Tetracycline derivatives

Abstract

The present invention relates to tetracycline derivatives and their use as medicaments, in particular in the treatment or prevention of diseases selected from the group comprising or consisting of amyloidosis, pain, neurodegenerative diseases and neuroinflammatory diseases.

Description

Technical Field

[0001] The present invention relates to tetracycline derivatives and their use as medicaments, in particular in the treatment or prevention of diseases selected from the group comprising or consisting of amyloidosis, pain such as neuropathic pain, neuroinflammatory diseases and neurodegenerative diseases. Background Art

[0002] Neurons are involved in the pathophysiology of many diseases, particularly through aggregation of proteins or through inflammation. For example, aggregation of alpha-synuclein into amyloid fibrils contributes to the pathogenesis of synucleinopathies, a group of neurodegenerative diseases that include Parkinson's disease and other related disorders. Another example is the aggregation of tau proteins into neurons, which contributes to the pathogenesis of Alzheimer's disease.

[0003] In the prior art, a wide range of tetracycline derivatives for the treatment of neurodegenerative diseases have been described. For example, WO 2004 / 064728 discloses specific tetracycline derivatives and their use for the treatment of diseases or conditions involving underlying inflammatory processes, including but not limited to neurological conditions. However, the antibacterial activity of tetracyclines is a potential obstacle to the treatment of neurodegenerative diseases, as the chronic treatment required for these pathologies may lead to the emergence of antibiotic-resistant pathogens.

[0004] Therefore, there is still a need to develop tetracycline derivatives that have anti-protein aggregation and anti-inflammatory properties without antibacterial activity.

[0005] The inventors of the present invention unexpectedly found that the tetracycline derivatives of the compound of formula (I) according to the present invention have better neuroprotective effect and / or anti-inflammatory effect and / or anti-aggregation activity than the tetracycline derivatives of the prior art, have no antibacterial activity, and are easy to prepare, in particular, prepared from doxycycline or oxytetracycline with good safety. Summary of the invention

[0006] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof for use in treating or preventing a disease selected from amyloidosis, pain, neurodegenerative diseases and neuroinflammatory diseases, wherein the formula (I) is as follows:

[0007]

[0008] (I)

[0009] wherein R1 and R3 are each independently selected from a hydrogen atom and a hydroxyl group.

[0010] Advantageously, the compound of formula (I) is a compound of formula (Ibis) or a pharmaceutically acceptable salt, solvate or mixture thereof, wherein the formula (Ibis) is as follows:

[0011]

[0012] (Ibis).

[0013] More advantageously, the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ia) is as follows:

[0014]

[0015] (Ia).

[0016] More advantageously, the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ib) is as follows:

[0017]

[0018] (Ib).

[0019] Advantageously, the compound of formula (I) is a compound of formula (Ic) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ic) is as follows:

[0020]

[0021] (Ic).

[0022] Advantageously, the disease is selected from amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases.

[0023] Advantageously, the neurodegenerative disease or neuroinflammatory disease is selected from the group consisting of Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, Alzheimer's disease, prion disease, multiple sclerosis, limbic predominant age-related TDP-43 encephalopathy (LATE) and Huntington's disease.

[0024] Advantageously, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease, preferably the neurodegenerative disease is Parkinson's disease.

[0025] The present invention also relates to a process for preparing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, the process comprising the following steps:

[0026] a) reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof with a reducing system, wherein formula (II) is as follows:

[0027]

[0028] (II)

[0029] wherein R2 and R3 are each independently selected from a hydrogen atom or a hydroxyl group,

[0030] And then

[0031] b) isolating the compound of formula (I) or a pharmaceutically acceptable salt, a solvate or a mixture thereof as defined above and produced in step a).

[0032] Advantageously, the reducing system in step a) comprises a reducing metal, preferably zinc metal, and optionally an acid, preferably acetic acid.

[0033] Advantageously, the reducing system in step a) is an acid. More advantageously, the acidic reducing system in step a) comprises acetic acid.

[0034] Advantageously, the separation of the compounds of formula (I) as defined above or their pharmaceutically acceptable salts, solvates or mixtures thereof is carried out by chromatography, preferably by a chromatography method selected from column chromatography and reverse phase high performance liquid chromatography (reverse phase HPLC).

[0035] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, a solvate or a mixture thereof, and at least one pharmaceutically acceptable excipient.

[0036] Advantageously, the at least one pharmaceutically acceptable excipient is selected from the group consisting of: microcrystalline cellulose, magnesium stearate, povidone, hydrogenated castor oil, colloidal anhydrous silicon dioxide, sodium carboxymethyl starch, and combinations thereof.

[0037] The invention also relates to a pharmaceutical composition as defined above for use as a medicament.

[0038] The present invention also relates to a pharmaceutical composition as defined above for use in the treatment or prevention of a disease selected from amyloidosis, pain, neurodegenerative diseases and neuroinflammatory diseases. Preferably, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, Alzheimer's disease, prion disease, multiple sclerosis, limbic predominant age-related TDP-43 encephalopathy (LATE) and Huntington's disease. More preferably, the neurodegenerative disease is Parkinson's disease.

[0039] The present invention also relates to a pharmaceutical composition as defined above for use in the treatment or prevention of a disease selected from amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases. Preferably, the neurodegenerative disease is selected from the group consisting of: Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, Alzheimer's disease, prion disease, multiple sclerosis, limbic predominant age-related TDP-43 encephalopathy (LATE) and Huntington's disease. More preferably, the neurodegenerative disease is Parkinson's disease.

[0040] Advantageously, the pharmaceutical composition is administered via an administration route selected from the group consisting of oral route, intrathecal route, intraarterial route, intravenous route, intramuscular route and subcutaneous route, preferably the pharmaceutical composition is administered via oral route.

[0041] The present invention also relates to 12a-deoxytetracycline for use in the treatment of pain.

[0042] Advantageously, the 12a-deoxytetracycline is selected from the following compounds:

[0043]

[0044] (Ia),

[0045]

[0046] (Ib),

[0047]

[0048] (Ic),

[0049]

[0050] (C)

[0051]

[0052] (E),

[0053] and

[0054]

[0055] (K).

[0056] Advantageously, the pain is selected from: neuropathic pain, nociceptive pain or central pain.

[0057] More advantageously, the pain is nociceptive pain caused by a disease selected from osteoarthritis, rheumatoid arthritis and cancer, preferably nociceptive pain caused by cancer.

[0058] More advantageously, the pain is neuropathic pain caused by diabetic neuropathy.

[0059] More advantageously, the pain is central pain caused by a disease selected from fibromyalgia, irritable bowel syndrome or tension headache.

[0060] definition

[0061] In the present invention, the following terms have the following meanings:

[0062] "About" before a numerical value or a number refers to ±10% of the nominal value of the numerical value or number. In one embodiment, "about" before a numerical value or a number refers to ±5% of the nominal value of the numerical value or number.

[0063] "Active agent" refers to an agent that has a therapeutic effect. The agent can be a chemical substance or a biological substance. Preferably, the active agent is a chemical substance. The therapeutic effect can be the prevention, delay, reduction of severity and / or frequency or inhibition of at least one symptom associated with a pathological condition, or the prevention, mitigation or inhibition of the underlying cause of the pathological condition, or the amelioration or repair of an injury.

[0064] "Alzheimer's disease" (AD) refers to a neurodegenerative disease that usually develops slowly and progressively worsens. It typically involves impairment of memory, judgment, attention span and problem-solving abilities, as well as an overall loss of cognitive abilities.

[0065] "Aureomycin" refers to a molecule of the formula:

[0066] .

[0067] "Including" or "comprising" should be interpreted as an open-ended, inclusive sense, but not limited to. In embodiments, "including" or "comprising" means "consisting essentially of". In embodiments, "including" or "comprising" means "consisting of", which should be interpreted as limited to.

[0068] "Demeclocycline" refers to a molecule of the formula:

[0069] .

[0070] "Dose" refers to the amount of active agent administered at one time. Preferably, oral doses are administered to a subject at intervals of 8 hours to 1 week, preferably at intervals of 12 hours to 24 hours, more preferably at intervals of about 24 hours. More preferably, the oral dose is a human dose, wherein the human dose is a standard human dose for a person weighing 70 kg.

[0071] "Doxycycline" refers to a molecule of the formula:

[0072] .

[0073] "Excipient" refers to any inactive ingredient required to formulate an active agent into a suitable dosage form. In one embodiment, "excipient" refers to any and all solvents, diluents, carriers, fillers, extenders, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonic agents, thickeners or emulsifiers, stabilizers, absorption enhancers, fragrances, preservatives, antioxidants, buffers, gelling agents, solubilizers, or any combination thereof.

[0074] “X to Y” refers to a range of values ​​between X and Y, with the extreme values ​​X and Y included in the range.

