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WO2004085395A1 - Derives de melatonine et leur utilisation dans le traitement de dysfonctionnements neurologiques - Google Patents

Derives de melatonine et leur utilisation dans le traitement de dysfonctionnements neurologiques Download PDF

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WO2004085395A1
WO2004085395A1 PCT/EP2004/003117 EP2004003117W WO2004085395A1 WO 2004085395 A1 WO2004085395 A1 WO 2004085395A1 EP 2004003117 W EP2004003117 W EP 2004003117W WO 2004085395 A1 WO2004085395 A1 WO 2004085395A1
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Prior art keywords
compounds
disorders
acetylcholine
formula
dementia
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Stephan Schann
Pascal Neuville
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Domain Therapeutics SA
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Faust Pharmaceuticals SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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

Definitions

  • the present invention relates to compounds, combination products, compositions including them and methods for controlling neurotransmitter levels in mammals using these compounds, products or compositions. It further concerns methods for treating and/or preventing various diseases or pathological conditions which are associated with neurological dysfunctions caused by alteration in neurotransmitters levels, especially in the nervous tissues. According to particular aspects, the present invention relates to compounds, combination products, compositions and methods useful for controlling acetylcholine levels and for treating and/or preventing various diseases and conditions mediated by the imbalance of said neurotransmitter. The properties of the compounds, combination products and compositions of the invention make them particularly useful in the treatment and/or prevention, for example, of cognitive disorders and/or neurological dysfunction and/or mood disturbances such as, but not limited to, degenerative nervous system diseases or dementia. Additionally, these combination products can be used as reagents in studies on the biochemical mechanism of neurotransmitter based diseases.
  • neurotransmitters rapidly diffuse across the synaptic cleft and provoke an electrical change in the postsynaptic cell by binding to neurotransmitter specific receptors leading to ion exchanges throughout ion channels.
  • the excess neurotransmitters are rapidly removed, either by specific enzymes in the synaptic cleft or by reuptake into the presynaptic cell or surrounding glial cells.
  • Reuptake is mediated by a variety of neurotransmitter transporters. Rapid removal ensures both spatial and temporal precision of signalling at a synapse. For example, rapid reuptake can prevent excess neurotransmitters from influencing neighbouring cells and can clear the synaptic cleft before the next pulse of neurotransmitter release so that the timing of repeated, rapid signalling events is accurately communicated to the postsynaptic cell. This tight intercellular communication is disrupted when an imbalance of neurotransmitters occurs (e.g. when not enough neurotransmitter is synthesized and/or released from presynaptic cells or the reuptake of neurotransmitters by presynaptic cells is too rapid) leading thereby to neurological dysfunctions.
  • an imbalance of neurotransmitters occurs (e.g. when not enough neurotransmitter is synthe
  • Neurotransmitters are numerous, with new candidates being discovered continuously.
  • the main neurotransmitters are acetylcholine (ACh), norepinephrine (NE), gamma-amino- butyric acid (GABA), dopamine (DO), serotonin (S), glutamate (Glu), and nitric oxide (NO).
  • Literature provides numerous examples illustrating that neurotransmitters are closely involved in a wide array of diseases or pathological conditions which are associated with neurological dysfunctions caused by, for example, alteration in neurotransmitter levels and/or their ratio levels. Many of these diseases correlate with increasing age. Although in early stages of some diseases certain systems are rather specifically affected (e.g.
  • AD Alzheimer's Disease
  • Parkinson's Disease the dopaminergic system in Parkinson's Disease, etc.
  • multiple neurotransmitter system deficiencies acetylcholine, dopamine, norepinephrine, serotonin
  • senile dementia multi-infarct dementia
  • Huntington's disease mental retardation, etc .
  • symptoms leading to multiple symptoms that include cognitive, neurological, and effective/psychotic components.
  • Acetylcholine is one of the major modulators of brain functions and it is the main neurotransmitter at the peripheral nervous system. Modulation of acetylcholine levels is thereby crucial for nervous system function. It is synthesized and released at the cholinergic nerve terminals by the enzyme choline acetyltransferase (ChAT), is accumulated in synaptic vesicles by the activity of a vesicular acetylcholine transporter (VAChT) and is hydrolyzed by acetylcholinesterase AChE) or butyrylcholinesterase (BuChE).
  • ChoAT choline acetyltransferase
  • VAChT vesicular acetylcholine transporter
  • BuChE butyrylcholinesterase
  • AD Alzheimer disease
  • cholinergic system deficits such as, for example, decreases or deficiencies in choline acetyltransferase (ChAT) activity
  • AD related dementia dementia with Lewy bodies
  • Parkinson's disease dementia vascular dementia subtypes
  • behavioural and psychological symptoms such as aggressive behaviour, psychosis, apathy, anxiety, depression, hallucinations, delusions and overactivity
  • AD related dementia dementia with Lewy bodies
  • Parkinson's disease dementia dementia with Lewy bodies
  • vascular dementia subtypes dementia associated with multiple behavioural and psychological symptoms
  • aggressive behaviour psychosis
  • apathy anxiety, depression, hallucinations
  • delusions and overactivity have also been shown to be associated with disturbance of the cholinergic systems.
