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WO2005016276A2 - Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase - Google Patents

Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase Download PDF

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Publication number
WO2005016276A2
WO2005016276A2 PCT/US2004/025295 US2004025295W WO2005016276A2 WO 2005016276 A2 WO2005016276 A2 WO 2005016276A2 US 2004025295 W US2004025295 W US 2004025295W WO 2005016276 A2 WO2005016276 A2 WO 2005016276A2
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alkyl
composition
cycloalkyl
compound
pharmaceutical composition
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PCT/US2004/025295
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WO2005016276A3 (fr
Inventor
Vassilios Papadopoulos
Laurent Lecanu
Janet Greeson
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Georgetown University
Samaritan Pharmaceuticals Inc
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Georgetown University
Samaritan Pharmaceuticals Inc
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Priority to JP2006522719A priority Critical patent/JP2007501254A/ja
Priority to AU2004264342A priority patent/AU2004264342A1/en
Priority to CA002534777A priority patent/CA2534777A1/fr
Priority to EP04757425A priority patent/EP1651235A4/fr
Publication of WO2005016276A2 publication Critical patent/WO2005016276A2/fr
Publication of WO2005016276A3 publication Critical patent/WO2005016276A3/fr
Priority to US11/347,020 priority patent/US20060247248A1/en
Anticipated expiration legal-status Critical
Priority to US12/182,845 priority patent/US20090176802A1/en
Ceased legal-status Critical Current

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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