[0075] "Neurodegenerative disease" refers to a disease or condition involving progressive damage to the structure or function of neurons, including death or demyelination of neurons. According to the present invention, a neurodegenerative disease may also be a neuroinflammatory disease.

[0076] "Neuroinflammatory disease" refers to a disease or condition caused by an excessive inflammatory response of the nervous system.

[0077] "Neurodegenerative and / or neuroinflammatory diseases" refers to diseases or conditions involving progressive damage to the structure or function of neurons, including death or demyelination of neurons, and / or diseases or conditions caused by excessive inflammatory responses of the nervous system. Advantageously, neurodegenerative and / or neuroinflammatory diseases can be selected from the group consisting of Alzheimer's disease, dementia associated with Alzheimer's disease (e.g., Pick's disease), Parkinson's disease, diffuse Lewy body disease, senile dementia, Huntington's disease, encephalitis, Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis (ALS), advanced supranuclear paralysis, epilepsy, schizophrenia, depression, post-traumatic stress disorder, Lou Gehrig's disease, and / or neuroinflammatory diseases. disease), Creutzfeldt-Jakob disease, stroke, fragile X syndrome, multiple system atrophy (MSA), pure autonomic dysfunction (PAF) with synuclein deposition, hereditary neurodegeneration with brain iron deposition, sporadic Lewy body disease in the elderly, Lewy body subtype Alzheimer's disease, Down syndrome, progressive supranuclear palsy, essential tremor with Lewy bodies, familial Parkinsonism with or without dementia, dementia associated with tau and progranulin genes with or without Parkinsonism, bovine spongiform encephalopathy, secondary Parkinsonism, Parkinsonism caused by neurotoxin exposure, drug-induced Parkinsonism with alpha-synuclein deposition, limbic-dominant age-related TDP-43 encephalopathy (LATE), and a group of sporadic or hereditary spinocerebellar ataxias. Preferably, the neurodegenerative disease or neuroinflammatory disease is a synucleinopathy. More preferably, the neurodegenerative disease or neuroinflammatory disease is a synucleinopathy selected from the group comprising or consisting of Parkinson's disease, diffuse Lewy body disease and multiple system atrophy. Even more preferably, the neurodegenerative disease or neuroinflammatory disease is Parkinson's disease.

[0078] "Neuropathic pain" refers to pain initiated or caused by a primary injury, dysfunction or temporary perturbation of the peripheral or central nervous system.

[0079] "Oxytetracycline" refers to a molecule of the formula:

[0080] .

[0081] Parkinson's disease is a neurodegenerative disorder that causes unexpected or uncontrollable movements such as tremors, stiffness, and difficulty with balance and coordination.

[0082] "Pharmaceutical composition" refers to a combination of at least one active agent and at least one pharmaceutically acceptable excipient.

[0083] "Pharmaceutically acceptable" means generally safe, non-toxic and having no biologically, physiologically or otherwise adverse effects on mammals, particularly humans and non-human mammals.

[0084] "Placebo" or "vehicle" refers to a pharmaceutical composition that contains only one or more than one pharmaceutically acceptable excipient and no active agent.

[0085] "Prevention" or "prevention" refers to any action that prevents at least one symptom associated with a pathological condition, or prevents the underlying cause of a pathological condition.

[0086] "Proteinopathy" refers to a class of diseases in which certain proteins become structurally abnormal, thereby disrupting the function of cells, tissues and organs of the body. Examples of proteinopathies include, but are not limited to, Parkinson's disease, Huntington's disease, Alzheimer's disease, and limbic predominant age-associated TDP-43 encephalopathy (LATE). In one embodiment, the proteinopathies are selected from the group comprising or consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, and limbic predominant age-associated TDP-43 encephalopathy (LATE).

[0087] "Reduction system" refers to one or more than one reactant capable of reducing the compound of formula (II) according to the present invention to the compound of formula (I) according to the present invention. Advantageously, the reduction system may include a reduction metal. The reduction metal may be a reduction transition metal such as zinc, copper, iron, silver, gold, palladium, rhodium, iridium, platinum or nickel. Advantageously, the reduction metal is zinc metal. The reduction metal may be used, for example, in the form of a metal powder. Advantageously, the reduction metal of the reduction system may be combined with an acid, the acid being selected, for example, from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and mixtures thereof. More advantageously, the reduction metal of the reduction system may be combined with acetic acid.

[0088] "Salt of a compound" refers to an acid addition salt or a base addition salt of the compound. Acid addition salts are formed from pharmaceutically acceptable organic or inorganic acids; base addition salts are formed when an acidic proton present in the compound is replaced by a metal ion or coordinated with a pharmaceutically acceptable organic or inorganic base. In one embodiment, the acid addition salt is selected from acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide The invention also includes but is not limited to the following salts: anhydrous sodium, sodium, sodium, sodium sulfonate ... In one embodiment, the base addition salt is selected from the group consisting of aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diolamine salts, ethanolamine salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0089] "Solvate of a compound" refers to a molecular complex comprising the compound and one or more than one pharmaceutically acceptable solvent molecules. "Hydrate of a compound" refers to a molecular complex comprising the compound and one or more than one pharmaceutically acceptable solvent molecules, wherein the solvent is water.

[0090] "Subject" or "patient" refers to a mammal, wherein "mammal" refers to a human or non-human mammal. Preferably, "subject" or "patient" refers to a human (male or female). More preferably, "subject" or "patient" refers to a human who is at least 18 years old, advantageously at least 40 years old, more advantageously at least 50 years old, still more advantageously at least 60 years old, even more advantageously at least 70 years old or at least 80 years old.

[0091] "Synucleinopathy" refers to a neurodegenerative and / or neuroinflammatory disease characterized by the abnormal accumulation of alpha-synuclein aggregates in neurons, nerve fibers and / or glial cells. Advantageously, the synucleinopathy may be selected from the group comprising or consisting of Parkinson's disease, diffuse Lewy body disease (DLB), multiple system atrophy (MSA), pure autonomic dysfunction (PAF) with synuclein deposition, hereditary neurodegeneration with brain iron deposition, sporadic Lewy body disease in the elderly, Lewy body subtype Alzheimer's disease, Down syndrome, essential tremor with Lewy bodies, familial Parkinson's syndrome with or without dementia, dementia associated with tau and progranulin genes with or without Parkinson's syndrome, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, secondary Parkinson's disease, Parkinson's syndrome caused by neurotoxin exposure, drug-induced Parkinson's syndrome with alpha-synuclein deposition, sporadic or hereditary spinocerebellar ataxia and amyotrophic lateral sclerosis (ALS).

[0092] "Tetracycline" refers to a molecule of the formula:

[0093] ,

[0094] The atoms are numbered as follows:

[0095] .

[0096] "Tetracycline derivatives" refer to molecules whose chemical formula is close to that of tetracycline, particularly molecules having a skeleton of four fused rings, but having at least one chemical group different from the chemical formula of tetracycline, for example, molecules whose chemical formula differs from that of tetracycline by 1 to 6 chemical groups, preferably by 2 to 4 chemical groups.

[0097] "12a-deoxytetracycline" refers to a tetracycline derivative having a chemical formula in which the hydroxyl group attached to carbon number 12a in the tetracycline chemical formula is replaced by a hydrogen atom.

[0098] A "therapeutically effective amount" or "effective amount" of an active agent or composition refers to a non-toxic but sufficient amount of the active agent or composition to provide the desired therapeutic effect.

[0099] "Treatment" refers to any action that can delay, reduce severity and / or frequency, or inhibit at least one symptom associated with a pathological condition, or slow or inhibit the underlying cause of a pathological condition, or improve or repair damage. In one embodiment, "treatment" refers to curative treatment. DETAILED DESCRIPTION

[0100] Compound of formula (I)

[0101] The present invention describes a compound of formula (I) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (I) is:

[0102]

[0103] Formula (I),

[0104] wherein R1 and R3 are each independently selected from a hydrogen atom and a hydroxyl group.

[0105] Advantageously, the compound of formula (I) is a compound of formula (Ibis) or a pharmaceutically acceptable salt, solvate or mixture thereof, wherein the formula (Ibis) is as follows:

[0106]

[0107] Formula (Ibis),

[0108] Wherein R1 is a hydrogen atom or a hydroxyl group.

[0109] More advantageously, the compound of formula (Ibis) is selected from the compounds of formula (Ia) and formula (Ib), wherein formula (Ia) is as follows:

[0110]

[0111] (Ia),

[0112] And formula (Ib) is as follows:

[0113]

[0114] (Ib).

[0115] More advantageously, the compound of formula (I) is a compound of formula (Ia). The chemical name of the compound of formula (Ia) is (4aS, 5R, 5aR, 6R)-3,5,10,12-tetrahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydronaphthacene-2-carboxamide (named using ChemBioDraw® Ultra version 12.0 (PerkinElmer)).

