Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C251/32—Oximes
  • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/10—Laxatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
  • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
  • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
  • C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes

Definitions

• New oxime derivatives of 3,5-seco-4-nor-cholestane, pharmaceutical compositions containing them, and process for their preparation New oxime derivatives of 3,5-seco-4-nor-cholestane, pharmaceutical compositions containing them, and process for their preparation
• the present invention relates to novel chemical compounds, particularly oxime derivatives of 3,5-seco-4-nor-cholestane, their application as medicaments, especially as cytoprotective drugs, particularly as neuroprotective, cardioprotective and / or hepatoprotective drugs. .
• the said medicaments are particularly suitable for pathologies and traumas related to degeneration or cell death, particularly those of motor neurons and / or cardiomyocytes and / or hepatocytes.
• the invention also relates to pharmaceutical compositions comprising said compounds, and to a process for their preparation.
• Cell degenerative processes are characterized by cell dysfunction often resulting in unwanted cellular activities and cell death.
• Cells have developed coping mechanisms, in response to stress, that prolong their lifespan or delay or prevent cell death (cytoprotective mechanisms).
• cytoprotective mechanisms are sometimes insufficient, inadequate, or induced too late to be effective and the cells die. It may be interesting to have new drugs, cytoprotective, which would promote cytoprotection.
• necrosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis apoptosis .
• Necrosis is an "accidental" cell death that occurs during tissue damage. It is the plasma membrane of the cell that is the most affected, causing a change in the homeostasis of the cell. The cells will gorge with water to the point that it will cause the lysis of their plasma membrane. This cell lysis leads to the release into the surrounding environment of the cytoplasmic content. Necrosis is at the origin of the inflammatory process. Necrosis can affect a set of cells or tissue while other neighborhood parts remain alive. The resulting transformation is a mortification of cells or tissues.
• necrosis is defined by morphological changes occurring when a cell reaches the end of life following events such as major trauma such as a stop or a decrease in blood flow in an organ, hyperthermia (significant rise in temperature), intoxication by a chemical, physical shock, etc.
• major trauma such as a stop or a decrease in blood flow in an organ
• hyperthermia significant rise in temperature
• intoxication by a chemical, physical shock etc.
• necroses is that of the myocardium during infarction (circulatory failure of the cardiac muscle) due to obliteration (obstruction) of a coronary artery.
• Apoptosis is an integral part of the normal physiology of an organism. It is a physiological form of highly regulated cell death and is necessary for the survival of multicellular organisms. Apoptosis is a process that plays a vital role during embryogenesis.
• Apoptotic or apoptotic cells will isolate themselves from other cells.
• Apoptosis usually involves individual cells in a tissue and does not cause inflammation.
• One of the characteristic morphological points of apoptosis is the important condensation of both the nucleus and the cytoplasm, which induces a significant decrease in cell volume. The nucleus then breaks up, each fragment is surrounded by a double envelope. Apoptotic bodies
• cytoplasmic and nuclear elements are then released and will be absorbed by phagocytosis by neighboring cells.
• Apoptosis can be induced in different ways.
• a radiation, the presence of a chemical compound or a hormone are stimuli capable of inducing a cascade of apoptotic events in the cell.
• Intracellular signals such as incomplete mitosis or DNA damage can also induce apoptosis.
• Apoptosis also occurs after the action of a genotoxic or during a disease. Some pathologies are characterized by abnormal apoptosis, leading to the loss of certain cell populations, such as hepatotoxicity, retinopathies, cardiotoxicity. We therefore distinguish between physiological apoptosis and pathological apoptosis.
• the invention is advantageously directed to pathological apoptosis.
• necroptotic dying cell has characteristics similar to those of a necrotic dying cell, but the biochemical steps of this mechanism are more similar to those of apoptosis. This mechanism of cell death occurs for example in ischemia.
• Cellular degenerative processes can result, among other things, from pathological situations grouped under the term degenerative diseases or conditions, trauma, or exposure to various factors.
• These traumas and factors may include, for example, exposure to radiation (UV, gamma), hypoxia or oxygen deprivation, nutrient deprivation, deprivation of growth factors, poisons, cellular toxins, waste, environmental toxins, free radicals, reactive oxygen.
• osteoporosis diseases of bones, joints, connective tissue and cartilage
• osteomyelitis arthritis including, for example, rheoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, fibrodysplasia ossificans progressive, rickets, Cushing's syndrome
• rheoarthritis rheumatoid arthritis
• psoriatic arthritis avascular necrosis
• fibrodysplasia ossificans progressive rickets
• Cushing's syndrome Cushing's syndrome
• muscular diseases such as muscular dystrophy, such as Duchenne muscular dystrophy, myotonic dystrophies, myopathies and myasthenias;
• skin diseases such as dermatitis, eczema, psoriasis, aging, or alterations in healing;
• cardiovascular diseases such as cardiac and / or vascular ischemia, myocardial infarction, ischemic heart disease, chronic or acute heart failure, cardiac dysrhythmias, atrial fibrillation, ventricular fibrillation, paroxysmal tachycardia, heart failure, hypertrophic cardiomyopathy, anoxia, hypoxia, side effects due to therapies with anticancer agents, cardiac lesions associated with reperfusion following accidental or induced ischemia (surgical procedure); "circulatory diseases such as atherosclerosis, arterial sclerosis, peripheral vascular disease, stroke, aneurysms;
• B haematological and vascular diseases such as: anemia, vascular amyloidosis, haemorrhage, sickle cell anemia, red cell fragmentation syndrome, neutropenia, leukopenia, aplastic anemia, pancytopenia, thrombocytopenia, hemophilia; • lung diseases including pneumonia, asthma; chronic obstructive lung diseases such as chronic bronchitis and emphysema;
• liver diseases such as hepatitis especially hepatitis of viral origin or causative agent of other infectious agents, alcoholic hepatitis, autoimmune hepatitis, fulminant hepatitis, certain inherited metabolic disorders, Wilson's disease , cirrhosis, alcoholic liver disease (ALD), liver disease due to toxins or drugs; steatosis as for example:
• Non-alcoholic fatty liver disease or accompanying exogenous intoxication with alcohol, drugs, viral or toxic hepatitis, complications of surgical procedures, metabolic diseases (such as diabetes, glucose intolerance syndrome , obesity, hyperlipidemia, hypothalamic-pituitary axis dysfunction, abetalipoproteinemia, galactosemias, glycogen diseases, Wilson's disease, Weber-Christian disease, Refsum's syndrome, carnitine deficiency),
• metabolic diseases such as diabetes, glucose intolerance syndrome , obesity, hyperlipidemia, hypothalamic-pituitary axis dysfunction, abetalipoproteinemia, galactosemias, glycogen diseases, Wilson's disease, Weber-Christian disease, Refsum's syndrome, carnitine deficiency
• the compounds could have a preventive action on the development of liver fibrosis and the prevention of the occurrence of cirrhosis.
