The term xe2x80x9cmemoryxe2x80x9d subsumes many different processes and requires the function of many different brain areas. Overall, human memory provides declarative recall, e.g., for facts and events accessible to conscious recollection, and non-declarative recall, e.g., procedural memory of skills and operations not stored regarding time and place. Research in recent years has provided information necessary to understand many of the various components of memory and has identified associated brain regions. A newly acquired experience initially is susceptible to various forms of disruption. With time, however, the new experience becomes resistant to disruption. This observation has been interpreted to indicate that a labile, working, short-term memory is consolidated into a more stable, long-term memory.
Behavioral research has found that the human mind consolidates memory at certain key time intervals. The initial phase of memory consolidation occurs in the first few minutes after an exposure to a new idea or learning experience. The next phase occurs over a longer period of time, such as during sleep. If a learning experience has on-going meaning to us, the next week or so serves as a further period of memory consolidation. In effect, in this phase, the memory moves from short-term to long-term storage.
Moreover, various mechanisms have been proposed to account for the formation of long-term memory. A wide range of observations suggest an evolutionarily conserved molecular mechanism involved with the formation of long-term memory. These include increased release of synaptic transmitter, increased number of synaptic receptors, decreased KD of receptors, synthesis of new memory factors either in the presynaptic or postsynaptic clement, sprouting of new synaptic connections, increase of the active area in the presynaptic membrane and many others. Synaptic plasticity, the change in the strength of neuronal connections in the brain, is thought to underlie long-term memory storage.
xe2x80x9cMemory consolidationxe2x80x9d, or long-term memory is also believed to play a crucial role in a variety of neurological and mental disorders, including mental retardation, Alzheimer""s disease and depression. Indeed, loss or impairment of long-term memory is a significant feature of such diseases, and no effective therapy for that effect has emerged. Short-term, or xe2x80x9cworkingxe2x80x9d memory, is generally not significantly impaired in such patients.
Accordingly, methods and compositions that enhance long-term memory function and/or performance, or prophylactically (e.g., as a neuroprotective treatment) prevent or slow degradation of long-term memory function and/or performance would be desirable. Similarly, methods and compositions for restoring long-term memory function and/or performance are needed.
The present invention relates to the discovery that the amphetamine class of compounds (collectively referred to herein as xe2x80x9camphetamine compoundsxe2x80x9d) can be used to enhance, prevent and/or restore long-term memory function and performance, e.g., to improve long-term memory (LTM) in animal subjects. More particularly, the invention relates to the discovery that a particular enantiomer of amphetamine compounds is effective for such therapeutic use.
One aspect of the invention features a pharmaceutical kit comprising one or more amphetamine compound(s) in an amount sufficient to enhance long-term memory in a patient, a pharmaceutically acceptable carrier, and instructions (written and/or pictorial) describing the use of the formulation for enhancing memory.
Another aspect of the invention features a pharmaceutical preparation comprising one or more amphetamine compounds provided as a single oral dosage formulation in an amount sufficient to enhance long-term memory in a patient but resulting in a concentration in the patient lower than its EC50 as a CNS stimulant.
Another aspect of the invention features a pharmaceutical preparation comprising one or more amphetamine compounds provided in the form of a transdermal patch and formulated for sustained release of the amphetamine(s) in order to administer an amount sufficient to enhance long-term memory in a patient but resulting in a concentration in the patient lower than its EC50 as a CNS stimulant.
In preferred embodiments the pharmaceutical kits and preparations of this invention comprise at least one of the amphetamine compounds represented by Formula I, or a pharmaceutically acceptable salt, solvate, metabolite or pro-drug thereof: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aratkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulflydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido.
In certain embodiments, R3 represents hydrogen, while in other embodiments, R3 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., hydroxy, amino, or carbonyl.
In certain embodiments, R4 represents hydrogen, while in other embodiments, R4 represents from 1 to 3 substituents on the ring to which it is attached selected from halogen, hydroxy, amino, sulfhydryl, cyano, nitro, lower alkyl, and sulfate.
In certain embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen. In certain embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represents hydrogen. In certain embodiments, R4 represents hydrogen and at least three of R1, R2, and R3 represent hydrogen. In certain embodiments, R4 represents hydrogen and all four of R1, R2, and R3 represent hydrogen.
In certain embodiments, one R1 represents hydrogen, one R1 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., R2 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., R3 and R4 represent hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 3 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In other preferred embodiments the pharmaceutical kits and preparations of this invention comprise at least one of the amphetamine compounds as a pharmaceutically acceptable salt represented by Formula II: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; and
L is a non-toxic organic or inorganic acid.