[0116] More advantageously, the compound of formula (I) is a compound of formula (Ib). The chemical name of the compound of formula (Ib) is (4aS, 5R, 5aR, 6S)-3,5,6,10,12-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydronaphthacene-2-carboxamide (named using ChemBioDraw® Ultra version 12.0 (PerkinElmer)).

[0117] Advantageously, the compound of formula (I) is a compound of formula (Ic) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ic) is as follows:

[0118]

[0119] (Ic).

[0120] Compounds of formula (I) for use as medicines

[0121] The present invention also describes a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof for use as a medicament in a subject in need thereof.

[0122] The present invention also describes a method for preventing and / or treating a disease by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof to a subject in need thereof.

[0123] The present invention also describes the use of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof for preparing a medicament.

[0124] The present invention also describes the use of a compound of formula (I) or a pharmaceutically acceptable salt, a solvate or a mixture thereof for preventing and / or treating a disease in a subject.

[0125] Compounds of formula (I) for use in treating diseases

[0126] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof according to the present application, for use in preventing and / or treating a disease selected from the group consisting of amyloidosis, pain (preferably neuropathic pain), neurodegenerative diseases and neuroinflammatory diseases.

[0127] The present invention also relates to a method for preventing and / or treating a disease selected from the group consisting of amyloidosis, pain (preferably neuropathic pain), neurodegenerative diseases and neuroinflammatory diseases by administering an effective amount of a compound of formula (I) according to the present application or a pharmaceutically acceptable salt, a solvate thereof or a mixture thereof to a subject in need thereof.

[0128] The present invention also relates to the use of the compound of formula (I) according to the present application or its pharmaceutically acceptable salt, its solvate or its mixture in the preparation of a medicament for preventing and / or treating a disease in a subject, wherein the disease is selected from the group including or consisting of amyloidosis, pain (preferably neuropathic pain), neurodegenerative diseases and neuroinflammatory diseases.

[0129] The present invention also relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt, its solvate or its mixture according to the present application for preventing and / or treating a disease in a subject, wherein the disease is selected from the group including or consisting of amyloidosis, pain (preferably neuropathic pain), neurodegenerative diseases and neuroinflammatory diseases.

[0130] Advantageously, the compound of formula (I) is a compound of formula (Ibis) according to the invention.

[0131] More advantageously, the compound of formula (I) is a compound of formula (Ia) according to the invention.

[0132] More advantageously, the compound of formula (I) is a compound of formula (Ib) according to the invention.

[0133] Advantageously, the compound of formula (I) is a compound of formula (Ic) according to the invention.

[0134] In one embodiment, the disease is pain. Preferably, the pain is selected from: neuropathic pain, nociceptive pain or central pain. More preferably, the pain is nociceptive pain. Even more preferably, the pain is nociceptive pain caused by a disease selected from osteoarthritis, rheumatoid arthritis and cancer, preferably nociceptive pain caused by cancer. More preferably, the pain is neuropathic pain caused by diabetic neuropathy. More preferably, the pain is central pain caused by a disease selected from fibromyalgia, irritable bowel syndrome or tension headache.

[0135] In one embodiment, the disease is a neurodegenerative disease and / or a neuroinflammatory disease.

[0136] In one embodiment, the disease is a proteinopathy.

[0137] Advantageously, the neurodegenerative or neuroinflammatory disease is selected from the group consisting of Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, Alzheimer's disease, prion disease, multiple sclerosis, limbic predominant age-related TDP-43 encephalopathy (LATE) and Huntington's disease.

[0138] More advantageously, the neurodegenerative disease is selected from the group consisting of: Parkinson's disease and Alzheimer's disease.

[0139] In one embodiment, the neurodegenerative disease is Parkinson's disease.

[0140] In one embodiment, the neurodegenerative disease is Alzheimer's disease.

[0141] In one embodiment, the neurodegenerative disease is limbic predominant age-associated TDP-43 encephalopathy (LATE).

[0142] In one embodiment, the disease is a neuroinflammatory disease. The inflammatory disease can be caused by a variety of causes, including, for example, toxic compounds, autoimmunity, aging, infectious agents such as viruses, bacteria or parasites, nervous system damage and pollution.

[0143] In one embodiment, the neuroinflammatory disease is caused by a virus. Examples of viruses that can cause neuroinflammatory diseases include, for example, encephalitis viruses, human immunodeficiency viruses, polio viruses, and coronaviruses.

[0144] In one embodiment, the neuroinflammatory disease is caused by a coronavirus, such as severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Thus, in one embodiment, the neuroinflammatory disease is COVID-19.

[0145] In one embodiment, a subject in need thereof is a subject in which a disease as defined above is to be prevented.

[0146] In one embodiment, the subject in need thereof is affected by, preferably diagnosed with, a disease as defined above.

[0147] In one embodiment, the subject is presymptomatic, meaning that the subject does not exhibit symptoms of the disease. In one embodiment, the subject is symptomatic, meaning that the subject exhibits at least one symptom of the disease.

[0148] In one embodiment, the subject in need thereof is affected by, preferably diagnosed with, Parkinson's disease.

[0149] Examples of Parkinson's disease symptoms include, but are not limited to, tremors in the hands, arms, legs, jaw, or head, muscle rigidity in which muscles remain contracted for long periods of time, slowed movements, or impaired balance and coordination, sometimes leading to falls.

[0150] Methods for diagnosing Parkinson's disease are well known to those of skill in the art and include, for example, neurological examinations and tests such as the Unified Parkinson's Disease Rating Scale (UPDRS) and dopamine transporter scan (DaTscan).

[0151] In one embodiment, the subject in need thereof is affected by, preferably diagnosed with, Alzheimer's disease.

[0152] Examples of Alzheimer's disease symptoms include, but are not limited to, confusion, disorientation, difficulty planning or making decisions, speech and language problems, personality changes, and depressed mood or anxiety.

[0153] Methods for diagnosing Alzheimer's disease are well known to those skilled in the art and include, for example, physical examination, neurological examination, and psychiatric examination.

[0154] In one embodiment, the subject in need thereof is affected by, and preferably diagnosed with, neuropathic pain.

[0155] Examples of neuropathic pain symptoms include, but are not limited to, spontaneous pain, evoked pain, pain that is relieved in response to normally painful stimuli.

[0156] Process for preparing the compound of formula (I)

[0157] The present invention also relates to a process for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof according to the present invention.

[0158] The method comprises the following consecutive steps

[0159] a) reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof with a reducing system, wherein formula (II) is as follows:

[0160]

[0161] (II)

[0162] wherein R2 and R3 are each independently selected from a hydrogen atom or a hydroxyl group,

[0163] And then

[0164] b) isolating the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof produced in step a).

[0165] Preferably, the method comprises the following consecutive steps:

[0166] a) reacting a compound of formula (IIbis) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof with a reducing system, wherein formula (IIbis) is as follows:

[0167]

[0168] (IIbis),

[0169] Wherein R2 is a hydrogen atom or a hydroxyl group,

[0170] And then

[0171] b) isolating the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof produced in step a).

[0172] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ibis) and formula (Ic) according to the present application.

[0173] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ia), formula (Ib) and formula (Ic) according to the present application.

[0174] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ia) according to the invention and the compounds of formula (Ib) according to the present application.

[0175] Advantageously, the compound of formula (I) is a compound of formula (Ia) according to the present application.

[0176] Advantageously, the compound of formula (I) is a compound of formula (Ib) according to the present application.

[0177] Advantageously, the compound of formula (I) is a compound of formula (Ic) according to the present application.

[0178] Advantageously, R2 is a hydrogen atom.

[0179] Advantageously, the compound of formula (II) is doxycycline, preferably doxycycline hydrochloride.

[0180] Advantageously, R2 is hydroxy.

[0181] Advantageously, the compound of formula (II) is oxytetracycline.

[0182] Advantageously, the compound of formula (I) is a compound of formula (Ia) according to the invention and the compound of formula (II) is doxycycline, preferably doxycycline hydrochloride.

[0183] Advantageously, the compound of formula (I) is a compound of formula (Ib) according to the invention and the compound of formula (II) is oxytetracycline.

[0184] Step a) is performed before step b).

[0185] Advantageously, the reducing system in step a) comprises a reducing metal, preferably zinc metal.

[0186] Advantageously, the reducing system in step a) is an acid. More advantageously, the acidic reducing system in step a) comprises acetic acid. In fact, the inventors of the present invention have surprisingly found that an acidic reducing system allows mainly obtaining and preferably obtaining the compound of formula (I). In addition, when the reducing system in step a) is an acid, there is only one reduction step in the method, which step is able to double reduce the compound of formula (II) and obtain the compound of formula (I).