• pancreas diseases of the pancreas such as acute or chronic pancreatitis
• metabolic diseases such as diabetes mellitus and tasteless, thyroiditis
• Kidney diseases such as, for example, acute renal disorders or glomerulonephritis
• disorders associated with aging such as accelerated aging syndrome; > inflammatory diseases, such as Crohn's disease, rheumatoid arthritis;
• autoimmune diseases such as lupus erythematosus
• dental disorders such as those leading to tissue damage such as periodontitis
• Ophthalmic diseases or disorders including diabetic retinopathies, glaucoma, macular degeneration, retinal degeneration, retinitis pigmentosa, retinal holes or tears, retinal detachment, retinal ischemia, acute retinopathies associated with trauma, inflammatory degeneration, post-surgical complications, drug retinopathies, cataracts;
• B mitochondrial diseases mitochondrial diseases (mitochondrial pathologies), such as Friedrich ataxia, congenital muscular dystrophy with structural mitochondrial abnormality, certain myopathies (MELAS syndrome, MERFF syndrome, Pearson syndrome), MIDD syndrome (diabetes mitochondria and deafness), Wolfram syndrome, dystonia.
• mitochondrial diseases such as Friedrich ataxia, congenital muscular dystrophy with structural mitochondrial abnormality, certain myopathies (MELAS syndrome, MERFF syndrome, Pearson syndrome), MIDD syndrome (diabetes mitochondria and deafness), Wolfram syndrome, dystonia.
• neurodegenerative processes are characterized by the dysfunction and death of neurons resulting in the loss of neurological functions mediated by the brain (central nervous system, CNS) 1 the spinal cord and the peripheral nervous system (PNS). They can result, among others, pathological situations grouped under the term of diseases or neurodegenerative affections, of traumatism, or of exposure to toxins.
• CNS central nervous system
• PNS peripheral nervous system
• chronic neurodegenerative diseases especially chronic demyelinating, hereditary or sporadic diseases, advantageously Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal amyotrophies, particularly infantile, Creutzfeldt's disease.
• Jakob multiple sclerosis, amyotrophic lateral sclerosis, leukodystrophies including adrenoleukodystrophy, epilepsy, dementia, schizophrenia, and neurological syndromes associated with AIDS;
• hereditary or lesional peripheral neuropathies such as Fabry, Charcot-Marie-Tooth, Krabbe diseases, leukodystrophies, diabetic neuropathies and those induced by anti-cancer treatments;
• the degeneration hereditary, lesion-related or aging-related sensory neurons of vision, such as macular degeneration, retinitis pigmentosa, or degeneration of the optic nerve induced by glaucoma;
• Alzheimer's disease is the most common dementia. It shows atrophy of the brain, a predominant neuronal loss in the Ammon's horn and it also affects cholinergic neurons.
• Other pathologies such as lobar atrophy (Pick's disease, Creutzfeld-Jakob disease), Lewy body dementia, vascular dementia, Parkinson's disease, are associated with significant neuronal death causing symptoms. of these dementias.
• a therapeutic approach to protect neurons from death is the supply of neurotrophic proteins.
• BDNF brain-derived neurotrophic factor
• CNFF ciliary neurotrophic factor
• NGF nerve growth factor
• GDNF glia-derived neurotrophic factor
• neurotrophic molecules for the treatment of neuronal degeneration has three objectives:
• motor neurons are neurons especially present in the spinal cord and the brainstem. Their degeneration or death can lead to a progressive weakness of the limb muscles, then to atrophy and possibly to spasticity (ie permanent contraction) of the muscle.
• amyotrophic lateral sclerosis also known as Charcot's disease or Lou Gehrig's disease
• spinal amyotrophies particularly infantile ones.
• Werdnig-Hoffmann disease also known as Werdnig-Hoffmann disease or Kugelberg-Welander disease.
• ALS Amyotrophic Lateral Sclerosis
• the compounds of the present invention in addition to being new, have very interesting pharmacological properties.
• cytoprotective particularly neuroprotective and / or cardioprotective and / or hepatoprotective.
• some of these new compounds may also have advantageous properties in relation to their pharmacological activity, such as their pharmacokinetics, bioavailability, solubility, stability, toxicity, absorption and / or metabolism. This makes them very useful for the preparation of a medicament, particularly for the preparation of a cytoprotective drug, very particularly neuroprotective and / or cardioprotective and / or hepatoprotective.
• R 1 may represent a hydrogen atom or a group -CH 3 , -CH 2 -CN, -CH 2 -OR 3 , -CH 2 -SR 3 , -CH 2 -SeR 3 , -C (O) OR 3 , -OC (O) NR 3 R b , -C (O) NR 3 R "wherein
• R a and R b may be chosen from a hydrogen atom or an alkyl group C 1 -C 6 cycloalkyl, C 3 - C 6 alkyl, aryl, heteroaryl or
• R a and R b taken together with the nitrogen to which they are attached may form a non-aromatic C 3 -C 6 heterocyl, said heterocycle possibly having one or more double bonds and / or one or more atoms ( s) oxygen, sulfur or nitrogen;
• R 2 may represent a hydrogen atom or an alkyl group Ci-C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8, or a halogen atom or a group of the formula (AT) :
• n can represent an integer that can take any of the values from 1 to 8.