  • CDP-choline phosphatidyl choline,...
  • acetylcholine e.g., phosphatidyl serine, CDP-choline, huperzine A ...
  • agents that facilitate improved binding at the receptor site e.g., phosphatidyl serine and dioleylphosphatidic acid
  • the Inventors have now identified novel compounds having regulatory activities towards control of neurotransmitter levels, and more particularly, being able to increase extracellular acetylcholine levels, particularly in nervous tissue.
  • Glutamate (Glu) is the main excitatory neurotransmitter in the nervous system, especially brain and spinal cord, of mammals wherein it is working at a variety of excitatory synapses playing thereby a central role in functions such as learning, pattern recognition, and memory (Bliss and Collingridge, Nature 361, 31-39, 1993).
  • excitotoxicity Watkins and Collingridge, The NMDA receptor, IRL Oxford, 1989.
  • glutamate receptors especially glutamate receptors of the N-methyl-D-aspartate ("NMDA") receptor subtype, is crucial in a number of neuronal damages and injuries (Appel, Trends Neurosci.,16, 3-5, 1993).
  • NMDA N-methyl-D-aspartate
  • Many neurological disorders involving epileptic seizures and chronic or acute degenerative processes such as for example Alzheimer's, Huntington's, Parkinson's diseases, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), retinopathy, stroke, depression and traumatic brain injury, involve neuronal cell death caused by over-stimulation of the glutamate receptors.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • retinopathy stroke, depression and traumatic brain injury
  • neuronal cell death caused by over-stimulation of the glutamate receptors.
  • glutamate excitotoxicity are actually associated with abnormal elevation of extracellular glutamate levels.
  • the mechanisms of the elevation of extracellular glutamate include enhanced efflux of glutamate and/or the reduction of glutamate uptake by cells.
  • glutamate neurotoxicity may play a part in neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.
  • glutamate neurotoxicity may play a part in neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.
  • Said special compounds will be referred in the followings as combination products.
  • Huperzine A which is a therapeutic agent for Alzheimer's disease, inhibits acetylcholinesterase in primary cultures derived from forebrain, hippocampus, cortex and cerebellum of embryonic rat brain, and that pre-treatment of cell cultures with Huperzine A reduced cell toxicity, as evidenced by cytotoxicity assay and general morphology and glutamate-induced calcium mobilization.
  • Huperzine A could be a potent neuroprotective agent not only where cholinergic neurons are impaired, but also under conditions in which glutamatergic functions are compromised. Nevertheless, the authors conclude that said neuroprotective effect should result from antagonist effect of Huperzine A on NMDA receptor, hereby preventing its interaction with glutamate. No indication referring to the extracellular glutamate levels modulation by Huperzine A is provided.
  • the Inventors have now identified novel combination products, the various constituents of which are chosen so as to obtain a surprisingly synergistic effect of their respective regulatory activities towards control of neurotransmitter levels. More particularly, the combination products of the Invention make them possible to enhance extracellular acetylcholine levels and to decrease or to obviate glutamate levels extracellular increase.
  • the present invention pertains to the surprising discovery that NO or NO donor compounds and melatonin or melatonin derivatives, when combined, act synergistically to increase acetylcholine levels, with no or limited glutamate levels increase, or glutamate levels decrease.
  • glutamate levels control This absence of effect of the compounds, products or compositions of the Invention on glutamate levels, or their decreasing activity on glutamate levels, is generally referred to as "glutamate levels control" herein.
  • These combined activities are particularly advantageous, as it allows maintaining neurons alive by limiting glutamate excitotoxicity, and thus extends the beneficial period of the treatment resulting from increasing the acetylcholine levels which is actually efficient only if neurons are present.
  • the gas NO is known as a messenger that modulates neuronal function.
  • NO donors and NO synthase inhibitors as pharmacological tools revealed that endogenous NO increases the release of several neurotransmitters, such as acetylcholine, catecholamines, excitatory and inhibitory amino acids, serotonin, histamine, and adenosine (for a review, refer to Prast and Philippu, 2001, Prog. Neurobiol, 64, 51-68).
  • Lawrence and Jarrott (1993, Neurosci. Lett., 151, 126-129) have shown that NO donors like linsidomine, SNAP, hydroxylamine, NO gas additionally enhance the release of glutamate (see also Experimental Section).
  • the present invention thus offers an advantageous, unexpected and effective alternative to the techniques of the prior art, in particular for treating and/or preventing various diseases and conditions mediated or associated by the imbalance of at least one of said two neurotransmitters in humans or in animals.
