Therapeutic regimens for treating neurological diseases or conditions

Abstract

To provide a new treatment regimen for treating neurological diseases or conditions.SOLUTION: The present invention relates to a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of the compound of formula (I) or of the pharmaceutically or veterinary acceptable salt thereof, for use in the treatment or prevention of a neurological disease or condition resulting in the destruction or degeneration of neurons, axons or myelin: The treatment comprises a) a first time period of 1 to 7 days during which the compound is administered once or several times to a subject in need thereof, and b) a second time period of 13 days or more during which no compound is administered and which takes place after the first time period and before the next administration of the compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is European Patent Application No. 19382950, ​​filed October 30, 2019. Claiming the benefits of No. 4.

[0002] The present invention is applicable to the field of medicine. More specifically, the present invention relates to the treatment of neurons, axons or is a discontinuous therapeutic regimen for the treatment of neurological diseases or conditions that result in the destruction or degeneration of myelin. Regarding the development of men. [Background technology]

[0003] Inflammatory neurological diseases or conditions that result in the destruction or degeneration of neurons, axons, or myelin These include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, Baro's disease, and Schilder's disease. , transverse myelitis, acute hemorrhagic leukoencephalitis (i.e., Hurst disease), and Marburg disease ( These include various central nervous system (CNS) diseases such as acute MS, Neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Chinton's disease, frontotemporal dementia, amyotrophic lateral sclerosis, hereditary ataxia, or glaucoma The optic neuropathy may include optic neuritis, preischemic optic neuropathy, Leber's disease, dominant optic atrophy, or Diseases that damage the optic nerve include glaucoma and toxic, traumatic, and tumor-related optic neuropathies.

[0004] MS is a degenerative autoimmune disease of the central nervous system (CNS) in which the immune system attacks axons and nerve fibers. MS attacks and damages the protective myelin sheath that surrounds the fibers, causing significant disability. It is characterized by multifocal inflammation, reactive gliosis, and oligodendrocyte and axonal loss.

[0005] NMO (also known as Devic's disease or Devic's syndrome) or NMO spectrum Non-metastatic optic neuropathy-associated disorder (NMOSD) occurs when immune system cells and antibodies mistakenly act on astrocytes in the optic nerve, brain, and spinal cord. It is an autoimmune disorder of the CNS that attacks and destroys the CNS, causing secondary demyelination and axonal loss. Damage to the nerve causes optic neuritis, which causes swelling and inflammation, resulting in pain and vision loss. Spinal cord injuries can result in weakness or paralysis of the legs or arms, loss of sensation, and bladder and It causes problems with bowel function. Both diseases have similar symptoms and include attacks of optic neuritis and myelitis. NMO can be confused with MS because of the potential for these conditions, and until recently, However, recent studies have shown that NMO and MS are distinct and This suggests a disease.

[0006] Optic neuritis is a demyelinating inflammation of the optic nerve that can be caused by many different conditions It is a common disease, but is often associated with MS and NMO. Inflammation often covers the optic nerve. It can cause loss of vision or even blindness due to swelling and destruction of the myelin sheath. Symptoms of optic neuritis include blurred vision, loss of color, pain when moving the eyes, blind spots, and corneal stenosis. loss of contrast sensitivity.

[0007] Treatment of MS and other demyelinating diseases (including optic neuritis, myelitis, and neuromyelitis optica) includes: It includes three types of treatment: 1) Disease-modifying drugs (DMDs): These drugs stop the pathogenesis of the disease and reduce the accumulation of damage. 2) Treatment of relapse: shortening the duration of relapse and reducing residual disability 3) Symptomatic treatment: The purpose is to alleviate symptoms caused by MS disorders (e.g., pain, spasticity, It is intended to improve symptoms such as bladder problems.

[0008] All currently approved treatments for DMD for MS are either drug- or administration-specific. It is intended for chronic (long-term) administration, which requires different administration protocols depending on the patient. Oral medications (fingolimod, siponimod, ozanimod, dimethyl fumarate and teriflunomide) The chemotherapy (mitoxantrone and cladribine) is given every day, but the chemotherapy (mitoxantrone and cladribine) is given for several days. 2) Subcutaneous medications (interferon beta, glatiramer acetate) were administered daily or every few days, and 3) intravenous medications (natalizumab, rituximab, ocrelizumab, azathioprine, ribosomal acidosis, thiazolinone ... lemtuzumab, daclizumab, or ofatumumab) every few months depending on the mechanism of action (MoA). and (1-6-12). They all deplete immune cell populations or stimulate T cells. These drugs are monoclonal antibodies (MABs) that act by preventing migration. All of these are immunomodulatory therapies, and none of them have clearly demonstrated primary neuroprotective activity ( Secondary neuroprotection stops inflammation through its immunomodulatory activity, preventing central nervous system (CNS) damage. The reason some drugs are not given chronically (chemotherapy and mabs) is that These MoAs extend far beyond the point of exposure (e.g., recovery from the bone marrow may take several months). by reducing specific immune cell populations that require months of treatment.

[0009] Regarding the treatment of recurrence, there are currently no drugs approved to treat recurrence. However, the standard of care (SoC) is either intravenous methylprednisolone or oral prednisone. The use of high doses (1 g / day for 3-5 days) of corticosteroids is Although it exerts immunomodulatory activity that terminates inflammation, it has not been shown to have neuroprotective effects. Therefore, the physical disability does not improve.

[0010] Regarding symptomatic treatment, several drugs are used to improve MS symptoms. Most are oral medications that are taken chronically (daily) to prevent symptoms such as Some drugs such as phenytoin, amiloride, aminopyridine, epigallate Gallocatechin has been studied as a neuroprotective agent (in chronic administration), but No neuroprotective drugs have been tested to date that can alter (MS lesions or their relapses) do not have.

[0011] Therefore, currently, there are no Gods approved for MS or used as SoCs. There are no neuroprotective drugs. Current drugs are immunomodulatory (neuroprotective claims are secondary This is due to its neuroprotective activity, i.e. less inflammation means less damage Pulsed medications include either corticosteroids or chemotherapy. , have effects that extend beyond exposure due to their MoA.

[0012] Furthermore, current treatments are associated with serious side effects, such as adverse immune reactions or severe opportunistic infections. is doing.

[0013] On the other hand, those diseases or conditions that result in the destruction or degeneration of neurons, axons, or myelin Generally, damage is present for a short period of time (e.g., ischemia, inflammation, trauma), but damage can last for weeks to "Hit and go" syndrome occurs over several months, increasing the patient's disability and reducing their quality of life. Therapies that provide long-lasting efficacy are therefore desirable.

[0014] Patent Document 1 discloses in vitro and in vivo methods for preventing neuronal and axonal loss and preserving myelin. Neuroprotective peptoids that demonstrate efficacy in animal models have been disclosed, e.g. It is associated with better clinical outcomes in models of multiple sclerosis, optic neuritis, and glaucoma. However, this document does not mention the in vivo effects of the compounds over time. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Publication No. WO2012 / 028959 Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, it is possible to develop a drug that can treat these types of neurological disorders or conditions with sustained efficacy while reducing side effects. There is a need in the art for new methods of treating these conditions. [Means for solving the problem]

[0017] The inventors have demonstrated increased demyelination, increased axonal loss in the optic nerve, and retinal ganglion cells in the retina of the eye. In an animal model of acute optic neuritis (AON), which is characterized by a significant decrease in the number of When the neuroprotective peptoids disclosed in are administered for a short period of time (e.g., about 5-7 days), the expected It has shown not only short-term effectiveness, but also surprising long-term effectiveness (up to 1 month). I found that...

