Masitinib for the treatment of Alzheimer's disease

Abstract

The present invention relates to 2-aminoarylthiazole derivatives, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of less severe Alzheimer's disease and / or early Alzheimer's disease in patients in need thereof. In particular, the present invention relates to masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Alzheimer's disease in patients who have a baseline ADCS-ADL (Alzheimer's Disease Cooperative Study Activities of Daily Living) score of 32 or greater, preferably greater than 32, and / or a baseline MMSE (Mini-Mental State Examination) score of 13 or greater, and / or a time from diagnosis to initiation of treatment with masitinib, or a pharmaceutically acceptable salt or solvate thereof, of 5 years or less, and / or a baseline ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive Subscale) score of 40 or less.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to the treatment of Alzheimer's disease in patients who require it, particularly the treatment of less severe Alzheimer's disease and / or early Alzheimer's disease or Alzheimer's type dementia. [Background technology]

[0002] Background of the Invention Alzheimer's disease (AD) is the most common cause of dementia among older adults, and is estimated to account for approximately 60-70% of all dementia cases, particularly in Western countries. Dementia is a syndrome characterized by memory impairment (i.e., impaired memory), decreased intellectual activity, personality changes, and behavioral abnormalities. These symptoms ultimately lead to a decline in social and occupational functioning.

[0003] Alzheimer's disease is an irreversible neurodegenerative disorder that causes impairments in memory and cognitive skills. It begins with mild cognitive impairment, such as memory loss, and eventually progresses to a stage where independent living is no longer possible. The primary risk factor for developing Alzheimer's disease is age; after age 65, the probability of developing the disease doubles approximately every five years. About one-third of all individuals over 85 years of age may have Alzheimer's disease. Family history also increases the risk of developing the disease, which can be due to genetic or environmental factors.

[0004] Two histopathological features of Alzheimer's disease observed in the brain are amyloid plaques (also called neurite plaques or senile plaques) that occur between neurons and neurofibrillary tangles that occur within neurons. Amyloid plaques arise from the aggregation of β-amyloid peptides produced by the cleavage of amyloid precursor proteins. Neurofibrillary tangles mainly arise from the abnormal accumulation of phosphorylated protein tau (τ), which binds together to form filaments. The deposition of amyloid plaques and the formation of neurofibrillary tangles are thought to be intricately related to the cause, onset, and course of the disease.

[0005] Meta-analyses of epidemiological studies indicate that 5 to 10 million individuals in the United States and Europe are affected by Alzheimer's disease. Alzheimer's disease is already the sixth leading cause of death in the United States and the fifth among Americans over 65 years of age. In the European Union, there are over 3 million people with dementia, and it is estimated that approximately 70% of these are affected by Alzheimer's disease. The worldwide prevalence of Alzheimer's disease is predicted to quadruple to over 100 million by 2050, and by then, one in 85 people in the world will be living with this disease. More than 40% of those cases will progress to late-stage Alzheimer's disease and will require a high level of care equivalent to that of a long-term care facility.

[0006] Currently, the approved treatments for Alzheimer's disease consist of two types of medications: cholinesterase inhibitors (such as donepezil, rivastigmine, and galantamine) and NMDA (N-methyl-D-aspartic acid) receptor antagonists (memantine). Cholinesterase inhibitors increase cholinergic transmission by inhibiting acetylcholinesterase in the synaptic cleft. Memantine is a voltage-dependent, moderately affinity non-competitive NMDA receptor antagonist. It modulates the effects of pathologically elevated, sustained levels of glutamate that can lead to neuronal dysfunction. Currently approved treatments have shown effectiveness against some cognitive and non-cognitive symptoms of Alzheimer's disease. However, their effectiveness is limited and may decline over time.

[0007] Therefore, effective treatments for Alzheimer's disease are still needed, particularly for mild Alzheimer's disease and / or early Alzheimer's disease or Alzheimer's type dementia. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0008] For this reason, the present invention relates to the use of 2-aminoarylthiazole derivatives, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of Alzheimer's disease in patients who require it, particularly patients suffering from Alzheimer's disease and / or early Alzheimer's disease or Alzheimer's type dementia with low severity as defined herein.

Means for Solving the Problems

[0009] Overview The present invention relates to masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Alzheimer's disease in patients who require it. Before the start of treatment with masitinib, or a pharmaceutically acceptable salt or solvate thereof, the patient suffering from Alzheimer's disease has an Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score of 32 or more, preferably more than 32, and / or a Mini-Mental State Examination (MMSE) score of 13 or more, and / or a time of 5 years or less from diagnosis to the start of treatment with masitinib, or a pharmaceutically acceptable salt or solvate thereof, and / or an Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) score of 40 or less.

[0010] In one embodiment, the patient suffering from Alzheimer's disease has an ADCS-ADL score of 32, 35, 38, 39, 41, 47, 50, or 55 or more, preferably more than 32, 35, 38, 39, 41, 47, 50, or 55, before the start of treatment with masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the patient suffering from Alzheimer's disease has an ADCS-ADL score of 38 or 50 or more before the start of treatment with masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the patient suffering from Alzheimer's disease has an ADCS-ADL score of 39 or more than 55 before the start of treatment with masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0011] In one embodiment, a patient with Alzheimer's disease has an MMSE score of 13, 14, 15, 16, or 17 or higher, preferably 14 or higher, before initiating treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a patient with Alzheimer's disease has an MMSE score in the range of 21 to 25 before initiating treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0012] In one embodiment, a patient with Alzheimer's disease has a time interval of 5 years, 4 years, 3 years, or 2 years or less, preferably 3 years or less, from diagnosis to the initiation of treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0013] In one embodiment, a patient with Alzheimer's disease has an ADAS-Cog score of 40, 35, 32, or 25 or less before initiating treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, a patient with Alzheimer's disease has an ADAS-Cog score of 35 or less before initiating treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0014] In one embodiment, the pharmaceutically acceptable salt of masitinib is masitinib mesylate.

[0015] In one embodiment, masitinib, or a pharmaceutically acceptable salt or solvate thereof, is intended to be administered in doses ranging from about 1 to about 12 mg / kg / day (mg per kilogram of body weight per day), preferably about 3 mg / kg / day, 4.5 mg / kg / day, or 6 mg / kg / day. In one embodiment, masitinib, or a pharmaceutically acceptable salt or solvate thereof, is intended to be administered at an initial dose of about 4.5 mg / kg / day for at least 12 weeks, and thereafter at a dose of about 6 mg / kg / day, with each dose increase being used for toxicity management. In one embodiment, masitinib, or a pharmaceutically acceptable salt or solvate thereof, is intended for oral administration. In one embodiment, masitinib, or a pharmaceutically acceptable salt or solvate thereof, is intended to be administered by taking it twice daily.

[0016] In one embodiment, masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered together with at least one further pharmaceutically active agent. In one embodiment, the at least one further pharmaceutically active agent is selected from the group consisting of donepezil, rivastigmine, galantamine, and memantine.

[0017] definition In this invention, the following terms have the following meanings.

[0018] The term "approximately" preceding a number encompasses a range of ±10% of the given number. It should be understood that the value itself referred to by the term "approximately" should also be specifically and preferably disclosed.

[0019] As used herein, “baseline” refers to the time before the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, “baseline” corresponds to the state before the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. For example, in one embodiment, the baseline score is the score before the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, “baseline” corresponds to the state at the time of initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. For example, in one embodiment, the baseline score is the score at the time of initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0020] A "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an excipient or carrier that, when administered to a patient, does not cause any harmful, allergic, or other adverse reactions. It includes all solvents, such as dispersions, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. A pharmaceutically acceptable excipient or carrier refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulant, or any type of compounding aid. For administration to humans, the preparation must meet the sterility, pyrogenicity, general safety, and purity standards required by regulatory authorities such as the FDA (U.S. Food and Drug Administration) or EMA (European Medicines Agency).

[0021] "Patient" refers to a human subject who has Alzheimer's disease. In one embodiment, the patient is waiting for or receiving medical treatment, has been / is / is scheduled to be subject to medical treatment, or is being monitored for the onset of Alzheimer's disease.

[0022] As used herein, “AD patient” refers to a patient who has been diagnosed with Alzheimer’s disease (AD).

[0023] In the term "Alzheimer's disease progression (AD progression)," "progression" refers to the gradual worsening of symptoms over time, particularly the gradual worsening of memory impairment and / or cognitive impairment during the course of the disease. AD progression can be assessed, for example, by the Alzheimer's Disease Rating Scale - Cognitive Subscales (ADAS-Cog), the Activities of Daily Living Scale (ADCS-ADL) scale of the Alzheimer's Disease Collaborative Study, and / or the Mini-Mental State Examination (MMSE).

[0024] As used herein, “score progression,” such as progression of the ADAS-Cog score, progression of the ADCS-ADL score, or progression of the MMSE score, refers to the change over time of a score (such as the ADAS-Cog score, ADCS-ADL score, or MMSE score) used to assess a patient with Alzheimer's disease. As the disease progresses, the score may increase (i.e., the ADAS-Cog score) or decrease (i.e., the ADCS-ADL score or MMSE score). Score progression can be used to assess the effectiveness of treatment. In one embodiment, score progression therefore corresponds to the difference between the baseline score (i.e., before the initiation of treatment) and the score after the initiation of treatment (measured at a specific point in time after the initiation of treatment). No difference in the score over time indicates no disease progression in the AD patient and a stable state. In the case of the ADAS-Cog score, a small increase (or a positive difference between a given point in time and baseline) indicates slight disease progression. Therefore, the smaller the increase in ADAS-Cog score (i.e., the smaller the positive difference), the more stable the AD patient is. Thus, a small increase in ADAS-Cog score compared to the progression of ADAS-Cog score over the same period before treatment indicates a slowing of disease progression. Conversely, a decrease in ADAS-Cog score (or a negative difference between a given time point and baseline) indicates no disease progression and improvement in the AD patient. In the case of ADCS-ADL score and / or MMSE score, a small decrease (or a negative difference between a given time point and baseline) indicates slight disease progression. Therefore, the smaller the decrease in ADCS-ADL score and / or MMSE score (i.e., the smaller the negative difference), the more stable the AD patient is. Thus, a small decrease in ADCS-ADL score and / or MMSE score compared to the progression of ADCS-ADL score and / or MMSE score over the same period before treatment indicates a slowing of disease progression. Conversely, an increase in ADCS-ADL scores and / or MMSE scores (or a positive difference between a given time point and baseline) indicates no disease progression and improvement in AD patients.

