`

`Use of Un-Competitive NMDA Antagonists in the Treatment of TSC
`
`NMI-13
`
`Background
`
`Tuberous sclerosis Complex (TSC) is an autosomal dominant disorder
`
`characterized by widespread development of growths in many tissues and organs. TSC
`
`afflicts 1110,000 people. Typically, persons suffering from TSC display a wide range of
`
`neural effects including seizures and a variety of tumors. There are two genes that have
`
`been associated with TSC -- TSC1 and TSC2. Although the mechanism are unknown,
`
`recent work with TSC knock-out models and basic molecular biology are leading to a
`
`better understanding of the role of these genes in neural development and function.
`
`In particular, Ultman et al. (Ann Neurol. 2002 Sep;52(3):285-96.) have shown
`
`that a conditional TSC 1 knockout mouse exhibits seizures at an age of 1 month and dies
`
`within 4 months. Moreover, analysis of gene and protein expression in this model
`
`indicates that proteins involved in glutamate transport are down regulated. If this is
`
`indeed the case in TSC, then the region around affected cells should exhibit elevated
`
`concentrations of glutamate, making those cells susceptible to cell death via a number of
`
`mechanisms, including excess NMDAr activity.
`
`Certain adamantane derivatives have been used to treat illnesses. Rimantadine 5
`
`( 1-( 1-aminoethyl)adamantane) is used for the prophylaxis and treatment of influenza in
`
`humans. Amantadine has been used for the treatment of both influenza and Parkinson's
`
`disease (Schwab et al., J. Am. Med. Assoc. (1969) 208: 1168). Another derivative,
`
`memantine, is currently under clinical investigation for the treatment of various
`
`neurodegenerative diseases and has been licensed for the treatment of Parkinson's
`
`associated spasticity in Germany (Schneider et al., Dtsch. Med. Wschr. (1984) 1 09:987).
`
`Memantine protects cortical and retinal neuron cultures from the toxicity of
`
`glutamate, NMDA and the HIV-1 coat protein gp120 (Dreyer et al., Science (1990)
`
`248:364). Recent studies demonstrate that it prevents quinolinic acid-induced
`
`hippocampal damage in rats (Keihoff and Wolf., Eur. J Pharmacal. ( 1992) 219:45 1 ).
`
`Memantine demonstrates antiphypoxic properties in vitro and in vivo. It is thought that
`
`1
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`NMI-13
`
`Preferably the compound is memantine, rimantadine, 1-adamantanamine, 1-
`
`acetamido-3 ,5-dimethyl-7 -hydroxyadamantane, 1-amino-3,5-dimethyl-7-
`
`hydroxyadamantane hydrochloride, 1-tert-butylcarbamate-3,5-dimethyl-7-hydroxy(cid:173)
`
`adamantane, 1-tert-butylcarbamate-3,5-dimethyl-7-nitrate-adamantane, 1-acetamido-
`
`3,5-dimethyl-7 -nitrateadamantane, 1, 1-dibenzylamino-3,5-dimethyl-7 -hydroxy(cid:173)
`
`adamantane, 1-amino-3,5-dimethyl-7 -acetoxyadamantane hydrochloride, 1-
`
`(benzyloxycarbonyl)arnino-3,5-dimethyl-7 -hydroxyadamantane, 1-
`
`(benzy1oxycarbonyl)amino-3,5-dimethyl-7 -(3-bromopropylcarbonyloxy)adamantane, 1-
`
`(benzyloxycarbonyl)arnino-3,5-dimethyl-7 -(3-nitratepropylcarbonyloxy)adamantane, 1-
`
`(benzyloxycarbonyl)amino-3,5-dimethyl-7 -hydroxymethyl adamantane, 1-
`
`(benzyloxycarbonyl)amino-3,5-dimethyl-7 -nitratemethyl-adamantane, 1-amino-3,5-
`
`dimethyl-7-nitratemethyladamantane hydro bromide, 1-acetamido-3,5-dimethyl-7-
`
`nitratemethyl-adamantane, or 1, 1-dibenzylamino-3,5-dimethyl-7 -acetoxyadamantane
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`As used herein, the term "Alkyl" refers to unsubstituted or substituted linear,
`
`branched or cyclic alkyl carbon chains of up to 15 carbon atoms. Linear alkyl groups
`
`include, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n(cid:173)
`
`octyl. Branched alkyl groups include, for example, iso-propyl, sec-butyl, iso-butyl, tert(cid:173)
`
`butyl and neopentyl. Cyclic alkyl groups include, for example, cyclopropyll, cyclobutyl,
`
`cyclopentyl and cyclohexyl. Alkyl groups can be substituted with one or more
`
`substituents. Nonlimiting examples of such substituents include N02, ON02, F, Cl, Br, I,
`
`OH, OCH3, C02H, C02CH3, CN, aryl and heteroaryl. Where "alkyl" is used in a context
`
`such as "alkyl-ON02," it refers to an alkyl group that is substituted with a ON02 moiety.