[0018] This is demonstrated in the following examples (Figures 6-8). In particular, the results show that peptoid BN201 (i.e., ([N-(2-(2'-fluorophenyl)ethyl)glycyl]-[N-( 2-methylpropyl)glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl ]glycinamide) was administered intraperitoneally (IP) or Short-term (7 days, Figure 5) and long-term administration of 100 mg / kg ... (Up to 28 days after injury, Figure 8) Indeed, such efficacy was further increased at later time points. Furthermore, BN201 treatment Compared with the untreated group, the retinal This resulted in significant improvements in the transganglionic and demyelination scores.

[0019] As mentioned above, damage in these diseases occurs over weeks or months, These results are extremely important from a clinical point of view. The long-lasting efficacy exhibited by the neuroprotective peptoids studied is consistent with the short-term administration of the drug. followed by an extended period without drug administration (extending well beyond the drug's half-life (8 hours)) This allows for a discontinuous treatment regimen including

[0020] Drug exposure compared with exposure to the same drug for the entire duration of the disorder Reduced exposure leads to fewer side effects, improved safety, and improved patient compliance with treatment regimens. The applicability improves.

[0021] Additionally, the discontinuous treatment regime of the present invention has an extended period of time in which no drug is administered before the next drug administration. It also improves patient compliance with treatment and therefore patient adherence. and increased therapeutic efficacy. In many cases, patients do not require additional injections or administrations. They are treated at the time of acute injury while in hospital, without any need for treatment, and benefit after that period.

[0022] The phosphorylation event is very transient (10-30 min), and receptor binding is initiated by the receptor itself. It is localized and degraded, so it can be used for extensions of less than one day. In addition, target binding is In some cases, the dissociation constant is not permanent and can be very short.

[0023] BN201 inhibits the phosphorylation of some of its targets, such as Foxo3 or NDRG1. It has been shown to activate the serum glucocorticoid (SGK) pathway. Activation triggers trophic factor pathways that result in altered gene expression patterns over the next few days. The half-life of BN201 is comparable to that seen in human studies, as seen in a Phase 1 study in healthy volunteers. Active transport into the CNS, drug delivery, was observed in the same phase 1 study. Assuming a lack of accumulation and rapid clearance of the drug, BN201 exposure is expected to occur after the last dose. (Day 6) It was considered unlikely that the duration of the treatment period would have been extended beyond one day.

[0024] Without being bound by theory, an unexpected result is that activation of the SGK pathway continues for several weeks. These changes can affect cells in ways that go far beyond the specific molecular events induced by drugs. These results suggest that the phenotype of the cells may be altered by the protein. and translocates it in neurons, astrocytes, oligodendrocytes and / or microglia. The expression of several genes related to the SGK pathway produces beneficial cell phenotypes such as It is mediated by

[0025] Thus, a first aspect of the present invention is a method for treating the destruction or degeneration of neurons, axons or myelin. a compound of formula (I) or a compound thereof for use in the treatment or prevention of a neurological disease or condition resulting in A pharmaceutically or veterinarily acceptable salt, or a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof. or any stereoisomer or mixture of stereoisomers of any veterinarily acceptable salt thereof Regarding, [ka] During the ceremony, R1 is substituted with halogen or trifluoromethyl, and further substituted with halogen, (C1-C6) from the group consisting of alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl R1 is phenyl optionally substituted with one or two selected substituents; or R1 is pyrrolidin-1-yl, R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl , R3 is propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1- Methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, and 1-methylpentyl; The treatment comprises: a) a first period of 1 to 7 days during which the compound is administered once or several times to a subject in need thereof; , and b) No compound is administered, followed by a first period and before the next administration of compound Includes a second period of 13 days or more.

[0026] This aspect therefore involves the destruction or degeneration of neurons, axons or myelin. a compound of formula (I) as defined above for the manufacture of a medicament for the treatment of a medical disease or condition. With respect to the use of the compound or its derivatives, the treatment is a) a first period of 1 to 7 days during which the compound is administered once or several times to a subject in need thereof; , and b) No compound is administered, followed by a first period and before the next administration of compound Includes a second period of 13 days or more.

[0027] Alternatively, this aspect may also involve the destruction or degeneration of neurons, axons, or myelin. The composition can be formulated as a method for treating a medical disease or condition, the method comprising: a) The compound is administered once or several times to a subject in need thereof, including a mammal, particularly a human. a first period of 1 to 7 days in which b) No compound is administered, followed by a first period and before the next administration of compound Includes a second period of 13 days or more.

[0028] The compounds of the present invention can be formulated into compositions that include excipients or carriers. Thus, a second aspect of the present invention is a pharmaceutical composition comprising one or more pharmaceutically or veterinarily acceptable excipients or A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a derivative thereof as defined above, together with a carrier. In relation to a product or veterinary composition, Treatment of neurological diseases or conditions that result in the destruction or degeneration of neurons, axons, or myelin; For use in prevention, the treatment is a) a first period of 1 to 7 days during which the compound is administered once or several times to a subject in need thereof; , and b) No compound is administered, followed by a first period and before the next administration of compound Includes a second period of 13 days or more. [Brief explanation of the drawings]

[0029] [Figure 1]FIG. 1 shows plasma drug concentrations assessed on day 7 after 6 days of daily intraperitoneal (IP) administration of BN201 to rats at different doses (10, 25 and 70 mg / Kg). [Figure 2] FIG. 1 shows plasma drug concentrations assessed on day 7 after intravenous (IV) administration of BN201 at 25 mg / Kg in rats for 6 days. [Figure 3] Figure 1 shows the number of retinal ganglion cells in an animal model of acute optic neuritis (AON) assessed on day 7 for sham (healthy) and pathological (disease, untreated) control groups, and pathological groups treated with BN201 intraperitoneally (IP) or intravenously (IV) daily for 6 days at different doses (mpk = mg / Kg). (*) P-value 0.05, (***) P-value 0.001. [Figure 4] Figure 1 shows the demyelination score (scale: 0-4) of AONs assessed on day 7 for sham (healthy) and pathological (disease, untreated) control groups, and pathological groups treated intraperitoneally (IP) or intravenously (IV) with BN201 at different doses (mpk = mg / Kg) daily for 6 days. [Figure 5] Figure 1 shows the axonal loss scores (scale: 0-4) of AONs assessed on day 7 for sham (healthy) and pathological (disease, untreated) control groups, and pathological groups treated with BN201 intraperitoneally (IP) or intravenously (IV) at different doses (mpk = mg / Kg) daily for 6 days. (*) P value 0.05, (***) P value 0.001. [Figure 6] Figure 1 shows the number of retinal ganglion cells in AONs assessed on days 7, 14, and 28 for sham (healthy) and pathological (disease, untreated) control groups, and pathological groups treated with BN201 intraperitoneally (IP) or intravenously (IV) at different doses (mpk = mg / Kg) daily for 6 days. RGC numbers were significantly higher in the 25mpk group by day 28 than in placebo (p<0.05). [Figure 7]Figure 1 shows the demyelination scores (scale: 0-4) of AONs assessed on days 7, 14, and 28 for sham (healthy) and pathological (disease, untreated) control groups, and pathological groups treated with BN201 intraperitoneally (IP) or intravenously (IV) at different doses (mpk = mg / Kg) daily for 6 days. Demyelination scores were significantly lower in the 10 and 25 mpk groups by day 28 than in the placebo group (p<0.05). [Figure 8] Figure 1 shows the axon loss scores (scale: 0-4) of AONs assessed on days 7, 14, and 28 for sham (healthy) and pathological (disease, untreated) control groups, and pathological groups treated with BN201 intraperitoneally (IP) or intravenously (IV) at different doses (mpk = mg / Kg) daily for 6 days. Axon loss scores were significantly lower in the 10 and 25 mpk groups by day 28 than in the placebo group (p<0.05). [Figure 9] Figure 1 shows histopathological images of luxol-fast blue (LFB) stained optic nerves in AONs evaluated on day 14 for Set 1 - pathological (disease, untreated) control group and Set 1 pathological group treated intraperitoneally (IP) with BN201 at 10 or 25 mg / Kg daily for 6 days to assess demyelination under different magnifications 10x (left) and 20x (right). [Figure 10] Figure 1 shows histopathological images of luxol-fast blue (LFB) stained optic nerves in AONs evaluated on day 28 for Set 1 - pathological (disease, untreated) control group and Set 1 pathological group treated intraperitoneally (IP) with BN201 at 10 or 25 mg / Kg daily for 6 days to assess demyelination under different magnifications 10x (left) and 20x (right). [Figure 11] Figure 1 shows histopathological images of optic nerves stained with Bielschowsky's silver stain (BSS) in AONs evaluated on day 14 for Set 1 - pathological (disease, untreated) control group and Set 1 pathological group treated intraperitoneally (IP) with BN201 at 10 or 25 mg / Kg daily for 6 days to assess axonal density under different magnifications 10x (left) and 20x (right). [Figure 12]Figure 1 shows histopathological images of optic nerves stained with Bielschowsky's silver stain (BSS) in AONs evaluated on day 28 for Set 1 - pathological (disease, untreated) control group and Set 1 pathological group treated intraperitoneally (IP) with BN201 at 10 or 25 mg / Kg daily for 6 days to assess axonal density under different magnifications 10x (left) and 20x (right). DETAILED DESCRIPTION OF THE INVENTION