  • the term "combination product” means that these two activities (i.e. acetylcholine levels enhancement and glutamate levels control) are characteristic of a single compound, as the one disclosed below.
  • “combination product” designates at least two separate compounds having independently from one another these two activities and which (i) are non combined or combined in a single mixture and (ii) are intended for an administration which is simultaneous (i.e. separate compounds are administered together), consecutive (i.e. separate compounds are administered separately but consecutively) or spread out over time (i.e. separate compounds are administered separately at different period of time).
  • the present invention concerns the use of compounds of the general formula (I):
  • R represents -O-R in which R represents H, or a Cl to C4 alkyl group
  • R 2 and R 3 independently from one another, represent H, or a halogen atom
  • R 4 represents H, methyl, or a halogen atom
  • Ra represents H, or a Cl to C4 alkyl group
  • Rb represents H, a Cl to C4 alkyl group, or a Cl to C4 alkoxy group, for the manufacture of a medicament for the treatment and/or prevention of :
  • disorders of extrapyramidal motor function such as Parkinson's Disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome and tardive dyskinesia ; Parkinsonism-dementia-complex of Guam ; Dementia with Lewy bodies ; Down's syndrome ; Dementia pugilistica ; Pick's disease ; Post-alcoholic dementia ; Vascular dementia ; Creutzfeldt- Jakob's disease; progressive supranuclear palsy ; olivoponto-cerebellar atrophie ; subacute sclerosing panencephalitis with dementia ; cognitive disorders including disorders of attention, focus and concentration ; cognitive dysfunction ; mood and emotional disorders such as depression, panic, anxiety and psychosis ; neuroendocrine disorders ; affective disorders ; substance abuse including withdrawal syndromes and substitution therapy ; disorders and dysregulation of food intake, including
  • the present invention concerns the use mentioned above of compounds of the general formula (II):
  • R and Rb are as defined above.
  • the invention relates more particularly to the use as mentioned above, of compounds of the general formula (II) wherein :
  • - R 2 is H or Cl
  • Rb is H, CH 3 , CH 2 -CH 3 , CH(CH 3 ) 2 , O-C(CH 3 ) 3 , C(CH 3 ) 3 , (CH 2 ) 2 -CH 3 , (CH 2 ) 3 - CH 3 , or analogues, derivatives, solvates or salts thereof.
  • the invention also relates more particularly to the use as mentioned above, of compounds of formula (IT) chosen among the followings :
  • the present invention concerns compounds of the general formula (III) corresponding to the formula (II)
  • R 2 is H or a halogen atom
  • Rb is H, a C2 to C4 alkyl group, or a Cl to C4 alkoxy group
  • the invention relates more particularly to compounds of formula (Ilia) corresponding to the formula (II) wherein : - R 2 is H or Cl,
  • Rb is H, CH 2 -CH 3 , CH(CH 3 ) 2 , O-C(CH 3 ) 3 , C(CH 3 ) 3 , (CH 2 ) 2 -CH 3 , (CH 2 ) 3 -CH 3 .
  • Preferred compounds of formula (Ilia) according to the invention are the followings :
  • the invention also relates to pharmaceutical compositions comprising at least one compound of formula (III) as mentioned above, in association with a pharmaceutically acceptable carrier.
  • compositions as defined above, comprising at least one compound of the formula (Ilia) corresponding to the formula (IT) wherein :
  • - R 2 is H or Cl
  • compositions as mentioned above, comprising at least one of the following compounds :
  • analogues, derivatives, solvates or salts of compounds of the present invention include both the structural derivatives and analogues of said compounds, their pharmaceutically acceptable solvates or salts, their stereoisomers, esters, prodrug forms, or their polymorphs. All these type of compounds are herein designated by the generic term "compounds”.
  • the physiologically acceptable salts of the compounds of Formula (I), (II) or (III) include conventional salts prepared with pharmaceutically acceptable acids or bases, depending on the particular substituents found on the compounds described herein for dosing in mammals, especially humans.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, formic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, perchloric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, lactic, propionic, isobutyric, palmoic, maleic, glutamic, hydroxymaleic, malonic, benzoic, succinic, glycolic, suberic, fumaric, mandelic, phthalic, salicylic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, hydroxynaphthoic, hydroiodic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, formic, monohydr
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, lithium, calcium, aluminium, ammonium, barium, zinc, organic amino, or magnesium salt, NjN'-dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine salts (e.g. chloroprocaine) and the like.
  • salts of amino acids such as arginate and the like
  • salts of organic acids like glucuronic or galactunoric acids and the like
  • certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • solvates may be prepared by conventional methods such as dissolving the compounds of formula (I), (II) or (III) in solvents such as methanol, ethanol and the like.