[0187] Advantageously, the reducing system in step a) comprises an acid, such as acetic acid.

[0188] More advantageously, the reducing system in step a) comprises a reducing metal and an acid, preferably zinc metal and acetic acid.

[0189] Advantageously, the amount of the reducing metal can be a catalytic amount, a stoichiometric amount or an excess, preferably an excess, relative to the compound of formula (II). In particular, the amount of the reducing metal can be comprised of 3 equivalents to 30 equivalents, preferably 5 equivalents to 15 equivalents, relative to the compound of formula (II).

[0190] Advantageously, step a) may be carried out at a temperature ranging from 0°C to 50°C, preferably from 15°C to 35°C, more preferably about 25°C.

[0191] Advantageously, step a) may be carried out over a period of at least 2 hours, preferably at least 4 hours, more preferably about 8 hours.

[0192] Advantageously, step a) may be carried out at a pressure of 1 atm.

[0193] Advantageously, in step b), the compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof is separated by chromatography. Preferably, the chromatography is selected from: column chromatography and reversed phase high performance liquid chromatography (reverse phase HPLC). More preferably, the chromatography is column chromatography.

[0194] Pharmaceutical composition

[0195] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt, a solvate or a mixture thereof, and at least one pharmaceutically acceptable excipient.

[0196] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ibis) and formula (Ic) according to the present application.

[0197] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ia), formula (Ib) and formula (Ic) according to the present application.

[0198] Advantageously, the compound of formula (I) is a compound of formula (Ibis) according to the invention.

[0199] More advantageously, the compound of formula (I) is a compound of formula (Ia) according to the invention.

[0200] More advantageously, the compound of formula (I) is a compound of formula (Ib) according to the invention.

[0201] Advantageously, the compound of formula (I) is a compound of formula (Ic) according to the present application.

[0202] Advantageously, the pharmaceutical composition comprises 0.1% to 99% by weight, preferably 1% to 50% by weight, more preferably 5% to 25% by weight, even more preferably about 20% by weight of a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, relative to the total weight of the pharmaceutical composition.

[0203] Advantageously, for oral administration, the pharmaceutical composition can be formulated into conventional oral dosage forms such as tablets, gels, capsules, powders, granules, and liquid preparations such as syrups, elixirs, and concentrated drops. Nontoxic solid carriers or diluents can be used, including for example pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonates, etc. For compressed tablets, a binder is also necessary, which is an agent that imparts adhesion to the powder material. For example, starch, gelatin, sugars such as lactose or dextrose, and natural gums or synthetic gums can be used as binders. Disintegrants are also needed in tablets to promote the disintegration of tablets. Disintegrants include starch, clay, cellulose, algin, gum, and cross-linked polymers. In addition, lubricants and glidants are also included in the tablets to prevent the tablet material from adhering to the surface during the preparation process, and to improve the flow characteristics of the powder material during the preparation process. Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acid are most commonly used as lubricants.

[0204] Advantageously, the at least one pharmaceutically acceptable excipient of the pharmaceutical composition is selected from the group consisting of microcrystalline cellulose, magnesium stearate, povidone, hydrogenated castor oil, colloidal anhydrous silicon dioxide, sodium carboxymethyl starch, and combinations thereof.

[0205] Advantageously, the pharmaceutical composition may be formulated to release the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof substantially immediately after administration or at any predetermined time or period after administration.

[0206] Uses of the pharmaceutical composition

[0207] The present invention also relates to a pharmaceutical composition according to the invention as described above for use as a medicament.

[0208] The present invention also relates to a method for preventing and / or treating a disease by administering an effective amount of the pharmaceutical composition according to the present invention as described above to a subject in need thereof.

[0209] The present invention also relates to the use of the pharmaceutical composition according to the present invention as described above for the preparation of a medicament.

[0210] The present invention also relates to the use of a pharmaceutical composition according to the present invention as described above for preventing and / or treating a disease in a subject.

[0211] The present invention also relates to a pharmaceutical composition according to the invention as described above for use in the prevention and / or treatment of a disease selected from the group comprising or consisting of amyloidosis, pain, neurodegenerative diseases and neuroinflammatory diseases.

[0212] The present invention also relates to the pharmaceutical composition of the present invention as described above, for use in preventing and / or treating a disease selected from the group comprising or consisting of amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases.

[0213] The present invention also relates to a method for preventing and / or treating a disease selected from the group consisting of amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases by administering an effective amount of the pharmaceutical composition according to the present invention as described above to a subject in need thereof.

[0214] The present invention also relates to the use of a pharmaceutical composition according to the present invention as described above for the preparation of a medicament for preventing and / or treating a disease in a subject, the disease being selected from the group comprising or consisting of amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases.

[0215] The present invention also relates to the use of the pharmaceutical composition according to the present invention as described above for preventing and / or treating a disease in a subject, the disease being selected from the group comprising or consisting of amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases.

[0216] In one embodiment, the disease is pain. Preferably, the pain is selected from: neuropathic pain, nociceptive pain or central pain. More preferably, the pain is nociceptive pain. Even more preferably, the pain is nociceptive pain caused by a disease selected from osteoarthritis, rheumatoid arthritis and cancer, preferably nociceptive pain caused by cancer. More preferably, the pain is neuropathic pain caused by diabetic neuropathy. More preferably, the pain is central pain caused by a disease selected from fibromyalgia, irritable bowel syndrome or tension headache.

[0217] The advantageous features described in the "Compounds of formula (I) for use in the treatment of diseases" section of the present application apply mutatis mutandis to pharmaceutical compositions for the prevention and / or treatment of diseases selected from the group comprising or consisting of amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases.

[0218] Route of administration and dosage

[0219] Advantageously, the compound of formula (I) or a pharmaceutically acceptable salt, a solvate or a mixture thereof according to the present invention or the pharmaceutical composition according to the present invention is administered enterally or parenterally.

[0220] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ibis) and formula (Ic) according to the present application.

[0221] Advantageously, the compound of formula (I) is chosen from the compounds of formula (Ia), formula (Ib) and formula (Ic) according to the present application.

[0222] Advantageously, the compound of formula (I) is a compound of formula (Ibis) according to the invention.

[0223] More advantageously, the compound of formula (I) is a compound of formula (Ia) according to the invention.

[0224] More advantageously, the compound of formula (I) is a compound of formula (Ib) according to the invention.

[0225] Advantageously, the compound of formula (I) is a compound of formula (Ic) according to the invention.

[0226] More advantageously, the enteral route can be selected from: buccal route (including perilingual route and sublingual route), oral route and rectal route. Preferably, the compound of formula (I) or its pharmaceutically acceptable salt, its solvate or mixture thereof according to the present invention or the pharmaceutical composition according to the present invention is administered by oral route.

[0227] The parenteral route includes any non-enteral route. More advantageously, the parenteral route can be selected from: epidural route, intraspinal route, intracerebral route, intraventricular route, epidermal route, transdermal route, intradermal route, subcutaneous route, nasal route, intraarterial route, intraarticular route, intravenous route, intramuscular route, intraperitoneal route, intraocular route, intravitreal route, intrathecal route and intravitreal route. Preferably, the compound of formula (I) according to the present invention or its pharmaceutically acceptable salt, its solvate or its mixture or the pharmaceutical composition according to the present invention is administered by intravenous route.

[0228] Advantageously, a dose of a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof or a pharmaceutical composition according to the present invention is administered regularly, preferably three times a day to once a month, more preferably three times a day to once a week, even more preferably three times a day to once a day. More advantageously, a dose of a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof or a pharmaceutical composition according to the present invention is administered once, twice or three times a day, preferably once a day.

[0229] Advantageously, the dosage of the compound of formula (I) according to the present invention or its pharmaceutically acceptable salt, solvate or mixture thereof administered to the subject by intravenous injection, intramuscular injection or oral route, preferably oral route, is about 1 mg / kg to 100 mg / kg of the subject's body weight.

[0230] Advantageously, the dose range of the compound of formula (I) according to the present invention or its pharmaceutically acceptable salt, solvate or mixture thereof administered to a subject is 50 mg to 150 mg, preferably 70 mg to 130 mg, more preferably a dose of about 100 mg.

[0231] 12a-deoxytetracycline for pain management

[0232] The present invention also relates to 12a- Deoxytetra Cyclic acid.

[0233] The present invention also relates to a method of administering an effective amount of 12a- Deoxytetra Methods of preventing and / or treating pain using cycline.

[0234] The present invention also relates to 12a- Deoxytetra Use of a cyclin in the preparation of a medicament for preventing and / or treating pain in a subject in need thereof.

[0235] The present invention also relates to 12a- Deoxytetra Use of a cyclin for preventing and / or treating pain in a subject in need thereof.

