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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to a novel combination of 8-cyclopropyl-3- [2- (3-fluoro-phenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6,5-g] [1,2] Benzotriazine-4,9-dione of formula (I):
• 8-cyclopoiOpyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6,5-g] - [1,2,3] benzotriazine-4 9-dione is an AMPA glutamatergic receptor positive allosteric modulator described in patent application WO 2008/085506. More specifically, the compound of formula (I) has procognitive properties, improves synaptic plasticity and demonstrates neuroprotective properties, giving it an interesting activity in the treatment of disorders of the central nervous system and, more particularly, in the treatment of cognitive deficits associated with brain aging and neurodegenerative diseases.
• the present invention relates to the association between the 8-cyclopropyl-3- [2- (3-fluorophenyl) ethyl] -7 8 3-dihydiO-3H- [i, 3] oxazino [6 J 5-g] [l, 2,3] benzotriazine-4,9-dione of formula (I) or its addition salts with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor, as well as its advantageous properties for the treatment of disorders cognitive effects associated with cerebral aging and neurodegenerative diseases.
• Neurodegenerative diseases related to cerebral aging such as the disease Alzheimer's are characterized by memory disorders and cognitive dysfunctions.
• Cognitive disorders are generally associated with a decrease in the ability of neurons to synthesize and release certain neurotransmitters such as, for example, glutamate and acetylcholine (Obbins et al., Prends in Pharmacol Sci., 2006 (3), 27, 141-148).
• glutamate and acetylcholine Obbins et al., Prends in Pharmacol Sci., 2006 (3), 27, 141-148.
• there is a gradual loss of synaptic plasticity and neuronal processes with this neuronal loss being accelerated in specific regions of the brain.
• Pathophysiological studies have clearly indicated that a deficiency of glutamatergic neurotransmission is closely associated with the development of Alzheimer's disease (Advokat et al., Nenroscience & Biobehav, Rev. 1992, 16, 13-24, Francis et al. Progress in Newobiology 1992,
• the AMPA receptor (“-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid”) appears to be the most involved in physiological neuronal excitability phenomena and, in particular, in those involved in the memorization process. For example, learning has been shown to be associated with increased binding of AMPA to its receptor in the hippocampus, one of the brain areas essential to cognitive processes.
• Acetylcholinesterase inhibitors such as donepezil are commonly used in the symptomatic treatment of Alzheimer's disease to limit the decrease of acetylcholine levels in the brain by blocking the action of acetylcholinesterase.
• Acetylcholinesterase inhibitors, as well as AMPA-positive allosteric modulators have been shown to improve cognitive properties in different animal models of episodic memory and working memory (Black, Psychopharmacol., 2005, 179, 154). O'Neill et al., IDrugs 2007, 10 (3), 185-192, Yuede et al., Behav Pharmacol., 2007, 18 (5-6), 347-363).
• the improvement of cognitive functions can therefore be based on two types of strategy, targeting either AMPA receptors or glutamate or acetylcholine.
• the present invention has shown that the effects of acetylcholinesterase inhibitors are potentiated by those of 8-cyclopropyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] ] oxazino [6.5-g] [1,2,3] benzotriazine-4,9-dione or its salts addition to a pharmaceutically acceptable acid or base.
• the coadministration of these compounds could improve the cognitive performance of patients compared to the simple administration of an acetylcholinesterase inhibitor without however observing or increasing the deleterious effects associated with the treatment (in particular, gastrointestinal disorders). such as nausea or diarrhea, headache or fatigue).
• treatments using therapeutic doses of acetylcholinesterase inhibitor lower than those conventionally used in mono-administration therefore become possible, with equivalent or even higher cognitive performance and less deleterious effects.
• 8-cyclopi py3-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6,5-g] [1,2,3] benzotriazine -4,9-dione is used in the basic form in the context of the invention.
• the inhibitor of acetylcholinesterase is chosen from the group consisting of or galantamine.
• Donepezil is preferentially used in the form of a hydrochloride, rivastigmine in the form of a hydrogen tartrate and galantamine in the form of a hydrobromide.
• the acetylcholinesterase inhibitor is donepezil.
• the invention also relates to the use of the combination of 8-cyclopropyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6,5- [1, 2,3] benzotriazine-4,9-dione or its addition salts with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor, for obtaining pharmaceutical compositions for the treatment cognitive disorders associated with cerebral aging and neurodegenerative diseases.
• the invention relates to the use of the combination of 8-cyclopiOpyl-3- [2 "(3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6, 5-g] [1,2,3] benzotriazine-4,9-dione or its addition salts with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor selected from the group consisting of donepezil, rivastigmine or galantamine, for obtaining pharmaceutical compositions for the treatment of cognitive disorders associated with Alzheimer's disease and, more particularly, cognitive disorders associated with Alzheimer's disease in patients having depressive symptoms.
• the invention also relates to pharmaceutical compositions containing the combination of 8-cyclopylpyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6,5].
• -g] [1,2,3] benzotriazine-4,9-dione or its addition salts with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor in combination with one or more pharmaceutically acceptable excipients.
• the invention relates to pharmaceutical compositions containing the combination of 8-cyclopropyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6.5 -g] [1,2,3] henzotriazine-4,9-dione or its addition salts with a pharmaceutically acceptable acid or base, and an acetylcholinesterase inhibitor selected from the combination of donepezil, rivastigmine or galantamine, in combination with one or more pharmaceutically acceptable excipients.
• the mass fraction of active principles is between 5 and 50%.
