the approved dosage of dimethyl fumarate is 120 mg twice daily for one week and then approximately 240 mg twice daily thereafter. The sub-optimal doses of dimethyl fumarate are doses that are less than approximately 120 mg twice daily for one week and less than approximately 240 mg twice daily thereafter. Thus, in a specific embodiment, when administered in the said combination, composition, or multi-part kit, the amount of the compound of formula (I) and the amount of one or more compounds selected from the group consisting of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator, and a STAT3 inhibitor are lower than the effective amount when used as a single active agent.

[0176] The phrases "dose" and "dosage" are used interchangeably herein.

[0177] In another specific embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the present invention also relates to a multi-part pack or kit comprising:

[0178] i) a first pharmaceutical or veterinary composition comprising an amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof as defined above, and one or more pharmaceutically or veterinarily acceptable excipients or carriers;

[0179] ii) A second pharmaceutical or veterinary composition comprising an amount of one or more drugs selected from the group consisting of a compound of formula (IV) as previously defined or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator, and a STAT3 inhibitor, and one or more pharmaceutically or veterinarily acceptable excipients or carriers; and

[0180] iii) Instructions for the combined use of i) and ii);

[0181] wherein the first composition and the second composition are separate compositions, and wherein the amount of the compound of formula (I) in i) and the amount of one or more drugs in ii) in combination are therapeutically effective.

[0182] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the multi-part kit as defined above, the amount of the compound of formula (I) alone and the amount of one or more drugs in ii) are both therapeutic amounts; and the amount of the compound of formula (I) in i) and the amount of one or more drugs in ii) in combination are therapeutically effective.

[0183] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the multi-part kit as defined above, the amount of the compound of formula (I) in i) alone is a sub-therapeutic amount; and the amount of the compound of formula (I) in i) and the amount of one or more drugs in ii) in combination are therapeutically effective.

[0184] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the multi-part kit as defined above, the amount of one or more drugs in ii) alone is a sub-therapeutic amount; and the amount of the compound of formula (I) in i) and the amount of one or more drugs in ii) in combination are therapeutically effective.

[0185] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the multi-part kit as defined above, the amount of the compound of formula (I) in i) and the amount of one or more drugs in ii) alone are sub-therapeutic amounts; and the amount of the compound of formula (I) in i) and the amount of one or more drugs in ii) in combination are therapeutically effective.

[0186] A specific embodiment of the multi-part kit, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, includes: a medicine box having separate compartments each containing one of the pharmaceutical or veterinary compositions; and instructions for the combined use of i) and ii), said instructions being specifically in a form selected from a booklet, a data carrier (i.e., CD, QR code).

[0187] The choice of the pharmaceutical or veterinary formulation will depend on the nature of the active compound and its route of administration. Any route of administration can be used, such as oral, parenteral and topical administration.

[0188] For example, the pharmaceutical or veterinary composition can be formulated for oral administration and can contain one or more physiologically compatible carriers or excipients in solid or liquid form. These formulations can contain conventional ingredients such as binders, fillers, lubricants and acceptable wetting agents.

[0189] The pharmaceutical or veterinary composition can be formulated in combination with a conventional injectable liquid carrier such as water or a suitable alcohol for parenteral administration. Conventional pharmaceutical or veterinary excipients for injection, such as stabilizers, solubilizers and buffers, can be included in such compositions. These pharmaceutical or veterinary compositions can be injected intramuscularly, intraperitoneally or intravenously.

[0190] The pharmaceutical composition can be formulated for topical administration. Formulations include creams, lotions, gels, powders, solutions and patches, in which the compound is dispersed or dissolved in a suitable excipient.

[0191] The pharmaceutical composition can be in any form, especially in the form of tablets, pills, capsules, aqueous or oily solutions, suspensions, emulsions or dry powders, suitable for reconstitution with water or other suitable liquid media before use for immediate or delayed release.

[0192] Suitable excipients and / or carriers and their amounts can be readily determined by those skilled in the art according to the type of formulation to be prepared.

[0193] Treating inflammatory neurological diseases or disorders leading to axonal or myelin damage or degeneration

[0194] The composition, single pharmaceutical or veterinary composition, multi-part pack or kit forms part of the present invention, said composition, single pharmaceutical or veterinary composition, multi-part pack or kit 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 formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor, wherein the compound of formula (I) and these drugs are as defined above, for treating and / or preventing in a subject in need thereof an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration.

[0195] This aspect can also be expressed as a method of treating and / or preventing an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration, said method comprising administering to a mammalian subject in need thereof (including a human subject)

[0196] a) A therapeutically effective combination, which comprises (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 formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor; wherein the compound of formula (I) and these drugs are as defined above, and one or more pharmaceutically or veterinarily acceptable excipients or carriers; or alternatively

[0197] b) A multi-part pack or kit as defined in the above examples.

[0198] The use of the combination for the preparation of a medicament for the treatment and / or prevention of an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration also forms part of the present invention, said 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 formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor, wherein the compound of formula (I) and these drugs are as defined above..

[0199] In a specific embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the medicament comprises a single drug or veterinary composition as defined in the above examples or a multi-part pack or kit also as defined above.

[0200] In another specific embodiment of any single drug or veterinary composition, or multi-part pack or kit, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the treatment comprises administering simultaneously, concurrently, separately or sequentially (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 formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor, wherein the compound of formula (I) and these drugs are as defined above.

[0201] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination, single drug or veterinary composition, multi-part pack or kit for use as described above comprises:

[0202] a) A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof as previously defined, and

[0203] b) a medicament selected from the group consisting of: i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor, as previously defined.

[0204] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the combination, single medicament or veterinary composition, multi-part pack or kit for said use, as described above, comprises:

[0205] a) a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, as previously defined, and

[0206] b) one or more medicaments selected from the group consisting of: i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor, as previously defined,

[0207] wherein the amounts of a) and b) of the combination are therapeutically effective.

[0208] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single medicament or veterinary composition, multi-part pack or kit for said use, as described above, both the amount of a) alone and the amount of b) alone are therapeutic amounts; and the amounts of a) and b) of the combination are therapeutically effective.

[0209] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single medicament or veterinary composition, multi-part pack or kit for said use, as described above, the amount of a) alone is sub-therapeutic; and the amounts of a) and b) of the combination are therapeutically effective.