  • references hereinafter to a compound according to the invention include both compounds of Formula (I), (II) or (III) and their pharmaceutically acceptable salts and solvates. Additionally, those skilled in the art will recognize that stereocenters exist in compounds of Formula (I), (II) or (III). Accordingly, the present invention includes all possible stereoisomers including optical and geometric isomers of Formula (I). It further includes not only racemic compounds, or racemic mixtures thereof, but also the optically active isomers as well. When a compound of Formula (I), (IT) or (ITI) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by a stereospecific synthesis from either optically pure starting material or any convenient intermediate.
  • the present invention is intended to include all tautomeric forms of the compounds.
  • diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography.
  • Pure stereoisomers may also be prepared synthetically from the appropriate stereochemically pure starting materials, or by using stereoselective reactions.
  • the compounds of the present invention might be in a prodrug form.
  • a prodrug is in most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. Therefore, prodrugs of a compound of general formula (I), (II) or (III) is a compound which has chemically or metabolically cleavable groups and which readily undergoes chemical changes under physiological conditions to provide a compound of formula (I), (IT) or (III) in vivo.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, alkyl esters prepared by reaction of the parent acid compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • Particularly preferred j alkyl esters as prodrugs are formed from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.
  • Methyl ester prodrugs for example, may be prepared by reaction of the acid form of a compound of general formula (I), (IT) or
  • Ethyl ester prodrugs are prepared in similar fashion using ethanol in place of methanol. Details regarding prodrugs are available for example in US 5,498,729.
  • Those skilled in the art are further able to prepare various polymorphs of a compound of general formula (T), (IT) or (III) for example by crystallization of compound of formula (I), (IT) or (III) under different conditions. For example, he can use different solvents or mixtures commonly used for crystallization. Similarly, he can crystallize compounds of general formula (I) at different temperatures, according to various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the compounds of the invention may be labeled in a variety of ways.
  • the compounds may contain radioactive isotopes such as, for example H 3 (tritium), I 125 , 1 123 , or C 14 at one or more of the atoms that constitute compounds of general formula (I), (II) or (III).
  • the compounds may be advantageously joined directly, covalently or noncovalently, or through a linker molecule, to a wide variety of other moieties, which may provide function as carriers, labels, adjuvents, coactivators, stabilizers, etc. Such labeled and joined compounds are contemplated within the present invention.
  • the present invention concerns combination products as above defined.
  • said combination product consists in a compound selected in the group consisting of compounds of general formulas (I), (LT) and
  • the combination product is a compound presenting itself both the acetylcholine levels enhancement and the glutamate levels control activities.
  • said combination product consists in :
  • the combination product of the invention consists in a mixture comprising both (i) and (ii).
  • the combination product of the invention consists in a kit of product comprising (i) and (ii) separately, i.e. not mixed.
  • NO means invariably nitric oxide or nitrogen oxide. It refers to uncharged nitric oxide, as well as negatively charged nitric oxide (i.e. nitroxyl ion, NO " ) and positively charged nitric oxide (i.e. nitrosonium ion, NO + ). It can be provided by gaseous nitric oxide however because of the somewhat cumbersome nature of said delivery, preferably NO is provided indirectly by compounds which generate NO or related N-oxide species, directly or indirectly, i.e.
  • NO donors encompass precursor of nitric oxide, i.e. substrates of NO synthase (NOS) which are metabolized in cells and thus induce NO formation, such as for example L-Arginine (2-amino-5-guanidinovaleric acid) or its derivatives, e.g. hydroxy-arginine or its boron derivatives.
  • NOS NO synthase
  • Other “NO donors” are well known by those skilled in the art (see for example Feelisch, 1998, Naunyn-Schiedeberg's Arch Pharmacol, 358, 113-122). As disclosed in said performance, known examples of NO donors are organic nitrates (RONO 2 s) (e.g.
  • glyceryl trinitrate pentaerythrityl tetranitrate, isosorbide dinitrate or isosorbide 5-mononitrate
  • S-nitrosothiols e.g. S-nitrosoglutathione or GSNO, S-nitroso-N-acetyl-DL-penicillamine or SNAP and S-notrosoalbumin
  • linsidomine hydroxylamine
  • sydnonimines e.g. N-ethoxycarbonyl-3-morpholino-sydnonimine or molsidomine and 3-morpholino-sydnonimine or SL -1
  • NONOates e.g.
  • melatonin or N-acetyl, 5-methoxytryptamine refers to a hormone naturally secreted by the pineal gland. This compound is well known in the art and is widely commercially available (ref. 63610, Sigma-Aldrich).
  • Melatonin derivative refers to any substituted or modified melatonin, wherein said substitution or modification does not significantly affect its property towards acetylcholine and glutamate levels control, i.e. said substituted or melatonin derivative acts as do the melatonin when present in a combination product of the invention.
  • Examples of melatonin derivatives are available, in Leclerc et al, 2002, J. Med. Chem ., 45, 1853-1859 ; Bonnefont- Rousselot et al., 2002, J . Pineal Res., 33, 109-117 (e.g.