[0025] "Therapeutic dose" refers to the amount or concentration of a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, that is targeted to prevent, reduce, or slow (decrease) memory impairment and / or cognitive impairment in patients with AD without causing significant negative or adverse side effects in patients requiring treatment. In one embodiment, the therapeutic dose is targeted to result in at least one of the following in patients requiring treatment without causing significant negative or adverse side effects: - Slowing of the progression of Alzheimer's disease, corresponding to a slowing of the increase in ADAS-Cog score over time, the stabilization of ADAS-Cog score over time, or a slowing of the decrease in ADAS-Cog score over time; - Slowing of the progression of Alzheimer's disease, corresponding to a decrease in ADCS-ADL scores over time, stabilization of ADCS-ADL scores over time, or a slowing of the increase in ADCS-ADL scores over time; and / or - Slowing of the progression of Alzheimer's disease, corresponding to a decrease in MMSE scores over time, stabilization of MMSE scores over time, or a slowing of the increase in MMSE scores over time.

[0026] "To treat" or "treatment" refers to a therapeutic treatment, a preventive (or deterrent) treatment, or both a therapeutic and a preventive (or deterrent) treatment, whose purpose is to prevent, reduce, or slow (reduce) one or more symptoms or manifestations of Alzheimer's disease in a patient requiring treatment. In one embodiment, the purpose of a treatment according to this application is to prevent, reduce, or slow (reduce) memory impairment and / or cognitive impairment in an AD patient requiring treatment. In one embodiment, the purpose of a treatment according to this application is to result in at least one of the following: - Slowing of the progression of Alzheimer's disease, corresponding to a slowing of the increase in ADAS-Cog score over time, the stabilization of ADAS-Cog score over time, or a slowing of the decrease in ADAS-Cog score over time; - Slowing of the progression of Alzheimer's disease, corresponding to a decrease in ADCS-ADL scores over time, stabilization of ADCS-ADL scores over time, or a slowing of the increase in ADCS-ADL scores over time; and / or - Slowing of the progression of Alzheimer's disease, corresponding to a decrease in MMSE scores over time, stabilization of MMSE scores over time, or a slowing of the increase in MMSE scores over time.

[0027] As used herein, “time from diagnosis to initiation of treatment” refers to the period from the date of the first clinically definitive diagnosis of Alzheimer’s disease (expressed as day / month / year, month / year, or year) to the date of initiation of treatment with a 2-aminoarylthiazole derivative as defined herein, in particular macitinib, or a pharmaceutically acceptable salt or solvate thereof (expressed as day / month / year, month / year, or year). In one embodiment, the diagnosis of Alzheimer’s disease is based on the DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) and / or the NINCDS-ADRDA criteria (National Institute of Neurological Disorders and Stroke – Alzheimer’s Disease and Related Disorders Association). In one embodiment, when the date is expressed as month / year (i.e., no information on the day), the day is considered to be the last day of the month. In one embodiment, when the date is expressed as year (i.e., no information on the day and month), the month is considered to be June, and the day is considered to be the last day of the month, i.e., the last day of June. [Modes for carrying out the invention]

[0028] Detailed description The present invention relates to 2-aminoarylthiazole derivatives described herein, particularly macitinib, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment of Alzheimer's disease in patients who require it, as defined later. According to one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly macitinib, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment of Alzheimer's disease with low severity and / or early Alzheimer's disease in patients who require it, as defined later. According to one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly macitinib, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment of Alzheimer's disease with low severity in patients who require it, as defined later. According to one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease or early Alzheimer's dementia in patients who require it, in particular patients who require it as defined later.

[0029] In particular, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Alzheimer's disease in patients having an Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score of 60 or less prior to the initiation of treatment, an Alzheimer's Disease Collaborative Activities of Daily Living (ADCS-ADL) score of 20 or higher, preferably more than 20 prior to the initiation of treatment, a Mini-Mental State Examination (MMSE) score of 12 or higher prior to the initiation of treatment, and / or a time of 10 years or less from diagnosis to the initiation of treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0030] As used herein, “before initiation of treatment” means before initiation of treatment with the 2-aminoarylthiazole derivatives described herein, in particular masitinib, or a pharmaceutically acceptable salt or solvate thereof. In other words, “before initiation of treatment” means the baseline. Therefore, in one embodiment, the pre-treatment score (such as the ADAS-Cog score, ADCS-ADL score, or MMSE score) is the baseline score (such as the baseline ADAS-Cog score, baseline ADCS-ADL score, or baseline MMSE score).

[0031] According to one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Alzheimer's disease in patients having an ADAS-Cog score of 40 or less prior to the initiation of treatment, an ADCS-ADL score of 32 or higher, preferably greater than 32 prior to the initiation of treatment, an MMSE score of 13 or higher prior to the initiation of treatment, and / or a time of 5 years or less from diagnosis to the initiation of treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof. In other words, according to one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of Alzheimer's disease in a patient having a baseline ADAS-Cog score of 40 or less, a baseline ADCS-ADL score of 32 or greater, preferably greater than 32, a baseline MMSE score of 13 or greater, and / or a time of 5 years or less from diagnosis to initiation of treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0032] According to one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of less severe Alzheimer's disease as defined herein in patients requiring such treatment.

[0033] In one embodiment, the severity of Alzheimer's disease is determined using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Activities of Daily Living (ADCS-ADL) scale of the Alzheimer's Disease Collaborative Study, and / or the Mini-Mental State Examination (MMSE).

[0034] In one embodiment, the severity of Alzheimer's disease is determined using ADAS-Cog. ADAS-Cog is widely used to determine the severity of cognitive symptoms in dementia. ADAS-Cog tests 11 aspects: oral language, auditory comprehension, word retrieval, language retrieval, naming, orientation, commands, ideomotor, constructive actions, language recognition, and instruction retrieval (Rosen et al., Am J Psychiatry. 1984 Nov;141(11):1356-64). The ADAS-Cog score is based on the number of errors made in each rating item, with the total score ranging from 0 to 70. A score of 70 represents the most severe cognitive impairment, and a score of 0 represents the least cognitive impairment. Therefore, an increase in ADAS-Cog score over time, for example, compared to a baseline ADAS-Cog score, corresponds to a deterioration of cognitive function, i.e., progression of Alzheimer's disease. Conversely, the absence of an increase in the ADAS-Cog score over time (i.e., a stable ADAS-Cog score) or a decrease compared to, for example, the baseline ADAS-Cog score corresponds to stabilization of Alzheimer's disease. In one embodiment, an ADAS-Cog score of 40 or less corresponds to Alzheimer's disease with low severity. In one embodiment, an ADAS-Cog score of 35 or less corresponds to Alzheimer's disease with low severity.

[0035] In one embodiment, the severity of Alzheimer's disease is determined using the ADCS-ADL. The ADCS-ADL is widely used to assess the abilities of patients with dementia, such as Alzheimer's disease, in basic and tool-using activities of daily living. The ADCS-ADL consists of 23 questionnaires, and the total score ranges from 0 to 78 (Galasko et al., Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9). A score of 78 represents the least functional impairment, and a score of 0 represents the most severe functional impairment. Therefore, a decrease in the ADCS-ADL score over time, for example, compared to the baseline ADCS-ADL score, corresponds to an exacerbation of functional impairment, i.e., progression of Alzheimer's disease. Conversely, no decrease in the ADCS-ADL score over time (i.e., a stable ADCS-ADL score) or an increase, for example, compared to the baseline ADCS-ADL score, corresponds to stabilization of Alzheimer's disease. In one embodiment, an ADCS-ADL score of 32 or higher, preferably greater than 32, corresponds to a mild Alzheimer's disease. In another embodiment, an ADCS-ADL score of 38 or higher, preferably greater than 38, corresponds to a mild Alzheimer's disease.

[0036] In one embodiment, the severity of Alzheimer's disease is determined using the Mini-Mental State Examination (MMSE). The MMSE is widely used to screen for cognitive impairments associated with Alzheimer's disease, focusing on dementia. The MMSE consists of 11 items that assess orientation, immediate recall, attention and calculation ability, delayed recall, and language ability, with a total score ranging from 0 to 30 (Folstein et al., J Psychiatr Res. 1975 Nov;12(3):189-98). A score of 30 represents the least cognitive impairment, and a score of 0 represents the most severe cognitive impairment. Therefore, a decrease in MMSE score over time, for example, compared to a baseline MMSE score, corresponds to worsening cognitive function, i.e., progression of Alzheimer's disease. Conversely, no decrease in MMSE score over time (i.e., a stable MMSE score) or an increase, for example, compared to a baseline MMSE score, corresponds to stabilization of Alzheimer's disease. In one embodiment, an MMSE score of 26 or higher corresponds to normal cognitive function, an MMSE score in the range of 21 to 25 corresponds to mild cognitive impairment, an MMSE score in the range of 12 to 20 corresponds to moderate cognitive impairment, and an MMSE score of less than 12 corresponds to severe cognitive impairment.

[0037] In one embodiment, an MMSE score of 13 or higher, preferably 14 or higher, corresponds to mild Alzheimer's disease. Therefore, in one embodiment, an MMSE score of 14 or higher excludes moderately severe and severe Alzheimer's disease. In one embodiment, an MMSE score in the range of 12 to 25, preferably 13 to 25, corresponds to mild Alzheimer's disease. In one embodiment, an MMSE score in the range of 21 to 25 corresponds to mildly severe or mild Alzheimer's disease. In one embodiment, an MMSE score in the range of 12 to 20, preferably 13 to 20, corresponds to moderately severe or moderate Alzheimer's disease. In one embodiment, an MMSE score less than 13, preferably less than 12, corresponds to severe Alzheimer's disease.

[0038] In one embodiment, low-severity Alzheimer's disease is defined as a baseline ADAS-Cog score of 40 or less, a baseline ADCS-ADL score of 32 or greater, preferably greater than 32, and / or a baseline MMSE score of 13 or greater. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of low-severity Alzheimer's disease in patients requiring such use, wherein the patient has a baseline ADAS-Cog score of 40 or less, a baseline ADCS-ADL score of 32 or greater, preferably greater than 32, and / or a baseline MMSE score of 13 or greater.