[0210] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single medicament or veterinary composition, multi-part pack or kit for said use, as described above, the amount of b) alone is sub-therapeutic; and the amounts of a) and b) of the combination are therapeutically effective.

[0211] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single medicament or veterinary composition, multi-part pack or kit for said use, as described above, both the amount of a) alone and the amount of b) alone are sub-therapeutic; and the amounts of a) and b) of the combination are therapeutically effective.

[0212] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug or veterinary composition, multi-part pack or kit for the use as described above, the sub-therapeutic amount of a) is from 0.5 mg / kg to 25 mg / kg (which corresponds to a human equivalent dose (HED) of from 0.04 mg / kg to 2 mg / kg).

[0213] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug or veterinary composition, multi-part pack or kit for the use as described above, b) is a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, more specifically dimethyl fumarate, and the sub-therapeutic amount of the compound of formula (IV) is less than 120 mg twice daily for one week (equivalent to 1.7 mg / kg twice daily for a human patient of 70 kg body weight), and thereafter less than about 240 mg twice daily (equivalent to 3.4 mg / kg twice daily for a human patient of 70 kg body weight).

[0214] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug or veterinary composition, multi-part pack or kit for the use as described above, b) is an SP1R modulator, and the sub-therapeutic amount in humans is from 0.05 mg / day to 0.4 mg / day. More specifically, an amount from 0.05 mg / day to 0.1 mg / day.

[0215] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug or veterinary composition, multi-part pack or kit for the use as described above, b) is a STAT3 inhibitor, and the sub-therapeutic amount in mice is from 0.1 to 5 mg / kg (which corresponds to a HED of from 0.01 mg / kg to 0.4 mg / kg).

[0216] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug or veterinary composition, multi-part pack or kit for the use as described above, comprises the following or consists of the following: a) a compound of formula (I) as previously defined, which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119) and G81 (BN120), even more specifically G79 (BN201); and b) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, which is specifically selected from dimethyl fumarate, monomethyl fumarate and monoethyl fumarate, even more specifically dimethyl fumarate.

[0217] Other salts in combination with a compound of formula (I) as defined previously, which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically G79 (BN201), are disodium fumarate (sodium fumarate) and ferrous fumarate (ferrous fumarate (II)), which the inventors have recognized as being active in combination.

[0218] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug, or veterinary composition, multi-part pack, or kit for said use as described above, comprises or consists of: a) a compound of formula (I) as defined previously, which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically G79 (BN201); and b) an S1PR modulator, which is specifically selected from the group consisting of fingolimod, siponimod, and ozanimod, and even more specifically fingolimod.

[0219] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug, or veterinary composition, multi-part pack, or kit for said use as described above, comprises or consists of: a) a compound of formula (I) as defined previously, which is specifically selected from the group consisting of compound G79 (BN201), G80 (BN119), and G81 (BN120), and even more specifically G79 (BN201); and b) a STAT3 inhibitor as defined herein, which is S3I-201.

[0220] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the combination, single drug or veterinary composition, multi-part pack or kit for use as described above, comprises or consists of the following: a) a compound of formula (I) as previously defined; specifically selected from the group consisting of compounds G79 (BN201), G80 (BN119) and G81 (BN120), even more specifically G79 (BN201); and b) a STAT3 inhibitor as defined herein, specifically S3I-201, wherein the amounts of a) and b) in the combination are therapeutically effective; and for the chronic or progressive phase of an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration, specifically for the chronic or progressive phase of a disease or disorder selected from multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Baló disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease or some combination thereof.

[0221] The following also forms part of the present invention: a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, and one or more pharmaceutically or veterinarily acceptable excipients or carriers, for combined administration with one or more drugs and one or more pharmaceutically or veterinarily acceptable excipients or carriers, said drugs selected from the group consisting of i) a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, ii) an S1PR modulator, and iii) a STAT3 inhibitor; for simultaneous, parallel, separate or sequential use in treating and / or preventing in a subject in need an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration, wherein the compound of formula (I) and the one or more drugs are as previously defined.

[0222] The following also forms part of the present invention: 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) an S1PR modulator, and iii) a STAT3 inhibitor; and one or more pharmaceutically or veterinarily acceptable excipients or carriers, for combined administration with a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, and one or more pharmaceutically or veterinarily acceptable excipients or carriers, for simultaneous, parallel, separate or sequential use in treating and / or preventing in a subject in need an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration, wherein the compound of formula (I) and the drugs are as previously defined.

[0223] In another specific embodiment of the combinations, single drugs or veterinary compositions, or multi-part packs or kits for use as described above, the inflammatory neurological diseases or disorders capable of causing axonal or myelin damage or degeneration are selected from the group consisting of multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Baló disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease or some combination thereof.

[0224] As used herein (see the examples below), the terms "neuroprotection", "neuroprotective" or "neuroprotective effect" refer to the ability to prevent or reduce the death or injury of nerve cells (including neurons and glia), or to rescue, revive or restore nerve cells and their extensions (such as axons, dendrites and synapses) after injury (e.g., injury caused by or associated with a pathological or harmful condition in the brain, central nervous system or peripheral nervous system). Thus, such neuroprotective effects include endowing neuronal cells with the ability to maintain or restore their neuronal function. The neuroprotective effect stabilizes the cell membrane of neuronal cells or contributes to the normalization of neuronal cell function. It prevents the loss of neuronal cell viability or function. It includes inhibiting the progressive degeneration of neurons leading to cell death. It is any detectable protection that shields neurons from stress. Neuroprotection includes the regeneration of nerve cells and myelin, i.e., the regrowth of nerve cell populations after disease or trauma.

[0225] The pharmaceutical compositions as described herein can be administered to a subject in need thereof once or more per day up to once or every few months.

[0226] Additionally, it may also be considered to adjust the therapeutic or sub-therapeutic amounts of each compound of formula (I) and one or more drugs as previously described based on the body weight of the subject receiving the combinations, single drugs or veterinary compositions disclosed above. Those skilled in the art will be able to determine such amounts given the guidance in this specification.