  • the melatonin in (ii) of the combination product of the invention is replaced by serotonin.
  • Serotonin is commercially available (e.g. Sigma-Aldrich ref. 85036).
  • the combination product according to the invention can be administered simultaneously or consecutively or so as to be staggered over time.
  • Simultaneously refers to a co-administration.
  • the two essential components (i) and (ii) can be mixed to form a composition prior to being administered, or can be administered at the same time to the patient in need thereof. It is also possible to administer them "consecutively", that is to say one after the other, irrespective of which component of the combination product according to the invention is administered first.
  • a mode of administration which is "staggered over time” or is intermittent and which stops and restarts at intervals which may or may not be regular.
  • the time interval between the administrations is not critical and can be defined by the skilled person. It is possible to recommend an interval of from 10 min to 72 h, advantageously of from 30 min to 48 h, preferably of from 1 to 24 h and, very preferably, of from 1 to 6 h. It is pointed out that the routes and sites of administration of the two components can be different (systemic delivery and targeted administration, for example).
  • the (i) NO or at least one NO donor compound is mixed with (ii) melatonin or at least one melatonin derivative compound before admimstration.
  • composition comprising at least one compound of the general formulas (I), (II) and (III) and/or combination products as above disclosed.
  • the compounds, combination products or compositions of the present invention have the ability to modulate neurotransmitters levels, and more particularly they have the ability to "act to increase acetylcholine extracellular levels".
  • Said special property can be tested by routine in vitro methods by the one skilled in the art, for example in brain slices, cultured neurons, nerve ending preparations (i.e., synaptosomes) or in nerve tissue or organs preparation (see for example WOOl 13108 the full content of which is incorporated herein by reference). See also the Experimental Section.
  • typical compounds, combination products or compositions useful in carrying out the present invention provide for the improvement of acetylcholine levels in amounts of at least one third, typically at least about 10 times more, frequently at least about 100 times more, and sometimes at least about 1,000 times more, than those measured in absence of the said compounds, combination products or compositions tested in identical conditions.
  • the compounds, combination products or compositions of the present invention have the ability to modulate neurotransmitters levels, and more particularly they have the ability to "act to control glutamate levels".
  • Said special property can be tested by routine in vitro methods by the one skilled in the art, for example in nerve ending preparations (i.e., synaptosomes) or in nerve tissue preparation (see for example WOOl 13108 the full content of which is incorporated herein by reference). See also the Experimental Section.
  • typical compounds, combination products or compositions useful in carrying out the present invention allow to control of extracellular glutamate levels in the sense that the glutamate levels measured in presence of the said compounds, combination products or compositions is not significantly different or is reduced compared to the one measured in absence of the said compounds, combination products or compositions in identical conditions.
  • "Is not significantly different” means that the extracellular glutamate levels increase, if any, is less than about 20%, preferably less than 10%, advantageously less than 5%, and highly advantageously is about 0%.
  • the compounds, combination products or compositions of the present invention "act to increase acetylcholine extracellular levels" without modifying the extracellular glutamate levels.
  • the compounds, combination products or compositions useful in carrying out the present invention : (a) improve the acetylcholine levels in amounts of at least one third, typically at least about 10 times more, frequently at least about 100 times more, and sometimes at least about 1,000 times more, than those measured in absence of the said compounds, combination products or compositions tested in identical conditions, and (b) do not significantly affect, neither by increasing nor by decreasing, extracellular glutamate levels tested in identical conditions in presence or absence of said compounds, combination products or compositions.
  • the compounds, combination products or compositions of the present invention "act to increase acetylcholine extracellular levels" and “act to control extracellular glutamate levels", these terms being as above defined.
  • the compounds, combination products or compositions of the present invention can further be characterized by their properties leading to the observed increase of acetylcholine extracellular levels. More specifically, the Applicant has shown that said increase activity of the compounds of general formula (I), (II), (III) or combination products of the invention is, at least in part, related to an anticholinesterase activity. More specifically, the compoimds or combination products of the Invention are, at least in part, an acetylcholinesterase and/or butyrylcholinesterase inhibitor, said inhibition activity being partial or total.
  • the cholinesterase inhibiting activity of the active compounds of the invention may be determined by a number of standard biological or pharmacological tests.
  • Another aspect of the present invention is a method for modulating the acetylcholine, and eventually the glutamate, levels in a cell, a tissue and/or a patient in need thereof.
  • the cell, tissue or patient is contacted with a sufficient concentration of at least one compound, combination product or composition of the Invention for an increase of extracellular acetylcholine levels, and eventually a control of the extracellular glutamate levels to be detected.