[0039] In one embodiment, low-severity Alzheimer's disease is defined as a baseline ADAS-Cog score of 40 or less and / or a baseline ADCS-ADL score of 32 or greater, preferably greater than 32. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of low-severity Alzheimer's disease in patients requiring such use, wherein the patient has a baseline ADAS-Cog score of 40 or less and / or a baseline ADCS-ADL score of 32 or greater, preferably greater than 32.

[0040] In one embodiment, low-severity Alzheimer's disease is defined as a baseline ADAS-Cog score of 35 or less and / or a baseline ADCS-ADL score of 38 or greater, preferably greater than 38. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of low-severity Alzheimer's disease in patients requiring such use, wherein the patient has a baseline ADAS-Cog score of 35 or less and / or a baseline ADCS-ADL score of 38 or greater, preferably greater than 38.

[0041] According to one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease as defined herein in patients requiring such treatment.

[0042] In one embodiment, the stage of Alzheimer's disease is determined using the MMSE described above.

[0043] In one embodiment, an MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher, preferably 13 or higher, more preferably 14 or higher, corresponds to early Alzheimer's disease. In one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in a patient having a baseline MMSE of 13 or higher, preferably 14 or higher, more preferably 21 or higher.

[0044] According to one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease as defined herein in patients requiring such treatment.

[0045] In one embodiment, the stage of Alzheimer's disease is determined using the ADCS-ADL scale described above, the MMSE described above, and / or the time from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0046] According to one embodiment, the stage of Alzheimer's disease is determined using the ADCS-ADL scale described above. In one embodiment, an ADCS-ADL score of 50 or higher, preferably greater than 50, corresponds to early Alzheimer's disease. In another embodiment, an ADCS-ADL score of 55 or higher, preferably greater than 55, corresponds to early Alzheimer's disease.

[0047] According to one embodiment, the stage of Alzheimer's disease is determined using the above-mentioned MMSE. In one embodiment, an MMSE score of 14 or higher corresponds to early Alzheimer's disease. In another embodiment, an MMSE score in the range of 21 to 25 corresponds to early Alzheimer's disease.

[0048] According to one embodiment, the stage of Alzheimer's disease is determined based on the time from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, a time of 3 years or less from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof corresponds to early Alzheimer's disease. In another embodiment, a time of 2 years or less from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof corresponds to early Alzheimer's disease.

[0049] According to one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, in particular macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients who require such treatment, wherein the patient has the baseline ADCS-ADL score defined above and / or the baseline MMSE score defined above.

[0050] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, and / or a baseline MMSE score of 14 or higher, or in the range of 21-25. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, and / or a baseline MMSE score of 14 or higher, or in the range of 21-25.

[0051] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, and / or a baseline MMSE score of 14 or higher, or in the range of 21-25. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, and / or a baseline MMSE score of 14 or higher, or in the range of 21-25.

[0052] According to one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has the baseline ADCS-ADL score defined above and / or has the time defined above from diagnosis to initiation of treatment with the 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0053] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0054] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0055] According to one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has the baseline MMSE score defined above and / or has the time defined above from diagnosis to initiation of treatment with the 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0056] In one embodiment, early Alzheimer's disease is defined as a baseline MMSE score of 14 or higher, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline MMSE score of 14 or higher, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0057] In one embodiment, early Alzheimer's disease is defined as having a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0058] According to one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has the baseline ADCS-ADL score defined above, the baseline MMSE defined above, and / or the time defined above from diagnosis to initiation of treatment with the 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0059] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score of 14 or higher, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score of 14 or higher, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0060] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score of 14 or higher, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score of 14 or higher, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0061] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0062] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score in the range of 21 to 25, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 50 or higher, preferably greater than 50, a baseline MMSE score in the range of 21 to 25, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0063] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score of 14 or higher, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score of 14 or higher, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0064] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score of 14 or higher, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score of 14 or higher, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0065] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0066] In one embodiment, early Alzheimer's disease is defined as a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score in the range of 21 to 25, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. Therefore, in one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of early Alzheimer's disease in patients requiring such treatment, wherein the patient has a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, a baseline MMSE score in the range of 21 to 25, and / or a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0067] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 or less. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less.

[0068] In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, preferably 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 or higher. Preferably, the patient has a baseline ADCS-ADL score greater than 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In one embodiment, the AD patient treated by the present invention has a baseline ADCS-ADL score of 32, 35, 38, 39, 41, 47, or 55 or higher, preferably 32, 35, 38, 39, 41, 47, or 55 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or higher than 55. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 38 or 50 or higher, or 39 or 55 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 50 or higher, preferably 50 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 55 or higher, preferably 55 or higher.

[0069] In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score of 13 or higher, preferably 14 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score in the range of 12 to 20. In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score in the range of 21 to 25.

[0070] In one embodiment, an AD patient treated according to the present invention has a time interval of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2 years, 1.5, or 1 year or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a time interval of 5, 4, 3, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a time interval of 3 years or less, preferably 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0071] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, and / or a baseline ADCS-ADL score greater than 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, and / or 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, The patient has a baseline ADCS-ADL score of 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or higher, preferably 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or greater than 55. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or greater than 55. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline ADCS-ADL score of 50 or higher, preferably greater than 50. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline ADCS-ADL score of 55 or higher, preferably greater than 55.

[0072] In one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of AD in patients having a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline ADCS-ADL score of 38 or 50 or greater, or 39 or 55 or greater.

[0073] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, and / or a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, and / or a baseline MMSE score of 13, 14, 15, 16, 17, 18, 19, or 20 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline MMSE score of 13 or higher, preferably 14 or higher, or in the range of 21 to 25. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline MMSE score of 14 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or a baseline MMSE score in the range of 21 to 25.

[0074] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, and / or has a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1 year or less between diagnosis and initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, and / or has a time of 5, 4.5, 4, 3.5, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or has a time of 5, 4, 3, or 2 years or less, preferably 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or has a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, and / or has a time of 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0075] In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, preferably 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, and / or has a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or higher, preferably 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or higher, and / or has a baseline MMSE score of 13, 14, 15, 16, or 17 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or higher than 55, and / or a baseline MMSE score of 13 or higher, preferably 14 or higher, or in the range of 21-25.

[0076] In one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of AD in patients having a baseline ADCS-ADL score of 38 or 50 or greater, or 39 or 55 or greater, and / or a baseline MMSE score of 13 or greater, preferably 14 or greater, or in the range of 21 to 25.

[0077] In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score greater than 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70, and / or has a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1 year or less between diagnosis and initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or higher, preferably 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or higher, and / or has a time of 5, 4.5, 4, 3.5, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or 55 or higher, and / or a time of 5, 4, 3, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0078] In one embodiment, the present invention relates to having a baseline ADCS-ADL score of 38 or 50 or greater, or 39 or 55 or greater, and / or a time of 5, 4, 3, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0079] In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher, and / or a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1 year or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score of 13, 14, 15, 16, or 17 or higher, and / or a time of 5, 4.5, 4, 3.5, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline MMSE score of 13 or higher, preferably 14 or higher, or in the range of 21 to 25, and / or a time of 5, 4, 3, or 2 years or less, preferably 3 years or less, more preferably 2 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0080] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, a baseline ADCS-ADL score of 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, preferably 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, and / or a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, and has a baseline ADAS-Cog score of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 , 52, 53, 54, or 55 or higher, preferably 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or higher, and / or have a baseline MMSE score of 13, 14, 15, 16, or 17 or higher. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or lower, a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or 55 or higher, and / or has a baseline MMSE score of 13 or higher, preferably 14 or higher, or in the range of 21-25. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 50 or more, preferably greater than 50, and / or a baseline MMSE score of 14 or more, preferably in the range of 21 to 25.In one embodiment, an AD patient treated by the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 55 or higher, preferably greater than 55, and / or a baseline MMSE score of 14 or higher, preferably in the range of 21 to 25.

[0081] In one embodiment, the present invention relates to 2-aminoarylthiazole derivatives described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of AD in patients having a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, a baseline ADCS-ADL score of 38 or 50 or greater, or greater than 39 or 55, and / or a baseline MMSE score of 13 or greater, preferably 14 or greater, or in the range of 21 to 25.