`
`Where "alkyl" is used in a context such as "C(O)alkyl-ON02,'' it refers to an alkyl group
`that is connected to a carbonyl group at one position and that is substituted with a ON02
`moiety.
`
`The term " Heteroalkyl" refers to unsubstituted or substituted linear, branched or
`
`cyclic chains of up to 15 carbon atoms that contain at least one heteroatom (e.g., nitrogen,
`
`oxygen or sulfur) in the chain. Linear heteroalkyl groups include, for example, CH2CH2,
`
`CH2CH2N(CH3)2 and CH2CH2SCH3. Branched groups include, for example,
`
`3
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`NMI-13
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`CH2CH(OCH3)CH3, CH2CH(N(CH3) 2)CH3 and CH2CH(OCH3)CH3. Cyclic heteroalkyl
`
`groups include, for example, CH(CH2CH2) 20, CH(CH2CH2) 2NCH3 and CH(CHzCH2)
`
`2S. Heteroalkyl groups can be substituted with one or more substituents. Nonlimiting
`
`examples of such substituents include N02, ON02, F, Cl, Br, I, OH, OCH3, C02H,
`
`C02CH3, CN, aryl and heteroaryl. Where "heteroalkyl" is used in a context such as
`
`"heteroalkyl-ONOz," it refers to a heteroalkyl group that is substituted with an ON02
`moiety. Where "heteroalkyl" is used in a context such as "C(O)heteroalkyl-N02," it
`
`refers to an alkyl group that is connected to a carbonyl group at one position and that is
`
`substituted with a ON02 moiety.
`
`The term "Halo" refers to F, Cl, Br or I.
`
`The term "Aryl" refers to an unsubstituted or substituted aromatic, carbocyclic
`
`group. Aryl groups are either single ring or multiple condensed ring compounds. A
`
`phenyl group, for example, is a single ring, aryl group. An aryl group with multiple
`
`condensed rings is exemplified by a naphthyl group. Aryl groups can be substituted with
`
`one or more substituents. Nonlimiting examples of such substituents include N02,
`ONOz, F, Cl, Br, I, OH, OCH3, COzH, C02CH3, CN, aryl and heteroaryl.
`
`The term "Heteroaryl" refers an unsubstituted or substituted aromatic group
`having at least one heteroatom (e.g., nitrogen, oxygen or sulfur) in the aromatic ring.
`
`Heteroaryl groups are either single ring or multiple condensed ring compounds. Single
`
`ring heteroaryl groups having at least one nitrogen include, for example, tetrazoyl,
`
`pyrrolyl, pyridyl, pyridazinyl, indolyl, quinolyl, imidazolyl, isoquinolyl, pyrazolyl,
`
`pyrazinyl, pyrimidinyl and pyridazinonyl. A furyl group, for example is a single ring
`
`heteroaryl group containing one oxygen atom. A condensed ring heteroaryl group
`
`containing one oxygen atom is exemplified by a benzofuranyl group. Thienyl, for
`
`example, is a single ring heteroaryl group containing one sulfur atom. A condensed ring
`
`heteroaryl group containing one sulfur atom is exemplified by benzothienyl. In certain
`
`cases, heteroaryl groups contain more than one kind of heteroatom in the same ring.