[0236] Advantageously, 12a- Deoxytetra The cyclin is selected from the following compounds:

[0237]

[0238] (Ia),

[0239]

[0240] (Ib),

[0241]

[0242] (Ic),

[0243]

[0244] (C)

[0245]

[0246] (E),

[0247] and

[0248]

[0249] (K).

[0250] In fact, as shown in Example 10 of the present application, 12a- Deoxytetra Cyclamate has anti-nociceptive effects.

[0251] Advantageously, the pain is selected from: neuropathic pain, nociceptive pain or central pain.

[0252] More advantageously, the pain is nociceptive pain caused by a disease selected from osteoarthritis, rheumatoid arthritis and cancer, preferably nociceptive pain caused by cancer.

[0253] More advantageously, the pain is neuropathic pain caused by diabetic neuropathy.

[0254] More advantageously, the pain is central pain caused by a disease selected from fibromyalgia, irritable bowel syndrome or tension headache.

[0255] Advantageously, 12a- Deoxytetra The cycline is a compound of formula (Ia), and the subject is a female or a woman.

[0256] Advantageously, 12a- Deoxytetra The cyclin is a compound of formula (C), and the subject is a male or a man.

[0257] In fact, as shown in Example 10 of the present application, the compound of formula (C) and the compound of formula (Ia) have gender-dependent analgesic effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0258] Figure 1 is a histogram showing the aggregation of α-synuclein as a function of the concentration of the compound of formula (Ia) according to the present invention ( Figure 1 A) and two TEM images of α-synuclein fibrils in the absence and presence of compounds of formula (Ia) according to the invention ( Figure 1 B) In Figure 1 In A: Fluorescence emission intensity of Thioflavin T (ThT) in a solution containing 70 µM α-synuclein in the presence of 0 µM (aS = control), 5 µM, 10 µM, 20 µM or 50 µM of a compound of formula (Ia) according to the invention, after incubation for 120 hours at 37°C. Statistical analysis: Kruskal-Wallis test, *p<0.05; **p<0.01; ***p<0.0001 (n=3) compared to αS. Error bars = mean + SEM. Figure 1In B: TEM images of α-synuclein samples incubated at 37°C with orbital stirring for 5 days in the absence (upper panel "αS") and presence (lower panel "aS: DR2 20 μM") of 20 μM of the compound of formula (Ia) according to the invention. Magnification equal to 44000 times. Scale bar = 1 μm.

[0259] Figure 2 It is a histogram showing the neuroprotective effect of 10 μM doxycycline (DOX) and 3 μM and 5 μM of the compound of formula (Ia) according to the present invention, and compared with the neuroprotective effect of 100 μg / mL apo-transferrin (APO) (used as a positive control). Values ​​are expressed as mean ± SEM. One-way ANOVA followed by Dunnett's multiple comparison test (n=6 to 8). Compared to control (-), ***p<0.0001; doxycycline (DOX; 10 μm); compound of formula (Ia) is used at 3 μM or 5 μM; APO (apo-transferrin; 100 μg / mL).

[0260] Figure 3 It is a histogram showing the anti-inflammatory effect of the compound of formula (B) shown in Example 1 of 5 μM and 20 μM, the compound of formula (Ia) according to the present invention of 5 μM and 20 μM, and 50 μM of doxycycline (DOX), and compared with the effect of 2.5 μM dexamethasone (DEX) (used as a positive control). Values ​​are expressed as mean ± SEM. Mann-Whitney, u test (n=4). Compared to LPS, **p=0.01; ***p=0.004; Untreated (-), dexamethasone (DEX; 2.5 μM); doxycycline (DOX; 50 μM).

[0261] Figure 4 10 μM and 20 μM of the compound of formula (C) and 10 μM and 20 μM of the compound of formula (Ia) according to the present invention are shown in a histogram compared with the effect of 2.5 μM dexamethasone (DEX) (used as a positive control). Condition "NT" represents a control condition without LPS treatment. Values ​​are expressed as mean ± SEM. Dunnett's multiple comparison test (n = 4). **p = 0.0008; ****p < 0.0001 compared to LPS; untreated (NT); dexamethasone (DEX; 2.5 μM).

[0262] Figure 510 μM doxycycline (DOX) and 0.5 μM, 1 μM and 5 μM of the neuroprotective effect of the compound of formula (Ib) according to the present invention are shown, and compared with the neuroprotective effect of 100 μg / mL apo-transferrin (APO) (used as a positive control). The data expressed as a percentage of APO-treated cultures are expressed as mean ± SEM (n = 4 to 16). ANOVA was followed by Dunnett's post hoc test. Compared to untreated cultures, ***p < 0.001.

[0263] Figure 6 0.5 μM, 1 μM and 5 μM of the neuroprotective effect of the compound of formula (Ic) according to the present invention are shown, and the neuroprotective effect of 100 μg / mL of apo-transferrin (APO) (used as a positive control) is compared with the histogram. The data expressed as a percentage of APO-treated cultures are expressed as mean ± SEM (n = 3). One-way ANOVA was followed by Dunnett's post hoc test. ***p < 0.001 compared to untreated cultures.

[0264] Figure 7 Depict the histogram showing the analgesic effect of the compound of formula (Ia) and formula (C) according to the present invention compared with morphine.The figure shows the effect of formalin-induced pain behavior of male adult mice treated with formula (C) compound (5mg / kg animal, 10mg / kg animal, 20mg / kg animal) or formula (Ia) compound (10mg / kg animal, 20mg / kg animal, 40mg / kg animal) for 3 days (2 subcutaneous injections / day).Morphine (MOR) is used with a single injection of a dosage of 10mg / kg animal.The data represented by the time (seconds) spent by licking / biting behavior are mean ± SEM (n=6).Compared to vehicle, *p<0.05.Bonferroni post-hoc test (Bonferroni post-hoc test) was carried out after one-way ANOVA.Vehicle=vehicle (placebo).

[0265] Figure 8 Depicted is a histogram showing the analgesic effect of the compound of formula (Ia) and formula (C) according to the present invention compared with morphine. The figure shows the effect of a single subcutaneous injection of formula (C) compound (10mg / kg animal) or formula (Ia) compound (40mg / kg animal) on the pain behavior caused by formalin in male adult mice. Morphine (MOR) is used at a dosage of 10mg / kg animal. The data represented by the time (seconds) spent in licking / biting behavior are mean ± SEM (n=6). Compared to vehicle, *p<0.05. Bonferroni post hoc test was performed after one-way ANOVA. Vehicle=vehicle (placebo).

[0266] Fig. 9Depicted is a histogram showing the analgesic effect of the compound of formula (Ia) and formula (C) according to the present invention compared with morphine. The figure shows a comparison of the effect of a single subcutaneous injection of formula (C) compound (10 mg / kg animals) or formula (Ia) compound (40 mg / kg animals) on the pain behavior caused by formalin in male adult mice and female adult mice. Morphine (MOR) is used at a dosage of 10 mg / kg animals. The data represented by the time (seconds) spent on licking / biting behavior are mean ± SEM (n=7). Compared to vehicle, *p<0.05. One-way ANOVA followed by Bonferroni post hoc test. Vehicle=vehicle (placebo).

[0267] Fig.10 is a histogram showing the anti-inflammatory effect of the compound of formula (Ib) according to the present invention in cultured microglia challenged with LPS. The figure shows the anti-inflammatory effect of the compound of formula (Ib) in LPS-activated mouse microglia. The results expressed as mean ± SEM (n = 3 to 6) are given in pg / mL. Compared to untreated cells, ****p < 0.0001; compared to LPS, #### p < 0.0001. One-way ANOVA followed by Bonferroni post hoc test.

[0268] Example

[0269] The present invention is further illustrated by the following examples.

[0270] Example 1: Synthesis of the compound of formula (Ia) according to the present invention

[0271] Materials and methods

[0272] In a 500mL round-bottomed flask, doxycycline monohydrate (5.5g, 11.9 mmol, 1.0 equivalent) was suspended in water (50mL) and stirred, followed by the addition of 35% HCl (1.5mL, 17 mmol, 1.4 equivalent) and AcOH (50mL). After the mixture was dissolved, zinc powder (7.8g, 119 mmol, 10 equivalent) was added, and the reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was filtered through a small diatomaceous earth pad with acetic acid (AcOH). The organic phase was extracted with CH2Cl2, washed with HCl (1M) and brine, dried with MgSO4, filtered and concentrated in vacuo. Purification of the residue was performed on automated combined flash chromatography [petroleum ether:acetone + 1% HCOOH; silica column Buchi Flashpure 120 g; 0% to 10% acetone in 20 minutes, then 10% to 11.3% acetone in 5.1 minutes, then isocratic elution in 22.7 minutes, then 11.3% to 20% acetone in 10.4 minutes (total 58.2 minutes)].