[0082] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, a baseline ADCS-ADL score of 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, preferably 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, and / or a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1 year or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, and has a baseline ADAS-Cog score of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or more, preferably 30, 31, 3 Having a baseline ADCS-ADL score greater than 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, and / or having a time of 5, 4.5, 4, 3.5, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or 55 or higher, and / or a time of 5, 4, 3, 2.5, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 50 or higher, preferably 50 or higher, and / or a time of 3 years or less, preferably 2 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 55 or greater, preferably greater than 55, and / or a time of 3 years or less, preferably 2 years or less, from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0083] In one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of AD in patients having a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, a baseline ADCS-ADL score of 38 or 50 or greater, or greater than 39 or 55, and / or a time of 5, 4, 3, 2.5, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0084] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or more, and / or a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1 year or less between diagnosis and initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, a baseline MMSE score of 13, 14, 15, 16, or 17 or higher, and / or a time of 5, 4, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, a baseline MMSE score of 13 or greater, preferably 14 or greater, or in the range of 21 to 25, and / or a time of 5, 4, 3, 2.5, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline MMSE score of 14 or greater, and / or a time of 3 years or less, preferably 2 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline MMSE score in the range of 21 to 25, and / or a time of 3 years or less, preferably 2 years or less, from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0085] In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, preferably 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, a baseline MMSE score of 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or higher, and / or a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, or 1 year or less between diagnosis and initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or higher, preferably 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or higher, a baseline MMSE score of 13, 14, 15, 16, or 17 or higher, and / or a time of 5, 4.5, 4, 3.5, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or 55 or higher, an MMSE score of 13 or higher, preferably 14 or higher, or in the range of 21-25, and / or a time of 5, 4, 3, or 2 years or less, preferably 3 years or less, from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0086] In one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of AD in patients having a baseline ADCS-ADL score of 38 or 50 or greater, or 39 or 55 or greater, a baseline MMSE score of 13 or greater, preferably 14, or in the range of 21-25, and / or a time of 5, 4, 3, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0087] In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 or less, and a baseline ADCS-ADL score of 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, preferably 20, 25, 30, 35, 39, 45, 50, 55, 60, 65, or 70 or higher, and 12, 13, 1 Having a baseline MMSE score of 4, 15, 16, 17, 18, 19, 20, or 21 or higher, and / or having a time of 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2 years, 1.5, or 1 year or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 or less, and a baseline ADAS-Cog score of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 or more, preferably 30, 31, 32, 33, 34, 35, 36, 37, 38 Having a baseline ADCS-ADL score greater than 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, and a baseline MMSE score of 13, 14, 15, 16, or 17 or higher, and / or a time of 5, 4.5, 4, 3.5, 3, 2.5, or 2 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, a baseline ADCS-ADL score of 38, 39, 50, or 55 or higher, preferably 38, 39, 50, or 55 or higher, a baseline MMSE score of 13 or higher, preferably 14 or higher, or in the range of 21-25, and / or a time of 5, 4, 3, 2.5, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 50 or more, preferably greater than 50, a baseline MMSE score of 14 or more, preferably in the range of 21 to 25, and / or has a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 55 or more, preferably greater than 55, a baseline MMSE score of 14 or more, preferably in the range of 21 to 25, and / or has a time of 3 years or less from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly macitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 50 or greater, preferably greater than 50, a baseline MMSE score of 14 or greater, preferably in the range of 21 to 25, and / or a time of 2 years or less from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.In one embodiment, an AD patient treated according to the present invention has a baseline ADAS-Cog score of 25 or less, a baseline ADCS-ADL score of 55 or greater, preferably greater than 55, a baseline MMSE score of 14 or greater, preferably in the range of 21 to 25, and / or a time of 2 years or less from diagnosis to the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0088] In one embodiment, the present invention relates to a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of AD in patients having a baseline ADAS-Cog score of 40, 35, 32, or 25 or less, a baseline ADCS-ADL score of 38 or 50 or greater, or greater than 39 or 55, a baseline MMSE score of 13 or greater, preferably 14, or in the range of 21-25, and / or a time of 5, 4, 3, or 2 years or less, preferably 3 years or less, from diagnosis to initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0089] In one embodiment, the patient is 50, 55, 60, 65, 70, 75, 80, or older than 80 years old. In one embodiment, the patient is 50, or older than 50 years old. In one embodiment, the patient is at least 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 years old.

[0090] At an affordable price, the patient is younger than 95 years old, younger than 90 years old, younger than 85 years old, younger than 80 years old, younger than 75 years old, or younger than 70 years old.

[0091] In one embodiment, the patient is male. In another embodiment, the patient is female.

[0092] In one embodiment, the patient presents with at least one risk factor selected from the group including, or comprising, a family history of Alzheimer's disease, Down syndrome, a history of severe head injury, cardiovascular disease, active smoking, obesity, diabetes, hypertension, and high cholesterol.

[0093] As used herein, “risk factors” refers to any pre-existing condition, state, habit, or behavior that may increase the risk of developing Alzheimer’s disease.

[0094] In the present invention, a 2-aminoarylthiazole derivative refers to a compound characterized by the presence of a thiazolyl group in which the nitrogen atom of the amine is substituted with at least one aryl group, and the 2-position (i.e., between the heterocyclic nitrogen and sulfur atoms) is substituted with a secondary or tertiary amine.

[0095] According to one embodiment, the aryl group is substituted with an arylamide group (i.e., -NH-CO-aryl).

[0096] In one embodiment, the 2-aminoarylthiazole derivative of the present invention is of the following formula (I): [ka] (In the formula, - R1 and R2 are independently hydrogen, halogen, (C1~C 10 ) alkyl, (C3~C 10 )Cycloalkyl groups, trifluoromethyl groups, alkoxy groups, cyano groups, dialkylamino groups, solubilizing groups, and C1-C1 groups substituted with solubilizing groups. 10 ) Selected from alkyl groups; - m is between 0 and 5; - n is between 0 and 4; - R3 is one of the following: (i) an aryl group (such as phenyl), optionally substituted by one or more substituents such as halogen, (C1-C 10 ) alkyl, trifluoromethyl, cyano, and alkoxy; (ii) a heteroaryl group (such as 2-, 3-, or 4-pyridyl), optionally substituted by one or more substituents such as halogen, (C1-C 10 ) alkyl group, trifluoromethyl, and alkoxy; (iii) a 5-membered aromatic heterocyclic group (such as 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl), optionally substituted by one or more substituents such as halogen, (C1-C 10 ) alkyl group, trifluoromethyl, and alkoxy.

[0097] Thus, in one embodiment, the 2-aminoarylthiazole derivative of the present invention, or a pharmaceutical or solvate thereof, is a 2-aminoarylthiazole derivative represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0098] In one embodiment, the 2-aminoarylthiazole derivative of the present invention has the following formula (II):

Chemical formula

[0099] In one embodiment, R1 in formula (II) is a solubilizing group. In one embodiment, R1 in formula (II) is substituted with a solubilizing group (C1~C 10 It is alkyl.

[0100] In one embodiment, R1 in formula (II) is (C1~C 10 )Alkyl-(C2~C 11 ) Heterocycloalkyl-(C1~C 10 )alkyl-. In one embodiment, R1 in formula (II) is (C1~C4)alkyl-(C2~C 11 ) Heterocycloalkyl-(C1~C 10 )alkyl-, preferably (C1~C2)alkyl-(C2~C 11 ) Heterocycloalkyl-(C1~C 10 )alkyl-. In one embodiment, R1 of formula (II) is (C1~C 10 )Alkyl-(C2~C 11 ) Heterocycloalkyl-(C1~C4)alkyl-, preferably (C1~C 10 )Alkyl-(C2~C 11 )heterocycloalkyl-(C1~C2)alkyl-. In one embodiment, R1 in formula (II) is (C1~C 10 )alkyl-(C2~C6)heterocycloalkyl-(C1~C 10 )alkyl-, preferably (C1~C 10 )alkyl-(C4)heterocycloalkyl-(C1~C 10)alkyl-. In one embodiment, R1 of formula (II) is (C1~C4)alkyl-(C2~C6)heterocycloalkyl-(C1~C4)alkyl-, preferably (C1~C2)alkyl-(C4)heterocycloalkyl-(C1~C2)alkyl-. In one embodiment, R1 of formula (II) is (C1~C4)alkyl-piperazinyl-(C1~C4)alkyl-, preferably (C1~C2)alkyl-piperazinyl-(C1~C2)alkyl-. In one embodiment, R1 of formula (II) is methylpiperazinyl-(C1~C2)alkyl-, preferably methylpiperazinyl-methyl-, more preferably 4-methylpiperazinyl-methyl.

[0101] Therefore, in one embodiment, the 2-aminoarylthiazole derivative of the present invention or a pharmaceutically acceptable salt or solvate thereof is the 2-aminoarylthiazole derivative represented by formula (II) above or a pharmaceutically acceptable salt or solvate thereof.

[0102] As used herein, the term “aryl group” refers to a polyunsaturated aromatic hydrocarbyl group having a single aromatic ring (i.e., phenyl) or multiple aromatic rings condensed with each other (e.g., naphthyl) or covalently linked, typically containing 5 to 12, preferably 6 to 10, atoms, with at least one ring being aromatic. The aromatic ring may optionally include one or more additional condensed rings (any of which are cycloalkyl, heterocyclyl, or heteroaryl). Aryl also encompasses the partially hydrogenated derivatives of the carbocyclic systems listed herein. Suitable examples of aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azlenyl, and naphthyl, as well as benzo-condensed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. The aryl group may be unsubstituted or substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring containing six carbon atoms and is referred to herein as “(C6)aryl.”

[0103] As used herein, the term "alkyl group" refers to a saturated linear or branched acyclic hydrocarbon having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative saturated linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Examples of saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, and 3,3-dimethylpentyl. Examples include, but are not limited to, ethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. The alkyl groups contained in the compounds of the present invention may optionally be substituted with one or more substituents.

[0104] As used herein, the term "alkoxy" refers to an alkyl group bonded to another part by an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, isopropoxy, ethoxy, and tert-butoxy. The alkoxy group may optionally be substituted with one or more substituents.

[0105] As used herein, the term "cycloalkyl" refers to a saturated cyclic alkyl radical having 3 to 10 carbon atoms. Typical cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyls may optionally be substituted with one or more substituents.

[0106] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0107] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic ring comprising a carbon atom ring member and one or more heteroatom ring members (e.g., oxygen, sulfur, or nitrogen). Typically, a heteroaryl group has 1 to about 5 heteroatom ring members and 1 to about 14 carbon atom ring members. Representative heteroaryl groups include pyridyl, 1-oxopyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxynyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, and ben Examples include, but are not limited to, zofuryl, indolidinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, prinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzo(b)thienyl. Heteroatoms may be substituted with protecting groups known to those skilled in the art, for example, the hydrogen on the nitrogen may be substituted with a tert-butoxycarbonyl group. Heteroaryl groups may optionally be substituted with one or more substituents. In addition, nitrogen or sulfur heteroatom ring members may be oxygenated. In one embodiment, the heteroaromatic ring is selected from 5- to 8-membered monocyclic heteroaryl rings. The attachment site of a heteroaromatic ring or heteroaryl ring to another group may be on either a carbon atom or a heteroatom of the heteroaromatic ring or heteroaryl ring.

[0108] As used herein, the term "heterocyclic ring" collectively refers to heterocycloalkyl groups and heteroaryl groups.

[0109] As used herein, the term "heteroalcroalkyl" refers to a monocyclic or polycyclic group having at least one heteroatom selected from O, N, or S, having 2 to 11 carbon atoms, and which may be saturated or unsaturated but not aromatic. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopyrrolidinyl, 4-piperidonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxylanil, oxetanyl, tetrahydropyranil, tetrahydrothiopyranil, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiopyranylsulfone, tetrahydrothiopyranylsulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, 1,3-dioxolane, tetrahydrofuranil, dihydrofuranil-2-one, tetrahydrothienyl, and tetrahydro-1,1-dioxothienyl. Typically, monocyclic heterocycloalkyl groups have 3 to 7 members. Preferred 3- to 7-membered monocyclic heterocycloalkyl groups are those having 5 or 6 ring atoms. The heteroatoms may be substituted with protecting groups known to those skilled in the art, for example, the hydrogen atom on the nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocycloalkyl group may optionally be substituted with one or more substituents. In addition, the bonding site of the heterocycle to another group may be on either the carbon atom of the heterocycle or the heteroatom. Only stable isomers of such substituted aromatic groups are intended in this definition.