[0227] For the purposes of the present invention, the term "treatment" or variations of the word mean reducing, stabilizing or inhibiting the development of an inflammatory neurological disease or disorder that can lead to the destruction or degeneration of axons or myelin in a patient already suffering from the disease. The term "prevention" as used herein refers to both preventing the onset of a clinically apparent inflammatory neurological disease or disorder as described above and delaying its onset. Thus, the term "treat / treating / treatment" as used herein can refer to producing a complete or partial remission of the disease; eliminating, reducing, preventing or delaying the development of symptoms associated with the disease; preventing, delaying or reducing the risk of disease development or onset; preventing, delaying or reducing the recurrence rate and / or the occurrence of recurrence; preventing, delaying or reducing the increased time of disability progression; providing a neuroprotective effect; or some combination thereof. For example, treatment can refer to reducing the accumulation of disability in a subject in need thereof. In certain embodiments, treatment can also refer to providing a neuroprotective effect, an immunomodulatory response or some combination thereof.

[0228] The phrases "patient" and "subject" are used interchangeably herein.

[0229] As used herein, the term "about" means within 5% or 10% of a set value or range of values.

[0230] Salts of formula (II): fumaric acid derivative salts of compounds of formula (I)

[0231] The present invention also relates to salts of formula (II) which are fumaric acid derivative salts of specific compounds of formula (I):

[0232]

[0233] wherein R1, R2 and R3 are as defined above for the compounds of formula (I) and R4 is (C1-C6) alkyl.

[0234] The preparation of the salts of formula (II) can be carried out by methods known in the art. For example, they can be prepared from the parent compounds of formula (I) containing a basic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free acid form of these compounds of formula (I) with a stoichiometric amount of a suitable pharmaceutically or veterinarily acceptable acid of formula (III) in water or an organic solvent (such as methanol, ethanol) or a mixture thereof (water and organic solvent):

[0235]

[0236] wherein R4 is as defined above.

[0237] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a fluorophenyl group, more particularly 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl, and even more particularly 2-fluorophenyl.

[0238] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a fluorophenyl group which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy and halogen(C1-C6) alkyl; preferably by one or two substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy and halogen(C1-C4) alkyl; more preferably by one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0239] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a chlorophenyl group, more particularly 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl, and even more particularly R1 is 2-chlorophenyl.

[0240] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a chlorophenyl group which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy and halogen(C1-C6) alkyl; preferably by one or two substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy and halogen(C1-C4) alkyl; more preferably by one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trifluoromethyl.

[0241] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (I), R1 is a bromophenyl group, more particularly 2-bromophenyl, 3-bromophenyl or 4-bromophenyl, and even more particularly 2-bromophenyl.

[0242] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a bromophenyl group which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halogen(C1-C6) alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, and halogen(C1-C4) alkyl; more preferably one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0243] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is an iodophenyl group, more particularly 2-iodophenyl, 3-iodophenyl or 4-iodophenyl, and even more particularly 2-iodophenyl.

[0244] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is an iodophenyl group which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halogen(C1-C6) alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4) alkyl, (C1-C4) alkoxy, and halogen(C1-C4) alkyl; more preferably one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0245] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a trifluoromethylphenyl group, more particularly 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or 4-trifluoromethylphenyl, and even more particularly 2-trifluoromethylphenyl.

[0246] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is a trifluoromethylphenyl, which is further substituted by one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halogen(C1-C6)alkyl; preferably one or two substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, and halogen(C1-C4)alkyl; more preferably one or two substituents selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, and trifluoromethyl.

[0247] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R1 is pyrrolidin-1-yl.

[0248] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R2 is 2-oxo-pyrrolidin-1-yl-methyl.

[0249] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R2 is a sulfamoylphenyl, more particularly 2-sulfamoylphenyl, 3-sulfamoylphenyl, or 4-sulfamoylphenyl, even more particularly 4-sulfamoylphenyl.

[0250] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), R3 is 2-methylpropyl.

[0251] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), and thus in the compound of formula (III), R4 is (C1-C4)alkyl, more preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0252] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compound of formula (II), and thus in the compound of formula (III), R4 is (C1-C4)alkyl, more preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0253] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, in the compounds of formula (II) and thus in the compounds of formula (III), R4 is methyl.

[0254] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the compound of formula (II) is:

[0255]

[0256] A specific salt of formula (II) was generated, more specifically the fumarate of BN201 (hereinafter referred to as BN201-fumarate, or the compound of formula (IIa)) (see Example 5), and its neuroprotective effect was evaluated relative to BN201 alone or fumarate (see Example 6). The results showed that both BN201 and fumarate partially rescued neurons from death induced by oxidative stress. However, BN201-fumarate exhibited a significantly higher level of protection than either compound alone, indicating a synergistic neuroprotective effect.

[0257] Accordingly, all these salts of formula (II) can be added as active agents to pharmaceutical or veterinary compositions for protecting the health of neurons and / or rescuing damaged neurons.

[0258] Accordingly, the present invention also relates to a pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound of formula (II) and one or more pharmaceutically or veterinarily acceptable excipients or carriers.

[0259] The present invention also relates to a salt of formula (II), or a pharmaceutical or veterinary composition comprising said salt of formula (II), for treating and / or preventing inflammatory neurological diseases or disorders in a subject in need thereof that can cause axonal or myelin damage or degeneration.

[0260] This aspect can also be formulated as a method for treating and / or preventing inflammatory neurological diseases or disorders that can cause axonal or myelin damage or degeneration, which comprises administering to a mammalian subject in need thereof (including a human subject) a therapeutically effective amount of a salt of formula (II) or a pharmaceutical or veterinary composition comprising said salt of formula (II), and one or more pharmaceutically or veterinarily acceptable excipients or carriers.

[0261] The use of the salt of formula (II) also forms part of the present invention; it is used for preparing a medicament for treating and / or preventing inflammatory neurological diseases or disorders that can cause axonal or myelin damage or degeneration.

[0262] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, a salt of formula (II), or a pharmaceutical or veterinary composition, or a multi-part kit comprising the same, for an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration, said disease or disorder being selected from the group consisting of multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Baló disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease, or some combination thereof.

[0263] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout the specification, the salt of formula (II), or the pharmaceutical or veterinary composition, is a salt of formula (IIa).