[0273] The reaction scheme is as follows:

[0274]

[0275] By proton NMR spectrometry ( 1 H) and carbon ( 13 C) NMR (nuclear magnetic resonance) analysis was used to verify the chemical structure of the compound of formula (Ia) obtained according to the present invention. Chemical shifts (δ) are expressed in parts per million (ppm). The residual solvent peak is used as a reference. The following abbreviations are used to write 1 H spectrum: s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet. The coupling constants (J) were determined for doublets, triplets and quartets in Hz.

[0276] result

[0277] The compound of formula (Ia) according to the invention has been obtained in a yield of 21 wt.-% and a purity of > 95%, relative to the total weight of the doxycycline product.

[0278] For the compounds of formula (Ia) according to the present invention:

[0279]

[0280]

[0281] The calculated mass of the compound of formula (Ia) according to the present invention is 386.1234 g·mol -1 , the mass measured in HRMS (high resolution mass spectrometry) is 386.1238 g·mol -1 (HRMS(ESI) m / z: for [M+H] + C 20 H 19 NO7 calculated as 386.1234; found as 386.1238).

[0282] Example 2: Evaluation of the anti-aggregation effect of the compound of formula (Ia) according to the present invention estimate

[0283] Materials and methods

[0284] The anti-aggregation effect of the compound of formula (Ia) according to the present invention on α-synuclein (αS) was evaluated in vitro by measuring the fluorescence intensity of the probe Thioflavin T (ThT), which is a molecule that specifically binds to the cross-β structure characteristic of amyloid aggregation. The compound of formula (Ia) was dissolved in dimethyl sulfoxide to a concentration of 50μM. In this assay, 70μm of α-synuclein was incubated with or without 10μM, 20μM and 50μM of the compound of formula (Ia) at 37°C for 5 days under orbital stirring (600 rpm). After the incubation time, Tht was added to each sample and the emission fluorescence spectrum (λ ex = 450nm and λ em =48nm).

[0285] By using transmission electron microscopy (TEM), we studied α-synuclein aggregation in the presence of 20 μM of the compound of formula (Ia) under the same conditions as above. For sample mounting, 5 μL of 7 μM α-synuclein solution was adsorbed onto formvar carbon film-coated copper grids (Electron Microscopy Sciences) and stained with uranium-free stain.

[0286] result

[0287] The data obtained related to the changes in the emission fluorescence spectrum showed that the compound of formula (Ia) according to the present invention significantly inhibited α-synuclein aggregation in a dose-dependent manner at concentrations of 10 μM (p=0.0360), 20 μM (p=0.0077) and 50 μM (p=0.0002) compared to the control (αS) (see Figure 1 A).

[0288] Images taken from different areas reveal that, in contrast to the Tht results ( Figure 1 A), the presence of 20 μM of the compound of formula (Ia) according to the invention significantly reduced the amount of α-synuclein fibrils compared to the control (α-synuclein alone), in which a typical fibril morphology could be seen ( Figure 1 B).

[0289] Example 3: Comparison of the antibacterial activity of the compound of formula (Ia) according to the present invention and the prior art compounds

[0290] Materials and methods

[0291] The bacterial strains used in this study were: Staphylococcus aureus (S. Aureus, ATCC25923), Escherichia coli (E. coli, ATCC25922), Enterococcus faecalis (E. faecalis, ATCC29212), and Pseudomonas aeruginosa (P. aeruginosa, PA01). The strains were kept in 15% (vol / vol) glycerol at -80°C for cryoprotection. Bacteria were usually grown in Mueller-Hinton (MH) broth at 37°C.

[0292] The susceptibility of bacterial strains to antibiotics and compounds was determined in microtiter plates using the standard broth dilution method according to the recommendations of the Antibiogram Committee of the French Society of Microbiology (CA-SFM). (Members of the SFM Antibiogram Committee, R. Int. J. Antimicrob. Agents 2003, 21, 364). Briefly, the minimum inhibitory concentration (MIC) was calculated by inoculating 10 cells of 200 μL of MH broth containing two-fold serial dilutions of each drug. 5 The MIC was defined as the lowest drug concentration that completely inhibited visible growth after 18 h of incubation at 37°C. For all MIC determinations, the assay was repeated three times independently.

[0293] The inhibitory effect of the compound of formula (Ia) according to the present invention on clinically isolated Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis) was tested. The minimum inhibitory concentration (MIC) was initially determined and compared with the known antibiotic tetracycline (doxycycline, demeclocycline, chlortetracycline) and the compound of formula (B) disclosed in Example 1 of the present application. The test was repeated twice, and the average MIC was calculated.

[0294] result

[0295] The results are shown in the following table:

[0296] Table 1:

[0297]

[0298] As can be seen in Table 1, surprisingly and interestingly, the compound of formula (Ia) according to the present invention did not show any activity against Gram-positive and Gram-negative bacteria up to 200 mg / mL and was less active against Staphylococcus aureus than the compound of formula (B).

[0299] Example 4: Comparison of neuroprotective effects of the compounds of formula (Ia) according to the present invention and prior art compounds

[0300] Materials and methods

[0301] In the primary culture of dopaminergic neurons, TH+ neurons are subjected to oxidative stress, resulting in neuronal death after a few days. When cultured in the presence of a positive reference (apo-transferrin), dopaminergic neurons survive. The neuroprotective effect of 10 μM doxycycline (DOX) and 3 μM or 5 μM of the compound of formula (Ia) according to the present invention was assessed and compared with the effect of 100 μg / mL apo-transferrin (APO).

[0302] result

[0303] The results are as follows Figure 2 As shown. Figure 2 As can be seen in the Figures, compared to doxycycline which exhibits a neuroprotective effect at 10 μM, the compound of formula (Ia) according to the present invention has a high protective effect at only 3 μM and 5 μM.

[0304] Example 5: Comparison of the anti-inflammatory effects of the compounds of formula (Ia) according to the present invention and prior art compounds

[0305] Materials and methods

[0306] Microglia are responsible for protecting neurons. However, under stress conditions, microglia can cause inflammatory phenomena that ultimately lead to neuronal death.

[0307] The anti-inflammatory effects of 5 µM and 20 µM of the compound of formula (B) shown in Example 1, 5 µM and 20 µM of the compound of formula (Ia) according to the present invention, and 50 µM of doxycycline (DOX) were evaluated and compared with the effect of 2.5 µM of dexamethasone (DEX).

[0308] result

[0309] The results are as follows Figure 3 As shown. Figure 3 As can be seen, the compound of formula (Ia) combats the inflammatory process (generated by LPS) in an effective manner, outperforming doxycycline and the compound of formula (B).

[0310] Example 6: Comparison of the anti-inflammatory effects of the compounds of formula (Ia) according to the present invention and prior art compounds

[0311] Materials and methods

[0312] Microglia are responsible for protecting neurons. However, under stress conditions, microglia can cause inflammatory phenomena that ultimately lead to neuronal death.

[0313] The anti-inflammatory effects of 10 μM and 20 μM of the compound of formula (C) ("10 μM (C)" and "20 μM (C)") and 10 μM and 20 μM of the compound of formula (Ia) according to the present invention ("10 μM (Ia)" and "20 μM (Ia)") were evaluated and compared with the effects of 2.5 μM dexamethasone ("DEX").

[0314] "Compound of formula (C)" refers to a molecule of the formula:

[0315]

[0316] A compound of formula (C).

[0317] result

[0318] The results are as follows Figure 4 As shown. Figure 4 As can be seen, the compound of formula (Ia) combats the inflammatory process (generated by LPS) in an effective manner, whereas the compound of formula (C) does not.

[0319] Example 7: Comparison of the properties of the compound of formula (Ia) according to the present invention with the properties of the prior art compounds

[0320] Materials and methods

[0321] The properties of tetracycline derivatives including compounds of formula (Ia) according to the present invention were compared in terms of neuroprotection, anti-inflammatory effect, anti-aggregation activity and antibacterial activity. The properties were evaluated as described above. The following compounds were tested: compounds of formula (Ia) according to the present invention, compounds of formula (C) as disclosed in Example 6 of the present application, compounds of formula (D), compounds of formula (E), doxycycline, compounds of formula (B) as disclosed in Example 1 of the present application, chlortetracycline, compounds of formula (F), compounds of formula (G) and compounds of formula (H).

[0322] "Compound of formula (D)" refers to a molecule of the formula:

[0323]

[0324] A compound of formula (D).

[0325] "Compound of formula (E)" refers to a molecule of the formula:

[0326]

[0327] A compound of formula (E).

[0328] "Compound of formula (F)" refers to incyclinide (CMT-3, COL-3), which has CAS No. 15866-90-7 and the following formula:

[0329]

[0330] A compound of formula (F).