In certain embodiments, R3 represents hydrogen, while in other embodiments, R3 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., hydroxy, amino, or carbonyl.
In certain embodiments, R4 represents hydrogen, while in other embodiments, R4 represents from 1 to 3 substituents on the ring to which it is attached selected from halogen, hydroxy, amino, sulfhydryl, cyano, nitro, lower alkyl, and sulfate.
In certain embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen. In certain embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represents hydrogen. In certain embodiments, R4 represents hydrogen and at least three of R1, R2, and R3 represent hydrogen. In certain embodiments, R4 represents hydrogen and all four of R1, R2, and R3 represent hydrogen.
In certain embodiments, one RI represents hydrogen, one R1 represent lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., R2 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, etc., R3 and R4 represent hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In other preferred embodiments the pharmaceutical kits and preparations of this invention comprise at least one of the amphetamine compounds as an amphetamine metabolite represented by Formula III: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R2 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy,
R3 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy,
R4 represents from 1 to 3 substituents on the ring to which it is attached, e.g., selected from hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido;
R5 independently for each occurrence, represents hydrogen or hydroxy.
In certain embodiments, R3 represents hydrogen, while in other embodiments, R3 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., hydroxy, amino, or carbonyl.
In certain embodiments, R4 represents hydrogen, while in other embodiments, R4 represents from 1 to 3 substituents on the ring to which it is attached selected from halogen, hydroxy, amino, sulflydryl, cyano, nitro, lower alkyl, and sulfate.
In certain embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen. In certain embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen. In certain embodiments, R4 represents hydrogen and at least three of R1, R2, and R3 represent hydrogen. In certain embodiments, R4 represents hydrogen and all four of R1, R2, and R3 represent hydrogen.
In certain embodiments, one R1 represents hydrogen, one R1 represent lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., R2 represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc., R3 and R4 represent hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In certain preferred embodiments a metabolite of amphetamine compounds is selected from p-hydroxyamphetamine, benzyl methyl ketone, 1-phenylpropan-2-ol, benzoic acid, glycine, hippuric acid, p-hydroxynorephedrine, and N-hydroxylaamphetamine.
In certain preferred embodiments of the kits, preparations, compositions and methods, the invention features a pharmaceutical kit or preparation comprising a mixture of at least a single species of amphetamine compounds-or at least two different species of amphetamine compounds. The different species of amphetamine compounds can be present in equal or in differing amounts with respect to one another.
In other preferred embodiments of the kits, preparations, compositions and methods, the invention features a composition comprising at least 51 mol percent, 75 mol percent, 95 mol percent, or 99 mol percent of the eutomer with respect to the distomer of that amphetamine compound.
In other preferred embodiments of the kits, preparations, compositions and methods, the invention features one or more amphetamine compound(s) provided in an amount sufficient to enhance long-term memory in a patient by a statistically significant amount when assessed by a standardized performance test.
In certain embodiments of the kits, preparations, compositions and methods, the invention features one or more amphetamine compound(s) comprising at least 2-fold less, or at least 4-fold less of R-(xe2x88x92)-amphetamine as compared to an equally effective long term memory enhancing dose of S-(+)-amphetamine.
In certain embodiments of the kits, preparations, composition and methods, the invention features one or more amphetamine compound(s) provided in an amount sufficient to enhance long-term memory in a patient by a statistically significant amount when assessed by one or more of a Cambridge Neuropsychological Test Automated Battery (CANTAB); a Children""s Memory Scale (CMS); a Contextual Memory Test; a Continuous Recognition Memory Test (CMRT); a Denman Neuropsychology Memory Scale; a Fuld Object Memory Evaluation (FOME); a Graham-Kendall Memory for Designs Test; a Guild Memory Test; a Learning and Memory Battery (LAMB); a Memory Assessment Clinic Self-Rating Scale (MAC-S); a Memory Assessment Scales (MAS); a Randt Memory Test; a Recognition Memory Test (RMT); a Rivermead Behavioral Memory Test; a Russell""s Version of the Wechsler Memory Scale (RWMS); a Test of Memory and Learning (TOMAL); a Vermont Memory Scale (VMS); a Wechsler Memory Scale; and a Wide Range Assessment of Memory and Learning (WRAML).
In certain embodiments of the kits, preparations, compositions and methods, the invention features one or more amphetamine compound(s) provided in an amount sufficient to enhance long-term memory in a patient by a statistically significant amount when assessed by a Providence Recognition Memory Test.