  • the compounds, combination products or compositions of the present invention due to their properties towards neurotransmitter levels, especially acetylcholine and/or glutamate levels, can serve as pharmaceuticals for controlling the biological effects of alteration in neurotransmitters levels, especially in the nervous tissues and the neurological dysfunctions produced thereby. More specifically they are capable of specifically increase the extracellular acetylcholine levels to reduce an associated pathology or provide or enhance a prophylaxis.
  • the present invention further concerns a composition
  • a composition comprising at least one compound or combination product of the invention as disclosed above and a pharmaceutically acceptable carrier or diluent.
  • These pharmaceutical compositions may be prepared by conventional techniques, e.g. as described in Remington, 1995, The Science and
  • compositions of the present invention comprise a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compounds can be adsorbed on a granular solid container for example in a sachet.
  • liquid oral pharmaceutical compositions are in the form of, for example, suspensions, elixirs and solutions; solid oral pharmaceutical compositions are in the form of, for example, powders, capsules, caplets, gelcaps and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • suitable carriers or diluents are, without being limited, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolarnines, phophatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes, and stearylamine, neutral lipids such as triglycerides, and combinations thereof. They may either contain cholesterol or may be cholesterol-free.
  • amphipathic lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolarnines, phophatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphat
  • compositions of the invention can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • compositions of the invention will typically be those which contain an effective amount of a compound of the invention. In general, such compositions should contain at least 0.5% of active compound(s), but the concentration may vary depending upon the particular form and may be from 4 to 70 weight percent (based on the total weight of the unit).
  • the oral dosage unit typically contains between 1.0 mg to 300 mg of active compound.
  • compositions of the present invention can further comprise additional agents.
  • additional agents are, for example, substrate for synthesis of acetylcholine (e.g., choline, CDP-choline, phosphatidyl choline,...), agents stimulating the production and secretion of acetylcholine (e.g., phosphatidyl serine, CDP-choline, huperzine A), inhibitors of acetylcholinesterase/ butyrylcholinesterase (AChE/BuChE) (e.g., tacrine (Cognex), E2020 (Aricept), donepezil, galanthamine (Reminyl), rivastigmine (Exelon), huperzine A), inhibitors of acetylcholine re-uptake , agents that facilitate improved binding at the receptor site (e.g., phosphatidyl serine and dioleylphosphatidic acid), agents mimicking the effects of acetylcholine (
  • the compounds, combination products or compositions of the present invention exhibit modulating activity toward neurotransmitters, and preferably towards acetylcholine and glutamate extracellular levels, which are important factors at the occurrence of neurological disorders.
  • the compounds, combination products or compositions of the present invention are specially adapted to cure, improve or prevent one or more symptoms of diseases or pathologic conditions associated with the imbalance of acetylcholine and are therefore particularly useful in the treatment and/or prevention, for example, of cognitive disorders and/or neurological dysfunction and/or mood disturbances such as, but not limited to, degenerative nervous system diseases or dementia.
  • a further aspect of the present invention is a method for the treatment and/or prevention of diseases and conditions mediated by the imbalance of acetylcholine, the method comprising admimstering to the patient in need a therapeutically effective amount of at least one compound selected in the group consisting in compounds of Formula (I), (II), (III), or a pharmaceutically composition as above disclosed.
  • the present invention concerns a method for modifying the acetylcholine extracellular levels, and more specifically for increasing said levels, comprising administering to the patient in need a therapeutically effective amount of at least one combination products of the invention, or a pharmaceutically composition as above disclosed.
  • a further aspect of the present invention is a method for the treatment and/or prevention of diseases and conditions mediated by the imbalance of acetylcholine, the method comprising administering to the patient in need a therapeutically effective amount of at least one combination products or a pharmaceutically composition as above disclosed, wherein said treatment is further associated with no increase (i.e. no change), and preferably with a reduction of the extracellular glutamate levels.
  • treatment and/or prevention extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • Diseases and conditions mediated by the imbalance of acetylcholine refers to a variety of therapeutic applications, such as the treatment of neurodegenerative disorders such as Alzheimer's disease, and other disorders involving dysfunction of the central or autonomic nervous systems including memory loss and/or dementia ; cognitive disorders including disorders of attention, focus and concentration ; cognitive dysfunction ; disorders of extrapyramidal motor function such as Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome and tardive dyskinesia ; Parkinsonism- dementia-complex of Guam ; Dementia with Lewy bodies ; Down's syndrome ; Dementia pugilistica ; Pick's disease ; Post-alcoholic dementia ; Vascular dementia ; Creutzfeldt- Jakob's disease; progressive supranuclear palsy ; olivoponto-cerebellar atrophie ; subacute sclerosing panencephalitis with dementia ; mood and emotional disorders such as
  • the Invention further concerns a method of alleviating or limiting the negative effects of a neurological disorder or neurodegenerative disease stemming from the aberrant synthesis, production, release or uptake or degradation of acetylcholine in a subject comprising administering to a patient suffering from said disorder or disease an effective amount of a compound, combination product or composition of the Invention.