[0331] "Compound of formula (G)" refers to a molecule of the formula:

[0332]

[0333] A compound of formula (G).

[0334] "Compound of formula (H)" refers to a molecule of the formula:

[0335]

[0336] A compound of formula (H).

[0337] result

[0338] The properties of tetracycline derivatives are summarized in the table below.

[0339] Table 2

[0340]

[0341] EC50 and IC50 are determined graphically. * Rescue of dopamine neurons from spontaneous oxidative stress; ** Inhibition of TNFα release under LPS exposure, # It only had weak antibacterial activity against one of the three bacterial strains (i.e., Staphylococcus aureus). ## It has strong antibacterial activity against all 3 bacterial strains. ### It has significant antibacterial activity against two bacterial strains.

[0342] As shown above, the compounds of formula (Ia) according to the present invention exhibit advantageous properties compared to other tetracycline derivatives. In particular, the compounds of formula (Ia) according to the present invention have neuroprotective, anti-inflammatory and anti-aggregation effects and have no antibacterial activity.

[0343] Example 8: Comparison of neuroprotective effects of the compound of formula (Ib) according to the present invention and prior art compounds

[0344] Materials and methods

[0345] Midbrain mouse cultures undergo a maturation step until day 7 in vitro (div) and are then gradually exposed to DMEM / nutrient mixture F12 Ham supplemented with phenol red supplemented with 20 μg / mL insulin and 2 μM NMDA receptor blocker MK-801. Under these conditions, which are favorable for low-level, sustained oxidative damage and ultimately dopamine cell death, treatment with a compound of formula (Ib) according to the invention (concentration range of 0.1 μM to 5 μM) is performed or not, as well as treatment with a reference tetracycline antibiotic doxycycline (DOX; 10 μM) and apotransferrin (APO; 100 μg / mL), the latter being used as a reference neuroprotectant. At div14 days, the cultures are fixed and then subjected to tyrosine hydroxylase (TH) immunocytochemistry to assess the survival of dopamine neurons.

[0346] result

[0347] The results are as follows Figure 5 As shown. Figure 5 As can be seen from the results, compared to doxycycline, which exhibited a neuroprotective effect at 10 μM, the compound of formula (Ib) according to the present invention had a high protective effect at only 0.5 μM, 1 μM and 5 μM. Therefore, these results indicate that the compound of formula (Ib) according to the present invention effectively protects dopamine neurons from degeneration.

[0348] In addition, the effect of the compound of formula (Ib) according to the present invention was reproduced by the molecule glycoprotein apotransferrin with iron chelating ability, which indicates that the compound of formula (Ib) according to the present invention acts by preventing the harmful consequences of Fenton-type reactions that generate hydroxyl radicals and thus lead to lipid oxidative degradation. Overall, these results confirm that the compound of formula (Ib) according to the present invention has a potential value in combating low-level oxidative stress damage, which is particularly chronically developed during the course of PD neurodegeneration.

[0349] Example 9: Comparison of the antibacterial activity of the compound of formula (Ib) according to the present invention and the prior art compounds

[0350] Materials and methods

[0351] The bacterial strains used in this study were: Staphylococcus aureus (ATCC25923), Escherichia coli (ATCC28922), Enterococcus faecalis (ATCC29212), and Pseudomonas aeruginosa (PA01). Minimum inhibitory concentrations (MICs) were estimated using a standardized protocol (Mawabo et al., J. Infect. Public Health 2015).

[0352] result

[0353] The results are shown in the following table:

[0354] Table 2:

[0355]

[0356] As can be seen from Table 2, surprisingly and interestingly, the data show that oxytetracycline has an antibacterial effect against 3 of the 4 tested bacterial strains, while the compound of formula (Ib) according to the present invention is ineffective against none of them.

[0357] Example 10: Analgesic effects of the compound of formula (Ia) according to the present invention and the compound of formula (C) described in Example 6 use

[0358] Materials and methods

[0359] The analgesic effect of the compound of formula (C) described in Example 6 (administered at a dose of 5 mg / kg animal, 10 mg / kg animal and 20 mg / kg animal) and the compound of formula (Ia) according to the present invention (administered at a dose of 10 mg / kg animal, 20 mg / kg animal and 40 mg / kg animal) was tested using the formalin-induced nociceptive pain model (as disclosed in the publication LopesDM, Cater HL, Thakur M et al. “A refinement to the formalin test in mice [Version 2; Peer Review: Two Passed]” F1000Research 2019, 8:891).

[0360] result

[0361] The results show that the non-antibiotic tetracyclines of Formula (Ia) and Formula (C) reduce pain-related responses in mice subjected to the formalin test.

[0362] In particular, a subchronic treatment regimen (6 subcutaneous injections per day) of male adult C57 / BL 6 mice with 5 mg / kg of the compound of formula (C) was found to be highly effective in reducing nociceptive pain in both phases 1 and 2 of the trial. These effects were indistinguishable from the effects of similarly administered morphine (10 mg / kg). The compound of formula (Ia) was also effective in both phases 1 and 2 of the trial and exerted analgesic effects at 20 mg / kg and 40 mg / kg. Interestingly, a single injection of the compound of formula (C) (10 mg / kg) prior to formalin injection produced a strong antinociceptive effect in both phases 1 and 2 of the trial that was indistinguishable from the effects of morphine (10 mg / kg). A single injection of the compound of formula (Ia) (40 mg / kg) prior to formalin injection exerted an antinociceptive effect in both phases. Notably, male mice showed better responses to a single injection of the compound of formula (C) (10 mg / kg) townThe nociceptive response of female mice was significantly reduced in the first two days of the formalin test, while female mice responded more effectively to the corresponding treatment with the compound of formula (Ia) (40 mg / kg) in stage 2 of the formalin test; this indicates the sex-dependent analgesic effect of the compound of formula (C) and the compound of formula (Ia).

[0363] Therefore, the results showed that 12a- Deoxytetra Cyclamate has anti-nociceptive effects.

[0364] Example 11: Penetration of the brain by the compound of formula (Ia) according to the present invention and the compound of formula (C) described in Example 6 Capabilities

[0365] Materials and methods

[0366] Adult Swiss mice received a single subcutaneous injection of 40 mg / kg of the compound of formula (Ia) according to the present invention, the compound of formula (C) or doxycycline diluted with 5% DMSO and 5% Tween 80 (doxycycline was used as a reference tetracycline). Mice were killed 30 minutes, 1 hour, 8 hours and 24 hours after treatment. After killing, brain and serum samples were collected and processed at each time point to determine the tetracycline dose using a UHPLC system coupled to a triple quadrupole mass spectrometer LCMS-8030 (Shimadzu Corporation, Kyoto, Japan).

[0367] result

[0368] For the compound of formula (C), the compound of formula (Ia) and doxycycline, the brain-to-plasma ratios calculated from the areas under the concentration-time curves in brain and plasma were 0.27±0.13, 0.21±0.05 and 0.11±0.03 (n=3), respectively, indicating that the compound of formula (C) and the compound of formula (Ia) penetrate the brain better than doxycycline.

[0369] Example 12: Treatment of proteins with the compound of formula (Ib) according to the present invention and the compound of formula (C) described in Example 6 Inhibition of tau phosphorylation

[0370] Materials and methods

[0371] A culture model of cortical neurons from mouse embryonic brain was used, in which neuronal cells underwent a maturation step until day 7 in vitro (div) and were then gradually exposed to phenol red-enriched DMEM / Nutrient Mixture F12 Ham supplemented with 20 μg / mL insulin and 2 μM of the NMDA receptor blocker MK-801 (DF12i).

[0372] result

[0373] Under these conditions, which promote sustained low-level oxidative damage due to the presence of small amounts of catalytic iron in the DF12i culture medium, a significant proportion of MAP2+ neurons were found to exhibit high levels of p-tau (AT8 immunosignal) in their cell bodies and neurite extensions when undergoing degeneration (p-tau = tau protein phosphorylated at residues Ser 202, Thr205). Specifically, after 4 days of exposure to DF12i, 10% to 15% of surviving neurons exhibited very strong AT8 immunosignals in their cell bodies, while under conditions in which oxidative stress was inhibited by treatment with bovine apotransferrin (APO; 100 μg / mL, Sigma Aldrich), a glycoprotein with iron chelating properties, only 1% to 1.5% of neuronal cell bodies were found to be immunopositive. Similarly, two non-antibiotic tetracycline compounds of formula (C) (3 μM) and formula (Ib) (3 μM) reduced the overexpression of p-tau in cortical cell bodies: see the table below:

[0374] Table: Effects of the compound of formula (Ib) and the compound of formula (C) on pathological tau expression in cultured cortical neurons

[0375]

[0376] p-tau+ (AT8 antibody) cell bodies were estimated in mature mouse cortical cultures exposed to DF12i from div7 to div11, followed by formaldehyde fixation and immunofluorescence and microscopy.