Definitions

  • the present invention relates generally to a method of preventing or treating a neurodegenerative disease by inhibiting acetylcholinesterase, and particularly to therapeutic compounds and pharmaceutical compositions for preventing or treating neurodegenerative diseases or disorders that involve nerve cell death.
  • Nerve cell degeneration and death can cause potentially devastating and irreversible effects in an individual and may occur as a result of stroke, heart attack, or other brain or spinal chord ischemia or trauma, among other things.
  • Neurodegenerative disorders that involve nerve cell death include Alzheimer's disease, Parkinson s disease, Huntington s disease, Amyotrophic Lateral Sclerosis, Down's Syndrome, and Korsakoff s disease.
  • Alzheimer s disease (AD) is a degenerative disease of nerve cells in the cerebral cortex that leads to atrophy of the brain and senile dementia. AD currently affects more than four million people in the United States and is the most common form of dementia in the elderly, affecting about 10% of people over the age of 65 and about 40% of people over 80.
  • Familial AD is the early- onset form of the disease involving mutations of the amyloid protein precursor (APP) gene and accounts for about 5% of the total AD cases.
  • Sporadic AD is the late-onset form of the disease and accounts for about 95% of the total AD cases.
  • the cause of sporadic AD remains unknown.
  • the average duration of AD is eight years.
  • AD is a costly disease, in terms of medical care, nursing home care, social services, lost productivity, and shortened life span.
  • Clinically, AD is characterized by a progressive and irreversible impairment of cognitive processes and memory alteration.
  • AD is characterized by the presence in the brain of neuritic plaques from deposition of insoluble amyloid aggregates, the formation of neurofibrillay tangles from hyperphosphorylation of the tau protein, and the degeneration of cholinergic neurons.
  • Current therapeutic strategies for AD include inhibitors of ⁇ -amyloid peptide (A ⁇ ) production, compounds that prevent A ⁇ oligomerization and f ⁇ brillization, anti-inflammatory agents, inhibitors of cholesterol synthesis, antioxidants, neurorestorative agents, and vaccines.
  • a ⁇ ⁇ -amyloid peptide
  • AchE acetylcholinesterase
  • Alzheimer 's disease advances in etiology, pathogenesis and therapeutics, 707- 723 (2001) (ed. Iqbal et al.); Waldemar et al., Alzheimer s disease: advances in etiology, pathogenesis and therapeutics, 725-738 (2001) (ed. Iqbal et al.).
  • memantine an antagonist of the glutamatergic NMDA-subtype receptor, no further advances have been made in Alzheimer's disease therapeutics.
  • memantine an antagonist of the glutamatergic NMDA-subtype receptor
  • the ⁇ -1 receptor is present in different brain structures, such as the cortex or the hippocampus, localized on cell membranes, endoplasmic reticulum membranes, and mitochondrial membranes. Alonso et al., Neuroscience, 97:155- 170 (2000). The significance of the different sub-cellular localizations of the ⁇ -1 receptor remains unknown. However, ⁇ -1 receptor agonists are known to protect neuronal cells against cerebral ischemia in rat, to exert antidepressant effects in A ⁇ 25 - 35 treated mice, to enhance the acetylcholine release in the rat brain, and to facilitate neurite sprouting in PC 12 cells induced by nerve growth factor. Kume et al., Eur. J.
  • SA4503 a ⁇ -1 receptor agonist, enhanced the acetylcholine release in the hippocampus of rat brain slices and in vivo, suggesting that the anti-amnesic effect could be due in part to the activation of the cholinergic pathway.
  • the effect of SA4503 on the release of acetylcholine appeared to be more pronounced than with tacrine. Kobayashi et al., J. Pharmacol. Exp. Tlier., 279:106- 113 (1996).
  • Igmesine another ⁇ -1 receptor agonist, has been recently demonstrated to exert antidepressant activity on mice that were intracerebroventrically injected with the amyloid fragment A ⁇ 25 - 35 , probably by a modification of the monoaminergic system.
  • Urani et al. Behav. Brain Res., 134:239-247 (2002); Akunne et al., Neuropharmacology, 41:138-149 (2001).
  • This antidepressant effect was observed with yet another ⁇ -1 receptor agonist, PRE-084, in mice submitted to the forced swimming test.
  • the antidepressant activity displayed by ⁇ -1 receptor agonists involves a modulation of intracellular calcium mobilization, partly through regulation of the ryanodine receptor.
  • Urani et al. Psychopharmacology, 163:26-34 (2002); Hayashi et al., J. Pharmacol. Exp. Ther. 293:788-798 (2000).
  • the disruption of calcium homeostasis which leads to a pathological alteration of calcium signaling, is currently a theory proposed to explain the origin of AD. Kachaturian, Neurobiol. Aging, 8:345-346 (1987).
  • the invention provides compounds, pharmaceutical compositions and methods for preventing or treating neurodegenerative diseases and disorders by inhibiting acetylcholinesterase and binding the sigma-1 receptor.
  • novel compounds of formula I :
  • R 1 and R 2 are individually H, (d-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl((CrC 6 )alkyl), (C 2 -C 6 )alkenyl, wherein cycloalkyl optionally comprises 1-2, S, nonperoxide O or N(R ! ); aryl, aryl(C 2 - C 6 )alkenyl, heteroaryl, heteroaryl(C !