  • a method for treating and/or preventing diseases and conditions mediated by the imbalance of acetylcholine and glutamate comprising administering to a patient in need of such treatment an amount of at least one combination product or a composition of the invention.
  • a method for treating and/or preventing diseases and conditions mediated by the imbalance of acetylcholine and for treating and/or preventing glutamate excitotoxicity comprising administering to a patient in need of such treatment an amount of at least one combination product or a composition comprising it of the invention.
  • the neuroprotective effect of the combination products of the invention can be evaluated by known methods of the art, for example as disclosed in Ved et al, NeuroReport, 1997, 8, 963-968.
  • Many neurological disorders involving epileptic seizures and chronic or acute degenerative processes such as for example Alzheimer's, Huntington's, Parkinson's diseases, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), eye injuries, retinopathy, cerebral deficits due to cardiac bypass surgery and grafting, stroke, ischemia, hypoxia, hypoglycaemia, various traumatic brain injuries, drug-induced neurotoxicity, muscle spasms, convulsions, migraine, urinary incontinence, vomiting, dyskinesia, psychosis, schizophrenia, cognitive disorders and memory deficits, chronic and acute pain, anxiety, depression., involve neuronal cell death caused by over-stimulation of the glutamate receptors.
  • a method for improving memory capability comprising administering to a patient in need of such treatment an amount of at least one combination product or a composition comprising it of the invention.
  • the term "patient” means a mammal, e.g., a primate, e.g., a human.
  • pharmaceutically effective dose an amount of a pharmaceutical compound or composition having a therapeutically relevant effect in the frame of treatment and/or prevention of conditions mediated by the imbalance of acetylcholine.
  • a therapeutically relevant effect relieves to some extent one or more symptoms of conditions mediated by the imbalance of acetylcholine, in a patient or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of said conditions.
  • the compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapeutic effect that is intended to be achieved, the form in which the dosage is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. Dosages and treatment schedules are readily attainable by routine experimentation to those having ordinary skill in this art.
  • the compounds are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • the compounds or compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the treatment can be adapted to administer the compounds or compositions of the invention in a single weekly or monthly dose.
  • the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per adult human per day, e.g., 1-1500 mg per adult human per day.
  • compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 30 mg/kg of body weight per day. Particularly, the range is from about 0.03 to about 15 mg/kg of body weight per day, and more particularly, from about 0.05 to about 10 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 2 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages. Toxicity and therapeutic efficacy of the compounds included in the compound or composition of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, special care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to mimmize potential damage to uninfected cells and, thereby, leads to a reduction of j side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • the route of administration of the compound or composition of the present invention may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral or intratumoral route being preferred.
  • the present invention further concerns compounds and compositions of the present invention for use in therapy. Similarly, it concerns the use of at least one compound, combination product or composition according of the present invention for the manufacture of a medicament for the treatment of diseases and conditions where modification of the acetylcholine, and eventually glutamate, levels is of therapeutic benefit. Examples of these diseases and conditions are provided above.
  • the compounds, combination products and compositions of the present invention may also find use in a variety of in vitro and in vivo assays, including diagnostic assays. In certain assays and in in vivo distribution studies, it is desirable to use labeled versions of the subject compounds, combination products and compositions, e.g. in radioligand displacement assays. Accordingly, the invention provides the compounds, combination products and compositions of the invention comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
  • a detectable label which may be spectroscopic (e.g. fluorescent), radioactive, etc.
  • nitrosation reaction was made according to Rinderknecht et al (J. Org. Chem., 1953, 18, 971-982). Typical conditions are illustrated in the following example: a concentrated aqueous solution containing 5.8 eq. (160mg, 2.32mmol) of sodium nitrite was added dropwise to an ice-cold solution of commercial N-[2-(5-methoxy-lH-indol-3-yl)-ethyl]-acetamide (93mg, 0.4mmol) in 1.7ml of glacial acetic acid. The mixture was then poured into 17ml of ice-water, and the yellow precipitate was recovered, dried over phosphorus pentoxide to give the expected product in 90%.
  • the expected product is obtained according to the process described in Example 1 using the commercial N-[2-(6-chloro-5-methoxy-lH-indol-3-yl)-ethyl]-acetamide as starting material. Yield: 99%.
  • the expected product is obtained by nitrosation of [2-(5-Methoxy-lH-indol-3-y ⁇ )-ethyl]- carbamic acid tert-butyl ester following the process described in Example 1; [2-(5-Methoxy- lH-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester being obtained by reaction of commercial 5-methoxytryptamine with (Boc) 2 O. Yield for nitrosation: 53%.