[0030] Detailed Description of the Invention All terms used herein in this application are of the art unless otherwise specified. Other specific terms used in this application are to be understood as having their ordinary meanings as known in the art. More specific definitions of are as follows, and the definitions explicitly stated are particularly Unless a broader definition is provided, it is intended to be applied uniformly throughout the specification and claims. It is intended.

[0031] As used herein, the terms "about" or "approximately" refer to a range of ±10% of a particular value. For example, the expression "about 10" or "approximately 10" means ±10% of 10, That is, numbers 9 to 11 inclusive.

[0032] Compounds of formula (I)

[0033] As mentioned above, the present invention relates to the administration of the compounds of formula (I) or derivatives thereof referred to herein. The present study concerns a new treatment regimen involving administration of rivaroxaban.

[0034] For the purposes of this invention, (C1 to C n The term alkyl refers to 1 to n carbon atoms and refers to a saturated branched or straight hydrocarbon chain containing only single bonds.

[0035] (C1~C nNon-limiting examples of alkyl include methyl, ethyl, 1-propyl, 2- -propyl, 1-butyl, 2-methyl-1-propyl, etc.

[0036] (C1~C n The term alkoxy refers to the attachment of an oxygen atom to the rest of a molecule or to another The above-defined (C1-C n ) refers to alkyl. (C1~C n ) Arco Non-limiting examples of oxy include methoxy, ethoxy, n-propoxy, and isopropoxy. Examples include:

[0037] Halo (C1~C n The term alkyl refers to groups in which some or all of the hydrogen atoms are replaced by fluorine, chlorine, (C1-C2) n ) refers to alkyl Haro (C1~C n Non-limiting examples of alkyl include chloromethyl, difluoromethyl, ethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2, 2-trifluoroethyl and the like.

[0038] A halogen substituent means fluoro, chloro, bromo or iodo.

[0039] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, in compounds of formula (I), R1 is fluoro Phenyl, more particularly 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl and even more particularly 2-fluorophenyl.

[0040] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is halo Gen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl fluorophenyl further substituted with one or two substituents selected from the group consisting of alkyl Specifically, R1 is a halogen, a (C1-C4) alkyl, a (C1-C4) alkenyl, or a one or two substituents selected from the group consisting of alkoxy and halo(C1-C4)alkyl; and more particularly, R is a fluorophenyl further substituted with a halogen atom. , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and and a fluoromethyl group, further substituted with one or two substituents selected from the group consisting of: It is fluorophenyl.

[0041] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is chloro. chlorophenyl, more specifically 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl phenyl, and even more particularly, R1 is 2-chlorophenyl.

[0042] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is halo Gen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl chlorophenyl further substituted with one or two substituents selected from the group consisting of alkyl Specifically, R1 is a halogen, a (C1-C4) alkyl, a (C1-C4) alkoxy group, one or two substituted alkyl groups selected from the group consisting of halo(C1-C4)alkyl, and more particularly, R1 is a halogen, methyl, methylphenyl ... methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trimethyl chloro, further substituted with one or two substituents selected from the group consisting of fluoromethyl; It is phenyl.

[0043] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is bro bromophenyl, more specifically 2-bromophenyl, 3-bromophenyl or 4-bromophenyl It is phenyl, and even more particularly 2-bromophenyl.

[0044] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is halo Gen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl bromophenyl further substituted with one or two substituents selected from the group consisting of alkyl Specifically, R1 is a halogen, a (C1-C4) alkyl, a (C1-C4) alkoxy group, one or two substituted alkyl groups selected from the group consisting of halo(C1-C4)alkyl, and more particularly, R is a bromophenyl further substituted with a halogen, methyl, or methyl group. methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trimethyl bromo which is further substituted with one or two substituents selected from the group consisting of fluoromethyl It is phenyl.

[0045] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is iodine. dophenyl, more specifically 2-iodophenyl, 3-iodophenyl or 4-iodophenyl It is phenyl, and even more particularly 2-iodophenyl.

[0046] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is halo Gen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl iodophenyl further substituted with one or two substituents selected from the group consisting of alkyl Specifically, R1 is a halogen, a (C1-C4) alkyl, a (C1-C4) alkoxy group, one or two substituted alkyl groups selected from the group consisting of halo(C1-C4)alkyl, and more particularly, R is an iodophenyl further substituted with a halogen, methyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl and trimethyl Iodine further substituted with one or two substituents selected from the group consisting of fluoromethyl It is phenyl.

[0047] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is trimethylsilyl. Fluoromethylphenyl, more specifically, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl fluoromethylphenyl or 4-trifluoromethylphenyl, and even more particularly, 2 -trifluoromethylphenyl.

[0048] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is halo Gen, (C1-C6) alkyl, (C1-C6) alkoxy, and halo(C1-C6) alkyl a trifluoromethyl group further substituted with one or two substituents selected from the group consisting of alkyl, Specifically, R1 is a halogen, a (C1-C4) alkyl, a (C1 one or more selected from the group consisting of halo(C1-C4)alkyl, halo(C1-C4)alkoxy, and halo(C1-C4)alkyl; is trifluoromethylphenyl further substituted with two substituents, and even more specifically R1 is halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , one or two substituted aryl groups selected from the group consisting of fluoromethyl and trifluoromethyl; and trifluoromethylphenyl further substituted with a group.

[0049] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R1 is pyrrolo It is lysine-1-yl.

[0050] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R2 is 2- It is oxo-pyrrolidin-1-yl-methyl.

[0051] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in the compound of formula (I), R2 is sulphur sulfamoylphenyl, more specifically, 2-sulfamoylphenyl, 3-sulfamoylphenyl phenyl, or 4-sulfamoylphenyl, and even more particularly 4-sulfamoyl It is ethyl.

[0052] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiments, in the compound of formula (I), R3 is 2- It is methylpropyl.

[0053] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiments, in the compound of formula (I), R1 is 2- fluorophenyl or pyrrolidin-1-yl, and R2 is 2-oxo-pyrrolidine- 1-ylmethyl or 4-sulfamoylphenyl.