• Q may represent an oxygen atom or a group -NR a in which R a is as defined above and R c may represent a hydrogen atom or a C 1 -C 6 alkyl, aryl, heteroaryl group , a heterocycle, C 1 -C 6 alkyl -C (O) -, aryl-C (O) -, heteroaryl-C (O) -, heterocycle-C (O) -, in particular a group represented by the one of the formulas (C) or (D)
• Q may represent a group -O-C (O) - or a group -NR a -C (O) - in which R a is as defined above and R c may represent a hydrogen atom or a group -C 6 alkyl, aryl, heteroaryl, heterocycle,
• R 3 may represent a hydrogen atom or an alkyl group Ci-C 6 cycloalkyl, C 3 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkyl, aryl, heterocycle, or a halogen atom or a group -CN, -CF 3 , -NO 2 , -OR a , -SR a , -SO 2 R a , -NR a R b , -OC (O) R a , -OC ( O) NR a R h , -C (O) OR 3 , -CONR a R b , R a and R b may be as defined above;
• R 4 can represent a hydrogen atom or a C 1 -C 6 alkyl group, or R 3 and R 4 taken together with the carbon to which they are attached, can form a (C 3 -C 6 ) - cycloalkyl;
• R 5 may represent a hydrogen atom or a C 1 -C 6 alkyl group, preferentially a hydrogen atom or a hydroxyamino (-NH 2 -OH) group or • R 4 and R 5 taken together can form an additional carbon-carbon bond between the carbon atoms to which they are attached, or a cycloalkyl group;
• R 6 may represent a hydrogen atom or an alkyl group Ci-C 6 cycloalkyl, C 3 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 aryl, or a group - CN 1 - OR a , -SR a , -SO 2 R 3 , -NR a R b , -OC (O) R 3 , -OC (O) NR a R b , R a and R b may be as defined previously, or a hydroxyamino group (-NH 2 -OH);
• R 7 may represent alkyl C 2 -C 4 alkenyl, C 4 -C 12 alkynyl group or a C 4 -C 2 in particular a group selected from
• C x -C y alkyl refers to a linear or branched hydrocarbon radical containing from x to y carbon atoms.
• the invention according to the listed cases covers linear or branched hydrocarbon radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, n-hexyl and the like.
• C 1 -C 6 alkyl groups are preferred.
• the alkyl groups may optionally be substituted with an aryl group as defined below, in which case arylalkyl groups are preferred. Examples of arylalkyl groups include benzyl and phenethyl.
• the alkyl groups may be substituted one or more times with one of the substituents independently selected from a halogen atom or a group -CN, -CF 3 , -COOR a , -CONR a R b , -O-CONR a R b , -NR a R b , -OR a , -SR b , the groups R a and R b may be as described above.
• C x -C y alkenyl refers to a linear or branched or cyclic hydrocarbon radical, comprising one or more double bonds, having from x to y carbon atoms.
• the alkenyl groups may be substituted one or more times with one of the substituents independently selected from a halogen atom or a group -CN, -CF 3 , -COOR a , -C (O) NR a R, -O-C (O) NR 3 R ", -NR a R b , -OR a -SR b , the groups R a , R b may be as previously described;
• C x -C y cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon radical having from x to y carbon atoms.
• Cycloalkyl groups include, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl substituents.
• the cycloalkyl groups may be substituted one or more times with one of the substituents independently selected from a halogen atom or a group -CN, -CF 3 , -COOR a , -C (O) NR 3 R “, -OC (O) NR a R b , -NR 3 R “, -OR 3 , -SR 3 , the group R 3 , R b may be as previously described;
• alkynyl, C x -C y refers to a hydrocarbon radical straight, branched, including at least one triple bond, having from x to y carbon atoms.
• the alkynyl groups include, in particular, the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-heptynyl, 2-heptynyl, 1-octynyl and 2-octynyl substituents.
• the alkynyl groups may be substituted one or more times with one of the substituents chosen independently from a halogen atom or a group -CN, -CF 3 , -COOR 3 , -C (O) NR 3 R “, -O -C (O) NR 3 R “, -NR a R b , -OR 3 , -SR 3 , the groups R a , R b may be as described above; the term "C x -C y aryl" refers to an aromatic hydrocarbon radical having x to y carbon atoms.
• aromatic hydrocarbon radicals having 6 carbon atoms are preferred.
• the aryl groups include in particular the phenyl, naphthyl and bi-phenyl radicals.
• the aryl groups may be substituted one or more times with one of the substituents chosen independently from a halogen atom or an alkyl group, -CN, -CF 3 , -N 3 , -NO 2 , -COOR 3 , -C (O) NR 3 R ", -OC (O) NR a R b , -NR 3 R", -OR a , -SR a , the groups R 3 , R b may be as previously described;
• heterocycle C x -Cy refers to a mono- or polycyclic, saturated, unsaturated or aromatic, optionally substituted, which may contain from x to y carbon atoms and comprising one or more heteroatoms.
• the heteroatoms are selected from oxygen, sulfur and nitrogen.
• heterocycle examples include furyl, thienyl, pyrrole, imidazole, isothiazole, thiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine, quinazoline, pyrrolidine, imidazolidine, pyrrazolidine, piperidine, piperazine, morpholine, thiazolidine or phthalimide. benzimidazole.
• the heterocyl groups can be substituted one or more times with one of the substituents chosen independently from a halogen atom or an alkyl group, -CN, -CF 3 , -N 3 , -NO 2 , -COOR a , -C (O) NR 3 R “ , -OC (O) NR a R b, -NR a R b, -0R a, -SR a, R a, R b being as previously described;> the term "halogen” refers to an atom preferably, chlorine, bromine, fluorine and iodine, the halogen being a fluorine atom;
• treatment refers to preventive, curative and palliative treatment, as well as the management of patients (reduction of suffering, improvement of the duration of life, slowing of progression of the disease), etc.
• the treatment may also be carried out in combination with other ingredients or treatments, such as in particular other active compounds for treating the pathologies or traumas specified in the present application;
• cytoprotective refers to the ability of agents, for example chemical compounds, natural or not, to maintain cell interactions with each other or with other tissues, to protect cells against degenerative phenomena leading to a loss of cellular function or unwanted cellular activities, with or without cell death, and / or against cellular dysfunctions and / or against degenerative diseases or conditions leading to these cellular dysfunctions, said dysfunctions or said diseases or conditions leading or not leading to cell death;
• neuroprotective or “cardioprotective” or “hepatoprotective” refer to the same properties of said agents but specifically for the cells of the nervous system (“neuroprotector”) or specifically for the cells of the cardiac system (“cardioprotective”), or specifically for the cells of the hepatic system (“hepatoprotective”). It is thus understood that a cytoprotective or neuroprotective or cardioprotective or hepatoprotective compound is a compound which has the previously described properties.