  • (Alk) is (C ⁇ -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(C 2 -C 6 )alkyl or [(C 2 -C 6 )alkyl(C 3 -C 6 )cycloalkyl[(C 3 -C 6 )alkyl], each optionally substituted by 1-2 S, non-peroxide O or N(R !
  • n is 2 or 3, most preferably 3, wherein the carbamoyl substituents are preferably in the 2, 3 and 4 positions on the phenyl ring.
  • R 1 , R 2 and R 3 are individually (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl; most preferably (d-C 4 )alkyl, such as methyl, ethyl, butyl, or propyl.
  • (Alk) is (d-C6)alkyl, most preferably - (CH 2 ) ! - 4 -, such as -(CH 2 ) 3 -.
  • m is 0 and R 3 is ethyl.
  • Piperazinyl may be optionally substituted with 1-2 methyl or ethyl groups.
  • One or more of the moieties [(R 1 )(R 2 )NC(O)O] may be replaced by [HO-] groups, to yield compounds of formula II that are expected to exhibit antioxidant properties.
  • Some of the compounds of formula (I) are useful intermediates for the preparation of other compounds of formula (I).
  • the present invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula (I) in combination with a pharmaceutically-acceptable carrier and/or excipient(s), as well as a method to use such compounds and compositions to treat a neurodegenerative or neuropathological condition by administration of an effective amount or dosage thereof to a mammal, such as a human, afflicted with, or threatened by the onset of such a condition.
  • the resulting product can be reacted with a 1 -substituted piperazine, with the 1- C(O)R group reduced and/or protected as necessary, followed by deprotection of the phenolic OH groups and acyl group, as needed, to yield a compound of general formula (II): (4-substituted-piperazin-l-yl)(Alk)C(O)Ph(OH) n (II) wherein n is 1-3, and piperazin-1-yl is 4-substituted with (C(O)) m R 3 ).
  • Bioactive compounds of formula (II) are also within the scope of the invention.
  • Fig. 2 depicts the preparation of a representative compound of the invention, which is shown in Fig. 1.
  • Compounds of formula (I), such as dimethyl-carbamic acid 2,3-bis- dimethylcarbamoyloxy-6-[4-(4-ethyl-piperazin-yl)-butyryl]-phenyl ester can be used to inhibit acetylcholinesterase and bind the sigma-1 receptor, and also to generate metabolites that are active as both sigma-1 receptor ligands and as antioxidants.
  • a therapeutically effective amount of the novel compound of the invention can be administered as a pharmaceutical composition to improve cholinergic transmission and prevent or reduce ⁇ -amyloid peptide induced neurotoxicity in the brain, and thereby prevent or treat neurodegenerative diseases and disorders.
  • the invention provides a pharmaceutical composition that includes a therapeutically effective amount of a novel compound and a pharmaceutically acceptable carrier.
  • the invention provides a method for synthesizing the novel compound of the invention.
  • the invention provides a method for preventing or treating a neurodegenerative disease or disorder in a subject by administering a therapeutically effective amount of the novel compound of the invention.
  • FIG. 1 shows the chemical structure of dimethyl-carbamic acid 2,3-bis- dimethylcarbamoyloxy-6-[4-(4-ethyl-piperazin-yl)-butyryl]-phenyl ester (SP004);
  • FIG. 2 is a flowchart of steps in SP004 synthesis;
  • FIG. 3 is a graph depicting a competition curve for specific binding of SP004 vs. haloperidol at the human ⁇ -1 receptor;
  • FIG. 4 is a graph depicting a competition curve for specific binding of SP004 vs. haloperidol at the human ⁇ -2 receptor;
  • FIG. 5 is a graph depicting the effects of SP004 on human AchE activity;
  • FIG. 6 shows the mechanism of inactivation of AchE by SP004 and production of an active metabolite
  • FIG. 7 shows the chemical structure of 4-(4-ethyl-piperazin-yl)-l -(2,3,4- trihydroxy-phenyl)-butan-l-one (SP004m).
  • SP004m 4-(4-ethyl-piperazin-yl)-l -(2,3,4- trihydroxy-phenyl)-butan-l-one
  • acetylcholine (Ach); acetylcholinesterase (AchE); acetylcholinesterase inhibitor (AchEI); Alzheimer's disease (AD); ⁇ -amyloid peptide (A ⁇ ); dimethyl-carbamic acid 2,3-bis- dimethylcarbamoyloxy-6-[4-(4-ethyl-piperazin-yl)-butyryl]-phenyl ester (SP004); 4-(4-ethyl-piperazin-yl)-l-(2,3,4-trihydroxy-phenyl)-butan-l-one (SP004m); sigma-1 receptor ( ⁇ -1 receptor); sigma-2 receptor ( ⁇ -2 receptor).
  • cortisol-modulating agent means any agent possessing pharmacological activity as regulating, preventing or decreasing any pathological raise of cortisol synthesis, rebalancing, or tending to re-balance, cortisol synthesis, therefore the intensity of the cortisol effect at a physiological activity.
  • cortisol-modulating agent can also mean that the agent possessing cortisol-modulating or -regulating or -rebalancing pharmacological activity may, if desired, be in the form of a free base, a free acid, a salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a prodrug, a polymorph, a derivative or the like, provided the free base, free acid, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or derivative is suitable pharmacologically, that is, effective in the present methods, combinations, kits, and compositions.