[0054] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the compound of formula (I) may be G79([N-(2 -(2'-fluorophenyl)ethyl)-glycyl]-[N-(2-methylpropyl)- glycyl]-N-[3-(2'-oxopyrrolidinyl)-propyl]glycinamide, B N201, chemical formula: C 25 H 38 FN5O4, molecular weight 491.5987), G-80([ N-(2-(2'-fluorophenyl)ethyl)-glycyl]-[N-(2-methyl- [2-(4'-sulfamoyl-phenyl)ethyl]glycine Amide, BN119, Chemical formula: C 26 H 36 FN5O5S, molecular weight 549.658) and G81 ([N-(2-(1-pyrrolidinyl)ethyl)-glycyl]-[N-(2-methyl -propyl)glycyl]-N-[2-(4'-sulfamoyl-phenyl)ethyl]glycyl Cinamide, BN120, Chemical formula: C 24 H 40 N6OS, molecular weight 524.6766) The compound of formula (I) can be prepared as disclosed in WO 02 / 04749. This can be done.

[0055] [ka]

[0056] There is no limitation on the type of salt of the compound of formula (I) that can be used, provided that they are When used for therapeutic purposes, it must be pharmaceutically or veterinarily acceptable. The term "pharmaceutical or veterinary acceptable salts" refers to compounds that form alkali metal salts and are free or soluble in water. This includes salts commonly used to form addition salts of free bases. The preparation of pharmaceutically or veterinarily acceptable salts can be carried out by methods known in the art. For example, they can be prepared by conventional chemical methods to prepare compounds containing basic or acidic moieties. Generally, such salts can be prepared from the parent compound, for example, the compound of formula (I). The free acid or free base form of the compound is added to a stoichiometric amount of an appropriate pharmaceutically or veterinarily acceptable Prepared by reacting with a base or acid in water or an organic solvent or a mixture thereof The compounds of formula (I) and their respective salts have several physical properties. They may be different but are equivalent for the purposes of this invention.

[0057] The compounds of the present invention may be used either as free solvates or as solvates (eg, hydrates). Any crystalline form may be used, and both forms are intended to be within the scope of the present invention. Methods of mediation are generally known in the art. Generally, a solvent such as water, ethanol, etc. Solvated forms with pharmaceutical, cosmetic or veterinary acceptable solvents are also considered to be acceptable for the purposes of the present invention. It is equivalent to the unsolvated form.

[0058] Some compounds of the present invention may have chiral centers which can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to a stereoisomer that is a mixture of two or more molecules, each of which has a different orientation of atoms in space. The term stereoisomers refers to all isomers of an individual compound that differ only in their mirror image. Isomers (enantiomers), mixtures of mirror images (racemates, racemic mixtures), geometric (syn / trans or syn / anti or E / Z) isomers, and two or more isomers that are not mirror images of each other The present invention includes isomers of compounds having chiral centers (diastereoisomers). It relates to each of the stereoisomers and to mixtures thereof.

[0059] Diastereoisomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be separated by conventional techniques of optical resolution. This resolution can be used for any chiral synthetic intermediate. Optically pure isomers can be obtained by the enantiomerization of the isomer or the compound of the present invention. They can also be obtained individually using specific synthesis.

[0060] Compounds of formula (I), pharmaceutically or veterinarily acceptable salts thereof, and compounds of formula (I) or a pharmaceutically acceptable salt thereof. In all embodiments of the present invention that refer to mixtures, even if they are not specifically mentioned Always intended.

[0061] Pharmaceutical and veterinary compositions

[0062] The compounds of formula (I) may form part of a pharmaceutical or veterinary composition. The pharmaceutical or veterinary compositions used in the invention comprise a therapeutically effective amount of a compound of formula (I) as defined above. a compound, or a pharmaceutically or veterinarily acceptable salt thereof, or a compound of formula (I) or Any stereoisomer or stereoisomeric form of any of the pharmaceutically or veterinarily acceptable salts thereof The mixture of the compounds is then mixed with one or more pharmaceutically or veterinarily acceptable excipients or carriers. nothing.

[0063] As used herein, the phrase "therapeutically effective amount" refers to an amount that, when administered, is effective to treat the disease being treated. A compound that is sufficient to prevent or alleviate to some extent the onset of one or more symptoms of the disease. Specific doses of the compounds of the present invention to obtain therapeutic benefit include, inter alia, The patient's size, weight, age and sex, the nature and stage of the disease, the aggressiveness of the disease, and the history of administration These may vary depending on the specific circumstances of each patient, including the tract.

[0064] The expression "pharmaceutically or veterinarily acceptable excipient or carrier" means a pharmaceutical or veterinary Each component is a pharmaceutical or veterinary composition. It must be pharmaceutically or veterinarily acceptable in the sense of being compatible with the other ingredients of the and that there is no excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications. Use in contact with human and animal tissues or organs without a reasonable benefit / risk ratio It must be suitable for

[0065] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the morphology, the pharmaceutical or veterinary composition may be in saline. (NaCl). 2 mg / mL or 5 mg / mL of the compound of formula (I) as defined above in saline (NaCl) L solution.

[0066] Treatment regimen

[0067] As mentioned above, the therapeutic regimen of the present invention comprises a compound of formula (I) as defined above or a compound containing the same. a composition comprising the compound of formula (I) and (II) administered to a subject in need thereof one or more times over a first period of 1 to 7 days; This involves administering a single dose followed by a period of 13 days or more without administering the drug.

[0068] For purposes of the present invention, the term "several times" refers to more than one time.

[0069] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, the term several times means 2 to 42 times, more specifically Generally, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20 , 21, 22, 24, 26, 27, 28, 30, 32, 34, 36, 38, 40 or 42 It means times.

[0070] "Once per day" or "Once a day" The phrase "once daily" is used interchangeably and refers to one dose per day. This means that only the drug is administered.

[0071] The treatment regimen of the present invention includes a first period (drug administration period), and a second period before the drug is administered again (drug-free period, i.e., no drug is administered). ) Thus, at the end of the second period in which the drug is not administered, the drug is administered at least In one embodiment, the method described above or below, as appropriate throughout the description, is administered once more. In combination with one or more features of the various embodiments described, the treatment regimen of the present invention can , two or more, more specifically 2, 3, 4, 5, 6, 7, 8, 9 or 10 drug administration periods with corresponding drug-free periods between them.

[0072] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiments, the treatment regimen of the present invention comprises steps a) and a) and b) are repeated.

[0073] For purposes of the present invention, neurotransmitters that result in the destruction or degeneration of neurons, axons, or myelin are referred to as neurotransmitters. The term "treatment" of a disease or condition refers to a treatment for a subject who is or has shown symptoms or signs of the disease. When a drug is used in a clinical setting, it is intended to reduce, stabilize, or inhibit the progression of a disease / condition. The term treatment also refers to patients with no clinical history of the disease or condition, e.g., magnetic resonance imaging (MRI) Radiologically Isolated Syndrome (RAS) showing brain lesions on MRI Patients with RIS (rising ischemic stroke) or those undergoing planned brain surgery, endarterectomy or This includes patients undergoing other endovascular procedures who are at high risk of developing full-blown disease. For example, treatment can refer to the reduction of the accumulation of a disorder in a subject in need thereof. In some embodiments, treatment also provides a neuroprotective effect, an immunomodulatory response, or the like. It can refer to providing any combination.

[0074] The term "prevention" may be used interchangeably with the term "prophylactic treatment" and is intended to mean any treatment that is (I) or a composition thereof to a subject to prevent or treat a disease or disorder, or This includes preventing the onset, recurrence or spread of one or more symptoms of:

[0075] In the present invention, the terms "patient" and "subject" are used interchangeably.

[0076] The compound or composition of formula (I) as defined above is administered once or several times over a period of 1 to 7 days. The administration schedule of step a) can be used according to the present invention, provided that Thus, for example, a compound or composition of formula (I) as defined above may be It may be administered once or over a period of 1 to 7 days according to different administration schedules. Non-limiting examples of such dosing schedules include: Every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), every 12 hours (Q12h), once a day, twice a day, three times a day, four times a day, 1 Examples include every day, every two days, or every three days.