[0110] As used herein, the terms “substituent” or “substituted” mean that the hydrogen radical of a compound or group is replaced with any desired group that is substantially stable under reaction conditions, either in an unprotected form or protected by a protecting group. Examples of preferred substituents include halogens (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amide; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be monocyclic or condensed or uncondensed polycyclic; or heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiadinyl). Examples include, but are not limited to, monocyclic, condensed, or uncondensed polycyclic aryl or heteroaryl groups (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); aminos (primary, secondary, or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3, and such groups may also be optionally substituted with condensed ring structures or bridges, e.g., -CH2O-. These substituents may further optionally be substituted with substituents selected from such groups. In certain embodiments, the term "substituent" or the adjective "substituted" means alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C(O)NR 11 R 12 , -NR 13 C(O)R 14Hello, -OR 13 cyano, nitro, haloalkoxy, -C(O)R 13 , -NR 11 R 12 , -SR 13 , -C(O)OR 13 ,-OC(O)R 13 , -NR 13 C(O)NR 11 R 12 -OC(O)NR 11 R 12 , -NR 13 C(O)OR 14 ,-S(O)rR 13 , -NR 13 S(O)rR 14 -OS(O)rR 14 , S(O)rNR 11 R 12 -O, -S, and -NR 13 R refers to a substituent selected from the group consisting of , where r is 1 or 2; 11 and R 12 Independently with respect to each presence, is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R 11 and R 12 However, together with the attached nitrogen, it is optionally a substituted heterocycloalkyl or optionally a substituted heteroaryl; R 13 and R 14Independently with respect to each presence, these are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain embodiments, the term “substituted” or the adjective “substituted” refers to the solubilizing group.

[0111] As used herein, the term “solubilizing group” refers to any group that can be substantially ionized and enable a compound to dissolve in a desired solvent, such as water or a water-containing solvent (“water-solubilizing group”). Furthermore, the solubilizing group may increase the lipophilicity of the compound or complex. In one embodiment, the solubilizing group is selected from alkyl groups substituted with one or more heteroatoms such as N, O, and S, each independently substituted with an alkyl group, carboxyl, cyano, or cycloheteroalkyl or heteroaryl, or from phosphates, sulfates, or carboxylic acids. In one embodiment, the solubilizing group is one of the following: - Alkyl, cycloalkyl, aryl, and heteroaryl groups (including, but not limited to, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, hydantoinyl, valerolactamyl, oxyranil, oxetanil, tetrahydropyranil, morpholinil, 1,3-dioxolane, tetrahydrofuranil, and dihydrofuranil-2-one) comprising at least one nitrogen or oxygen heteroatom and / or substituted with at least one amino or oxo group; - Amino groups that may be saturated cyclic amino groups that can be substituted with groups consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl (non-limited to groups including methyl-piperidinyl, methyl-piperazinyl and methyl-pyrrolidinyl); - One of the structures a) to i) shown below (where the dashed and arrowed lines correspond to the bonding points with the core structure of the 2-aminoarylthiazole derivative of the present invention, e.g., formula (I) or (II)). [ka]

[0112] In one embodiment, the solubilizing group is one of the following: - Alkyl, cycloalkyl, aryl, and heteroaryl groups comprising at least one nitrogen or oxygen heteroatom and substituted with at least one amino or oxo group; - Amino groups that may be saturated cyclic amino groups that can be substituted with groups consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl, and dialkylcarbamoyl; - One of the structures a) to i) shown above (where the dashed and arrowed lines correspond to the bonding points with the core structure of the 2-aminoarylthiazole derivative of the present invention, e.g., formula (I) or (II)).

[0113] In one embodiment, the solubilizing group is a saturated cyclic amino group (including, but not limited to, piperidinyl, piperazinyl, and pyrrolidinyl) that can be substituted with groups consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl, and dialkylcarbamoyl (including, but not limited to, methyl-piperidinyl, methyl-piperazinyl, and methyl-pyrrolidinyl).

[0114] In one embodiment, the solubilizing group is structure c) shown above, where the dashed line corresponds to a bond point with the core structure of the 2-aminoarylthiazole derivative of the present invention, for example, formula (I) or (II).

[0115] As used herein, “pharmaceutically acceptable salt” refers to a salt of a free acid or free base that is not biologically undesirable and is generally prepared by reacting a free base with a suitable organic or inorganic acid, or an organic acid with a suitable organic or inorganic base. A suitable acid addition salt is formed from an acid that forms a non-toxic salt. Examples include acetate, adipine, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethion. Examples include acid salts, lactic acid, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, hydrogen phosphate, dihydrogen phosphate, phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include salts of aluminum, arginine, benzathine, calcium, chlorine, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine, and zinc. Hemi salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

[0116] In one embodiment, a pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt with an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or with a suitable organic carboxylic acid or sulfonic acid, such as aliphatic mono or dicarboxylic acid such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, or oxalic acid, or an amino acid such as arginine or lysine, an aromatic carboxylic acid such as benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, salicylic acid, or 4-aminosalicylic acid, an aromatic-aliphatic carboxylic acid such as mandelic acid or cinnamic acid, a heteroaromatic carboxylic acid such as nicotinic acid or isethionic acid, an aliphatic sulfonic acid such as methane-, ethane-, or 2-hydroxyethane-sulfonic acid, particularly methanesulfonic acid, or an aromatic sulfonic acid such as benzene-, p-toluene-, or naphthalene-2-sulfonic acid.

[0117] In one embodiment, the pharmaceutically acceptable salt of the 2-aminoarylthiazole derivative of the present invention is a mesylate.

[0118] Unless otherwise indicated, the term “mesylate” is used herein to refer to a salt of methanesulfonic acid with any of the named pharmaceutical substances (such as the 2-aminoarylthiazole derivative represented by formula (I) or (II)). The use of “mesilate” rather than “mesylate” is in compliance with the INNM (International Nonproprietary Names Modified) discussed by the WHO (e.g., World Health Organization (February 2006). International Nonproprietary Names Modified. INN Working Document 05.167 / 3. WHO).

[0119] As used herein, “pharmaceutically acceptable solvate” refers to a molecular complex comprising the above-mentioned 2-aminoarylthiazole derivative and one or more pharmaceutically acceptable solvent molecules, such as ethanol, in stoichiometric or substoichiometric amounts. The term “hydrate” refers to the case where the solvent is hydrogen.

[0120] In one particular embodiment, the above-mentioned 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof is masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0121] The chemical name of masitinib is 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-ylthiazole-2-ylamino)phenyl]benzamide - CAS number 790299-79-5: [ka] That is the case.

[0122] Macitinib was initially described in U.S. Patent No. 7,423,055 and European Patent No. 1,525,200.

[0123] In one embodiment, the 2-aminoarylthiazole derivative of the present invention or a pharmaceutically acceptable salt or solvate thereof is macitinib mesylate. Therefore, in one embodiment, the pharmaceutically acceptable salt of the above macitinib is macitinib mesylate. As stated above, in other words, the pharmaceutically acceptable salt of macitinib is the methanesulfonate of macitinib.

[0124] Detailed procedures for the synthesis of masitinib mesylate are given in WO2008 / 098949.

[0125] In one embodiment, "masitinib mesylate" is the orally bioavailable mesylate of masitinib - CAS 1048007-93-7(MsOH);C 28 H 30N6OS.CH3SO3H;MW594.76: [ka] It refers to.

[0126] According to one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in a therapeutically effective dose.

[0127] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in doses ranging from about 1 to about 12 mg / kg / day (mg per kilogram of body weight per day). In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in doses ranging from about 1.5 to about 7.5 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in doses ranging from about 3 to about 12 mg / kg / day, preferably about 3 to about 6 mg / kg / day.

[0128] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in doses within the range of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in doses within the range of about 1.5, 3, 4.5, 6, 7.5, 9, 10.5, or 12 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in doses within the range of about 3, 4.5, or 6 mg / kg / day.

[0129] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, may be administered in doses escalated in increments of about 1.5 mg / kg / day until a maximum dose of about 7.5 mg / kg / day, more preferably about 4.5 mg / kg / day, or about 6 mg / kg / day. Each dose escalation is subjected to toxicity control in the absence of any toxic events that would enable the dose escalation.

[0130] In one embodiment, dose escalation of a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is performed at any point at least 4 weeks after the initial dose and up to 26 weeks after the initial dose, for example, at weeks 4, 8, 12, 16, 20, or 24, preferably at week 12 after the initial dose. Each dose escalation is subjected to toxicity management, including, for example, a previous treatment period at a constant dose, no suspected severe adverse events have been reported, no suspected adverse events have resulted in treatment interruption, and suspected adverse events, regardless of their severity, have not progressed at the time of dose increase.

[0131] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of approximately 3 mg / kg / day for 6 weeks, and thereafter at a dose of approximately 4.5 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of approximately 4.5 mg / kg / day for 6 weeks, and thereafter at a dose of approximately 6 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of approximately 3 mg / kg / day for 12 weeks, and thereafter at a dose of approximately 4.5 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of approximately 4.5 mg / kg / day for 12 weeks, and thereafter at a dose of approximately 6 mg / kg / day. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of approximately 3 mg / kg / day for at least 4 weeks, followed by a dose of approximately 4.5 mg / kg / day for at least 4 weeks, and thereafter at a dose of approximately 6 mg / kg / day, with each dose increase being used for toxicity management.

[0132] According to one embodiment, any doses expressed herein refer to the amount of the active ingredient and not to the amount of a pharmaceutically acceptable salt or solvent form. Therefore, compositional variations of the pharmaceutically acceptable salts or solvates of the above-mentioned 2-aminoarylthiazole derivatives, particularly masitinib, will not affect the dose administered.

[0133] According to one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is adapted for administration in the above-mentioned dose.

[0134] According to one embodiment, the above-mentioned 2-aminoarylthiazole derivative, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof may be administered orally, intravenously, parenterally, topically, by inhalation, particularly by inhalation spray, rectally, nasally, or orally. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for oral administration.