• Particularly preferred compounds of formula (I) are those in which, individually or in combination: - the substituent R 1 can be chosen from a group -CH 3 and a group
• the substituent R 1 may represent a group -CH 3 ;
• the substituent R 2 may be chosen from a C 1 -C 8 alkyl group, optionally a C 1 -C 4 alkyl, -CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -CF 2 -CH 3, -CH 2 -CH 2 - CH (OH) -CF 3, CH 2 -CH (OH) -CF 3 and -CH 2 -CH 2 -OH.
• the substituent R 2 can be chosen from a group -CH 2 -CH 2 -CH 3 and -CH 2 -CH 2 -OH;
• the substituent R 3 can be chosen from a hydrogen atom, an alkyl group or a fluorine atom.
• the substituent R 3 can be chosen from a hydrogen atom or a fluorine atom;
• R 4 , R 5 and R 6 may be hydrogen atoms
• the group R 3 represents a halogen atom, preferably a fluorine atom.
• the preferred substituent R 2 may represent a group corresponding to the following formula (A):
• Q can represent a group -NR a in which R a may represent a group CH 3 and
• R - R c can represent the group corresponding to the formula (C)
• Q can represent a group NR a , in which R a may represent a group CH 3 , and
• R - R c may represent a group chosen from aryl, heteroaryl, heterocycle, in particular the group corresponding to the following formula (D):
• the compounds for which R 4 together with R 5 form an additional CC bond between the carbon atoms on which R 4 and R 5 are attached are also preferred.
• R 6 may represent an alkyl group, in particular a methyl or ethyl group, are also preferred compounds.
• the substituent R 7 which is particularly preferred according to the invention is chosen from the following groups G 1, G 2 and G 5:
• the preferred compounds according to the present invention are:
• the addition salts with pharmaceutically acceptable acids may be for example salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric acids, oxalic, glyoxylic, aspartic, alkane sulfonic acids such as methane or ethanesulphonic, arylsulphonic acids, such as benzene or paratoluenesulphonic acids, or carboxylic acids.
• Some preferred compounds of the present invention have one or more fluorine atoms.
• fluorine atoms such as 3,3-difluoro-3-methyl-4,5-secocholestan-5-one oxime and 4-nor-3,5-seco-3- (trifluoromethyl) cholestan oxime -3-ol-5-one are particularly preferred.
• the atom that can represent the general term "halogen” can also be a isotope, natural or synthetic, radioactive as for example for fluorine, fluorine-18 ( 18 F).
• the radiolabeled compounds of formula (I), particularly those labeled with the 18 F isotope, can be very useful for medical imaging, in particular for Positron Emission Tomography (PET) which is an in vivo imaging technique developed for the diagnosis of diseases, for example in the field of oncology, neurology and cardiology.
• PET Positron Emission Tomography
• bromine-75 75 Br
• iodine-124 124 I
• halogen may also cover, according to the present text, isotopes, natural or synthetic, non-radioactive, such as, for example, a non-radioactive isotope fluor-19 ( 19 F), useful for biomedical research, and in particular for cognitive neuroscience and neuroscience. particularly for Magnetic Resonance Imaging (MRI) technique.
• isotopes natural or synthetic, non-radioactive, such as, for example, a non-radioactive isotope fluor-19 ( 19 F), useful for biomedical research, and in particular for cognitive neuroscience and neuroscience. particularly for Magnetic Resonance Imaging (MRI) technique.
• 19 F non-radioactive isotope fluor-19
• the compounds which are the subject of the present invention possess very interesting pharmacological properties. They are endowed notably with remarkable cytoprotective properties, particularly neuroprotective, very particularly with regard to motor neurons, and cardioprotective and hepatoprotective.
• the compounds according to the invention exhibit remarkable activity with respect to motor neurons, neurons of the central nervous system, motor and peripheral nerves.
• the subject of the invention is also the use as a medicament of compounds of formula (I), including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino-4 methyl n-3,5-secostigmastan-3-oate, methyl 5-hydroxyimino-4-nor-3,5-secocho-3-oate, 4,5-secocholestan-3-yn-5 -one oxime, 24-methyl-N-nor-1,5-secocholest-22-en-5-one oxime, 4-methylidyne-4,5-secocholestan-5-one oxime, 4-methyl-4 5-secocholestan-3-yn-5-one oxime, methyl 5-hydroxyimino-4,5-secocholestan-4-oate, 3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime and
• the invention therefore also relates to the use of a compound of formula (I), including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino-4-nor- 3,5-secostigmastan-3-oate methyl, methyl 5-hydroxyimino-4-nor-3,5-secocho!
• the compounds according to the present invention can be used for the preparation of a medicament for the treatment or prevention of pathological necrosis and / or apoptosis and / or necroplosis (medicaments).
• antinecrotic and / or antiapoptotic and / or antinecroptotic) or the treatment or prevention of conditions such as: "diseases of bones, joints, connective tissue and cartilage, such as osteoporosis, osteomyelitis, arthritis for example, osteoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, fibrodysplasia ossificans progressive, rickets, Cushing's syndrome;
• muscular dystrophy such as Duchenne muscular dystrophy, myotonic dystrophies, myopathies and myasthenia
• skin diseases such as dermatitis, eczema, psoriasis, aging, or alterations in healing
• cardiovascular diseases such as cardiac and / or vascular ischemia, myocardial infarction, ischemic heart disease, chronic or acute heart failure, cardiac dysrhythmias, atrial fibrillation, ventricular fibrillation, paroxysmal tachycardia, heart failure, hypertrophic cardiomyopathy, anoxia, hypoxia, side effects due to therapies with anticancer agents, cardiac lesions associated with reperfusion following accidental or induced ischemia (surgical procedure); > circulatory diseases such as atherosclerosis, arterial sclerosis, peripheral vascular diseases, cerebrovascular accidents, aneurysms;
• hematologic and vascular diseases such as: anemia, vascular amyloidosis, haemorrhage, sickle cell disease, red cell fragmentation syndrome, neutropenia, leukopenia, bone marrow suppression, pancytopenia, thrombocytopenia, hemophilia;
• B lung diseases including pneumonia, asthma; chronic obstructive lung diseases such as chronic bronchitis and emphysema; diseases of the gastrointestinal tract, such as ulcers;
• liver diseases such as hepatitis, especially hepatitis of viral origin or the causal agent of other infectious agents, alcoholic hepatitis, autoimmune hepatitis, fulminant hepatitis, certain hereditary metabolic disorders, Wilson, cirrhosis, alcoholic liver disease (ALD), liver disease due to toxins or drugs; steatosis as for example:
• Non-alcoholic fatty liver disease or accompanying exogenous intoxication with alcohol, drugs, viral or toxic hepatitis, complications of surgical procedures, metabolic diseases (such as diabetes, glucose intolerance syndrome , obesity, hyperlipidemia, hypothalamic-pituitary axis dysfunction, abetalipoproteinemia, galactosemias, glycogen diseases, Wilson's disease, Weber-Christian disease, Refsum's syndrome, carnitine deficiency),
• metabolic diseases such as diabetes, glucose intolerance syndrome , obesity, hyperlipidemia, hypothalamic-pituitary axis dysfunction, abetalipoproteinemia, galactosemias, glycogen diseases, Wilson's disease, Weber-Christian disease, Refsum's syndrome, carnitine deficiency
• pancreatic diseases such as acute or chronic pancreatitis
• metabolic diseases such as diabetes mellitus and tasteless, thyroiditis
• kidney diseases such as, for example, acute renal disorders or glomerulonephritis
• "Viral and bacterial infections such as sepsis;
• autoimmune diseases such as lupus erythematosus
• dental disorders such as those leading to tissue damage such as periodontitis
• Ophthalmic diseases or disorders including diabetic retinopathies, glaucoma, macular degeneration, retinal degeneration, retinitis pigmentosa, retinal holes or tears, retinal detachment, retinal ischemia, acute retinopathies associated with trauma, inflammatory degeneration, post-surgical complications, drug retinopathies, cataracts;
• Mitochondrial-associated diseases such as Friedrich ataxia, congenital muscular dystrophy with structural mitochondrial abnormality, certain myopathies (MELAS syndrome, MERFF syndrome, Pearson syndrome), MIDD syndrome (diabetes mitochondrial and deafness), Wolfram syndrome, dystonia, etc.