[0077] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the morphology, the first period of step a) is 2 to 7 days, 3 ~7 days, 4-7 days, 5-7 days, or 6-7 days.

[0078] In one embodiment, various implementations described above or below, as the case may be, are implemented. In step a), a compound as defined above in combination with one or more characteristics of the form or a composition containing same for a first period of 1, 2, 3, 4, 5, 6, or 7 days. The dose is administered several times, more specifically for a period of 6 or 7 days.

[0079] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, in step a) a compound of the formula ( The compound of I) or a composition containing it is administered several times. More specifically, the compound is , every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours ( Q8h), every 12 hours (Q6h), once a day, twice a day, three times a day, four times a day, once a day and is administered every two or three days.

[0080] In a more particular embodiment, the compound is administered daily, more particularly once a day, every 3 hours ( Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h), or It is administered every 12 hours (Q12h).

[0081] In another more particular embodiment, the compound is administered every two days or every three days. More specifically, on the day of administration, the compound of formula (I) or a composition containing the same is administered once a day. Once, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8h) or every 12 hours (Q12h).

[0082] In another embodiment, various embodiments described above or below, optionally throughout the entire description, A compound or composition of formula (I) as defined above in combination with one or more features of the embodiments. is administered once daily for 6 or 7 days.

[0083] As described above, the second period of time in step b) during which the compound is not administered is 13 days or longer. In one embodiment, various implementations described above or below, as the case may be, may be implemented in various ways throughout the description. In combination with one or more features of the present invention, the second period during which the compound is not administered is 13 days. The period is between 10 and 12 months.

[0084] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the second period in which the compound is not administered may be 13 It lasts from days to 3 months.

[0085] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the second period in which the compound is not administered may be 13 It lasts from days to a month.

[0086] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, the second period during which the compound is not administered may be 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 2 9, 30, 32, 34, 37, 41, 44, 48, 51, 55, 58, 62, 69, 76 , 83, 84, 85, 86, 87, 88, 89, or 90 days or more. The second period is 21 or 22 days.

[0087] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the second period in which the compound is not administered may be 13 ~20 days, 13~21 days, 13~22 days, 13~23 days, 13~24 days, 13 ~25 days, 13~26 days, 13~27 days, 13~28 days, 13~29 days, 13 ~30 days, 13-34 days, 13-41 days, 13-48 days, 13-55 days, or 13-62 days, 13-69 days, 13-76 days, 13-83 days, 13-84 days, 13-85 days, 13-86 days, 13-87 days, 13-88 days, 13-89 days, Or 13 to 90 days.

[0088] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the second period in which the compound is not administered may be 13 ~358 days, 13~359 days, 13~360 days, 13~361 days, 13~362 days, 13 to 363 days, 13 to 364 days, or 13 to 365 days.

[0089] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the second period in which the compound is not administered is 2 weeks. Between, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, 15 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months , 11 months, or 12 months.

[0090] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, the first period may be 2 to 7 days, 3 to 7 days, 4 a second period of time of 7 days, 5-7 days, 6-7 days, or 7 days during which no compound is administered; 13, 14, 15, 16, 18, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 32, 34, 37, 41, 44, 48, 51, 55, 58, 62, 69, 76, 83, 84, 85, 86, 87, 88, 89 or 90 days or more, Specifically, the second period is 21 or 22 days.

[0091] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, the first period may be 2 to 7 days, 3 to 7 days, 4 a second period of time of 7 days, 5-7 days, 6-7 days, or 7 days during which no compound is administered; 13-20 days, 13-21 days, 13-22 days, 13-23 days, 13-24 days The following periods are indicated: 13-25 days, 13-26 days, 13-27 days, and 13-28 days.

[0092] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, the first period may be 2 to 7 days, 3 to 7 days, 4 a second period of time of 7 days, 5-7 days, 6-7 days, or 7 days during which no compound is administered; is equal to 13 days, which means that the compound of formula (I) or a composition thereof as defined above has been in use for 2 weeks. Alternatively, the first period may be 2 to 7 days, 3 to 7 days, 4 to 7 days, 7 days, 5-7 days, 6-7 days, or 7 days, and the second period during which the compound is not administered is , which is equivalent to 20 days, which means that the compound of formula (I) or a composition thereof as defined above is administered every 3 weeks. Alternatively, the first period may be 2 to 7 days, 3 to 7 days, 4 to 7 days, days, 5-7 days, 6-7 days, or 7 days, and the second period during which the compound is not administered is 27 days, which is equivalent to administering a compound of formula (I) or a composition thereof as defined above every 4 weeks. Alternatively, the first period may be 2 to 7 days, 3 to 7 days, or 4 to 7 days. The second period in which the compound is not administered is 3 days, 5-7 days, 6-7 days, or 7 days. 4 days, which is equivalent to administering a compound of formula (I) or a composition thereof as defined above every 5 weeks. Alternatively, the first period may be 2 to 7 days, 3 to 7 days, or 4 to 7 days. , 5-7 days, 6-7 days, or 7 days, and the second period in which the compound is not administered is 41 days, which is equivalent to a period of 6 weeks when the compound of formula (I) or a composition thereof as defined above is administered. In a more particular embodiment, the compound or composition is administered more specifically daily. Physically, once a day, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h) h), every 8 hours (Q8h), or every 12 hours (Q12h). In certain embodiments, during the first period, the compound or composition is administered every two days or every three days. Even more specifically, on the day of administration, the compound or composition is administered once daily for 3 Every hour (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), every 8 hours (Q8 h) or every 12 hours (Q12h).

[0093] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, the first period may be 2 to 7 days, 3 to 7 days, 4 a second period of time of 7 days, 5-7 days, 6-7 days, or 7 days during which no compound is administered; The effective period of the compound of formula (I) or a composition thereof is 27 to 30 days. Alternatively, the first period may be 2 to 7 days, 3 to 7 days, 4 to 7 days, 7 days, 5-7 days, 6-7 days, or 7 days, and the second period during which the compound is not administered is , 89 to 91 days, which is the time when the compound of formula (I) or a composition thereof as defined above is administered for 3 months. It is meant to be administered monthly, or the first period may be 2-7 days, 3-7 days, 4 a second period of time of 7 days, 5-7 days, 6-7 days, or 7 days during which no compound is administered; is 364 to 365 days, which is the compound of formula (I) or a composition thereof as defined above. is administered once a year. In a more particular embodiment, the compound or composition comprises Daily, more specifically, once a day, every 3 hours (Q3h), every 4 hours (Q4h), 6:00 Administered every 6 hours (Q6h), every 8 hours (Q8h), or every 12 hours (Q12h) In another more specific embodiment, during the first period, the compound or composition is administered every two days or is administered every three days. Even more specifically, on the day of administration, the compound or composition is Once a day, every 3 hours (Q3h), every 4 hours (Q4h), every 6 hours (Q6h), 8am It is administered every 8 hours (Q8h) or every 12 hours (Q12h).

[0094] In another embodiment, various embodiments described above or below, optionally throughout the entire description, A compound or composition of formula (I) as defined above in combination with one or more features of the embodiments. is administered intravenously.

[0095] In another embodiment, various embodiments described above or below, optionally throughout the entire description, A compound or composition of formula (I) as defined above in combination with one or more features of the embodiments. is administered intraperitoneally.

[0096] Compounds of formula (I) were administered in mice at a dose of 0.5-200 mg / kg / day according to the treatment regimen of the present invention. It can be administered in mg / Kg doses, which range from 0.04mg / Kg to 16.26mg / Kg [Maximum safe starting dose in early clinical trials of therapeutic agents in healthy adult volunteers HED calculations throughout this specification based on industry guidance estimating R, July 2005] corresponds to the human equivalent dose (HED).