  • the expected product is obtained by nitrosation of N-[2-(5-Methoxy-lH-indol-3-yl)-ethyl]- isobutyramide following the process described in Example 1; N-[2 i -(5-Methoxy-lH-indol-3- yl)-ethyl] -isobutyramide being obtained by reaction of commercial 5-methoxytryptamine with isobutyryl chloride following conditions described for Preparation A. Yield for nitrosation:
  • the expected product is obtained by nitrosation of N-[2-(5-Methoxy-lH-indol-3-yl)-ethyl]- propionamide following the process described in Example 1; N-[2-(5-Methoxy-lH-indol-3- yl)-ethyl]-propionamide being obtained by reaction of commercial 5-methoxytryptamine with propionyl chloride following conditions described for Preparation A. Yield for nitrosation: 99%.
  • the expected product is obtained by nitrosation of N-[2-(5-Methoxy-lH-indol-3-yl)-ethyl]- butyramide following the process described in Example 1 ; N-[2-(5-Methoxy-lH-indol-3-yl)- ethyl] -butyramide being obtained by reaction of commercial 5-methoxytryptamine with butyryl chloride following conditions described for Preparation A. Yield for nitrosation: 83%.
  • the expected product is obtained by nitrosation of Pentanoic acid [2-(5-methoxy-lH-indol-3- yl)-ethyl] -amide following the process described in Example 1; Pentanoic acid [2-(5- methoxy-lH-indol-3-yl)-ethyl]-amide being obtained by reaction of commercial 5- methoxytryptamine with pentanoyl chloride following conditions described for Preparation A.
  • the expected product is obtained by nitrosation of N-[2-(5-Methoxy-lH-indol-3-yl)-ethyl]- 2,2-dimethyl-propionamide following the process described in Example 1; N-[2-(5-Metho ⁇ y- lH-indol-3-yl)-ethyl]-2,2-dimethyl-propionamide being obtained by reaction of commercial 5-methoxytryptamine with 2,2-dimethyl-propionyl chloride following conditions described for Preparation A. Yield for nitrosation: 94%.
  • Table I Effect of compounds of the invention (at l ⁇ M - lO ⁇ M - and 50 ⁇ M) on acetylcholine release was measured using an ex vivo model, Neurocubes (WOOl/13108). Neurocubes are prepared from rat brain cortex and hippocampus. They are maintained in an oxygenized Krebs buffer and treated during 30 min with tested compounds. The measurement of acetylcholine levels is made on supernatant aliquots by chemilumescence assays (Israel et al., 1981, 1982, 1986). Table I

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Abstract

La présente invention concerne des composés de la formule générale (I) : dans laquelle R1 représente -O-R7 où R7 représente H, ou un groupe alkyle C1 à C3, R2 et R3, indépendamment l'un de l'autre, représentent H ou un atome d'halogène, R4 représente H, méthyle, ou un atome d'halogène, Ra représente H, ou un groupe alkyle Cl à C4, Rb représente H, un groupe alkyle C1 à C4, ou un groupe alcoxy C1 à C4, pour la production d'un médicament destiné au traitement et/ou à la prévention de maladies et d'états médiés par le déséquilibre de l'acétylcholine et de NO, des maladies et des états médiés par le déséquilibre de l'acétylcholine et du glutamate, ou pour améliorer la capacité de la mémoire.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2275096A3 (fr) * 2005-08-26 2011-07-13 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
CN103040750A (zh) * 2012-12-18 2013-04-17 海南百思特医药科技有限公司 阿戈美拉汀脂质体固体制剂
CN115124449A (zh) * 2022-05-24 2022-09-30 上海英诺富成生物科技有限公司 一种吲哚化合物及制备方法与应用

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Publication number Priority date Publication date Assignee Title
US6004991A (en) * 1995-08-08 1999-12-21 Cemaf And Laboratoires Besins Iscovesco S.A. Acylated derivatives of melationin and its analogues, useful as medicaments
US6436984B1 (en) * 1998-12-18 2002-08-20 Centre National De La Recherche Scientifique (Cnrs) Melatonin derivatives and medicine containing same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6004991A (en) * 1995-08-08 1999-12-21 Cemaf And Laboratoires Besins Iscovesco S.A. Acylated derivatives of melationin and its analogues, useful as medicaments
US6436984B1 (en) * 1998-12-18 2002-08-20 Centre National De La Recherche Scientifique (Cnrs) Melatonin derivatives and medicine containing same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2275096A3 (fr) * 2005-08-26 2011-07-13 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
CN103040750A (zh) * 2012-12-18 2013-04-17 海南百思特医药科技有限公司 阿戈美拉汀脂质体固体制剂
CN103040750B (zh) * 2012-12-18 2014-11-19 海南圣欣医药科技有限公司 阿戈美拉汀脂质体固体制剂
CN115124449A (zh) * 2022-05-24 2022-09-30 上海英诺富成生物科技有限公司 一种吲哚化合物及制备方法与应用
CN115124449B (zh) * 2022-05-24 2024-02-02 上海英诺富成生物科技有限公司 一种吲哚化合物及制备方法与应用

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