• the drugs according to the present invention find their use because of their neuroprotective properties in the treatment or at the prevention of neurodegenerative diseases, such as Huntington's disease, chronic neurodegenerative diseases, advantageously chronic demyelinating, hereditary or sporadic neurodegenerative diseases, aging-related neuronal lesions, peripheral neuropathies, hereditary or lesional neuropathies, diabetic neuropathies or those induced by neurodegenerative diseases.
• neurodegenerative diseases such as Huntington's disease, chronic neurodegenerative diseases, advantageously chronic demyelinating, hereditary or sporadic neurodegenerative diseases, aging-related neuronal lesions, peripheral neuropathies, hereditary or lesional neuropathies, diabetic neuropathies or those induced by neurodegenerative diseases.
• anti-cancer treatments trauma to the brain, peripheral nerves or spinal cord, ischemia of the brain or spinal cord, epilepsies, hereditary, lesion-related or age-related degeneration of sensory neurons of vision or degeneration of the optic nerve, hereditary, traumatic or age-related degeneration of sensory neurons of hearing, lobar atrophy and vascular dementia, and in particular spinal amyotrophies, amyot lateral sclerosis rophic and pathological conditions due to traumatisms of the spinal cord or peripheral motor nerves.
• the daily dose of the compound will be the minimum dose to achieve the therapeutic effect. This dose will depend on the various factors mentioned previously.
• the daily dose may be administered in two, three, four, five, six or more doses taken daily or in multiple sub-doses administered at appropriate intervals during the day.
• the amount selected will depend on multiple factors, in particular the route of administration, the duration of administration, the timing of administration, the rate of elimination of the compound, or the different products used in combination. with the compound, age, weight and physical condition of the patient, as well as its medical history, and other information known in medicine.
• the prescribing physician's prescription may begin at doses lower than those generally used, then these doses will be gradually increased to better control the appearance of possible side effects.
• the invention also relates to pharmaceutical compositions which comprise at least one compound of formula (I), including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino-4-nor Methyl 3,5-secostigmastan-3-oate, methyl 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate, 4,5-secocholestan-3-yn-5-one oxime, 24-methyl-N-nor-1,5-secocholest-22-en-5-one oxime, 4-methylidyne
• formula (I) including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino-4-nor Methyl 3,5-secostigmastan-3-oate, methyl 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate, 4,5-secocholestan-3-yn-5-one oxime, 24-methyl-N-nor-1,5-secochol
• 4,5-secocholestan-5-one oxime 4-methyl-4,5-secocholestan-3-yn-5-one oxime, methyl 5-hydroxyimino-4,5-secocholestan-4-oate, 3 -acetyloxy-4-nor-3,5-secocholestan-5-one oxime and / or 24-N, N-diethylcarbamoyl-3,5-seco-4- ⁇ -cholan-5-hydroxyimino-3-oic acid or one of its esters and / or its addition salts with pharmaceutically acceptable acids, as active principle.
• the active ingredient is advantageously present at physiologically effective doses; the aforementioned compositions may comprise in particular an effective neuroprotective dose of at least one active ingredient above.
• compositions according to the invention may also comprise at least one other therapeutically active ingredient, for simultaneous, separate or spread use over time, in particular during a treatment in a subject suffering from a pathology or trauma. related to the degeneration or death of cells particularly heart cells and / or motoneurons as defined above.
• compositions or medicaments according to the invention advantageously comprise one or more excipients or inert vehicles, that is to say pharmaceutically inactive and non-toxic.
• excipients or inert vehicles for example, saline, physiological, isotonic, buffered, etc., solutions compatible with a pharmaceutical use and known to those skilled in the art may be mentioned.
• the compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc.
• Agents or vehicles that can be used in formulations include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, cyclodextrins, polysorbate 80, mannitol, gelatin, lactose, vegetable oils or animal, acacia, etc.
• the compositions may be formulated as injectable suspension, gels, oils, tablets, suppositories, powders, capsules, capsules, etc., optionally using dosage forms or devices providing sustained and / or delayed release.
• an agent such as cellulose, carbonates or starches is advantageously used.
• the administration can be carried out by any method known to those skilled in the art, preferably orally or by injection, typically intraperitoneally, intra-cerebrally, intrathecally, intravenously, intra-arterially or intramuscularly. .
• Oral administration is preferred.
• the preferred route of administration will be sublingual, oral or transcutaneous.
• the compounds are generally packaged as liquid suspensions, which can be injected by means of syringes or infusions, for example. It is understood that the rate and / or the injected dose, or in general the dose to be administered, may be adapted by those skilled in the art depending on the patient, the pathology, the mode of administration, etc. It is understood that repeated administrations can be performed, optionally in combination with other active ingredients or any pharmaceutically acceptable carrier (buffers, saline, isotonic, in the presence of stabilizing agents, etc.).