[0097] Thus, in one embodiment, the present invention may be modified in any manner as described above or below throughout the entire description. Compounds of formula (I) as defined above in combination with one or more features of the various embodiments described below. Alternatively, the composition may be administered in a human dose equivalent to the dose administered in a mouse, in the range of 0.5 to 200 mg / kg. g / Kg, more specifically 2 to 100 mg / Kg, and even more specifically 5 to 75 mg / Kg g, and even more particularly 10-70 mg / Kg of a compound of formula (I), either once or alternately. It is administered daily.

[0098] In another embodiment, various embodiments described above or below, optionally throughout the entire description, A compound or composition of formula (I) as defined above in combination with one or more features of the embodiments. The substances are approximately 200mg / Kg, approximately 175mg / Kg, approximately 150mg / Kg, and approximately 125mg / Kg, about 100mg / Kg, about 75mg / Kg, about 70mg / Kg, about 60mg / Kg, Approx. 55mg / Kg, approx. 50mg / Kg, approx. 45mg / Kg, approx. 40mg / Kg, approx. 35m g / Kg, approx. 30mg / Kg, approx. 25mg / Kg, approx. 20mg / Kg, approx. 15mg / Kg , about 10mg / Kg, about 5mg / Kg, about 2.5mg / Kg, about 2mg / Kg, about 1.5 mg / Kg, about 1.0 mg / Kg, and about 0.5 mg / Kg of the compound of formula (I) A single or multiple doses of a compound selected from the group of compounds in a human equivalent to the dose in a mouse More particularly, the compounds or compositions of formula (I) as defined above are About 70 mg / Kg, about 25 mg / Kg and about 10 mg / Kg of the compound of formula (I) The compound is administered at a dose in humans equivalent to the dose in mice selected from the group.

[0099] The treatment regimen of the present invention comprises short-term administration of a compound or composition of formula (I) as defined above. is the area under the constant curve (AUC Last ) and Cmax values ​​can be provided.

[0100] “Area under the curve (AUC Last The term "(a)" is used in relation to the first period as previously defined. The area under the curve from the time of administration of a compound or composition of formula (I) as defined above to the last measurable concentration The maximum measurable plasma concentration of an administered drug is called "Cmax."

[0101] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, for the first period described above, the formula defined above The administration of the compound or composition of (I) is carried out for 1 to 100,000 hours. * ng / mL, more specifically 500~80,000h * ng / mL, and more specifically 6,000 to 66,000 h * Area under the curve (AUC) in ng / mL Last ) can be provided.

[0102] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be The administration of the compound or composition of formula (I) is for 6,000 to 9,000 hours. * Under the curve in ng / mL Area (AUC Last ) can be provided.

[0103] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be The administration of the compound or composition of formula (I) is for 12,000 to 16,000 hours. * ng / mL song Area under the line (AUC Last ) can be provided.

[0104] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be The administration of the compound or composition of formula (I) is for 60,000 to 66,000 hours. * ng / mL song Area under the line (AUC Last ) can be provided.

[0105] In one embodiment, various implementations described above or below, as the case may be, are implemented. In combination with one or more features of the form, for the first period described above, the formula defined above The administration of the compound or composition of (I) is in the range of 1 to 100,000 ng / mL, more particularly 50 C of 0 to 80,000 ng / mL, more specifically 3,000 to 40,000 ng / mL A max value can be provided.

[0106] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be Administration of the compound or composition of formula (I) results in a Cmax value of 3,000 to 5,000 ng / mL. can be provided.

[0107] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be Administration of the compound or composition of formula (I) results in a Cmax value of 6,000 to 9,000 ng / mL. can be provided.

[0108] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be The administration of the compound or composition of formula (I) is carried out at a Cmax of 12,000 to 16,000 ng / mL. The x value can be provided.

[0109] In another embodiment, various embodiments described above or below, optionally throughout the entire description, In combination with one or more features of the embodiment, the first period may be The administration of the compound or composition of formula (I) is carried out at a Cmax of 30,000 to 36,000 ng / mL. The x value can be provided.

[0110] Plasma concentrations AUC and Cmax can be measured, for example, by automated or manual immunoassays, liquid chromatography, etc. by standard analytical methods known in the art, such as fluoroscopy or liquid chromatography-mass spectrometry. It can be determined that:

[0111] neurological disease or condition

[0112] The present invention relates to neurological diseases or conditions that result in the destruction or degeneration of neurons, axons, or myelin. for example, MS, NMO, transverse myelitis, relapsing optic neuritis or any disease affecting the central nervous system. The present invention relates to a novel therapeutic regimen for treating rheumatic and neurological diseases. Diseases include inflammatory diseases, non-inflammatory neurological diseases such as optic neuropathy, and neurodegenerative diseases. can be.

[0113] Inflammatory diseases of the central nervous system are caused by activation of the immune system and damage the central nervous system. These lesions are characterized by the presence of inflammatory infiltrates or immune molecules that cause inflammation. loss of neurons and axons, and loss of myelin and oligodendrocytes and their precursors Inflammatory neurological diseases that result in the destruction or degeneration of neurons, axons, or myelin. Non-limiting examples of conditions include multiple sclerosis (MS), neuromyelitis optica (NMO), ophthalmopathy Neuritis, Baro's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, and Marburg disease Examples of demyelinating diseases include:

[0114] Optic neuropathy is a disease in which damage occurs specifically to the optic nerve, resulting in visual impairment. Non-limiting examples include glaucoma, preischemic optic neuropathy, and optic neuritis, hereditary optic neuropathies, For example, Leber's disease and dominant optic atrophy, toxic optic neuropathies, traumatic optic neuropathies, and tumor-related optic atrophies. Neurosis is one example.

[0115] Neurodegenerative diseases are characterized by the progressive loss of neurons and axons, accompanied by low-level reactive inflammation. Such losses are accompanied by different toxicities such as protein deposition and loss of trophic factor support. Examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and Johnsson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body disease, genetic These include, but are not limited to, inherited ataxia and glaucoma.

[0116] In one embodiment, various implementations described above or below, as the case may be, are implemented. Destruction or alteration of neurons, axons, or myelin in combination with one or more features of morphology The neurological disease or condition causing the disease is selected from the group consisting of demyelinating diseases, optic neuropathy, and neurodegenerative diseases. More specifically, the neurological disease or condition is selected from the group consisting of multiple sclerosis (MS), optic-spinal NMO, optic neuritis, Baro's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, myelitis Lebburg's disease, glaucoma, anterior ischemic optic neuropathy, Leber's disease, dominant optic atrophy, toxic optic nerve traumatic optic neuropathy, tumor-related optic neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease Tony's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body disease, hereditary ataxia, and Even more particularly, the neurological disease or condition is selected from the group consisting of: Multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, glaucoma, and combinations thereof and the like.

[0117] Throughout the description and claims, the word "comprises" and variations thereof refer to other technical features. It is not intended to exclude any feature, additive, component, or step. The word "comprises" encompasses the case of "consisting of." Additional objects, advantages, and features of the present invention are: , which will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and figures are offered by way of illustration and are not intended to limit the invention. Furthermore, it is not intended that the present invention be limited to all of the specific preferred embodiments described herein. Covers all possible combinations. [Example]

[0118] Some applications of lysolecithin-induced acute optic neuritis in Sprague-Dawley rats Evaluation of BN201 by volume

[0119] 1. Purpose of the test

[0120] The test was conducted in two blocks.

[0121] The purpose of Block 1 was to evaluate the efficacy of various doses of lysolecithin-induced optic neuritis in SD rats. BN201 administered intraperitoneally at 10mg / Kg, 25mg / Kg, and 70mg / Kg The purpose of this study was to determine the efficacy of BN201 administered intravenously at 25 mg / kg for 7 days. test).

[0122] The objective of Block 2 was to investigate the long-term lysolecithin-induced optic neuritis model in SD rats. The objective of this study was to determine the efficacy of BN201 (14 and 28 day studies).