[0264] Throughout the specification and claims, the word "comprising" and variations of that word are not intended to exclude other technical features, additives, components, or steps. Further, the word "comprising" encompasses the case of "consisting of". Other objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of the specification, or may be learned by practice of the present invention. The following examples and drawings are provided by way of illustration, but are not intended to limit the present invention. Further, the present invention encompasses all possible combinations of the specific and preferred embodiments described herein.

[0265] Examples

[0266] Example 1: Pharmacodynamic efficacy of BN201 (an example of a compound of formula (I))

[0267] Three in vivo studies were conducted to support the medical rationale of BN201 in the treatment of MS and optic neuritis. These studies attempted to test the neuroprotective effect of BN201 and were carried out in an experimental autoimmune encephalomyelitis (EAE) mouse model of neurodegeneration and demyelination. Immunization against myelin basic protein (MBP) or myelin proteolipid protein (PLP) induces lesions mainly in the spinal cord, while immunization against myelin oligodendrocyte glycoprotein (MOG) produces lesions mainly in the optic nerve and spinal cord. In the literature, the EAE model is commonly used as a model for MS and optic neuritis because it can lead to irreversible vision loss (Kezuka et al., Analysis of the pathogenesis of experimental autoimmune optic neuritis. J Biomed Biotechnol. 2011; 2011:294046; Guo et al., Decreased neural stem / progenitor cell proliferation in mice with chronic / nonremitting experimental autoimmune encephalomyelitis. Neurosignals. 2010; 18(1):1-8).

[0268] Study EAE-C03: According to the following experimental design, two different concentrations of BN201 were tested by daily intraperitoneal (i.p.) administration compared to placebo:

[0269] EAE-affected placebo-treated animals (pathological control group);

[0270] EAE-affected animals treated with BN201 at a dose of 50 mg / kg, and

[0271] EAE-affected animals treated with BN201 at a dose of 100 mg / kg.

[0272] Treatment was initiated at the chronic stage of the disease in order to test the therapeutic properties of the molecule. The data are depicted in Figure 1(A), which is a graph plotting the clinical scores (average of the clinical scores of the animals in each group) against the number of days post-immunization for each test group. The results showed that, compared to placebo, BN201 at doses of 50 or 100 mg / kg significantly reduced the clinical scores after day 17 of treatment.

[0273] The EAE animal model is characterized by an initial tail paralysis, followed by hind limb paralysis, and further progression to forelimb paralysis. The following rating scale is used to assign a clinical score to assess the disease severity: 0 = normal; 0.5 = mild limp tail; 1 = limp tail; 2 = mild hind limb paralysis, unsteady gait; 3 = moderate paralysis, still able to move voluntarily; 4 = severe paralysis, almost complete hind limb paralysis; 5 = paraplegia or quadriplegia; 6 = death.

[0274] Once 70% of the mice exhibited a clinical score of 2 or higher, therapeutic treatment was initiated on day 11.

[0275] It is generally accepted that EAE is a complex model because of the variability in the incidence and the severity of signs and symptoms among individuals. Therefore, once the disease has started at the clinical level, thus some days after immunization, and when all animals behave above a certain level in terms of clinical score (to be determined in the protocol), then any effect of the test drug is determined. If the observed parameters (such as clinical score) remain meaningful and over a period of several days between the test groups (assay, control, etc.), and remain meaningful between adjacent days within each group, then further meaningful data for a particular test compound or protocol is considered to have been achieved.

[0276] According to this rule of interpretation of the results, and applicable to all other figures in this specification, in Figure 1(A), the meaningful and conclusive data for the animals affected by EAE treated with different doses of BN201 are the data marked with an asterisk (*). The p-value for statistical significance is defined in the footnote or legend of each figure. This set of marked data corresponds to the values of the study parameter (in this case the clinical score) where the animals in each group maintained the parameter in a stable form between adjacent days, and are effectively distinguishable as a whole data set of the assay group from the control (statistical differences between the assay groups; e.g., the test dose of the compound relative to placebo, vehicle, or sham-treated animals).

[0277] Then a second experiment (study EAE-C05) was conducted using the same mouse model.

[0278] Study EAE-C05: In addition to the two dose levels of BN201 and the placebo treatment group (pathological control group), this study design introduced two active comparators, dimethyl fumarate (DMF) and fingolimod (FTY720), and a sham-treatment group (animals were manipulated as in the pathological group but without injection of MOG). All groups were administered daily.

[0279] Sham-treatment control of placebo-treated animals that were not diseased (healthy control group);

[0280] Placebo-treated animals affected by EAE (pathological control group);

[0281] Animals affected by EAE treated with 15 mg / kg DMF orally;

[0282] Animals affected by EAE treated with 2 mg / kg FTY720;

[0283] Animals affected by EAE treated with 50 or 100 mg / kg BN201.

[0284] The following ratings were used to assign clinical scores to evaluate disease severity: 0 = normal; 0.5 = partial tail paralysis; 1 = complete tail paralysis; 1.5 = tail paralysis and loss of righting reflex; 2 = partial hind limb paralysis / monoplegia; 2.5 = monoplegia and partial loss of movement in the other limb; 3 = bilateral hind limb paralysis; 4 = moribund; 5 = dead.

[0285] Once each mouse began to show complete tail paralysis (score 1), therapeutic treatment began on day 12 or 13.

[0286] The data are depicted in Figure 1(B), which is a graph plotting the clinical score (CS) each day from the start of treatment, showing the clinical scores for each test group (the average clinical score for the animals in the same group each day).

[0287] Then a third experiment (study EAE-C06) was conducted using the same mouse model to test the dose response of BN201.

[0288] Study EAE-C06: Five different concentrations of BN201: 12.5 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 150 mg / kg. A sham-treatment group, a pathological control group, and a FTY720 (2 mg / kg) comparator group were also included in the experiment. All groups were administered daily.

[0289] The following ratings were used to assign clinical scores to evaluate disease severity: 0 = normal; 0.5 = partial tail paralysis; 1 = complete tail paralysis; 1.5 = tail paralysis and loss of righting reflex; 2 = partial hind limb paralysis / monoplegia; 2.5 = monoplegia and partial loss of movement in the other limb; 3 = bilateral hind limb paralysis; 4 = moribund; 5 = dead.