`
`Examples of such groups include furazanyl, oxazolyl, isoxazolyl, thiazolyl arid
`
`phenothiazinyl. Heteroaryl groups can be substituted with one or more substituents.
`
`Nonlimiting examples of such substituents include N02, ON02, F, Cl, Br, I, OH, OCH3,
`COzH, COzCH3, CN, aryl and heteroaryl.
`
`4
`
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`Page 5
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`

`In one embodiment, the compounds of the present invention are
`
`aminoadamantane derivatives. The aminoadamantane derivatives are of the following
`
`formula:
`
`NMI-13
`
`The groups Rt, R2, R3, ~and Rs of the formula are independently defined. Rt is
`
`H, a!kyl, heteroalkyl, aryl, heteroaryl, C(O)ORo or C(O)Ro. R2 isH, alkyl, heteroalkyl,
`
`aryl, heteroaryl, C(O)ORo or C(O)Ro. R3 is H, alkyl, heteroalkyl, aryl or heteroaryl. R4
`isH, alkyl, heteroalkyl, aryl or heteroaryl. Rs is OR7, alkyl-OR7 or heteroalkyl-OR7. Ro
`is alkyl, heteroalkyl, aryl or heteroaryl. R7 is N02, C(O)Ro, C(O)alkyl-ON02 or
`C(O)heteroalkyl-ON02• The following substituents are preferred: R 1 and R2 are H; R3
`and ~ are H or alkyl; and, R1 is N02 or C(O)alkyl-ON02.
`
`Preferably, R 1 isH and R2 isH, C(O)O-alkyl or C(O)O-aryl. Where R2 is
`
`C(O)O-alkyl, it is preferred that the alkyl group is methyl, ethyl, n-propyl, iso-propyl, n(cid:173)
`
`butyl, sec-butyl, tert-butyl or benzyl. Where R2 is C(O)O-aryl, it is preferred that the aryl
`group is phenyl or a substituted phenyl. More preferably, R 1 and R2 are both H.
`Preferably, both R3 and~ are H or linear alkyl groups. R3 and ~ can be the
`
`same or different. Where R3 and ~ are both alkyl groups, it is preferred that the groups
`are methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl or benzyl.
`
`Preferably, Rs is ON02, O-alkyl-ON02 or OC(O)-alkyl-ONOz. Where Rs is O(cid:173)
`
`alkyl-ON02, it is preferred that the alkyl group be CH2, CH2CH2 or CH2CH2CH2. Where
`Rs is OC(O)-alkyl-ON02, it is preferred that the alkyl group be CH2, CH2CH2,
`
`CH2CH2CH2 or CH2CH2CH2. More preferably, Rs is ON02.
`In another preferred embodiment, the aminoadamantane derivative of the
`
`invention is memantine.
`
`5
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`NMI-13
`
`Chemically, memantine is 1-amino-3,5-dimethyladamantane of the adamantane
`
`class. Compared to the other NMDA antagonists, memantine has been reported to have
`
`the greatest effective potency for binding at the PCP and MK-801 receptor sites in human
`
`brain tissue (Komhuber et al., Eur J Pharmacol (Mod Pharmacol Sect) 1991;206: 297-
`
`300). Memantine binds to the PCP and MK.-801 binding sites of the NMDA receptor in
`
`postmortem human frontal cortex at therapeutic concentrations (Kornhuber et al., Eur J
`
`Pharmaco/1989; 166: 589-590), and reduces membrane currents (Bormann, Eur J
`
`Pharmaco/1989;66: 591-592). Memantine is well tolerated, and despite its wide use in
`
`Germany, only a few isolated cases of psychosis and cognitive deficits have been
`
`reported with its use.