• the invention is usable in mammals, especially in humans.
• the subject of the present invention is also a process for the preparation of a composition described above, characterized in that, by methods known per se, the active principle (s) are mixed with acceptable excipients, in particular pharmaceutically acceptable excipients. .
• the subject of the invention is particularly the use of a compound of formula (I) above, including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino-4- normal 3,5-secostigmastan-3-oate methyl, 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate methyl, 4,5-secocholestan-3-yn-5-one oxime, the 24-methyl-N-nor-1,5-secocholest-22-en-5-one oxime, 4-methylidyne-4,5-secocholestan-5-one oxime, 4-methyl-4,5-secocholestan 3-yn-5-one oxime, methyl 5-hydroxyimino-4,5-secocholestan-4-
• the invention more particularly relates to the use of a compound of formula (I) above, including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino Methyl 4-nor-3,5-secostigmastan-3-oate, methyl 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate, 4,5-secocholestan-3-yn-5- one oxime, 24-methyl-N-nor-1,5-secocholest-22-en-5-one oxime, 4-methylidyne-4,5-secocholestan-5-one oxime, 4-methyl-4, 5-secocholestan-3-yn-5-one oxime, methyl 5-hydroxyimino-4,5-secocholestan-4-oate, 3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime and or 24-N, N-diethylcarbamoyl-3,5-seco-4-nor-chol
• osteoporosis diseases of the bones, joints, connective tissue and cartilage
• osteomyelitis arthritis including, for example, rheoarthritis, rheumatoid arthritis and psoriatic arthritis, avascular necrosis, fibrodysplasia ossificans progressive, rickets, Cushing's syndrome;
• muscular dystrophy such as Duchenne muscular dystrophy, myotonic dystrophies, myopathies and myasthenia
• skin diseases such as dermatitis, eczema, psoriasis, aging, or alterations in healing
• cardiovascular diseases such as cardiac and / or vascular ischemia, myocardial infarction , ischemic heart disease, chronic or acute heart failure, cardiac dysrhythmia, atrial fibrillation, ventricular fibrillation, paroxysmal tachycardia, heart failure, hypertrophic cardiomyopathy, anoxia, hypoxia, side effects due to Has therapies with anticancer agents, cardiac lesions associated with reperfusion following accidental or induced ischemia (surgical procedure);
• Circulatory diseases such as atherosclerosis, arterial sclerosis, and peripheral vascular diseases, stroke, aneurysms;
• hematologic and vascular diseases such as: anemia, vascular amyloidosis, haemorrhage, sickle cell disease, red cell fragmentation syndrome, neutropenia, leukopenia, bone marrow suppression, pancytopenia, thrombocytopenia, hemophilia; - lung diseases including pneumonia, asthma; chronic obstructive lung diseases such as chronic bronchitis and emphysema;
• liver diseases such as hepatitis, especially hepatitis of viral origin or the causal agent of other infectious agents, alcoholic hepatitis, autoimmune hepatitis, fulminant hepatitis, certain hereditary metabolic disorders, Wilson, cirrhosis, alcoholic liver disease (ALD), liver disease due to toxins or drugs; steatosis such as: - non-alcoholic fatty liver disease (NASH), or accompanying exogenous intoxication with alcohol, drugs, viral or toxic hepatitis, complications of surgical procedures, metabolic diseases (such as diabetes, glucose intolerance syndrome, obesity, hyperlipidemia, hypothalamic-pituitary axis dysfunction, abetalipoproteinemia, galactosemias, glycogen diseases,
• metabolic diseases such as diabetes, glucose intolerance syndrome, obesity, hyperlipidemia, hypothalamic-pituitary axis dysfunction, abetalipoproteinemia, galactosemias, glycogen diseases,
• pancreatic diseases such as acute or chronic pancreatitis; • metabolic diseases such as diabetes mellitus and tasteless, thyroiditis; Kidney diseases such as, for example, acute renal disorders or glomerulonephritis;
• autoimmune diseases such as lupus erythematosus
• dental disorders such as those leading to tissue damage such as periodontitis
• Ophthalmic diseases or disorders including diabetic retinopathies, glaucoma, macular degeneration, retinal degeneration, retinitis pigmentosa, retinal holes or tears, retinal detachment, retinal ischemia, acute retinopathies associated with trauma, inflammatory degeneration, post-surgical complications, drug retinopathies, cataracts;
• mitochondrial diseases mitochondrial diseases (mitochondrial pathologies), such as Friedrich ataxia, congenital muscular dystrophy with structural mitochondrial abnormality, certain myopathies (MELAS syndrome, MERFF syndrome, Pearson syndrome), MIDD syndrome (diabetes mitochondria and deafness), Wolfram syndrome, dystonia, and especially
• Neurodegenerative diseases such as Huntington's disease, chronic neurodegenerative diseases, advantageously chronic demyelinating and neurodegenerative, hereditary or sporadic diseases, in particular multiple sclerosis and leukodystrophies, neuronal lesions associated with aging, hereditary peripheral neuropathies or lesions, Charcot-Marie-Tooth disease, diabetic or cancer-induced neuropathies, epilepsies, trauma to the brain, peripheral nerves or spinal cord, ischemia of the brain or spinal cord, degeneration hereditary, injury or aging sensory neurons of vision or degeneration of the optic nerve, hereditary, traumatic or age-related degeneration of sensory neurons of hearing, lobar atrophy and vascular dementia, diseases and trauma related to motor neuron degeneration and especially spinal muscular atrophy, especially amyotrophic lateral sclerosis, multiple sclerosis and spinal cord or peripheral motor nerve trauma.