[0135] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is intended for administration at least once daily, preferably twice daily. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is intended for long-term administration, such as for at least one month, two months, three months, six months, nine months, or twelve months.

[0136] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is adapted for oral administration or is in a form adapted for oral administration. Examples of forms adapted for oral administration include, but are not limited to, liquids, pastes, or solid compositions, and more specifically, tablets, pills, capsules, liquids, gels, syrups, slurries, and suspensions.

[0137] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered as a tablet, preferably a 100 mg or 200 mg tablet.

[0138] According to one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered together with at least one further pharmaceutically active agent.

[0139] According to the present invention, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, may be administered separately or sequentially with, or simultaneously with, the at least one further pharmaceutically active agent. In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with the at least one further pharmaceutically active agent, preferably as a compound preparation, pharmaceutical composition, or drug.

[0140] Further examples of pharmaceutically active agents that may be administered to patients with Alzheimer's disease as described herein include, but are not limited to, clonesterase inhibitors (also known as acetylcholinesterase inhibitors or Ache inhibitors) such as donepezil, rivastigmine, and galantamine, as well as memantine.

[0141] In one embodiment, at least one further pharmaceutically active agent is selected from the group comprising donepezil, rivastigmine, galantamine, and memantine, or from the group comprising these.

[0142] In one embodiment, at least one further pharmaceutically active agent is a cholinesterase inhibitor. In one embodiment, at least one further pharmaceutically active agent is selected from the group comprising donepezil, rivastigmine, and galantamine, or the group comprising them.

[0143] In one embodiment, at least one further pharmaceutically active agent is memantine.

[0144] In one embodiment, the above-mentioned 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a cholinesterase inhibitor (particularly donepezil, rivastigmine, or galantamine) and / or memantine.

[0145] Another object of the present invention is a method for treating Alzheimer's disease in a patient requiring the treatment as defined above, the method comprising administering to the patient a 2-aminoarylthiazole derivative, in particular masitinib, or a pharmaceutically acceptable salt or solvate thereof, as described above.

[0146] In one embodiment, the present invention relates to a method for treating Alzheimer's disease of low severity and / or early stage, as defined above, in patients who require it, particularly in patients who require it as defined above, the method comprising administering to the patient a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as defined above.

[0147] In one embodiment, the present invention relates to a method for treating early Alzheimer's disease as defined above in patients who require it, particularly in patients who require it as defined above, the method comprising administering to the patient one of the 2-aminoarylthiazole derivatives, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0148] In one embodiment, the present invention relates to a method for treating Alzheimer's disease in a patient in need thereof, the patient having a baseline ADAS-Cog score of 40 or less, a baseline ADCS-ADL score of 32 or greater, preferably greater than 32, a baseline MMSE score of 13 or greater, and / or a time of 5 years or less from diagnosis to initiation of treatment with masitinib or a pharmaceutically acceptable salt or solvate thereof, the method comprising administering to the patient a 2-aminoarylthiazole derivative, in particular masitinib or a pharmaceutically acceptable salt or solvate thereof, as described above.

[0149] In one embodiment, the above method includes administering at least one further pharmaceutically active agent as described above.

[0150] Another object of the present invention is a pharmaceutical composition for use in the treatment of Alzheimer's disease in patients as defined above, the pharmaceutical composition comprising the above-mentioned 2-aminoarylthiazole derivative, in particular macitinib, or a pharmaceutically acceptable salt or solvate thereof, and optionally at least one pharmaceutically acceptable excipient.

[0151] Another object of the present invention is a pharmaceutical composition for the treatment of Alzheimer's disease in patients as defined above, the pharmaceutical composition comprising the above-mentioned 2-aminoarylthiazole derivative, in particular macitinib, or a pharmaceutically acceptable salt or solvate thereof, and optionally at least one pharmaceutically acceptable excipient.

[0152] In one embodiment, the pharmaceutical composition of the present invention is for use in the treatment of low-severity Alzheimer's disease and / or early Alzheimer's disease as defined above. In one embodiment, the pharmaceutical composition of the present invention is for use in the treatment of early Alzheimer's dementia as defined above.

[0153] In one embodiment, the pharmaceutical composition of the present invention is intended for use in combination with at least one further pharmaceutically active agent as described above.

[0154] Another object of the present invention is the use of the above-mentioned 2-aminoarylthiazole derivatives, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of agents for the treatment of Alzheimer's disease in patients who require it as defined above.

[0155] In one embodiment, the drug is for the treatment of low-severity Alzheimer's disease and / or early Alzheimer's disease as defined above. In one embodiment, the drug is for the treatment of early Alzheimer's dementia as defined above.

[0156] In one embodiment, this is for use in combination with at least one further pharmaceutically active agent as described above.

[0157] Examples The present invention is further illustrated by the following embodiments. Example 1: Plan for Test AB09004

[0158] An international, multicenter, randomized, double-blind, placebo-controlled phase 3 trial was conducted to evaluate oral masitinib at a dose of 4.5 mg / kg / day as a treatment for Alzheimer's disease.

[0159] Eligible patients were at least 50 years of age and diagnosed with Alzheimer's disease-type dementia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, and with a probable Alzheimer's disease according to the NINCDS-ADRDA (National Institute of Neurological Disorders and Stroke – Alzheimer's Disease and Related Disorders) criteria. Patients had a baseline Mini-Mental State Examination (MMSE) score between 12 and 25. Patients with any other cause of dementia unrelated to Alzheimer's disease were ineligible for this study.

[0160] Eligible patients were treated with either masitinib at a dose of 4.5 mg / kg / day (mg per kilogram of body weight per day) or placebo for 24 weeks. Treatment was administered as an add-on therapy in patients who had been treated with a stable dose of a cholinesterase inhibitor (donepezil, rivastigmine, or grantamine) and / or memantine for at least 6 months and for whom no changes were expected during treatment throughout the study.

[0161] The primary analysis is, - Change from baseline in the Activities of Daily Living (ADCS-ADL) score in the Alzheimer's Disease Collaborative Study. ADCS-ADL assesses the ability of patients with Alzheimer's disease to perform basic and instrumental activities of daily living (ADL). - Change from baseline in the Alzheimer's Disease Assessment Scale - Cognitive Subscales (ADAS-Cog). The ADAS-Cog assesses cognition and memory. Based on the co-primary endpoint.

[0162] The treatment effect must be confirmed by at least one of these endpoints, and both endpoints are tested simultaneously at a significance level of 2.5% (p<0.025) using a fallback method.

[0163] Treatment efficacy (masitinib vs. placebo) was assessed based on absolute change from baseline to week 24 using a covariance model (ANCOVA linear model) analysis with the following factors: treatment, baseline values, and stratified criteria for baseline MMSE score, age, ADCS-ADL total score, and ADAS-Cog total score.

[0164] In the ADCS-ADL scale, the overall score (i.e., the sum of 23 items assessed by the nurse) is used on a scale of 0 to 78, where 78 means fully functional and free from impairment. Therefore, a higher score indicates greater functional capacity, while a lower score indicates greater impairment (worsening). The results are expressed as the least squares mean difference of the absolute change in the ADCS-ADL score from baseline, i.e., the change in the ADCS-ADL score over time, or in other words, the difference (δLSM) between the baseline (before treatment) ADCS-ADL score and the ADCS-ADL score after treatment with masitinib or placebo. An increase in the ADCS-ADL score relative to baseline (i.e., a positive δLSM) indicates improvement in the patient, i.e., disease stability, while a decrease in the ADCS-ADL score relative to baseline (i.e., a negative δLSM) indicates worsening in the patient, i.e., disease progression. The treatment effect is reported as the difference between treatment arms (ΔLSM) (calculated as δLSM [masitinib] - δLSM [placebo]), with a positive value indicating a beneficial effect of masitinib treatment compared to placebo treatment. In scenarios where both treatment arms show worsening of activities of daily living (i.e., negative δLSM), a positive ΔLSM in that case indicates a beneficial treatment effect of masitinib, i.e., the rate of deterioration in patients treated with masitinib is slower than that in patients in the placebo arm.

[0165] The ADAS-Cog version used in trial AB09004 included 11 reclassified items as follows: Language (items 1, 2, 3), Behavior and Cognition (items 5, 7, 8, 9), Memory (items 4, 10, 11), and Orientation (item 6). Items ranged from 0 to 5 (items 1, 2, 3, 5, 7, 8, 9, 11), 0 to 8 (item 6), 0 to 10 (item 4), or 0 to 12 (item 10). The overall score, the sum of the 11 items, ranged from 0 to 70, with the highest score indicating greater cognitive impairment. Results were expressed as the least squares mean difference of the absolute change in ADAS-Cog score from baseline, i.e., the change in ADAS-Cog score over time, or in other words, the difference (δLSM) between the baseline ADAS-Cog score and the ADAS-Cog score after treatment with masitinib or placebo. A decrease in ADAS-Cog score relative to baseline (i.e., a negative δLSM) indicates improvement in the patient, i.e., disease stability, while an increase in ADAS-Cog score relative to baseline (i.e., a positive δLSM) indicates exacerbation in the patient, i.e., disease progression. The treatment effect is reported as the difference between treatment arms (ΔLSM) (calculated as δLSM[masitinib]-δLSM[placebo]), where a negative value indicates a beneficial effect of masitinib treatment compared to placebo. In scenarios where both treatment arms show cognitive exacerbation (i.e., a positive δLSM), a negative ΔLSM in that case indicates a beneficial treatment effect of masitinib, i.e., the rate of deterioration in patients treated with masitinib is slower than that in patients in the placebo arm.

[0166] Example 2: Subgroup analysis using clinical markers: "time from diagnosis to initiation of treatment," "baseline ADAS-Cog score," "baseline ADCS-ADL score," and "baseline MMSE score." method Alzheimer's disease can be described as a biologically continuous disease progression (continuum) involving characteristic pathological processes such as amyloid-beta metabolic deficiency, amyloid deposition, and neurofibrillary tangles, along with neurodegeneration. While we do not wish to be bound by any particular theory, we suggest that the effects of masitinib treatment correlate with the pathophysiological effects of dynamic processes within the central nervous system (CNS), such as innate immunity-related inflammation, which have differential effects along the disease pathway, through the targeting mechanism of the drug. In other words, it may be possible to inhibit nerve damage and promote CNS repair pathways by targeting phases of Alzheimer's disease that are sensitive to treatment, for example, through the modulation or priming of macrophages / macroglia and mast cells. Strictly speaking, how such differential CNS innate immunity-related processes contribute to the chronological progression of Alzheimer's disease remains unknown.