`
`Compared to other NMDA antagonists, memantine appears to have a more
`
`favorable pharmacological profile and is less likely to induce psychosis and cognitive
`
`deficits. Without being bound by theory, one possibility why memantine is less likely to
`
`induce cognitive deficits and psychosis may be due its negligible effects on the
`
`hypothalamic-pituitary axis (HP A) compared to other NMDA antagonists such as
`
`ketarnine. NMDA receptors have been reported to be involved in the physiologic
`
`pulsatile regulation of hormone release from the HPA axis (Bhat et al., 1995) resulting in
`
`hypercortisolemia. Psychotic symptoms and cognitive deficits in depression has been
`
`linked to an increased dopamine activity secondary to this HPA overactivity (Walder et
`
`a/., Bioi Psychiatry 2000;48: 1121-1132). The lack ofmemantine's effect on the HPA
`
`axis and resulting increased dopamine activity may be an explanation for the low rates of
`
`psychosis seen with this drug. Another advantage of memantine over other NMDA
`
`antagonists is that contrary to, for example, dextromethorphan, memantine has no active
`
`metabolites that possess NMDA antagonizing properties (Ziemann et al., 1996).
`
`Furthermore, memantine serum levels are available for measurement. Memantine is one
`
`6
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`of the few NMDA antagonists available for use in humans and is ideal for treating major
`
`depression as it and its precursors amantadine, have been in clinical use for many years
`
`with minimal side-effects (Kornhuber et al., J Neural Transm Supp/1994;43: 91-104).
`
`Rarely bas memantine been associated with significant the side-effects of agitation,
`
`confusion, and psychosis (Rabey eta/., J Neural Transm 1992;4: 277-282; Riederer et
`
`a/., Lancet, 1991 Oct 19;338(8773):1022-3) as seen with otherNMDA antagonists, such
`
`as phencyclidine and ketamine. Memantine is well tolerated in the geriatric populations
`
`for which it is typically prescribed in Europe (Gortelmeyer eta/., Arzneim-Forsch/Drug
`
`Res 1992;42: 904-913).
`
`Memantine has significant neurotrophic and activating properties, and it can be
`
`used to modulate glutamatergic neurotransmission, while also providing for robust
`
`neurotrophic effects via direct intracellular mechanisms. Memantine displays potent non(cid:173)
`
`competitive voltage-dependent NMDA antagonist properties with effects comparable to
`
`MK-801 (see, Bormann, Eur J Pharmaco/1989;66: 591-592, incorporated herein by
`
`reference). Memantine also demonstrates anticonvulsant and neuroprotective properties
`
`and dopaminergic effects in vitro (see, Maj, Arzneim Forsch/Drug Res 1982;32: 1236-
`
`1273, incorporated herein by reference). Memantine has been used since 1978 and is
`
`approved in Germany for the treatment of mild and moderate cerebral performance
`
`disorders with the following cardinal symptoms: concentration and memory disorders,
`
`loss of interest and drive, premature fatigue, and dementia syndrome, as well as in
`
`diseases in which an increase of attention and alertness (vigilance) is required. Cerebral
`
`and spinal spasticity, Parkinson and Parkinson-like diseases are other indications.
`
`Memantine acts as a modulator of glutamatergic neurotransmission. In the states of a
`
`reduced glutamate release, after degeneration of neurons, memantine results in an
`
`improvement in signal transmission and activation of neurons. In the state of a massive
`
`glutamate release, e.g., ischemia, memantine blocks NMDA receptors that mediate the
`
`excitotoxic action of glutamate on neurons. It is believed that its neuroprotective
`
`properties are due to NMDA receptor antagonism in pathologies with increased
`
`glutamate. Memantine's efficacy in Parkinson's disease has been suggested to be a result
`
`of its ability to neutralize (or modulate) the increased activity of the glutamatergic
`
`cortico-striatal and subthalamicopallidal pathways (Klockgether and Turski, Trends
`
`7
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`Neurosci 1989;12: 285-286; Ann Neuro/1990;28: 539-546, and Schmidt eta/., Trends
`
`Neurosci 1990;13: 46-47., incorporated herein by reference). This effect is independent .
`
`of dopamine or norepinephrine release.