[0377] In the above table, a favorable response is synonymous with a decrease in the number of p-tau+ cell bodies in the presence of the treatment of interest and is represented by the symbols "+", "++", or "+++" (+++ = reference level). Conversely, an unfavorable response is represented by the symbol "-" and is synonymous with an increase in the number of p-tau+ cell bodies. Compounds of formula (Ib) and compounds of formula (C) reduce the number of p-tau+ cell bodies (possibly by limiting the effects of oxidative damage). APO reduces the number of p-tau+ cell bodies (possibly through its ability to chelate iron, thereby preventing iron-mediated oxidative stress).

[0378] In a word, the formula (C) compound described in formula (Ib) compound of the present invention and embodiment 6 suppresses the pathological phosphorylation of tau.The phosphorylation of tau protein is the first step of its aggregation.In fact, in Alzheimer's disease and the related diseases called tau disease, tau protein becomes hyperphosphorylated and mislocalized, which may contribute to its aggregation and toxicity.Therefore, the formula (Ib) compound of the present invention and formula (C) compound have therapeutic value in the treatment of the disease (particularly Alzheimer's disease and the related diseases called tau disease) related to protein tau.

[0379] Example 13: Comparison of neuroprotective effects of the compound of formula (Ic) according to the present invention and prior art compounds

[0380] Materials and methods

[0381] Midbrain mouse cultures undergo a maturation step until day 7 in vitro (div) and are then gradually exposed to DMEM / nutrient mixture F12 Ham supplemented with phenol red supplemented with 20 μg / mL insulin and 2 μM of the NMDA receptor blocker MK-801. Under these conditions, which favor low-level, sustained oxidative damage and ultimately dopamine cell death, treatment with a compound of formula (Ic) according to the invention (in a concentration range of 0.1 μM to 5 μM) and treatment with the glycoprotein apotransferrin (APO; 100 μg / mL), the latter being used as a reference neuroprotectant, are performed or not. At div14 days, the cultures are fixed and then subjected to tyrosine hydroxylase (TH) immunocytochemistry to assess the survival of dopamine neurons.

[0382] result

[0383] The results are as follows Figure 6 As shown. Figure 6 As can be seen from the above, the compound of formula (Ic) according to the present invention has high protection at only 0.5 μM, 1 μM and 5 μM. Therefore, these results show that the compound of formula (Ic) according to the present invention effectively protects dopamine neurons from degeneration in a concentration-dependent manner.

[0384] Furthermore, the compounds of formula (Ic) according to the present invention do not exhibit any antibacterial effect against bacteria.

[0385] Furthermore, the compound of formula (Ic) according to the present invention has an anti-inflammatory effect against 10 ng / mLLS at 5 µM, 25 µM and 50 µM.

[0386] Example 14: Analgesic effects of compounds of formula (Ia) and formula (C) according to the present invention

[0387] Materials and methods

[0388] In order to test the compounds (Ia) and (C) according to the present invention Analgesic effect , formalin pain test was performed, which included before pain behavior scoring, 50 μ L of 5.0% formalin solution was subcutaneously injected into the right hind paw of adult C57 / BL6 mice (Taylor and Basbaum, J Pain, 2000). The intensity of pain was estimated by recording the cumulative time (seconds) of the licking / biting behavior produced by the formalin injection reaction of animals. This reaction is divided into a short early stage (I phase) stage, followed by a longer late stage (II phase) stage. Pain scoring is carried out by using a video recording of the pain behavior caused by formalin by an experimenter who is not aware of the test treatment.

[0389] result

[0390] The results are as follows Figure 7 , Figure 8 and Fig. 9 As shown. It can be seen that both compound (Ia) and compound (C) according to the present invention showed analgesic effect. effect .

[0391] Example 15: Anti-inflammatory effect of the compound of formula (Ib) according to the present invention

[0392] Materials and methods

[0393] Primary mouse microglia cultured in serum-free Dulbecco's modified Eagle medium (DMEM) containing 15 mM Hepes were challenged with lipopolysaccharide (LPS, 10 ng / ml) for 24 hours in the presence or absence of 1 μM, 5 μM, 25 μM and 50 μM concentrations of the compound of formula (Ib) according to the present invention. Afterwards, the release of the proinflammatory cytokine TNF-α was assessed using an ELISA kit (ThermoFisherScientific).

[0394] result

[0395] The results are as follows Fig.10 As shown. Fig.10 As can be seen, the results show that the compound of formula (Ib) according to the present invention significantly reduced the pro-inflammatory effect of LPS at a concentration of 5 μM to 50 μM.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof for use in treating or preventing a disease selected from amyloidosis, pain, neurodegenerative diseases and neuroinflammatory diseases, wherein the formula (I) is as follows: ， wherein R1 and R3 are each independently selected from a hydrogen atom and a hydroxyl group.

2. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Ibis) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ibis) is as follows: ， Wherein R1 is a hydrogen atom or a hydroxyl group.

3. The compound for use according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ia) is as follows: 。 4. The compound for use according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ib) is as follows: 。 5. The compound for use according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (Ic) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ic) is as follows: 。 6. The compound for use according to any one of claims 1 to 5, wherein the disease is selected from the group consisting of amyloidosis, neuropathic pain, neurodegenerative diseases and neuroinflammatory diseases.

7. The compound for use according to any one of claims 1 to 6, wherein the neurodegenerative disease or neuroinflammatory disease is selected from the group consisting of Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, Alzheimer's disease, prion disease, multiple sclerosis, limbic predominant age-associated TDP-43 encephalopathy (LATE) and Huntington's disease.

8. The compound for use according to any one of claims 1 to 7, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease, preferably the neurodegenerative disease is Parkinson's disease.

9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, and at least one pharmaceutically acceptable excipient, wherein the formula (I) is as follows: ， wherein R1 and R3 are each independently selected from a hydrogen atom and a hydroxyl group.

10. The pharmaceutical composition according to claim 9, wherein the compound of formula (I) is a compound of formula (Ibis) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ibis) is as follows: ， Wherein R1 is a hydrogen atom or a hydroxyl group.

11. The pharmaceutical composition according to claim 9 or 10, wherein the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ia) is as follows: 。 12. The pharmaceutical composition according to claim 9 or 10, wherein the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt, a solvate thereof or a mixture thereof, wherein the formula (Ib) is as follows: 。 13. The pharmaceutical composition according to claim 9 or 10, wherein the compound of formula (I) is a compound of formula (Ic) or a pharmaceutically acceptable salt, a solvate or a mixture thereof, wherein the formula (Ic) is as follows: 。 14. The pharmaceutical composition according to any one of claims 9 to 13, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, magnesium stearate, povidone, hydrogenated castor oil, colloidal anhydrous silicon dioxide, sodium carboxymethyl starch, and combinations thereof.

15. A pharmaceutical composition according to any one of claims 9 to 14 for use as a medicament.

16. A pharmaceutical composition according to any one of claims 9 to 14 for use in the treatment or prevention of a disease selected from amyloidosis, pain, neurodegenerative diseases and neuroinflammatory diseases, Preferably, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, diffuse Lewy body disease, multiple system atrophy, Alzheimer's disease, prion disease, multiple sclerosis, limbic predominant age-associated TDP-43 encephalopathy (LATE) and Huntington's disease, More preferably, the neurodegenerative disease is Parkinson's disease.

17. The pharmaceutical composition for use according to any one of claims 15 to 16, wherein the pharmaceutical composition is administered by an administration route selected from the group consisting of oral route, intrathecal route, intraarterial route, intravenous route, intramuscular route and subcutaneous route, preferably the pharmaceutical composition is administered by oral route.

18. A 12a-deoxytetracycline for use in the treatment of pain.

19. The 12a-deoxytetracycline for use according to claim 18, wherein the 12a-deoxytetracycline is selected from the following compounds: 、 、 、 、 、 and 。 20. 12a-deoxytetracycline for use according to any one of claims 18 to 19, wherein the pain is selected from: neuropathic pain, nociceptive pain or central pain.

21. 12a-deoxytetracycline for use according to any one of claims 18 to 20, wherein the pain is nociceptive pain caused by a disease selected from osteoarthritis, rheumatoid arthritis and cancer, preferably nociceptive pain caused by cancer.

22. 12a-deoxytetracycline for use according to any one of claims 18 to 20, wherein the pain is neuropathic pain caused by diabetic neuropathy.

23. 12a-deoxytetracycline for use according to any one of claims 18 to 20, wherein the pain is central pain caused by a disease selected from fibromyalgia, irritable bowel syndrome or tension headache.

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