  • pharmaceutically effective amount refers to the amount of the compound that is required to confer therapeutic effect on the treated subject.
  • derivative refers to a compound that is produced from another compound of similar structure by the replacement or substitution of one atom, molecule, or group by another.
  • bioavailability refers to the extent to which an active moiety (drug or metabolite) is absorbed into the general circulation and becomes available at the site of drug action in the body.
  • composition therapy embraces the administration of at least one composition of the present invention in conjunction with another pharmaceutical agent that is indicated for treating or preventing a neurodegenerative disease or disorder in a subject, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents for the treatment of a neurodegenerative disease or disorder.
  • prevent or “prevention” in relation to a neurodegenerative disease or disorder in a subject, means no disease or disorder development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease.
  • prodrug refers to a drag or compound (active principal) that elicits the pharmacological action resulting from conversion by metabolic processes within the body.
  • Prodrugs are generally considered drug precursors that, following administration to a subject and subsequent absorption, are converted to an active or a more active species via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body. Prodrugs generally have a chemical group present on the prodrug which renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved from the prodrug the more active drug is generated. Prodrugs may be designed as reversible drug derivatives and utilized as modifiers to enhance drug transport to site-specific tissues. The design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent.
  • treat refers to any treatment of a disorder or disease associated with a neurodegenerative disease or disorder or neuropathology, in a subject, and includes, but is not limited to, preventing the disorder or disease from occurring in a subject who may be predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, for example, arresting the development of the disorder or disease; relieving the disorder or disease, for example, causing regression of the disorder or disease; or relieving the condition caused by the disease or disorder, for example, stopping one or more symptoms of the disease or disorder.
  • halo is fluoro, chloro, bromo, or iodo, alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as isopropyl" being specifically referred to.
  • Aryl denotes a phenyl radical or an orthofiised bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing about 5 or 6 ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(R ) wherein R is absent or is as defined above; as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms.
  • the present invention encompasses any racemic, optically-active polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic forn by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine anti-toxin activity using the standard tests described herein, or using other similar tests which are well known in the art.
  • (d-C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -C 12 )cycloalkyl can be monocyclic bicyclic or tricyclic and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicycle[2.2.2]octanyl, norbornyl, adamantyl as well as various terpene and terpenoid structures.
  • (C 3 -C 12 )cycloalkyl(C -C 6 )alkyl includes the foregoing cycloalkyl and can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2- cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl.
  • Heterocycloalkyl and (heterocycloalkyl)alkyl include the foregoing cycloalkyl wherein the cycloalkyl ring system is monocyclic, bicyclic or tricyclic and optionally comprises 1-2 S, non-peroxide 0 or N(R 7 ) as well as 2-12 ring carbon atoms; such as morpholinyl, piperidinyl, piperazinyl, indanyl, l,3-dithian-2-yl, and the like;
  • the cycloalkyl ring system optionally includes 1-3 double bonds or epoxy moieties and optionally is substituted with 1-3 OH, (C 1 -C6)alkanoyloxy, (CO), (d-C 6 )alkyl or (C 2 -C 6 )alkyny 1.
  • (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy
  • (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl
  • (C -C 6 )alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-penty
  • SP004 exhibit both AchE inhibition properties and ⁇ -1 receptor agonist capacities.
  • SP004 generates an active metabolite, SP004m (Fig. 7), that also binds the ⁇ -1 receptor and further exhibits antioxidant properties.
  • SP004 may therefore lack the apoptotic and cytotoxic properties associated with ⁇ -2 receptor agonists. Bowen, Pharm. Ada Helv., 74:211-218 (2000); Crawford et al., Eur. J. Pharmacol, 443:207-209 (2002). Upon or after inhibiting AchE, SP004 releases the active metabolite SP004m, as shown in FIG. 6. SP004 is a drag and a prodrug at the same time with the release of the active metabolite SP004m. While not wishing to be bound by theory, the structure of SP004m suggests that it is a ⁇ -1 receptor ligand and has antioxidant properties.