`
`Memantine has been reported for many years to have positive effects on deficit
`
`symptoms or depressive symptoms commonly found in other neuropsychiatric disorders
`
`such as Parkinson's disease and dementia. In studies of patients with dementia and
`
`Parkinson's disease, the symptoms of depressed mood, anxiety, lack of drive, somatic
`
`disturbances, impairment in vigilance, short-term memory and concentration were
`
`significantly improved with memantine. Some of these studies also reported the adverse
`
`events of hyperactivity, restlessness, and euphoria with memantine, suggesting that it
`
`may have activating or antidepressant properties.
`
`Other adamantane derivatives have been proven effective to treat a variety of
`
`afflictions, such as Rimantadine ( 1-(1 -aminoethyl)adamantane ),
`
`for the prophylaxis and treatment of influenza in humans, and Amantadine ( 1-
`
`amino adamantane) has been used for the treatment of both influenza and Parkinson's
`
`disease (Schwab et al., JAm. Med. Assoc. (1969) 208:1168).
`
`In another preferred embodiment the aminoadamantane derivative of the
`
`invention is 1-acetamido-3,5-dimethyl-7 -hydroxyadamantane, 1-amino-3,5-dimethyl-7-
`
`hydroxyadamantane hydrochloride, 1-tert-butylcarbamate-3,5-dimethyl-7-hydroxy(cid:173)
`
`adamantane, 1-tert-butylcarbamate-3 ,5-dimethyl-7 -nitrate-adamantane, 1-acetamido-
`
`8
`
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`Page 9
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`NMI-13
`
`3,5-dimethyl-7 -nitrateadamantane, 1, 1-dibenzylamino-3 ,5-dimethyl-7 -hydroxy(cid:173)
`
`adamantane, 1-amino-3,5-dimethyl-7 -acetoxyadamantane hydrochloride, 1-
`
`(benzyloxycarbonyl)amino-3,5-dimethyl-7 -hydroxyadamantane, 1-
`
`(benzyloxycarbonyl)amino-3,5-dimethyl-7 -(3-bromopropylcarbonyloxy)adamantane, 1-
`
`(benzyloxycarbonyl)amino-3 ,5-dimethyl-7 -(3-nitratepropylcarbonyloxy)adamantane, 1-
`
`(benzyloxycarbonyl)amino-3 ,5-dimethyl-7 -hydroxymethyl adamantane, 1-
`
`(benzyloxycarbonyl)amino-3,5-dimethyl-7 -nitratemethyl-adamantane, 1-amino-3,5-
`
`dimethyl-7 -nitratemethyladamantane hydro bromide, 1-acetamido-3,5-dimethyl-7-
`
`nitratemethyl-adamantane, or 1, 1-dibenzylamino-3,5-dimethyl-7-acetoxyadamantane.
`
`The aminoadamantane derivatives of the present invention can be administered to
`
`a patient in the form of a pharmaceutically acceptable salt or in a pharmaceutical
`
`composition. A compound that is administered in a pharmaceutical composition is mixed
`
`with a suitable carrier or excipient such that a therapeutically effective amount is present
`
`in the composition. The term "therapeutically effective amount" refers to an amount of
`
`the aminoadamantane derivative that is necessary to achieve a desired endpoint (e.g.,
`
`decreasing neuronal damage as the result ofTSC).
`
`A further aspect of the invention comprises a compound of the invention in
`
`combination with other compounds of the invention. A compound of the invention may
`
`also be administered in combination with an anti-inflammatory agent, an
`
`immunosuppressant, an antiviral agent, or the like. In general, the currently available
`
`dosage forms of the known therapeutic agents for use in such combinations will be
`
`suitable.