[0290] Once each mouse began to show complete tail paralysis (score 1), therapeutic treatment began on day 12.

[0291] The data are depicted in Figure 1(C), where the clinical scores for each test group were plotted daily after disease onset. The results showed a significant improvement in the clinical scores of animals in BN201 50 mg / kg, BN201 100 mg / kg, and FTY720 2 mg / kg for almost all observation / treatment days (days 2 to 30) (Table 1).

[0292] Table 1

[0293]

[0294] Example 2. Comparison of the combination of BN201 and fingolimod compared to BN201 or fingolimod alone

[0295] The effect on the clinical progression of EAE in 8 - 12 - week - old female C57BL / 6 mice was evaluated. The mice were administered once daily for six days a week at sub - optimal doses:

[0296] Sham - treated placebo - treated non - diseased animals (healthy control group);

[0297] EAE - affected placebo - treated animals (pathological control group);

[0298] EAE - affected animals treated with 0.1 mg / kg of FTY720,

[0299] EAE - affected animals treated with 25 mg / kg of BN201, or

[0300] EAE - affected animals treated with their combination

[0301] The effect of the combination of BN201 and fingolimod on the clinical progression of EAE in 8 - 12 - week - old female C57BL / 6 mice was evaluated. The EAE animal model is characterized by initial tail paralysis, followed by hind - limb paralysis, and further progression to fore - limb paralysis.

[0302] The following rating scale was used to assign clinical scores to assess disease severity: 0 = normal; 0.5 = mild limp tail; 1 = limp tail; 2 = mild hind - limb paralysis, unsteady gait; 3 = moderate paralysis, still able to move voluntarily; 4 = severe paralysis, almost complete hind - limb paralysis; 5 = paraplegia or quadriplegia; 6 = death.

[0303] Acclimation based on body weight and immunity, and mouse distribution were performed as in Example 1.

[0304] Starting from day 15, when the clinical scores of 70% of the animals were ≥1, the mice were administered fingolimod, BN201, or their combination once daily for six days a week at sub - optimal doses (0.1 mg / kg for fingolimod and 25 mg / kg for BN201).

[0305] The results are summarized inFigure 2 Among them, compared with the mice administered with any one compound alone, the mice administered with the combination of BN201 and fingolimod showed significantly greater improvement in the average daily clinical score from day 30 to day 35 (p≤0.05). These differences were greater than the sum of the effects from each compound, indicating that when administered together, doses far lower than the therapeutic doses of each compound administered alone were effective.

[0306] Example 3: Comparison of the combination of BN201 and dimethyl fumarate (DMF) compared to BN201 or DMF alone

[0307] Similar to Example 2, the effects in an MS animal model (i.e., EAE in C57BL6 mice immunized with MOG35-55).

[0308] Starting from day 15, the mice were administered once a day, six days a week, at sub-optimal doses (10 mg / kg for DMF and 25 mg / kg for BN201):

[0309] - Dimethyl fumarate (DMF) (Group A, 10 mice),

[0310] - BN201 (Group B, 10 mice),

[0311] - Their combination (Group C, 10 mice).

[0312] DMF was orally administered at a volume of 10 mL / kg in saline vehicle through a rigid cannula, while BN201 was administered via intraperitoneal injection at a volume of 5 mL / kg in saline vehicle. Control mice received only the vehicle (Group D, 10 mice) via both oral and intraperitoneal injection, or received nothing at all (Group E, 2 mice).

[0313] The purpose of this study was to evaluate the efficacy and safety of combination therapy using sub-optimal doses of BN201 (25 mg / kg) and dimethyl fumarate (DMF) (10 mg / kg) in the progression of chronic EAE in mice.

[0314] During a one-week acclimation period starting on day -7, mice were assigned to different experimental groups based on body weight stratification. On day 0, mice were immunized subcutaneously in both hind paw pads with 150 μg of MOG peptide 35-55 (Spikem, Florence) emulsified in 50 μg of Mycobacterium tuberculosis (H37Ra strain; Difco, Detroit, Michigan) in incomplete Freund's adjuvant (IFA). At the time of immunization and two days later, mice were injected intraperitoneally (i.p.) with pertussis toxin (Sigma) (500 ng). Clinical scores were assigned using the following rating to assess disease severity: 0 = normal; 0.5 = mild limp tail; 1 = limp tail; 2 = mild hind limb paralysis, unsteady gait; 3 = moderate paralysis, still able to move voluntarily; 4 = paraplegia or quadriplegia; 5 = moribund state; 6 = death. By day 14, 70% of the mice exhibited a clinical score of 1 or higher.

[0315] Starting on day 15, mice were administered dimethyl fumarate (DMF) (group A, 10 mice), BN201 (group B, 10 mice), or a combination thereof (group C, 10 mice) once daily for six days a week at suboptimal dosages (10 mg / kg for DMF and 25 mg / kg for BN201). DMF was administered orally via a rigid cannula at a volume of 10 mL / kg in saline vehicle, while BN201 was administered via intraperitoneal injection at a volume of 5 mL / kg in saline vehicle. Control mice received only the vehicle (group D, 10 mice) via oral and intraperitoneal injection, or received nothing at all (group E, 2 mice). Animals were weighed and examined for clinical signs of disease six days a week by blinded observers. On day 30, the mice were anesthetized and perfused intracardially with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.6). The eyes, optic nerves, spinal cords, and brains were dissected and fixed until use.

[0316] As Figure 3 shown, animals treated with suboptimal doses of BN201 or DMF suffered from EAE similar to that of mice treated with placebo. In contrast, from day 34 to day 38, the combination of suboptimal doses of BN201 and DMF improved the disease course in a significant manner (see Figure 3 the values marked with an asterisk (*) indicate p < 0.05). In summary, the combination therapy of BN201 and DMF showed a synergistic effect in improving the EAE course.

[0317] Example 4: Comparison of the combination of BN201 and a STAT3 inhibitor compared to BN201 or the STAT3 inhibitor alone

[0318] Effect during the chronic phase of disease in an animal model of multiple sclerosis (i.e., EAE in C57BL6 mice immunized with MOG35-55)

[0319] The efficacy and safety of combination therapy using the optimal doses of BN201 (50 mg / kg) and S31-201 (5 mg / kg) in the progression of chronic EAE in mice.