  • SP004m shares a common structure with SP004 and should therefore bind the ⁇ -1 receptor and reinforce the activity of SP004. Moreover, the polyphenolic groups attached to SP004m after removal of the three carbamoyl groups from SP004 should confer strong antioxidant activity on SP004m, which would be beneficial to the oxidatively stressed AD brain. Plant polyphenols are known to have antioxidant properties, anticarcinogenic effects, anti-platelet properties, protective properties against cardiovascular disease, and neuroprotective properties against oxidative stress. Rice-Evans, Biochem. Soc. Symp., 61:103-116 (1995); Damianaki et al., J. Cell Biochem., 78:429-441 (2000); Soleas et al., Clin.
  • An effective amount of SP004 and/or SP004m can be formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition before being administered for treatment of a disease or disorder.
  • the pharmaceutical composition of the present invention that is administered to a subject should be administered in an amount that achieves a therapeutically effective dose of the compound of the invention in the blood serum of the subject, within or during a period of time, sufficient to elicit a desired therapeutic effect.
  • the amount of the therapeutic agent sufficient to elicit a therapeutic effect can be experimentally determined based on variables such as the absorption rate of the agent into the blood serum, the bioavailability of the agent, and the potency for treating the disorder.
  • compositions of the present invention can be administered by any appropriate route including, but not limited to, oral, nasogastric, rectal, transdermal, parenteral, subcutaneous, intramuscular, intravenous, intramedullary, intradermal, intranasal, transmucosal, vaginal topical, buccal, and sublingual.
  • Such preparations may routinely contain buffering agents, preservatives, penetration enhancers, compatible carriers, and other therapeutic or non-therapeutic excipients as is well known to those skilled in the art.
  • Pharmaceutically acceptable cations include metallic ions and organic ions.
  • Preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth meal salts, and other physiologically acceptable metal ions.
  • Preferred organic ions include, but are not limited to, protonated tertiary amines and quarternary ammonium cations.
  • Pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
  • Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro or in vivo tests initially can provide useful guidance on the proper doses for subject administration.
  • a compound is found to demonstrate in vitro activity at, for example, a half-maximum effective dose of 200 nM
  • administer an amount of the drug that is effective to provide about a half-maximum effective dose of 200 nM concentration in vivo for a period of time that elicits a desired therapeutic effect, for example, treating a disorder related to high beta-amyloid-induced neurotoxicity and other indicators as are selected as appropriate measures by those skilled in the art. Determination of these parameters is well within the skill of the art. These considerations are well known in the art and are described in standard textbooks.
  • serum compound of the present invention concentrations can be measured using standard assay techniques.
  • the present compounds can also be used in combination with another pharmaceutical agent that is indicated for treating or preventing a neurodegenerative disease or disorder.
  • another pharmaceutical agent that is indicated for treating or preventing a neurodegenerative disease or disorder.
  • an additive or synergistic effect may be achieved such that many if not all of unwanted side effects can be reduced or eliminated.
  • the reduced side effect profile of these drags is generally attributed to, for example, the reduced dosage necessary to achieve a therapeutic effect with the administered combination.
  • the beneficial effect of combination therapy includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Combination therapy generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. Rather, combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, where each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, in a combined dosage form or in separate dosage forms of the therapeutic compounds. Sequential administration of each therapeutic agent can be effected by any appropriate route.
  • Combination therapy can also embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients, such as, but not limited to, an analgesic, for example, and with non-drag therapies such as, but not limited to, surgery.
  • the therapeutic compounds of the combined therapy may involve a regimen calling for administration of one therapeutic compound by oral route and another therapeutic compound by an oral route, a percutaneous route, an intravenous route, an intramuscular route, or by direct absorption through mucous membrane tissues, for example.
  • each such therapeutic compound will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents, or other formulation components.
  • the pharmaceutical composition can contain a desired amount of the compounds of the present invention, and be in the form of, for example, a tablet, a hard or soft capsule, a lozenge, a cachet, a troche, a dispensable powder, granules, a suspension, an elixir, a liquid, or any other form reasonably adapted for oral administration.