`
`Combination therapy" (or "co-therapy") includes the administration of a
`
`compound of the invention and at least a second agent as part of a specific treatment
`
`regimen intended to provide the beneficial effect from the co-action of these therapeutic
`
`agents. The beneficial effect of the combination includes, but is not limited to,
`
`pharmacokinetic or pharmacodynamic co-action resulting from the combination of
`
`therapeutic agents. Administration of these therapeutic agents in combination typically is
`
`carried out over a defined time period (usually minutes, hours, days or weeks depending
`
`upon the combination selected). "Combination therapy" may, but generally is not,
`
`intended to encompass the administration of two or more of these therapeutic agents as
`
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`part of separate mono therapy regimens that incidentally and arbitrarily result in the
`
`combinations of the present invention.
`
`"Combination therapy" is intended to embrace administration of these therapeutic
`
`agents in a sequential manner, that is, wherein 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, by administering to the subject a single
`
`capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for
`
`each of the therapeutic agents.
`
`Sequential or substantially simultaneous administration of each therapeutic agent
`
`can be effected by any appropriate route including, but not limited to, oral routes,
`
`intravenous routes, intramuscular routes, and direct absorption through mucous
`
`membrane tissues. The therapeutic agents can be administered by the same route or by
`
`different routes. For example, a first therapeutic agent ofthe combination selected may
`
`be administered by intravenous injection while the other therapeutic agents of the
`
`combination may be administered orally. Alternatively, for example, all therapeutic
`
`agents may be administered orally or all therapeutic agents may be administered by
`
`intravenous injection. The sequence in which the therapeutic agents are administered is
`
`not narrowly critical.
`
`"Combination therapy" also can embrace the administration of the therapeutic
`
`agents as described above in further combination with other biologically active
`
`ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the
`
`combination therapy further comprises a non-drug treatment, the non-drug treatment may
`
`be conducted at any suitable time so long as a beneficial effect from the co-action of the
`
`combination of the therapeutic agents and non-drug treatment is achieved. For example,
`
`in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is
`
`temporally removed from the administration of the therapeutic agents, perhaps by days or
`
`even weeks.
`
`The compounds of the invention and the other pharmacologically active agent
`
`may be administered to a patient simultaneously, sequentially or in combination. It will
`
`be appreciated that when using a combination of the invention, the compound of the
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`invention and the other pharmacologically active agent may be in the same
`
`pharmaceutically acceptable carrier and therefore administered simultaneously. They
`
`may be in separate pharmaceutical carriers such as conventional oral dosage forms which
`
`are taken simultaneously. The term "combination" further refers to the case where the
`
`compounds are provided in separate dosage forms and are administered sequentially.
`
`The compositions and combination therapies of the invention may be
`
`administered in combination with a variety of pharmaceutical excipients, including
`
`stabilizing agents, carriers and/or encapsulation formulations as described herein.
`
`A variety of preparations can be used to formulate pharmaceutical compositions
`
`containing the aminoadamantane derivatives, including solid, semi solid, liquid and
`
`gaseous forms. Remington's Pharmaceutical Sciences, Mack Publishing Company
`
`(1995) Philadelphia, PA, 19th ed. Tablets, capsules, pills, powders, granules, dragees,
`
`gels, slurries, ointments, solutions suppositories, injections, inhalants and aerosols are
`
`examples of such formulations. The formulations can be administered in either a local or
`
`systemic manner or in a depot or sustained release fashion. Administration of the
`
`composition can be performed in a variety of ways. Among others, oral, buccal, rectal,
`
`parenteral, intraperitoneal, intradermal, transdermal and intratracheal means can be used.
`
`Where the aminoadamantane derivative is ~ven by injection, it can be formulated
`
`by dissolving, suspending or emulsifying it in an aqueous or nonaqueous solvent.
`
`Vegetable or similar oils, synthetic aliphatic acid glycerides, esters ofhigher aliphatic
`
`acids and propylene glycol are examples of nonaqueous solvents. The compound is
`
`preferably formulated in aqueous solutions such as Hank's solution, Ringer's solution or
`
`physiological saline buffer.