In certain embodiments of the kits, preparations, compositions and methods, the invention features one or more amphetamine compound(s) provided in the form of a saccharate, a sulfate or an aspartate.
In another embodiment of the kits, preparations, compositions and methods, the invention further features a neuronal growth factor, a neuronal survival factor, a neuronal trophic factor, a cholinergic modulator, an adrenergic modulator, a nonadrenergic modulator, a dopaminergic modulator, a glutaminergic modulator or an agent that stimulates PKC, PKA, GABA, NMDA, cannabinoid, AMPA, kainate, phosphodiesterase (PDE), CREB or nootropic pathways. In another embodiment of the kits, preparations, compositions and methods, the invention further features methylphenidate.
Another aspect of the invention features the use of the pharmaceutical composition of amphetamine compounds in the manufacture of a medicament for prophylaxis or treatment of an animal susceptible to or suffering from anxiety, depression, age-associated memory impairment, minimal cognitive impairment, amnesia, dementia, learning disabilities, memory impairment associated with toxicant exposure, brain injury, brain aneurysm, Parkinson""s disease, head trauma, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, stroke, schizophrenia, epilepsy, mental retardation, Alzheimer""s disease, age, attention deficit disorder, attention deficit hyperactivity disorder, or AIDS-related dementia, which amphetamine compound is represented by Formula I, or a pharmaceutically acceptable salt, solvate, metabolite or pro-drug thereof: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylarnino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino; acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
Another aspect of the invention features the use of an amphetamine compound in the manufacture of a medicament for prophylaxis or treatment of an animal susceptible to or suffering from anxiety, depression, age-associated memory impairment, minimal cognitive impairment, amnesia, dementia, learning disabilities, memory impairment associated with toxicant exposure, brain injury, brain aneurysm, Parkinson""s disease, head trauma, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, stroke, schizophrenia, epilepsy, mental retardation, Alzheimer""s disease, age, attention deficit disorder, attention deficit hyperactivity disorder, or AIDS-related dementia, which amphetamine compound is represented by Formula II: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; and
L is a non-toxic organic or inorganic acid.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
Another aspect of the invention features the use of an amphetamine compound in the manufacture of a medicament for prophylaxis or treatment of an animal susceptible to or suffering from anxiety, depression, age-associated memory impairment, minimal cognitive impairment, amnesia, dementia, learning disabilities, memory impairment associated with toxicant exposure, brain injury, brain aneurysm, Parkinson""s disease, head trauma, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, stroke, schizophrenia, epilepsy, mental retardation, Alzheimer""s disease, age, attention deficit disorder, attention deficit hyperactivity disorder, or AIDS-related dementia, which amphetamine compound is represented by Formula m: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R2 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R3 is absent or represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R4 represents from 1 to 3 substituents on the ring to which it is attached, e.g., selected from hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido;
R5 independently for each occurrence, represents hydrogen or hydroxy.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In certain embodiments, the animal to be treated is a mammal. In certain preferred embodiments the animal to be treated is a human, dog, cat, cattle, horse, sheep, hog or goat.
In certain embodiments, the pharmaceutical composition is for oral administration.
In certain other embodiments the pharmaceutical composition is a transdermal patch. In certain embodiments the transdermal patch includes one or more penetration enhancers.
In certain embodiments, the pharmaceutical composition features an amphetamine compound provided as at least 51 mol percent, or at least mol 75 percent, or at least 95 mol percent, or at least 99 mol percent of the of the eutomer with respect to the distomer of that amphetamine compound.
In certain embodiments, the pharmaceutical composition features an amphetamine compound provided in an amount sufficient to enhance long-term memory in a patient by a statistically significant amount when assessed by a standardized performance test.
In certain embodiments, the pharmaceutical composition features one or more amphetamine compound(s) provided in an amount sufficient to enhance long-term memory in a patient by a statistically significant amount when assessed by one or more of a Cambridge Neuropsychological Test Automated Battery (CANTAB); a Children""s Memory Scale (CMS); a Contextual Memory Test; a Continuous Recognition Memory Test (CMRT); a Denman Neuropsychology Memory Scale; a Fuld Object Memory Evaluation (FOME); a Graham-Kendall Memory for Designs Test; a Guild Memory Test; a Learning and Memory Battery (LAMB); a Memory Assessment Clinic Self-Rating Scale (MAC-S); a Memory Assessment Scales (MAS); a Randt Memory Test; a Recognition Memory Test (RMT); a Rivermead Behavioral Memory Test; a Russell""s Version of the Wechsler Memory Scale (RWMS); a Test of Memory and Learning (TOMAL); a Vermont Memory Scale (VMS); a Wechsler Memory Scale; and a Wide Range Assessment of Memory and Learning (WRAML).