[0320] At the start of the chronic phase of the disease (day 34), mice were administered once daily, six days a week, at the optimal dosages (5 mg / kg for S31-201 and 50 mg / kg for BN201):

[0321] - the STAT3 inhibitor S31-201 (group A, 7 mice),

[0322] - BN201 (group B, 6 mice), or

[0323] - their combination (group C, 6 mice).

[0324] S31-201 and BN201 were administered via intraperitoneal injection at a volume of 5 mL / kg in saline vehicle. Control mice received only the vehicle (group D, 6 mice) via oral and intraperitoneal injection, or received nothing at all (group E, 2 mice). Mice were treated starting on day 34 (chronic EAE phase) until the end of the experiment on day 54.

[0325] Evaluate the effect of the combination of BN201 and the STAT3 inhibitor S31-201 during the chronic phase of the disease in an animal model of multiple sclerosis, namely EAE in C57BL6 mice immunized with MOG35-55. The aim of this study was to evaluate the efficacy and safety of combination therapy using the optimal doses of BN201 (50 mg / kg) and S31-201 (5 mg / kg) in the progression of chronic EAE in mice.

[0326] During a one-week acclimation period starting on day -7, mice were assigned to different experimental groups based on body weight stratification. On day 0, mice were immunized subcutaneously in two hind footpads with 150 μg of MOG peptide 35-55 (Spikem, Florence) emulsified in incomplete Freund's adjuvant (IFA) with 50 μg of Mycobacterium tuberculosis (H37Ra strain; Difco, Detroit, Michigan). Pertussis toxin (Sigma) (500 ng) was injected intraperitoneally (i.p.) into the mice at the time of immunization and again two days later. The following rating scale was used to assign clinical scores to assess disease severity: 0 = normal; 0.5 = mild tail limp; 1 = tail limp; 2 = mild hind limb paralysis, unsteady gait; 3 = moderate paralysis, still able to move voluntarily; 4 = paraplegia or quadriplegia; 5 = moribund state; 6 = death. By day 17, more than 70% of the mice exhibited a clinical score of 1 or higher.

[0327] Starting from day 34, mice were administered with the STAT3 inhibitor S31-201 (group A, 7 mice, Sigma), BN201 (group B, 6 mice), or their combination (group C, 6 mice) once daily for six days a week at the optimal dosages (5 mg / kg for S31-201 and 50 mg / kg for BN201). S31-201 and BN201 were administered via intraperitoneal injection in a saline vehicle at a volume of 5 mL / kg. Control mice received only the vehicle via oral and intraperitoneal injection (group D, 6 mice), or received nothing at all (group E, 2 mice). Mice were treated starting from day 34 (chronic EAE stage) until the end of the experiment on day 54. At the start of this study, mice were randomly assigned to each treatment group. At the start of the therapy, the groups may have had different levels of EAE severity (e.g., the group with BN201 alone had a more severe disease than the placebo group starting from the beginning of the therapy). Therefore, the comparison between groups was based on the change in EAE scores after the start of the therapy. Animals were weighed and examined for clinical signs of the disease six days a week by blinded observers. On day 55, the mice were anesthetized and intracardially perfused with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.6). The eyes, optic nerves, spinal cords, and brains were dissected and fixed until use.

[0328] As Figure 4 shown, during the chronic phase of the disease (i.e., day 34, see arrow), treatment with the optimal dose of BN201 alone or the optimal dose of S31-201 was ineffective at this stage of the disease. However, treatment with the combination of the optimal doses of BN201 and S31-201 improved the EAE course during the chronic phase of the disease in a significant manner. During the treatment, the clinical scores of the combination therapy were significantly lower than those of the other treatments. The combination therapy of BN201 and the STAT3 inhibitor S31-201 significantly protected mice from EAE in the late chronic phase. Since the magnitude of the effect was higher than the sum of the individual effects of each drug, this indicated the presence of synergistic activity between the two drugs.

[0329] Example 5. Preparation of BN201-monomethyl fumarate salt

[0330] To prepare the monomethyl fumarate salt of BN201, 100 mg of AM-G79_03 (BN201) (1 equivalent) and 26 mg of monomethyl fumarate (1 equivalent) were mixed in methanol, and the mixture was stirred for 1 hour. After that, it was concentrated under vacuum, and the residue obtained was analyzed by 1 1H-NMR.

[0331] 1 The 1H-NMR data effectively confirmed that the compound of the following formula (IIa) was obtained:

[0332]

[0333] Example 6. Comparison of BN201-monomethyl fumarate salt compared to BN201 or monomethyl fumarate alone

[0334] The aim of this study was to test the possible synergistic effects of BN201 monomethyl fumarate salt in a neuroprotection assay. Therefore, a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assay was used to test the ability of the BN201 monomethyl fumarate salt obtained as shown in Example 5 to protect the human neuroblastoma cell line SH-SY5Y from death induced by oxidative stress (i.e., hydrogen peroxide (H2O2)).

[0335] 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 / streptomycin. All cell cultures were maintained in a humidified incubator at 5% CO2 and 37 °C. SH-SY5Y cells were pre-incubated for 1 h with different concentrations (n = 5; 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 either BN201 alone, monomethyl fumarate alone, or BN201 monomethyl fumarate salt, and then H2O2 (15 μM) was added to induce stress. Pre-incubation with sodium pyruvate (10 mM) was used as a positive control. After 30 min of H2O2 incubation, the medium was changed, and thiazolyl blue tetrazolium bromide (MTT; Sigma Aldrich; stock concentration 10 mg / ml) was added to each well at a final concentration of 0.5 mg / ml. After 2 h of MTT incubation, the cell medium was removed, and the cells were resuspended in pure dimethyl sulfoxide (DMSO). Cell viability was determined by reading the absorbance at 570 nm. Each experiment was performed in quintuplicate.

[0336] The results showed that pre-treatment with BN201 monomethyl fumarate salt provided an increase in cell viability, expressed as a percentage compared to the control, compared to BN201 or the fumarate salt tested alone at the same concentration. The data are depicted in Figure 5 .