[0167] Because there are no established prognostic or predictive biomarkers to identify which Alzheimer's disease patients are most likely to benefit from masitinib treatment, readily available clinical markers should be used. Time since diagnosis (at baseline or at treatment initiation); Alzheimer's Disease Rating Scale-Cognitive Subscale (ADAS-Cog) score at a given threshold (at baseline or at treatment initiation); Alzheimer's Disease Collaborative Activities of Daily Living (ADCS-ADL) score at a given threshold (at baseline or at treatment initiation); and / or Mini-Mental State Examination (MMSE) score within a given range (at baseline or at treatment initiation) have potential predictive value in identifying patients most likely to benefit from masitinib treatment and indicating whether treatment may be beneficial at an earlier stage of the neurodegenerative disease process (i.e., patients before advanced nerve damage) or at a later stage of the neurodegenerative disease (i.e., patients with pre-existing advanced nerve damage).

[0168] The "time since diagnosis" for Alzheimer's disease is ideally based on the clinically definitive diagnosis of Alzheimer's disease determined by an Alzheimer's specialist neurologist. In practice, it is derived from the date of the first clinically definitive diagnosis of Alzheimer's disease, i.e., the date (year / month / day, year / month, or year) according to the DSM-IV and NINCDS-ADRDA criteria, along with the period calculated from the start of treatment.

[0169] Subgroup analysis of coprimary endpoint data from trial AB09004 assessed the impact of the clinical markers listed above.

[0170] The results, surprisingly, showed that only those patients treated in the early stages of the neurodegenerative disease process and / or before the onset of a certain threshold of functional impairment were more likely to benefit from masitinib treatment. Patients in more advanced phases of Alzheimer's disease development did not show a discernible response to masitinib compared to placebo. For this reason, the aforementioned clinical markers can be used as predictive indicators of a possible response to masitinib and thus can be used as a tool for selecting patients with Alzheimer's disease who are most likely to benefit from masitinib treatment, e.g., those with an ADAS-Cog score of 40 or less, an ADCS-ADL score of 32 or greater, an MMSE score of 13 or greater, preferably 14 or greater, and / or a time of 5 years or less, preferably 3 years or less, between diagnosis and initiation of masitinib treatment.

[0171] result More specifically, the aforementioned clinical data demonstrate that orally administered masitinib (4.5 mg / kg / day) provides greater therapeutic benefits to distinct subgroups of the Alzheimer's disease population (see Tables 1-6 below). This enhanced treatment effect, measured by changes in either the ADAS-Cog score or the ADCS-ADL score, is identified in subgroups defined by time since diagnosis, level of cognitive impairment, or level of impairment in daily living.

[0172] Because there are no established prognostic or predictive biomarkers to identify which Alzheimer's disease patients are most likely to benefit from masitinib treatment, readily available clinical markers are needed. The marker “time from diagnosis” (at baseline or at treatment initiation) has potential predictive value in indicating whether treatment at a specific point in the successive progression of Alzheimer's disease (i.e., early or late in the disease process) is beneficial. The results demonstrated that a subgroup of Alzheimer's disease patients, defined as having a time from diagnosis to treatment initiation with cutoffs of 5 years, 4 years, 3 years, or 2 years or less, showed a statistically significant difference (p<0.025) in ADAS-Cog change from baseline after masitinib treatment compared to placebo. This treatment effect was not evident in the relevant complementary subgroup (i.e., time from diagnosis to treatment initiation longer than 5 years, 4 years, 3 years, or 2 years).

[0173] For example, a subgroup of Alzheimer's disease patients, defined as those with a "time from diagnosis to treatment initiation of 3 years or less," demonstrated a statistically significant difference (p<0.025) in the change from baseline to ADAS-Cog after masitinib treatment compared to placebo. The difference between treatment arms (ΔLSM) was -2.8700 points, favorable to masitinib (p=0.00004) (see Table 1 below). In contrast, a complementary subgroup, defined as those with a "time from diagnosis to treatment initiation of 3 years or more," did not show a significant effect of masitinib treatment compared to placebo (ΔLSM of -0.3770 points, p=-0.74309).

[0174] For example, a subgroup of Alzheimer's disease patients, defined as those with a "time from diagnosis to treatment initiation of 2 years or less," demonstrated a statistically significant difference (p<0.025) in ADAS-Cog changes after masitinib treatment compared to placebo. The difference between treatment arms (ΔLSM) was -2.7754 points, favorable to masitinib (p=0.00009) (see Table 1 below). In contrast, a complementary subgroup, defined as those with a "time from diagnosis to treatment initiation of 2 years or more," did not show a significant effect of masitinib treatment compared to placebo (ΔLSM of -1.3581 points, p=0.112). [Table 1]

[0175] The baseline MMSE (or MMSE before or at the start of treatment) variable has potential predictive value in indicating whether treatment at a specific point in the continuous progression of Alzheimer's disease is beneficial. The results demonstrated that a subgroup of Alzheimer's disease, defined as having a baseline MMSE cutoff of 13, 14, 15, 16, or 17 or higher, showed a statistically significant difference (p<0.025) in ADAS-Cog change from baseline or ADCS-ADL change from baseline after masitinib treatment compared to placebo. This treatment effect was not evident in the relevant complementary subgroup (i.e., baseline MMSE less than 13, 14, 15, 16, or 17).

[0176] For example, a subgroup of Alzheimer's disease patients, defined as those with a baseline MMSE score of 14 or higher before treatment initiation, showed a significant masitinib effect compared to placebo in terms of changes in ADCS-ADL from baseline (ΔLSM=+2.4046, p=0.00875) and ADAS-Cog from baseline (ΔLSM=-2.4192, p=0.00012) (see Table 2 below). In contrast, a complementary subgroup, defined as those with a baseline MMSE score of less than 14 before treatment initiation, did not show a significant masitinib effect compared to placebo in terms of changes in ADCS-ADL from baseline (ΔLSM=-3.5751, p=0.26527) or ADAS-Cog from baseline (ΔLSM=1.0497, p=0.56013). [Table 2]

[0177] A subgroup of Alzheimer's disease patients, defined by a baseline MMSE score between 25 and 21 points prior to treatment initiation, showed a significant masitinib effect compared to placebo in terms of changes in ADCS-ADL from baseline (ΔLSM = +2.7435, p = 0.024) and ADAS-Cog from baseline (ΔLSM = -2.8929, p = 0.0008) (see Table 3 below). In contrast, a complementary subgroup, defined as having a baseline MMSE score between 20 and 12 points prior to treatment initiation, did not show a significant masitinib effect compared to placebo in terms of changes in ADCS-ADL from baseline (ΔLSM of +1.3770 points, p = 0.245) or ADAS-Cog from baseline (ΔLSM = -1.7387, p = 0.0284). This corresponds to an improved benefit of 99% to 66% in the subgroup with a baseline MMSE score between 25 and 21 points before treatment compared to the subgroup with a baseline MMSE score between 20 and 12 points before treatment. [Table 3]

[0178] The variable baseline ADAS-Cog score (or ADAS-Cog score before or at the start of treatment) has potential predictive value in indicating whether treatment at a specific point in the successive progression of Alzheimer's disease is beneficial. The results demonstrated that a subgroup of Alzheimer's disease, defined as having baseline ADAS-Cog scores with cutoffs of 25, 32, 35, or 40 or less, had a statistically significant difference (p<0.025) in the change from baseline ADAS-Cog or the change from baseline ADCS-ADL after masitinib treatment compared to placebo. This treatment effect was not evident in the relevant complementary subgroup (i.e., baseline ADAS-Cog scores greater than 25, 32, 35, or 40).

[0179] For example, a subgroup of Alzheimer's disease patients defined as having an ADAS-Cog score of 25 points or less before treatment showed a trend toward a masitinib effect compared to placebo in terms of ADCS-ADL change from baseline (ΔLSM = +2.3646, p = 0.0262) (see Table 4 below). In contrast, a complementary subgroup defined as having an ADAS-Cog score greater than 25 points before treatment did not show a significant masitinib effect compared to placebo (ΔLSM of +1.2592 points, p = 0.367). This corresponds to an 84% improvement in the subgroup with an ADAS-Cog score of 25 points or less before treatment compared to the subgroup with an ADAS-Cog score greater than 25 points before treatment.

[0180] For example, a subgroup of Alzheimer's disease patients, defined as those with an ADAS-Cog score of 35 points or less before treatment initiation, showed a significant masitinib treatment effect compared to placebo in terms of ADCS-ADL change from baseline (ΔLSM = +2.2189, p = 0.0216) (see Table 4 below). In contrast, a complementary subgroup, defined as those with an ADAS-Cog score greater than 35 points before treatment initiation, did not show a discriminable treatment effect compared to placebo (ΔLSM of -0.788 points, p = 0.7203). [Table 4]

[0181] For example, a subgroup of Alzheimer's disease patients, defined as having an ADAS-Cog score of 40 points or less before treatment initiation, showed a trend toward a masitinib treatment effect compared to placebo in terms of the change in ADAS-Cog from baseline (ΔLSM = -2.3299, p = 0.00020) (see Table 5 below). In contrast, a complementary subgroup, defined as having an ADAS-Cog score greater than 40 points before treatment initiation, did not show a significant treatment effect compared to placebo (ΔLSM of -0.2351 points, p = 0.91116). [Table 5]

[0182] The variable baseline ADCS-ADL score (or ADCS-ADL score before or at the start of treatment) has potential predictive value in indicating whether treatment at a specific point in the Alzheimer's disease continuum is beneficial. The results showed that a subgroup of Alzheimer's disease patients, defined as having a baseline ADCS-ADL score above the cutoffs of 32, 35, 38, 41, 47, or 50, or above the cutoffs of 39 and 55, demonstrated a statistically significant difference S (p<0.0225) or trend of difference in ADCS-ADL from baseline after masitinib treatment compared to placebo. This treatment effect was not evident in the relevant complementary subgroups.