In certain embodiments, the pharmaceutical composition features one or more amphetamine compound(s) provided in an amount sufficient to enhance long-term memory in a patient by a statistically significant amount when assessed by a Providence Recognition Memory Test.
In certain embodiments, the pharmaceutical composition features one or more amphetamine compound(s) provided in the form of a saccharate, a sulfate or an aspartate.
In other embodiments of the kits, preparations, compositions and methods, the invention further features amphetamine compound(s) being provided as a single oral dosage formulation in an amount sufficient to enhance long-term memory in a patient but resulting in a concentration in the patient lower than its EC50 as a CNS stimulant.
In other embodiments of the kits, preparations, compositions and methods, the invention further features amphetamine compound(s) being provided for treating and/or preventing memory impairment, wherein the memory impairment results from one or more of anxiety, depression, age-associated memory impairment, minimal cognitive impairment, amnesia, dementia, learning disabilities, memory impairment associated with toxicant exposure, brain injury, brain aneurysm, Parkinson""s disease, head trauma, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, stroke, schizophrenia, epilepsy, mental retardation, Alzheimer""s disease, age, attention deficit disorder, attention deficit hyperactivity disorder, or AIDS-related dementia.
In other embodiments of the kits, preparations, compositions and methods, the invention further features amphetamine compound(s) being provided for enhancing memory in normal individuals.
In certain preferred embodiments of the kits, preparations, compositions and methods, the invention features one or more amphetamine compound(s), wherein the amphetamine compound is (R)-(xe2x88x92)-amphetamine.
In certain preferred embodiments of the kits, preparations, compositions and methods, the invention features one or more amphetamine compound(s), wherein the amphetamine compound is (R)-(xe2x88x92)-methamphetamine.
In certain preferred embodiments of the kits, preparations, compositions and methods, the invention features single oral dosage formulations of 2.5 mg to 25, 50, 75, 100 or even 125 mg of (R)-(xe2x88x92)-amphetamine and a pharmaceutically acceptable carrier.
In certain embodiments, the invention features a method for enhancing memory in an animal, comprising administering to the animal a composition of an amphetamine compound in an amount sufficient to enhance long-term memory in the animal, wherein the composition includes at least 51 mol percent of the eutomer of the amphetamine compound represented by Formula I, or pharmaceutically acceptable salt, solvate, metabolite or pro-drug thereof, relative to the distomer of that amphetamine compound: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylaldyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylarnino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In certain embodiments, the invention features a method for enhancing memory in an animal, comprising administering to the animal a composition of an amphetamine compound in an amount sufficient to enhance long-term memory in the animal, wherein the composition includes at least 51 mol percent of the eutomer of the amphetamine compound, relative to the distomer of that amphetamine compound, wherein the amphetamine compound is a pharmaceutically acceptable salt represented by Formula II: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; and
L is a non-toxic organic or inorganic acid.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In certain embodiments, the invention features a method for enhancing memory in an animal, comprising administering to the animal a composition of an amphetamine compound in an amount sufficient to enhance long-term memory in the animal, wherein the composition includes at least 51 mol percent of the eutomer of the amphetamine compound, relative to the distomer of that amphetamine compound, wherein the amphetamine compound is an amphetamine metabolite represented by Formula III, or pharmaceutically acceptable salt, solvate, or pro-drug thereof. 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R2 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R3 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R4 represents from 1 to 3 substituents on the ring to which it is attached, e.g., selected from hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido;
R5 independently for each occurrence, represents hydrogen or hydroxy.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents hydrogen, or lower alkyl; R2 represents hydrogen or lower alkyl, R3 represents hydrogen or lower alkyl, and R4 represents hydrogen or from 1 to 2 substituents on the ring to which it is attached, selected from halogen, trifluoromethyl, hydroxy, amino, cyano, nitro, and lower alkyl.
In certain preferred embodiments, R4 represents hydrogen and at least one of R1, R2, and R3 represents hydrogen.
In certain preferred embodiments, R4 represents hydrogen and at least two of R1, R2, and R3 represent hydrogen.
In certain preferred embodiments, both occurrences of R1 represent independently hydrogen, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In certain preferred embodiments, one occurrence of R1 represents hydrogen, the second occurrence of R1 represents methyl, R2 represents methyl, R3 represents hydrogen and R4 represents hydrogen.
In most preferred embodiments, R1, independently and for each occurrence, represents hydrogen, R2 represents methyl, and R3 and R4 independently and for each occurrence represent hydrogen.