• the subject of the invention is particularly the use of a compound of formula
• (I) including, 3,4-nor-2,5-secocholestan-5-one oxime, methyl 5-hydroxyimino-4-nor-3,5-secostigmastan-3-oate, 5-hydroxyimino Methyl 4,5-secocholestan-3-yn-5-one oxime, 24-methyl-A-nor-1,5-secocholest-22- 5-one oxime, 4-methylidyne-4,5-secocholestan-5-one oxime,
• the use of these drugs usually comprises administering to patients, particularly mammals, particularly humans, a therapeutically effective amount of a compound of formula I 1 including 3,4-nor-2, 5-secocholestan-5-one oxime, methyl 5-hydroxyimino-4-nor-3,5-secostigmastan-3-oate, methyl 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate 4,5-Secocholestan-3-yn-5-one oxime, 24-methyl-A-nor-1,5-secocholest-22-en-5-one oxime, 4-methylidyne-4,5 secocholestan-5-one oxime, 4-methyl-4,5-secocholestan-3-yn-5-one oxime, methyl 5-hydroxyimino-4,5-secocholestan-4-oate, 3-acetyloxy-4 -nor-3,5-secocholestan-5-one oxime and / or 24-N, N-diethylcarbamoyl
• the subject of the invention is also a method for treating the aforementioned diseases, in particular neurodegenerative diseases, and in particular a method for treating pathologies or traumas related to the degeneration or death of neurons, in mammals (generally patients) suffering from such pathologies or traumas, comprising administering to these mammals a therapeutically effective amount of a compound of formula I, including 3,4-nor-2,5-secocholestan-5-one oxime, 5- hydroxyimino-4-nor-3,5-secostigmastan-3-oate methyl, methyl 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate, 4,5-secocholestan-3-yn-5-one oxime, 24-methyl-A-nor-1, 5-secocholest-22-en-5-one oxime, 4-methylidyne-4,5-secocholestan-5-one oxime, 4-methyl-4,5-secocholestan-3-yn-5-one oxime, Methyl 5-hydroxyimin
• the invention furthermore relates to a method of treating one of the conditions described above and in particular pathologies or traumas related to the degeneration or death of motor neurons, in mammals (generally patients) suffering from such diseases. pathologies or traumas, comprising administering to these mammals a therapeutically effective amount of a compound of formula I 1 including 3,4-nor-2,5-secocholestan-5-one oxime, 5-hydroxyimino- Methyl 4-nor-3,5-secostigmastan-3-oate, methyl 5-hydroxyimino-4-nor-3,5-secocholestan-3-oate, 4,5-secocholestan-3-yn-5- one oxime, 24-methyl-N-nor-1,5-secocholest-22-en-5-one oxime, 4-methylidyne-4,5-secocholestan-5-one oxime, 4-methyl-4, 5-secocholestan-3-yn-5-one oxime, methyl 5-hydroxyimino-4,5-secocholestan
• the invention also relates to compounds comprising a labeling group detectable and / or visualizable directly or indirectly by the detection and / or visualization techniques known to those skilled in the art, such as the technique of fluorescence microscopy or the technique taking advantage of the very high affinity of avidins (streptavidin or neutravidin) for biotin (Ka ⁇ 10 7 M).
• labeling means an entity such as a radioactive isotope or a non-isotopic entity such as a fluorophore agent, a dye, a hapten, biotin, etc.
• fluorophore refers in general to the peculiarity of a substance to be fluorescent, that is to say to absorb light energy (excitation light) when excited by an energy source and to quickly restore it as fluorescent light (emission light). This particularity of being fluorophore makes it possible to envisage the use of such substance as a marker fluorescent in biological systems (membranes, cells, neurons, mitochondria, etc.) to perform, for example, the imaging of the cells studied.
• Biotin is a coenzyme, also called Vitamin H 1 synthesized by plants, bacteria and certain fungi. Biotin is detected using avidins (streptavidin or neutravidin) which have a very high affinity for biotin (Ka ⁇ 10 7 M).
• avidins streptavidin or neutravidin
• the structure of biotin is as follows:
• the labeling group according to the present invention may be chosen from biotin or a fluorophore group such as 7-nitrobenz-2-oxa-1,3-diazol-4-yl (formula D); BODIPY® fluorophore; anthracene and fluorescein.
• the labeling group according to the present invention is chosen from biotin and the fluorophore group 7-nitrobenz-2-oxa-1,3-diazol-4-yl (formula D).
• Another object according to the invention is to provide compounds of formula (I) having a labeling group selected from the group NBD and biotin.
• the invention furthermore relates to the use, as probes in particular as tracers or labeling agents, of compounds of formula I, for which: R 2 may represent a group corresponding to the following formula (A) :
• n can represent an integer that can take any of the values of
• + Q may represent an oxygen atom or a group -NR a in which R a is as defined above, and + R c may represent a group corresponding to the formula (C) or (D)
• the compounds of formula (I) according to the invention may be obtained by various synthetic methods, in particular using the oximation reaction of ketones which is well known to those skilled in the art.
• the diagram below is illustrative of the process used for the preparation of the compounds of formula (I)
• the compounds of formula (I) can be isolated from the reaction medium by various methods well known to those skilled in the art.
• the compounds of formula (I) can be converted into one of their pharmaceutically acceptable salts.
• the compounds of formula (II) used as starting products for obtaining compounds of formulas (I) are commercially available or are prepared by methods known to those skilled in the art.
• the following examples illustrate the present invention but without limiting it.
• the structures of the compounds described in the examples and in the preparations were determined according to the usual techniques (nuclear magnetic resonance, mass spectroscopy, etc.).
• Example 1 Preparation of compounds of formula (II)
• Example 1a Synthesis of 3,3-difluoro-3-methyl-4,5-secocholestan-5-one Step i: preparation of 3,3-difluoro-5,5-ethylenedioxy -4.5-secocholestane
• Step i Preparation of 3 - [(N - (+) - biotinoyl-N-methyl) amino] -5,5- (ethylenedioxy) -4-nor-3,5-secocholestane
• Step iv Preparation of methyl 5,5- (ethylenedioxy) -25-fluoro-4-nor-3,5-secocholestan-3-oate 123 mg (0.282 mmol) of 25-fluoro-4-nor-5-oxo -3,5-secocholestan-3-oate methyl are dissolved in 2 mL of trimethylorthoformate and 2 mL of ethylene glycol. 5.4 mg (0.028 mmol) of anhydrous p-toluenesulfonic acid are added and the medium is stirred overnight at room temperature.
• the reaction medium is embedded in ethyl acetate, washed with a 10% solution of NaHCO 3 , then with a saturated solution of NaCl, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo.
• the residue obtained is purified by flash chromatography on silica gel (petroleum ether / ethyl acetate 95/5). 74 mg (yield 54%) of the expected product are obtained in the form of a yellow oil.
• the medium is then extracted 3 times with ethyl acetate, the organic phases are combined, washed with saturated NaCl solution 1 dried over anhydrous MgSO 4, filtered and concentrated in vacuo. 310 mg of the expected product are obtained and used as is in the next step.