[0337] Both BN201 and the fumarate provide partial rescue of neurons from oxidative stress-induced death, with efficacy similar to well-known antioxidants such as sodium pyruvate. On the other hand, BN201 - monomethyl fumarate exhibits a significantly higher level of neuroprotection than either compound alone, indicating that the BN201 - monomethyl fumarate salt exerts a synergistic neuroprotective effect.

[0338] Other aspects / embodiments of the present invention can be found in the following entries:

[0339] Entry 1. A combination comprising:

[0340] A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof

[0341]

[0342] Wherein:

[0343] R1 is phenyl substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from the group consisting of halogen, (C1 - C6) alkyl, (C1 - C6) alkoxy, and halogen (C1 - C6) alkyl; or alternatively R1 is pyrrolidin - 1 - yl;

[0344] R2 is 2 - oxo - pyrrolidin - 1 - ylmethyl or sulfamoylphenyl; and

[0345] R3 is selected from propyl, 1 - methylethyl, butyl, 2 - methylpropyl, pentyl, 1 - methylbutyl, 2 - methylbutyl, hexyl, 4 - methylpentyl, 3 - methylpentyl, 2 - methylpentyl, and 1 - methylpentyl; and

[0346] b) one or more drugs selected from the group consisting of:

[0347] (i) A compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof

[0348]

[0349] Wherein R6 and R5 are independently selected from hydrogen (H) and (C1 - C6) alkyl;

[0350] (ii) Sphingosine - 1 - phosphate receptor inhibitor (S1PR modulator); and

[0351] (iii) Signal transducer and activator of transcription 3 (STAT3) inhibitor.

[0352] Item 2. The combination according to Item 1, which comprises a compound of formula (I) and a drug selected from the group consisting of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator, and a STAT3 inhibitor.

[0353] Item 3. The combination according to any one of Items 1-2, wherein in the compound of formula (I), R3 is 2-methylpropyl, and R1 and R2 are as defined in claim 1.

[0354] Item 4. The combination according to Item 3, wherein the compound of formula (I) is selected from the group consisting of:

[0355]

[0356] Item 5. The combination according to any one of Items 1-4, wherein the compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof is selected from dimethyl fumarate, monoethyl fumarate, sodium fumarate, and iron(II) fumarate.

[0357] Item 6. The combination according to any one of Items 1-5, wherein the S1PR modulator is selected from the group consisting of fingolimod, siponimod, ozanimod, ponatinimod, and ceremod.

[0358] Item 7. The combination according to any one of Items 1-6, wherein the STAT3 inhibitor is selected from the group consisting of: 2-hydroxy-4-[[[[(4-methylphenyl)sulfonyl]oxy]acetyl]amino]-benzoic acid, (S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, 4-((3-(carboxymethylsulfonyl)-4-hydroxy-1-naphthyl)sulfamoyl)benzoic acid, the STAT3 inhibitor peptide of SEQ ID NO:1, 6-nitrobenzo[b]thiophene-1,1-dioxide, ethyl 1-(4-cyano-2,3,5,6-tetrafluorophenyl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, 5,15-diphenylporphyrin, PIAS3 protein, N-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-2-phenylquinoline-4-carboxamide, the STAT3 inhibitor XII SPI of SEQ ID NO:2, and N-(1',2-dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide.

[0359] Item 8. The combination according to any one of Items 1-7, which is selected from:

[0360] 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 alternatively,

[0361] The compound of formula (I) [N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N-(2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl]glycinamide and fingolimod; or alternatively

[0362] 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]oxy]acetyl]amino]-benzoic acid.

[0363] Item 9. The combination according to any one of Items 1 - 8, comprising:

[0364] a) A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, and

[0365] 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 as previously defined, ii) an S1PR modulator, and iii) a STAT3 inhibitor,

[0366] wherein the amounts of a) and b) of the combination are therapeutically effective.

[0367] Item 10. The combination according to any one of Items 1 - 9, wherein the amount of a) alone is sub-therapeutic; and the amounts of a) and b) of the combination are therapeutically effective.

[0368] Item 11. The combination according to any one of Items 1 - 9, wherein the amount of b) alone is sub-therapeutic; and the amounts of a) and b) of the combination are therapeutically effective.

[0369] Item 12. The combination according to any one of Items 1 - 9, wherein the amounts of a) alone and b) alone are sub-therapeutic; and the amounts of a) and b) of the combination are therapeutically effective.

[0370] Item 13. A single drug or veterinary composition comprising a therapeutically effective amount of:

[0371] a) A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof

[0372] and

[0373] b) one or more drugs selected from the group consisting of compounds of formula (IV) or pharmaceutically or veterinarily acceptable salts thereof, S1PR modulators, and STAT3 inhibitors

[0374]

[0375] and one or more pharmaceutically or veterinarily acceptable excipients or carriers; wherein the compound of formula (I) and the one or more drugs are as defined in any one of items 1 - 9, and wherein the amounts of a) and b) in the combination are therapeutically effective.

[0376] Item 14. A multi - part pack or kit, comprising:

[0377] i) a first pharmaceutical composition or a first veterinary composition, which comprises an amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof as defined in any one of items 1 - 9, and one or more pharmaceutically or veterinarily acceptable excipients or carriers; and

[0378] ii) a second pharmaceutical composition or a second veterinary composition, which comprises an amount of one or more drugs selected from the group consisting of compounds of formula (IV) or pharmaceutically or veterinarily acceptable salts thereof, S1PR modulators, and STAT3 inhibitors, and one or more pharmaceutically or veterinarily acceptable excipients or carriers;

[0379] wherein the first composition and the second composition are separate compositions, and wherein the amount of the compound of formula (I) in i) and the amount of the one or more drugs in ii) in the combination are therapeutically effective.

[0380] Item 15. A combination as defined in any one of items 1 - 12, a single pharmaceutical or veterinary composition as defined in item 13, or a multi - part pack or kit as defined in item 14, for treating and / or preventing an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration in a subject in need thereof.

[0381] Citation List

[0382] Patent Literature

[0383] - EP 2611775

[0384] Non - Patent Literature

[0385] - Patrick Vermersch et al., “Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis”; European Neurological Review - 2018; 13(1):25–30.

[0386] - Guidance for Industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers; FDA, CDER, July 2005.

[0387] - Kezuka et al., Analysis of the pathogenesis of experimental autoimmune optic neuritis. J Biomed Biotechnol. 2011; 2011:294046.