`
`Where the aminoadamantane derivative is given orally, it can be formulated
`
`through combination with pharmaceutically acceptable carriers that are well known in the
`
`art. The carriers enable the compound to be formulated, for example, as a tablet, pill,
`
`suspension, liquid or gel for oral ingestion by the patient. Oral use formulations can be
`
`obtained in a variety of ways, including mixing the compound with a solid excipient,
`
`optionally grinding the resulting mixture, adding suitable auxiliaries and processing the
`
`granule mixture. The following list includes examples of excipients that can be used in
`
`an oral formulation: sugars such as lactose, sucrose, mannitol or sorbitol; cellulose
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`preparations such as maize starch, wheat starch, potato starch, gelatin, gum tragacanth,
`
`methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and
`
`polyvinylpyrrolidone (PVP).
`
`The aminoadamantane derivative of the present invention can also be delivered in
`
`an aerosol spray preparation from a pressurized pack, a nebulizer or from a dry powder
`
`inhaler. Suitable propellants that can be used in a nebulizer include, for example,
`
`dichlorodifluoro-methane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon
`
`dioxide. The dosage can be determined by providing a valve to deliver a regulated
`
`amount of the compound in the case of a pressurized aerosol.
`
`Pharmaceutical compositions of the present invention contain a therapeutically
`
`effective amount of the aminoadamantane derivative. The amount of the compound will
`
`depend on the patient being treated. The patient's weight, severity of illness, manner of
`
`administration and judgment of the prescribing physician should be taken into account in
`
`deciding the proper amount. The determination of a therapeutically effective amount of
`
`an aminoadamantane derivative is well within the capabilities of one with skill in the art.
`
`Although a therapeutically effective amount of an arninoadamantane derivative
`
`will vary according to the patient being treated, suitable doses will typically include
`
`between about 0.1 mg and 1000 mg of the compound. Preferably, a dose contains
`
`between about 0.1 mg and 500 mg of the compound. More preferably, a dose contains
`
`between about 0.1 mg and 250 mg of the compound.
`
`In some cases, it may be necessary to use dosages outside of the stated ranges to
`
`treat a patient. Those cases will be apparent to the prescribing physician. Where it is
`
`necessary, a physician will also know how and when to interrupt, adjust or terminate
`
`treatment in conjunction with a response of a particular patient.
`
`Agonists of glutamate receptors of the N-methyl-D-aspartate (NMDA) type
`
`potentially have a wide range of use in the treatment of various neurological diseases.
`
`Memantine was found to be a micromolar antagonist of the NMDA receptor (Bormann,
`
`Eur. J Pharmacol. 166:591, 1989). Memantine protects cortical and retinal neuron
`
`cultures from the toxicity of glutamate, NMDA and the HN-1 coat protein gp120 (Deyer
`
`eta/., Science 248:364, 1990). Memantine has antihypoxic properties in vitro and in
`
`vivo. Recent studies demonstrate that memantine also prevents quinolic acid-induced
`
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`NMI-13
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`hippocampal damage in rats (Keilhoff eta/., Eur. J. Pharmacal. 219:451, 1992).
`
`Although structurally quite different from other NMDA channel blockers, memantine
`
`inhibits eH]dizocilpin.e (Chen eta/., J. Neurasci. 12: 4427, 1992) binding to brain
`
`membranes. Memantine also blocks other neurotransmitter-gated ionotropic receptors,
`
`including nicotinic acetylcholine receptors (Masou eta/., Eur. J. Pharmacal. 130: 187,
`
`1986) and 5-hydroxytryptamine 5-HT3 receptors (Reiser eta/., Brain Res. 443: 338,
`
`1988).
`
`References
`
`Wong M. Ess KC. Uh1mann EJ. Jansen LA. Li W. Crino PB. Mennerick Related Articles,
`S. Yamada K.A. Gutmann DH.
`IF=J Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model.
`D Ann Neurol. 2003 Aug;54(2):25 1-6.
`PMID: 12891680 [PubMed- in process]
`
`Links
`
`0
`
`Uhlmann EJ. Wong M. Baldwin RL. Bajenaru ML. Onda H.
`4
`: Kwiatkowski DJ. Yamada K. Gutmann DH.
`
`Related Articles,
`
`Links
`
`Astrocyte-specific TSC 1 conditional knockout mice exhibit abnormal neuronal
`organization and seizures.