• compositions according to the invention those which are suitable for oral, parenteral and especially intravenous, per or transcutaneous, nasal, rectal, perlingual, ocular and respiratory administration, and more specifically simple or sugar-coated tablets, are particularly suitable.
• the pharmaceutical compositions according to the invention contain one or more excipients or vehicles selected from diluents, lubricants, binders, disintegrating agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavoring agents, etc.
• lactose lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerine;
• silica, talc, stearic acid and its magnesium and calcium salts polyethylene glycol
• binders magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone
• agar for disintegrators: agar, alginic acid and its sodium salt, effervescent mixtures.
• the compounds of the combination can be administered simultaneously or sequentially.
• the preferred route of administration is the oral route.
• Another advantageous route of administration is the transdermal patch.
• the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.
• the compounds of the combination may be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition, in which the active ingredients are mixed.
• Preferred pharmaceutical compositions are tablets.
• the appropriate dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the condition and any associated treatments and ranges from 1 to 200 mg of 8-cyclopropyl-3- [2- (3-fluoiOphényl) ethyl] -7,8-dihydiO-3H- [l, 3] oxazino [6,5-g r] [l, 2,3] benzotriazine-4,9-dione base equivalent by 24 hours, and more preferably 5 to 50 mg per day.
• the dose of the acetylcholinesterase inhibitor will be equal to or less than that used when administered alone.
• the dosage is between 0.5 and 30 mg per day, the preferred daily doses being 5 and 10 mg.
• the dosage is between 0.5 and 20 mg per day, the preferred daily doses being 1.5 and 14 mg.
• the dosage is between 1 and 30 mg per day, the preferred daily doses being 8 and 24 mg.
• the middle-aged mice have a specific dysfunction of the contextual memory with respect to the young mice, without any deficit of spatial memory.
• This model is relevant for evaluating the effects of the products in Alzheimer's disease because patients with this dementia also present, at a very early stage, episodic contextual memory disorders (Gold et al., Expert Rev. Neurother. 2008, 8 (12), 1879-1891).
• mice placed in a box with high edges, learn two types of consecutive spatial discriminations (Dl: white floor then D2: black floor) on a floor with four holes, in which only one of the holes is baited, and this in the opposite way between D1 and D2.
• Dl white floor
• D2 black floor
• Each discrimination is carried out on a specific floor (white or black), which constitutes the internal context specific to each discrimination. Twenty-four hours after the learning step, the mice are placed back on the white pop-up floor and the following parameters are measured:
• EXAMPLE C Study of Post Synaptic Excitatory Potential (EPSP) Induced by Electrical Stimulation in Awake Mice 8-cyclopropyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydi-3H- [1, 3] oxazino [6.5-g] [1,2,3] benzotriazine-4,9-dione and rivastigmine were evaluated in electrophysiology in awake animals alone after single oral administration and in coadministration at subactive doses of both compounds to study a synergistic potential between these two compounds at the level of the hippocampus.
• EPP Post Synaptic Excitatory Potential
• EPSPs induced by electrical stimulation in awake mice allows to study in a physiological way an electrophysiological phenomenon at the base of the neuronal activity and in connection with the processes of memorization and learning. Indeed, learning and memory require changes in neural circuits. Also, the facilitation of synaptic responses by a product or product combination by acting on postsynaptic excitatory potentials would facilitate learning or counteract age-related memory deficits or occurring during neurodegenerative diseases such as the Alzheimer's disease (Shapiro, Arch Neurol 2001, 58, 874-881).
• mice aged 3 months are anesthetized with 0.8-3% halothane delivered using a mask.
• stimulation and recording electrodes are inserted into the perforating lane and the serrated gyrus of the hippocampus of the animals, respectively.
• the mice are kept for 5 to 7 days in cages with free access to food and water to allow complete recovery. Each implanted animal is alone per cage until the end of the experiment.
• a stable baseline of evoked responses is induced using pulses per pair (100 ⁇ pulse duration, negative-positive) delivered at 3 pulses / minute to the pacing electrode located in the perforating pathway.
• the Pulse intervals are set at 40 ms (Gruart et al., J Neurosci, 2006, 24, 1077-1087).
• Field EPSPs are monitored until a stable baseline is obtained (for 30 minutes). Then, the products or the vehicle are administered and the evoked field potentials are recorded.
• the compounds are administered alone or in coadministration at the following doses: rivastigmine (0.03 mg / kg, po); 8-cyclopropyl-3- [2- (3-fluorophenyl) ethyl] -7,8-dihydro-3H- [1,3] oxazino [6,5-g] [1,2,3] benzotriazine-4,9 -dione (compound designated S in Figure 4, 3 mg / kg, po); vehicle (1% (w / v) hydroxyethylcellulose and 1% (v / v) polysorbate 80 in distilled water).
• rivastigmine does not induce a significant change in field EPSP amplitudes relative to the vehicle group, except at 3 isolated times (at 45, 65 and at 15 minutes after the induction of pulses in pairs), indicating that it is a subactive dose (see Figure 4, curve with squares and Table 1); - the association of the two compounds, 8-cycIopiOpyl-3- [2- (3-fluorophenyl) ethyl] -7,8 dihydi -3H [l, 3] oxazino [6,5-g] [l 3 2,3] benzotriazine-4,9-dione at the single dose of 3 mg / kg po and rivastigmine at the single dose of 0.03 mg kg po induces a significant increase in the amplitudes of the field EPSP compared with the vehicle group over most of the recording period (especially 25 to 80 minutes and then 90 to 95 minutes, then 105 to 130 minutes and 140

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• 2014
  • 2014-04-07 FR FR1453046A patent/FR3019464B1/fr active Active
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