  • a pharmaceutical composition can be made in the form of a discrete dosage unit containing a predetermined amount of the active compound such as a tablet or a capsule.
  • Such oral dosage forms can further comprise, for example, buffering agents. Tablets, pills, and the like additionally can be prepared with enteric coatings.
  • compositions suitable for buccal or sublingual administration include, for example, lozenges comprising the active compound in a flavored base, such as sucrose, and acacia or tragacanth, and pastilles comprising the active compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise, for example, wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • compositions of the present invention can also be administered parenterally, as by injection (intravenous, intramuscular, subcutaneous).
  • injectable compositions can employ, for example, saline, dextrose, or water as a suitable carrier material.
  • the pH value of the composition can be adjusted, if necessary, with suitable acid, base, or buffer.
  • suitable bulking, dispersing, wetting, or suspending agents including mannitol and polyethylene glycol (such as PEG 400), can also be included in the composition.
  • a suitable parenteral composition can also include an active compound lyophilized in injection vials.
  • Aqueous solutions can be added to dissolve the composition prior to injection.
  • the pharmaceutical compositions can be administered in the form of a suppository or the like.
  • Carrier materials such as cocoa butter, theobroma oil, and other oil and polyethylene glycol suppository bases can be used in such compositions.
  • Other carrier materials such as coatings (for example, hydroxypropyl methylcellulose film coating) and disintegrants (for example croscarmellose sodium and cross-linked povidone) can also be employed if desired.
  • the subject compounds may be free or entrapped in microcapsules, in colloidal drag delivery systems such as liposomes, microemulsions, and macroemulsions. All of the above pharmaceutical compositions can be prepared by any suitable method of pharmaceutics, which includes the step of bringing into association active compound of the present invention and a carrier material or carriers materials.
  • compositions are uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Tablets of the present invention can also be coated with a conventional coating material such as OpadryTM White YS-1-18027A (or another color) and the weight fraction of the coating can be about 3% of the total weight of the coated tablet.
  • the compositions of the present invention can be formulated so as to provide quick, sustained or delayed release of the compositions after administration to the patient by employing procedures known in the art.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient.
  • compositions can be in the form of tablets, chewable tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syraps, aerosols (as a solid or in a liquid medium), soft and hard gelatin capsules, and sterile packaged powders.
  • the manufacturing processes may employ one or a combination of methods including: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Lachman et al, The Theory and Practice of Industrial Pharmacy (1986).
  • long-term sustained release implant may be suitable for treatment of neurodegenerative diseases or disorders in patients who need continuous administration of the compositions of the present invention.
  • Long-term release as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredients for at least 30 days, and preferably 60 days.
  • Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Based on the description contained herein, one skilled in the art can utilize the present invention to its fullest extent. The following specific examples are therefore to be construed as merely illustrative and not limiting of the remainder of the disclosure in any way.
  • IC 5 o value is not calculable because of less than 25% inhibition at the highest tested concentration.
  • SP004 is not a ligand for the I 2 , M, N ( ⁇ -BGTX insensitive) and sigma-2 receptors.
  • SP004 binds the sigma-1 receptor with IC 50 6.8E-07 M.
  • Acetylcholinesterase Assay This assay was performed with the following SP004 concentrations: 3E- 10, 1E-9, 3E-9, 1E-8, 3E-8, 1E-7, 3E-7, 1E-6, 3E-6, IE-5 M. Materials and Methods Recombinant human acetylcholinesterase expressed in HEK-293 cells was used for this assay.
  • the present invention while targeting the cholinergic pathway by inhibiting AchE, also targets the sigma-1 receptor. Consequently, the compound of the invention not only inhibits AchE, but through binding of the sigma-1 receptor at least also protects neuronal cells against cerebral ischemia, acts as an antidepressant, enhances acetylcholine release, and facilitates neurite sprouting.
  • SP004 may also have anti-amnesic activity as a result of its activating effects on the cholinergic pathway.
  • SP004 also generates an active metabolite that can further enhance the effect of the novel compound by also binding the sigma-1 receptor and by acting as an antioxidant.
  • SPO04m may reduce the oxidative stress present in the neuronal cells affected by a neurodegenerative disease or disorder.