• the 3,3-difluoro-4,5-secocholestan-5-one oxime is obtained from 3,3-difluoro-4,5-secocholestan-5-one (product of Example 1 a-step ii ) with a yield of 87% according to method A.
• the oxime of 3 - [(N - (+) - biotinoyl-N-methyl) amino] -4-nor-3,5-secocholestan-5-one is obtained from 3 - [(N- ( +) - biotinoyl-N-methyl) amino] -4-nor-3,5-secocholestan-5-one (product of Example 1d-step ii) in 25% yield according to method A.
• the oxime of 3- [methyl- (7-nitro-2,1,3-benzoxadiazol-4-yl) amino] -4-nor-3,5-secocholestan-5-one is obtained from 3- [methyl- (7-nitro-2,1,3-benzoxadiazol-4-yl) amino] -4-nor-3,5-secocholestan-5-one (product of Example 1e-step ii) with a yield of 87% according to method A.
• the 4-nor-3,5-secocholestan-5-one oxime is obtained from 4-nor-3,5-secocholestan-5-one (product of Example 1g-step iii) with a yield of 20% according to method A.
• 4-nor-3,5-secocholest-24-en-3-ol-5one with a yield of 74% according to method A.
• the preparation of 4-nor-3,5-secocholest-24-en-3- ol-5-one is described in international application WO2008 / 056059.
• the oxime 24 ⁇ -ethyl-4-nor-3,5-secocholest-22-en-3-ol-5-one oxime is obtained from 4-nor-3,5-secocholest-24-en-3 -ol-5one with a yield of 88% according to method A.
• the preparation of 24 ⁇ -ethyl-4-nor-3,5-secocholest-22-en-3-ol-5-one is described in the patent WO2008 / 056059.
• the spinal cord of rat E14 embryos is dissected and the ventral part is dissociated by trituration after trypsination.
• Motoneurons are separated from other spinal cells by a known method (Camu et al, 1993, Purification of spinal motoneurons from chicken and rat embryos by immunopanning.) In “Immunoselection Strategies for Neural Cell Culture", Neuroprotocols: A companion to Methods in Neurosciences 2, 191-199; Henderson et al., 1993, Neutrophins promote motor neuron survival and are present in embryonic limb bud. Nature 363 (6426): 266-70).
• the cells are centrifuged on a density gradient. Motor neurons are enriched in the fraction of large cells (the less dense ones). The cells of this fraction are incubated with an anti-p75 antibody, a surface antigen present on the motoneurons.
• Cardiotrophin-1 requires LIFRbeta to promote survival of mouse motoneurons purified by a novel technique J. Neurosci Res 55 (1): 119-26). Only motor neurons are retained: their purity is of the order of 90%.
• the motoneurons are seeded at low density in culture wells on a polyornithine-laminin substrate in a neurobasal medium (GIBCO) supplemented according to Raoul et al., 1999, Programmed cell death of embryonic motor neurons triggered through the death receptor.
• GEBCO neurobasal medium
• Negative controls absence of trophic factors
• positive controls in the presence of BDNF (Brain-Derived Neurotrophic Factor) at 1 ng / ml
• GDNF Glial-Derived Neurotrophic Factor
• Neurotrophic Factor at 1 ng / ml and CNTF (Ciliary Neurotrophic Factor) at 10 ng / ml, marketed by the American company PEPROTECH, Inc. and the Sigma-
• Aldrich are included in each series.
• the compounds to be tested are added 60 minutes after seeding and the cultures are maintained at 37 ° C. under 5% CO 2 for 3 days.
• the neuroprotective activity of the compounds to be tested was evaluated by their ability to prevent the death of motor neurons when they are added to the Neurobasal medium (GIBCO) in comparison with the survival of motor neurons in medium supplemented with neurotrophic factors.
• the compounds of formula I according to the invention have shown a neuroprotective activity at a concentration capable of allowing a better survival rate of motoneurons in the Neurobasal medium.
• This survival rate is expressed as the number of living cells after treatment with the test compound relative to the survival induced by neurotrophic factors. This ratio can therefore represent the percentage of survival due to the tested compound with respect to survival induced by neurotrophic factors. If the ratio is greater than 0, the effect of the compounds is positive on the survival of motor neurons.
• the compounds of formula (I) according to the invention are therefore potentially useful as a medicament, particularly in the treatment of amyotrophies, in particular in the treatment of amyotrophic lateral sclerosis or spinal amyotrophies. children, and in the treatment of traumatic spinal cord injuries.

Landscapes

• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Physical Education & Sports Medicine (AREA)
• Immunology (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Neurosurgery (AREA)
• Virology (AREA)
• Diabetes (AREA)
• Rheumatology (AREA)
• Hematology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Ophthalmology & Optometry (AREA)
• Dermatology (AREA)
• Obesity (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Molecular Biology (AREA)
• Tropical Medicine & Parasitology (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Transplantation (AREA)
• AIDS & HIV (AREA)
• Pain & Pain Management (AREA)
• Urology & Nephrology (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=40942520

Family Applications (1)

Country Status (11)

Families Citing this family (4)

Family Cites Families (7)

• 2008
  • 2008-12-29 FR FR0807476A patent/FR2940650B1/fr not_active Expired - Fee Related
• 2009
  • 2009-12-17 RU RU2011131855/04A patent/RU2508289C2/ru not_active IP Right Cessation
  • 2009-12-17 BR BRPI0923763A patent/BRPI0923763A2/pt not_active IP Right Cessation
  • 2009-12-17 JP JP2011542858A patent/JP5731397B2/ja not_active Expired - Fee Related
  • 2009-12-17 CN CN200980153023.3A patent/CN102271671B/zh not_active Expired - Fee Related
  • 2009-12-17 CA CA2745503A patent/CA2745503A1/fr not_active Abandoned
  • 2009-12-17 EP EP09803784A patent/EP2370071A1/fr not_active Withdrawn
  • 2009-12-17 AU AU2009334712A patent/AU2009334712B2/en not_active Ceased
  • 2009-12-17 WO PCT/FR2009/001434 patent/WO2010076418A1/fr active Application Filing
  • 2009-12-17 US US13/142,534 patent/US9115059B2/en not_active Expired - Fee Related
• 2011
  • 2011-06-27 IL IL213792A patent/IL213792A0/en unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events