[0123] 2. General Protocol

[0124] Animals (male Sprague-Dawley rats, age: 12-13 weeks, weight range at the start of the study: Receipt of a diet of 306.8–385.2 g) and acclimatization of the animals for a period of at least one week. Day 0: Lysolecithin was administered to the optic nerve. Various doses of the test compound (BN201) (10mg / Kg, 25mg / Kg, 70mg g / Kg) daily (Day 0-6 = 7 doses total) intraperitoneal (IP) administration and blockade 1 intravenously over 2 hours (infusion 25 mg / Kg). On day 6, plasma from block 1 at designated time points (time points 8-9) for PK was analyzed. blood sampling and tissue collection (eyes and optic nerves) for histopathological evaluation. Determination of plasma levels of BN201 by LC-MS / MS Determination of pharmacokinetic parameters of BN201 by WinNonlin analysis Test compound administration for Block 2 (10 and 25 mg / Kg IP) once daily (0 (Days 14-6 = 7 times in total), and tissue collection on Days 14 and 28 for histopathological evaluation (test (harvesting of eyes and optic nerves at the end of the study).

[0125] 3. Animal Conditioning

[0126] The animals were kept at a temperature of 22 ± 3°C, humidity of 50 ± 20%, and a 12-hour light / dark cycle. The animals were kept in a controlled environment with 15-20 changes of fresh air per hour. Animals were housed in groups (3 animals per cage) in individually ventilated cages (IVC) and autoclaved. The animals were kept in certified irradiation laboratory beds. Rodent chow was provided ad libitum.

[0127] 4. Test Implementation Plan

[0128] The animals were divided into different groups according to the following scheme:

number

[0129] 5. Experimental group

[0130] Block 1: 7-day efficacy group

number

[0131] Block 1: 7-day efficacy group

number

[0132] 6. Preparation of Test Items

[0133] BN201 was dissolved in physiological solution (NaCl 0.9%) at room temperature. The stock solution was 100 The solutions were prepared at 100 mg / mL strength and stored in aliquots at 20°C. The solution was thawed and a sufficient volume was withdrawn for further dilutions. 5 mg / ml for groups 3-5 A working solution of was prepared by diluting the stock solution with saline. A 2 mg / ml solution was prepared daily (days 0 to 6).

[0134] 7. Disease Induction Procedure

[0135] The animals were anesthetized, and the shaved skin was disinfected with 75% ethanol. A 3 mm incision was made to expose the optic nerve under a surgical microscope, and the lacrimal gland and extraocular muscles were removed. The dura and arachnoid membrane around the optic nerve were opened longitudinally. A small amount of dye was placed on the dura mater to identify focal lesions in histology. Microinjections were performed using a glass micropipette attached to a Hamilton syringe. The pipette was inserted 2 mm posterior to the eyeball and as superficial as possible to the optic nerve, and 0.8 μL of 1% Lysolecithin (containing 0.02% Evans blue) was slowly applied to the nerve over approximately 30 seconds. Sham control rats (animals without disease) were injected with 0.8 μL of lysolecithin-free lecithin. 0.02% Evans blue in saline was injected. After injection, the skin incision was sutured and the area was irritated. An antibiotic solution was administered to prevent infection.

[0136] 8. Treatment Procedure

[0137] Groups 1 and 2 served as sham and pathological controls, respectively, and were administered only saline. Given Test compounds were administered to each group at various doses by IP or IV injection (as described above). The first dose was administered 1 hour after the lysolecithin injection and continued for 1 hour until the end of the experiment. Repeated once a day. On day 6, blood samples were taken at various time points after administration of the test article for drug concentration measurement. Groups 3 to 5 (IP group): before administration, 0.25, 0.5, 1, 4, 8 hours, 12 hours and 24 hours (as of 8) Group 6 (IV infusion group): Before administration, then at the following times after infusion: 0 hours (end of infusion), 0. 25 hours, 0.5 hours, 1 hour, 4 hours, 8 hours, 12 hours and 24 hours (9 time points) Approximately 200 μL of blood was collected per time point in K2EDTA tubes. The blood was collected from the vein and stored at 4°C until plasma was separated within 30 minutes. All plasma samples were stored in two aliquots at -80°C until the time points were completed. One aliquot of the plasma sample was submitted together to DMG / KG for drug concentration analysis.

[0138] 9. Observation and reading

[0139] 9.1 Weight

[0140] Body weights were measured daily in the morning from day 0 to day 7. All animals were monitored regularly for clinical signs. was observed objectively.

[0141] 9.2 Histopathology

[0142] On day 7, animals were euthanized with CO2 and then resuspended in saline and 4% paraformaldehyde. The optic nerve (from the eyeball to the optic chiasm) and the eye were removed and perfused cardiacally with 1% paraformaldehyde. The eyes of all animals were fixed in Davidson's fixative overnight. All tissues were processed in an automated tissue processor and embedded in paraffin. Using a microscope, create 5-micrometer (5 μm) cross sections at the injection site (location of the dye). Made. Serial sections of each optic nerve were obtained (4-6 sections). The slides were analyzed for H&E, LFB, and Biel Staining with Schowsky silver impregnation stain (BSS) revealed inflammation, demyelination, and axonal lesions in the optic nerve. Retinal (eye) sections were stained with H&E stain and used for retinal ganglion cell (RGC) counting. did.

[0143] 10. Scoring Criteria

[0144] The demyelinated area was measured (in Luxol Fast Blue stained sections) and scored as follows: The following criteria were used: 0.5 Evidence of perivascular or subpial demyelination 1. Marked perivascular or subpial demyelination 2 Confluent perivascular or subpial demyelination 3 Massive confluent demyelination (half of the spinal cord) 4. Extensive demyelination

[0145] A scale of 0 to 4 used to assess the severity of axonal loss (in silver-impregnated stained sections). The coring scale is as follows: 0 Normal staining of axons by silver impregnation 0.5 Evidence of perivascular or subpial loss of axons 1. Evidence of significant perivascular or subpial loss of axons 2. Confluent perivascular or subpial loss of axons 3. Massive confluent axonal loss 4. Extensive axonal loss

[0146] Scoring criteria used to assess inflammation (H&E sections): 0 Normal: No infiltration 0.5 Evidence of perivascular or subpial infiltration 1. Evidence of significant perivascular or subpial infiltration 2 Evidence of confluent perivascular or subpial infiltration 3. Massive and dense penetration 4 Widespread infiltration

[0147] Leica DFC42 mounted on a Nikon Eclipse 80i microscope Representative photographs (10x and 20x) were taken using a 5C camera. Retinal ganglion cell (RGC) counts were determined using H&E stained sections of the eyes (six high-power fields per animal [ 40x] to compare ganglion cell density between treatment groups.

[0148] 11. Bioanalytical Procedures

[0149] 11.1 Sample Preparation

[0150] Test samples were processed by protein precipitation using cold acetonitrile. Specifically, 10 μL of plasma was added to a 100 ng / mL verapamil solution containing 100 ng / mL verapamil as an internal standard. The contents were mixed with 200 μL of acetonitrile. The contents were vortexed to ensure proper mixing and the precipitate was removed. The precipitated proteins were removed by centrifugation at 4000 rpm for 15 minutes at 4°C. The supernatant was collected and subjected to biological analysis.

[0151] 11.2 Analysis parameters

number

[0152] 12.Results

[0153] 12.1 Weight (Blocks 1 and 2)

[0154] When compared by t-test at each study day during the survival period, the sham control group and the pathological control group There was no significant change in the body weight of rats between the control and control groups. Treatment with BN201 did not result in pathological changes. There was no significant change in body weight when compared to the control group.