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Abstract

L'invention concerne un nouveau composé et une nouvelle méthode permettant de prévenir ou de traiter des maladies neurodégénératives par inhibition de l'acétylcholinestérase et liaison du récepteur sigma-1. L'ester 2,3-bis-diméthylcarbamoyloxy-6-[4-(4-éthyl-piperazin-yl)-butyryl]-phényl d'acide diméthylcarbamique et ses dérivés représentent une nouvelle stratégie thérapeutique contre la neurotoxicité induite par le peptide amyloïde bêta, pour inhiber l'acétylcholinestérase, améliorer la transmission cholinergique, lier le récepteur sigma-1, et lilbérer un métabolite qui est actif à la fois en tant que récepteur sigma-1 et en tant qu'anti-oxydant.
PCT/US2004/025295 2003-08-05 2004-08-05 Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase Ceased WO2005016276A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2006522719A JP2007501254A (ja) 2003-08-05 2004-08-05 アセチルコリンエステラーゼ阻害特性を有する、シグマ‐１受容体配位子
AU2004264342A AU2004264342A1 (en) 2003-08-05 2004-08-05 Sigma-1 receptor ligand with acetylcholinesterase inhibition properties
CA002534777A CA2534777A1 (fr) 2003-08-05 2004-08-05 Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase
EP04757425A EP1651235A4 (fr) 2003-08-05 2004-08-05 Ligand du recepteur sigma-1 presentant des proprietes d'inhibition de l'acetylcholinesterase
US11/347,020 US20060247248A1 (en) 2003-08-05 2006-02-03 Sigma-1 receptor ligand with acetylcholinesterase
US12/182,845 US20090176802A1 (en) 2003-08-05 2008-07-30 Antidotes to exogenous neurotoxic agents

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US49276903P 2003-08-05 2003-08-05
US60/492,769 2003-08-05

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Cited By (2)

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WO2007092458A1 (fr) * 2006-02-03 2007-08-16 Samaritan Pharmaceuticals, Inc. Antidotes contre des agents neurotoxiques exogènes
WO2010015040A1 (fr) * 2008-08-07 2010-02-11 Powmri Ltd Thérapie et prévention d'une protéinopathie tdp-43

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CN103420941B (zh) * 2013-08-26 2015-09-23 浙江大学 2-甲氧基苯基-二甲胺基甲酸酯衍生物及制备和用途

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092458A1 (fr) * 2006-02-03 2007-08-16 Samaritan Pharmaceuticals, Inc. Antidotes contre des agents neurotoxiques exogènes
WO2010015040A1 (fr) * 2008-08-07 2010-02-11 Powmri Ltd Thérapie et prévention d'une protéinopathie tdp-43

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AU2004264342A1 (en) 2005-02-24
JP2007501254A (ja) 2007-01-25
CA2534777A1 (fr) 2005-02-24
CN1863536A (zh) 2006-11-15
EP1651235A4 (fr) 2008-12-17
EP1651235A2 (fr) 2006-05-03

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