[0388] - Guo et al., 2009; Guo J, Li H, Yu C, Liu F, Meng Y, Gong W, Yang H, Shen X, Ju G, Li Z, Wang J. Decreased neural stem / progenitor cell proliferation in mice with chronic / nonremitting experimental autoimmune encephalomyelitis. Neurosignals. 2010; 18(1):1 - 8.

Claims

1. A combination, comprising: a) A compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, wherein: R1 is a phenyl group substituted by halogen or trifluoromethyl and further optionally substituted by one or two substituents selected from the group consisting of halogen, (C1-C6) alkyl, (C1-C6) alkoxy, and halogen(C1-C6) alkyl; or alternatively, R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and R3 is selected from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1-methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1-methylpentyl; and 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, wherein 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, provided that if R5 is H, then R6 is not H; (ii) A sphingosine-1-phosphate receptor inhibitor (S1PR modulator); and (iii) A signal transducer and activator of transcription 3 (STAT3) inhibitor.

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

3. The combination according to any one of claims 1-2, wherein in the compound of formula (I), R3 is 2-methylpropyl, and R1 and R2 are as defined in claim 1.

4. The combination according to claim 3, wherein the compound of formula (I) is selected from the group consisting of:

5. The combination according to any one of claims 1-4, wherein in the compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, R6 and R5 are independently selected from hydrogen (H) and (C1-C6) alkyl, and wherein at least one of R6 and R5 is (C1-C6) alkyl.

6. The combination according to any one of claims 1-5, wherein the compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof is selected from the group consisting of dimethyl fumarate and monoethyl fumarate.

7. The combination according to any one of claims 1-4, wherein in the compound of formula (IV), R6 is 2-(2,5-dioxopyrrolidin-1-yl)ethyl, and R5 is methyl.

8. The combination according to any one of claims 1-7, wherein the S1PR modulator is selected from the group consisting of fingolimod, siponimod, ozanimod, ponesimod, and selinimod.

9. The combination according to any one of claims 1 - 8, wherein the STAT3 inhibitor is selected from the group consisting of: 2 - hydroxy - 4 - [[[[(4 - methylphenyl)sulfonyl]oxy]acetyl]amino]benzoic acid, (S,E) - 3 - (6 - bromopyridin - 2 - yl) - 2 - cyano - N - (1 - phenylethyl)acrylamide, 4 - ((3 - (carboxymethylsulfonyl) - 4 - hydroxy - 1 - naphthyl)sulfamoyl)benzoic acid, the STAT3 inhibitor peptide of SEQ ID NO:1, 6 - nitrobenzo[b]thiophene - 1,1 - dioxide, ethyl 1 - (4 - cyano - 2,3,5,6 - tetrafluorophenyl) - 6,7,8 - trifluoro - 4 - oxo - 1,4 - dihydroquinoline - 3 - carboxylate, 5,15 - diphenylporphyrin, PIAS3 protein, N - (5 - (furan - 2 - yl) - 1,3,4 - oxadiazol - 2 - yl) - 2 - phenylquinolin - 4 - carboxamide, the STAT3 inhibitor XII SPI of SEQ ID NO:2, and N - (1',2 - dihydroxy - 1,2'- binaphth - 4'- yl) - 4 - methoxybenzenesulfonamide.

10. The combination according to any one of claims 1 - 9, which is 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 alternatively, the compound of formula (I) [N - (2 - (2'- fluorophenyl)ethyl)glycyl] - [N - (2 - methylpropyl)glycyl] - N - [3 - (2'- oxopyrrolidinyl) - propyl]glycinamide and fingolimod; or alternatively, 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]oxy]acetyl]amino]benzoic acid.

11. The combination according to any one of claims 1 - 10, 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 formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof as previously defined, ii) an S1PR modulator, and iii) a STAT3 inhibitor, wherein the amounts of a) and b) of the combination are therapeutically effective.

12. The combination according to any one of claims 1 - 11, wherein the amount of a) alone is a sub - therapeutic amount; and the amounts of a) and b) of the combination are therapeutically effective, the sub - therapeutic amount being defined as an amount of a particular compound that is less than the therapeutically effective amount for a particular disease.

13. The combination according to any one of claims 1 - 11, wherein the amount of b) alone is a sub - therapeutic amount; and the amounts of a) and b) in the combination are therapeutically effective, the sub - therapeutic amount being defined as an amount of a particular compound that is lower than the therapeutically effective amount for a particular disease.

14. The combination according to any one of claims 1 - 11, wherein the amounts of a) alone and b) alone are sub - therapeutic amounts; and the amounts of a) and b) in the combination are therapeutically effective, the sub - therapeutic amount being defined as an amount of a particular compound that is lower than the therapeutically effective amount for a particular disease.

15. A single pharmaceutical or veterinary composition comprising a therapeutically effective amount of: 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 a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator, and a STAT3 inhibitor and one or more pharmaceutically or veterinarily acceptable excipients or carriers; wherein the compound of formula (I) and the one or more drugs are as defined in any one of claims 1 - 11, and wherein the amounts of a) and b) in the combination are therapeutically effective.

16. A multi - part pack or kit comprising: i) a first pharmaceutical or veterinary composition comprising an amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof as defined in any one of claims 1 - 11, and one or more pharmaceutically or veterinarily acceptable excipients or carriers; ii) a second pharmaceutical or veterinary composition comprising an amount of one or more drugs selected from the group consisting of a compound of formula (IV) or a pharmaceutically or veterinarily acceptable salt thereof, an S1PR modulator, and a STAT3 inhibitor, and one or more pharmaceutically or veterinarily acceptable excipients or carriers; and iii) instructions for the combined use of i) and ii); wherein the first composition and the second composition are separate compositions, and wherein the amount of the compound of formula (I) in i) and the amount of the one or more drugs in ii) in the combination are therapeutically effective.

17. Use of the combination as defined in any one of claims 1 - 14, the single pharmaceutical or veterinary composition as defined in claim 15, or the multi - part pack or kit as defined in claim 16, in the manufacture of a medicament for treating and / or preventing an inflammatory neurological disease or disorder capable of causing axonal or myelin damage or degeneration in a subject in need thereof.

Images