[0183] For example, a subgroup of Alzheimer's disease patients, defined as those with an ADCS-ADL score greater than 39 points prior to treatment, showed a trend toward a masitinib effect compared to placebo in terms of ADCS-ADL change from baseline (ΔLSM = +2.0733, p = 0.0433) (see Table 6 below). In contrast, a complementary subgroup, defined as those with an ADCS-ADL score of 39 points or less prior to treatment, did not show a significant masitinib effect compared to placebo (ΔLSM of +0.7132 points, p = 0.686). This corresponds to a 191% improvement in the subgroup with an ADCS-ADL score greater than 39 points prior to treatment compared to the subgroup with an ADCS-ADL score of 39 points or less prior to treatment.

[0184] For example, a subgroup of Alzheimer's disease patients, defined as those with an ADCS-ADL score greater than 55 points prior to treatment, showed a significant masitinib treatment effect compared to placebo in terms of ADCS-ADL change from baseline (ΔLSM = +3.1871, p = 0.0077) (see Table 6 below). In contrast, a complementary subgroup, defined as those with an ADCS-ADL score of 55 points or less prior to treatment, did not show a significant masitinib treatment effect compared to placebo (ΔLSM of +0.4577 points, p = 0.727). This corresponds to approximately 600% improvement in the subgroup with an ADCS-ADL score greater than 55 points prior to treatment compared to the subgroup with an ADCS-ADL score of 55 points or less prior to treatment.

[0185] For example, a subgroup of Alzheimer's disease patients, defined as those with an ADCS-ADL score of 50 points or higher before treatment initiation, showed a significant masitinib treatment effect compared to placebo in terms of the change in ADCS-ADL from baseline (ΔLSM = +3.2315, p = 0.00704) (see Table 6 below). In contrast, a complementary subgroup, defined as those with an ADCS-ADL score of less than 50 points before treatment initiation, did not show a significant masitinib treatment effect compared to placebo (ΔLSM of +0.3062 points, p = 0.81375).

[0186] For example, a subgroup of Alzheimer's disease patients, defined as those with an ADCS-ADL score of 38 points or higher before treatment initiation, showed a significant masitinib treatment effect compared to placebo in terms of the change in ADCS-ADL from baseline (ΔLSM = +2.3285, p = 0.01996) (see Table 6 below). In contrast, a complementary subgroup, defined as those with an ADCS-ADL score of less than 38 points before treatment initiation, did not show a significant masitinib treatment effect compared to placebo (ΔLSM of -0.2109 points, p = 0.91442). [Table 6]

[0187] Example 3: Comparison of treatment effects observed in the entire study population compared to subgroups, using clinical markers: "time from diagnosis to treatment initiation," "baseline MMSE score," and "baseline ADCS-ADL score." As detailed above, masitinib (4.5 mg / kg / day) provides increased clinical benefit in a subgroup of Alzheimer's disease patients defined by “time from diagnosis to treatment initiation,” “baseline MMSE score,” “baseline ADAS-Cog score,” and “baseline ADCS-ADL score.” This increased clinical benefit was significantly observed as a substantial treatment effect in the subgroup of Alzheimer's disease patients as defined herein, compared to the relevant complementary subgroup (expressed in terms of statistical significance between treatment arms) (see Tables 1-6 above).

[0188] The treatment effects observed in subpopulations of Alzheimer's disease patients as defined herein (expressed in terms of statistically significant differences between treatment arms) were also compared to the treatment effects observed in the entire study population (expressed in terms of statistically significant differences between treatment arms).

[0189] The comparison was performed using the following information: - δLSM: The least squares mean difference of absolute change in endpoint scores from baseline to week 24, using either ADAS-Cog assessment or ADCS-ADL assessment. - ΔLSM: The difference between treatment arms (treatment effect) calculated as δLSM [masitinib] - δLSM [placebo]. - Δsub / Δoverall: The ratio of the placebo-controlled treatment effect in the entire study population (ΔLSM at week 24 in the parallel arm with masitinib 4.5 mg / kg / day) to the placebo-controlled treatment effect in the subgroup (ΔLSM at week 24 in the parallel arm with masitinib 4.5 mg / kg / day). A ratio greater than 1.0 indicates an improved placebo-controlled treatment effect in the subgroup compared to the entire study population (expressed as improvement rate in %). - Negative ΔLSM (ADAS-Cog) indicates a larger baseline difference for masitinib compared to placebo. - A positive ΔLSM (ADCS-ADL) indicates a larger baseline difference for masitinib compared to placebo.

[0190] As shown in Tables 7–11 below, the clinical benefit of masitinib was improved in a subgroup of Alzheimer's disease patients as defined herein, compared to the clinical benefit of masitinib observed in the entire study population.

[0191] For example, compared to the observed effect of masitinib treatment (compared to placebo) in the entire study population regarding the change in ADAS-Cog from baseline, the effect of masitinib treatment in a subgroup of Alzheimer's disease patients, defined as having a "time from diagnosis to treatment initiation of 3 years or less" in relation to the clinical marker of "time from diagnosis to treatment initiation," showed a 34% improvement (see Table 7 below). Similarly, compared to the observed effect of masitinib treatment (compared to placebo) in the entire study population regarding the change in ADAS-Cog from baseline, the effect of masitinib treatment in a subgroup of Alzheimer's disease patients, defined as having a "time from diagnosis to treatment initiation of 2 years or less," showed a 29% improvement (see Table 7 below). [Table 7]

[0192] For example, compared to the observed effect of masitinib treatment (compared to placebo) in the entire study population regarding changes in ADCS-ADL from baseline, the effect of masitinib treatment in a subgroup of Alzheimer's disease patients, defined as having a baseline MMSE score of 14 points or higher before the start of treatment, showed a 32% improvement in relation to the clinical marker "baseline MMSE score" (see Table 8 below). [Table 8]

[0193] Furthermore, compared to the observed masitinib treatment effect (compared to placebo) in the entire study population regarding ADCS-ADL changes from baseline, the masitinib treatment effect in a subgroup of Alzheimer's disease patients, defined as having a baseline MMSE score in the range of 25–21 points before treatment initiation, showed a 51% improvement (see Table 9 below). [Table 9]

[0194] Similarly, compared to the observed masitinib treatment effect (compared to placebo) in terms of ADAS-Cog change from baseline across the entire study population, the masitinib treatment effect in a subgroup of Alzheimer's disease patients, defined as having a baseline MMSE score in the range of 25–21 points before treatment initiation, showed a 35% improvement (see Table 10 below). [Table 10]

[0195] For example, regarding the clinical marker "baseline ADCS-ADL score," compared to the observed effect of masitinib treatment (compared to placebo) in the entire study population regarding the change in ADCS-ADL from baseline, the effect of masitinib treatment in a subgroup of Alzheimer's disease patients, defined as having an "ADCS-ADL score of 50 points or higher before treatment initiation," showed a 78% improvement (see Table 11 below). Similarly, compared to the observed effect of masitinib treatment (compared to placebo) in the entire study population regarding the change in ADCS-ADL from baseline, the effect of masitinib treatment in a subgroup of Alzheimer's disease patients, defined as having an "ADCS-ADL score greater than 55 points before treatment initiation," showed a 75% improvement (see Table 11 below). [Table 11]

Claims

1. 1. A pharmaceutical composition comprising masitinib, or a pharma- ceutical acceptable salt or solvate thereof, for use in the treatment of Alzheimer's disease in a patient in need thereof, wherein, prior to initiation of treatment with the pharmaceutical composition, the patient afflicted with Alzheimer's disease has an Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) score of 32 or greater, and / or a Mini-Mental State Examination (MMSE) score of 13 or greater, and / or has a time from diagnosis to initiation of treatment with the pharmaceutical composition of 5 years or less, and / or an Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score of 40 or less.

2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an ADCS-ADL score of greater than 32.

3. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an ADCS-ADL score of 32, 35, 38, 39, 41, 47, 50, or 55 or greater prior to initiation of treatment with the pharmaceutical composition.

4. The pharmaceutical composition for use according to claim 3, wherein the patient suffering from Alzheimer's disease has an ADCS-ADL score of greater than 32, 35, 38, 39, 41, 47, 50, or 55 prior to initiation of treatment with the pharmaceutical composition.

5. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an ADCS-ADL score of 38 or 50 or greater prior to initiation of treatment with the pharmaceutical composition.

6. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an ADCS-ADL score of greater than 39 or 55 prior to initiation of treatment with said pharmaceutical composition.

7. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an MMSE score of 13, 14, 15, 16, or 17 or greater prior to initiation of treatment with the pharmaceutical composition.

8. The pharmaceutical composition for use according to claim 7, wherein the patient suffering from Alzheimer's disease has an MMSE score of 14 or greater prior to initiation of treatment with the pharmaceutical composition.

9. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an MMSE score in the range of 21-25 before initiation of treatment with said pharmaceutical composition.

10. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has a time from diagnosis to initiation of treatment with the pharmaceutical composition of less than or equal to 5 years, 4 years, 3 years or 2 years.

11. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has a time from diagnosis to initiation of treatment with the pharmaceutical composition of less than or equal to 3 years.

12. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an ADAS-Cog score of 40, 35, 32, or 25 or less prior to initiation of treatment with the pharmaceutical composition.

13. 2. The pharmaceutical composition for use according to claim 1, wherein the patient suffering from Alzheimer's disease has an ADAS-Cog score of 35 or less prior to initiation of treatment with the pharmaceutical composition.

14. 14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the pharma- ceutically acceptable salt of masitinib is masitinib mesylate.

15. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the pharmaceutical composition is for administration at a dose within the range of about 1 to about 12 mg / kg / day (mg per kilogram body weight per day).

16. The pharmaceutical composition for use according to claim 15, wherein the pharmaceutical composition is for administration at a dose of about 3 mg / kg / day, 4.5 mg / kg / day, or 6 mg / kg / day.

17. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the pharmaceutical composition is for administration at an initial dose of about 4.5 mg / kg / day for at least 12 weeks, followed by doses of about 6 mg / kg / day thereafter, with each dose escalation being subject to toxicity management.

18. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the pharmaceutical composition is for oral administration.

19. A pharmaceutical composition for use according to any one of claims 1 to 13, wherein the pharmaceutical composition is for administration together with at least one further pharma- ceutical active agent.

20. 20. The pharmaceutical composition for use according to claim 19, wherein the at least one additional pharma- ceutical active agent is selected from the group consisting of donepezil, rivastigmine, galantamine, and memantine.