`Ann Neurol. 2002 Sep;52(3):285-96.
`PMID: 12205640 [PubMed- indexed for MEDLINE]
`
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`NMI-13
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`Claims
`
`1.
`
`A method of treating TSC comprising administering to a P.atient in need of such
`
`treatment of a non-toxic therapeutically effective amount of an un-competitive NMDA
`
`antagonist and a pharmaceutically acceptable carrier.
`
`2.
`
`The method claim 1, wherein the un-competitive NMDA antagonist is
`
`memantine.
`
`3.
`
`The method claim 1 wherein the un-competitive NMDA antagonist is a
`
`compound ofthe following formula or a pharmaceutically acceptable salt thereof:
`
`Rs
`wherein Rt isH, alkyl, beteroalkyl, aryl, heteroaryl, C(O)O~ or C(O)~; R2 is H, alkyl,
`
`heteroalkyl, aryl, heteroaryl, C(O)O~ or C(O)~; R3 isH, alkyl, heteroalkyl, aryl or
`heteroaryl; ~ is H, alkyl, heteroalkyl, aryl, or heteroaryl; Rs is OR7, alkyl-OR7 or
`heteroalkyl-OR7 ~ is alkyl, heteroalkyl, aryl or heteroaryl; R7 is N02, C(O)~,
`C(O)alkyl-ONOz or C(O)heteroalkyl-ONOz.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`A method according to claim 3, wherein Rs is OR7.
`A method according to claim 3, wherein Rs is CHzOR7.
`
`A method according to claim 3, wherein R1 and Rz are H.
`
`A method according to claim 3, wherein R1 isH and Rz is C(O)~.
`A method according to claim 3, wherein R3 and~ are H or alkyl.
`A method according to claim 4, wherein R3 and~ are H or alkyl.
`A method according to c1aim 5, wherein R3 and~ are H or alkyl.
`A method according to claim 6, wherein R3 and ~ are H or alkyl.
`A method according to claim 9, wherein R7 is N02 or C(O)alkyl-ON02.
`A method according to claim 10, wherein R7 is NOz or C(O)alkyl-ON02•
`A method according to claim 12, wherein R 1 isH and R7 is NOz.
`
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`NMI-13
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`A method according to claim 13, wherein R, isH and R1 is N02.
`
`A method according to claim 13, wherein Rt isH and R1 is C(O)alkyl-ON02.
`
`A method according to claim 14, wherein R2 is H.
`A method according to claim 15, wherein R2 is H.
`
`A method according to claim 16, wherein R2 is alkyl or C(O)O-aryl.
`
`A phannaceutical composition for treating TSC comprising a non-toxic
`
`therapeutically effective amount of n un-competitive NMDA antagonist and a
`
`pharmaceutically acceptable carrier.
`
`21.
`
`A pharmaceutical composition for treating TSC comprising a non-toxic
`
`therapeutically effective amount memantine and a pharmaceutically acceptable carrier.
`
`22.
`
`A pharmaceutical composition for treating TSC comprising a non-toxic
`
`therapeutically effective amount of a compound of the following formula or a
`
`pharmaceutically acceptable salt thereof:
`
`wherein R 1 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)O~ or C(O)~; R2 is H, alkyl,
`heteroalkyl, aryl, heteroaryl, C(O)O~ or C(O)~; R3 is H, alkyl, heteroalkyl, aryl or
`heteroaryl; ~ isH, alkyl, heteroalkyl, aryl, or heteroaryl; R5 is OR7, alkyl-OR7 or
`
`heteroalkyl-OR1 ~ is alkyl, heteroalkyl, aryl or heteroaryl; R1 is N02, C(O)~,
`
`C(O)alkyl-ON02 or C(O)heteroalkyl-ON02 and a pharmaceutically acceptable carrier.
`
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`NMI-13
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`ABSTRACT OF THE DISCLOSURE
`
`The present invention provides methods and compositions for the
`
`treatment and prevention ofTSC.
`
`TRA 1860083vl
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