[0155] 12.2 Pharmacokinetic Parameters (Block 1)

[0156] The pharmacokinetic parameters for the IP and IV groups are shown in Tables 1 and 2 below and in Figures 1 and 2. [Table 1]

[0157] [Table 2]

[0158] 12.3 Histopathological evaluation

[0159] 12.3.1 Retinal ganglion cell number (RGC)

[0160] The results of the RCG counts in the eyes (6 high-power fields) are shown in Figure 3 (Block 1) and Figure 6 (Block 2).

[0161] RGC (Block 1)

[0162] The pathological control group was compared to the sham control group (94±3.6) at six random high magnifications. Treatment with BN201 significantly reduced the number of RGCs (73.6 ± 2.2) in the RG The IV infusion group (25mg / Kg) showed a trend towards an increased number of Cs compared with the pathological controls. The IP of BN201 at 25 and 70 mg / Kg showed a statistically significant improvement in GC counts. The groups also showed improvement in RGC numbers, with 48% and 69% protection against retinal ganglion cell loss, respectively. He showed his protection.

[0163] RGC (Block 2)

[0164] The pathological control groups (14-day and 28-day groups) showed significantly lower levels of leukemia at six random high magnifications. Treatment with BN201 showed improvement on day 28 (25 mg / kg group).

[0165] 12.3.2 Demyelination (in Luxol Fast Blue-stained sections of the optic nerve)

[0166] The results of the demyelination scores are shown in Figure 4 (Block 1) and Figure 7 (Block 2). Histopathological images of LFB-stained optic nerves evaluated at 14 and 28 days were used to These are shown in Figures 9 and 10, respectively.

[0167] Demyelination (Block 1)

[0168] The pathological control group showed a mean demyelination score of 1.6 ± 0.4. IP treatment with BN201 at 100 mg / kg showed a trend towards a reduction in demyelination scores, with 1 mg / kg of BN201 and 1 mg / kg of BN201, respectively. The 25 mg / kg IV injection group showed 2% protection against demyelination. showed 2% protection

[0169] Demyelination (Block 2)

[0170] Moderate demyelination was observed in the pathological control group on days 14 and 28.

[0171] 12.3.3 Axonal loss (in BSS-stained sections of the optic nerve)

[0172] Axon loss scores (silver-impregnated sections, scale: 0–4) for block 1 are shown in Figure 5. Block 2 is shown in Figure 8. The axon density was assessed on days 14 and 28. Histopathological images of the evaluated BSS-stained optic nerves are shown in Figures 11 and 12, respectively.

[0173] Axonal loss (Block 1)

[0174] The pathological control group showed a significant increase in axon loss score (2.4 ± 0.3) (BSS (Observed in stained optic nerve sections). Treatment with IP showed a reduction in the score (36-39% protection). IV injection prevented axonal loss. provided significant protection against loss (62%).

[0175] Axonal loss (Block 2)

[0176] In the pathological control group, progressive axonal loss was observed on days 14 and 28 (day 14). (Scores of 1.9 and 2.2 on days 1 and 28, respectively). N201 showed a significant reduction in axonal loss at 28 days.

[0177] 13. Conclusion

[0178] Significant induction of optic neuritis and retinal ganglion cell loss was observed in the pathological control group ( Day 7 (Block 1), Day 14 and Day 28 (Block 2). Optic neuritis was compared with pathological controls. In the optic nerve, inflammatory cell infiltration (observed by H&E staining), demyelination (observed by LFB staining) were observed in the optic nerve. Increased axonal loss (BSS staining) and axonal loss (BSS staining), as well as an increase in the number of retinal ganglion cells in the retina of the eye. BN201 treatment was characterized by a significant improvement in retinal ganglion cells as well as inflammation and axonal inflammation. Daily IV administration of BN201 at 25 mg / Kg ( 2-hour infusion) compared with IP administration of BN201 at 10, 25, and 70 mg / Kg. provided excellent protection against optic neuritis.

Claims

1. Treatment of neurological diseases or conditions that result in the destruction or degeneration of neurons, axons, or myelin; A compound of formula (I) or a pharmaceutically or veterinarily acceptable derivative thereof for use in the prophylaxis or a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof. Any stereoisomer or mixture of stereoisomers: 【Chemistry 1】 During the ceremony, R １ is substituted with halogen or trifluoromethyl, and further substituted with halogen, (C １ ~C ６ ) Alkyl, (C １ ~C ６ ) alkoxy, and halo (C １ ~C ６ ) alkyl phenyl optionally substituted with one or two selected substituents, or R １ teeth, pyrrolidin-1-yl, R ２ is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl 、 R ３ is propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1- Methylbutyl, 2-methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, and 1-methylpentyl; wherein the treatment a) a first period of 1 to 7 days during which the compound is administered once or several times to a subject in need thereof; duration, and b) after a first period of time during which the compound is not administered and before the next administration of the compound; The present invention includes a second period of 13 days or more during which the

2. In the compound of formula (I), R ３ is 2-methylpropyl, and R １ and R ２ Request 2. The compound for use according to claim 1, as defined in claim 1.

3. 3. The method of claim 2, wherein the compound of formula (I) is selected from the group consisting of: A compound used for 【Chemistry 2】

4. 4. The method according to claim 1, wherein the first period of time in step a) is 3 to 7 days. Compounds for the described uses.

5. 5. The method of claim 1, wherein the first period is 7 days. compound.

6. In step a), the compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof is or a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof. Any stereoisomer or mixture of stereoisomers of any of the above is administered every 3 hours, every 4 hours, , every 6 hours, every 8 hours, every 12 hours, once a day, twice a day, three times a day, four times a day, 6. The method of claim 1, wherein the compound is administered every day, every two days, or every three days. Compounds for use in

7. In step a), the compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof is or a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof. any stereoisomer or mixture of stereoisomers of any of the above is administered once daily.

7. A compound for use according to claim 6.

8. 8. The method of claim 1, wherein the second period is between 13 days and 89 days. Compound for use.

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

10. a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or Any stereochemistry of any of the compounds of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof 10. The method according to claim 1, wherein the mixture of isomers or stereoisomers is administered intravenously. The compound for use as described above.

11. a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or Any stereochemistry of any of the compounds of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof 10. The method of claim 1, wherein the mixture of isomers or stereoisomers is administered intraperitoneally. The compound for use as described above.

12. a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, or Any stereochemistry of any of the compounds of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof A mixture of isomers or stereoisomers is administered to a subject in need thereof at a dose of 5-75 mg / Kg / 12. The method of claim 1, wherein the antibody is administered at a dose equivalent to the dose in mice administered in a day.

2. A compound for use according to claim 1.

13. The disease or condition is selected from the group consisting of multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, and basilar arthritis. Roth's disease, Schilder's disease, transverse myelitis, acute hemorrhagic leukoencephalitis, Marburg disease, glaucoma, anterior Ischemic optic neuropathy, optic neuritis, Leber's disease, dominant optic atrophy, toxic optic neuropathy, traumatic optic nerve Disease, tumor-associated optic neuropathy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis From the group consisting of lateral sclerosis, frontotemporal dementia, Lewy body disease, hereditary ataxia, and glaucoma 13. The compound for use according to any one of claims 1 to 12, selected from:

14. The disease or condition is selected from the group consisting of multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, and rheumatoid arthritis.

14. The method of claim 13, wherein the ophthalmologist is selected from the group consisting of peripheral ischemic optic neuropathy and glaucoma. Compound.

15. Treatment of neurological conditions that result in the destruction or degeneration of neurons, axons, or myelin For use in prophylaxis, a therapeutically effective amount of a compound according to any one of claims 1 to 3 is administered a pharmaceutical composition comprising the compound of formula (I) together with one or more pharmaceutically or veterinarily acceptable excipients or carriers; is a veterinary composition, wherein the treatment is as defined in any one of claims 1 to 14. The composition.

Images