In certain embodiments, the invention features a kit comprising an amphetamine compound formulation, e.g., as described herein and preferably provided in single oral dosage form or as a transdermal patch for enhancing memory in a patient (preferably a human), and in association with instructions (written and/or pictorial) describing the use of the formulation for enhancing memory, and optionally, warnings of possible side effects and drug-drug or drug-food interactions.
Another aspect of the invention relates to a method for conducting a pharmaceutical business, which includes: (a) manufacturing the kits, preparations, and compositions of the present invention; and (b) marketing to healthcare providers the benefits of using the kits, preparations, and compositions of the present invention to enhance memory of treated patients.
Another aspect of the invention relates to a method for conducting a pharmaceutical business, comprising: (a) providing a distribution network for selling the kits, preparations, and compositions of the present invention; and (b) providing instruction material to patients or physicians for using the kits, preparations, and compositions of the present invention to enhance memory of treated patients.
Yet another aspect of the invention relates to a method for conducting a pharmaceutical business, comprising: (a) determining an appropriate dosage of an amphetamine compound to enhance memory function in a class of patients; (b) conducting therapeutic profiling of one or more formulations of the amphetamine compound identified in step (a), for efficacy and toxicity in animals; and (c) providing a distribution network for selling the formulations identified in step (b) as having an acceptable therapeutic profile.
For instance, the subject business method can include an additional step of providing a sales group for marketing the preparation to healthcare providers.
Another aspect of the invention relates to a method for conducting a pharmaceutical business, comprising: (a) determining an appropriate dosage of an amphetamine compound to enhance memory function in a class of patients; and (b) licensing, to a third party, the rights for further development and sale of the amphetamine compound for enhancing memory.
In certain embodiments of the method, the class of patients suffer from memory impairment. In preferred embodiments of the method, the memory impairment results from one or more of anxiety, depression, age-associated memory impairment, minimal cognitive impairment, amnesia, dementia, learning disabilities, memory impairment associated with toxicant exposure, brain injury, brain aneurysm, Parkinson""s disease, head trauma, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, stroke, schizophrenia, epilepsy, mental retardation, Alzheimer""s disease, age, attention deficit disorder, attention deficit hyperactivity disorder, or AIDS-related dementia. In other preferred embodiments of the method, the class of patients are normal individuals.
Another aspect of the invention features solid dosage form comprising an amphetamine compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, metabolite or pro-drug thereof, in an amount of 25 mg or less: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylarnino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido.
Another aspect of the invention features solid dosage form comprising a pharmaceutically acceptable salt of an amphetamine compound represented by Formula II, solvate, metabolite or pro-drug thereof, in an amount of 25 mg or less: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R2 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R3 represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl;
R4 represents from 1 to 3 substituents on the ring to which it is attached, selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylarnino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylamino, acyloxy, lower alkyl, lower alkenyl, ester, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; and
L is a non-toxic organic or inorganic acid.
Another aspect of the invention features solid dosage form comprising an amphetamine metabolite represented by Formula III, solvate or pro-drug thereof, in an amount of 25 mg or less: 
wherein, as valence and stability permit,
R1, independently for each occurrence, represents hydrogen or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R2 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R3 represents hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, e.g., optionally substituted by one or more substitutents such as halogen, hydroxy, alkoxy;
R4 represents from 1 to 3 substituents on the ring to which it is attached, e.g., selected from hydrogen, halogen, hydroxy, alkoxy, amino, alkylarnino, sulfhydryl, alkylthio, cyano, nitro, ester, ketone, formyl, amido, acylarnino, acyloxy, lower alkyl, lower alkenyl, sulfonate ester, amidino, sulfonyl, sulfoxido, sulfamoyl, sulfonamido;
R5 independently for each occurrence, represents hydrogen or hydroxy.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of synthetic chemistry, organic chemistry, inorganic chemistry, organometallic chemistry, pharmaceutical chemistry, and behavioral science, which are within the skill of the art. Such techniques are described in the literature. See, for example, Advanced Organic Chemistry: Reactions, Mechanisms, And Structure by J. March (John Wiley and Sons, N.Y., 1992); The Chemist""s Companion: A Handbook Of Practical Data, Techniques, And References by A. J. Gordon and R. A. Ford (Wiley, N.Y., 1972); Synthetic Methods Of Organometallic And Inorganic Chemistry by W. A. Herrmann and Brauer (Georg Thieme Verlag, N.Y., 1996); Experimental Organic Chemistry by D. Todd (Prentice-Hall, N.J., 1979); Experimental Organic Chemistry: Standard And Microscale by L. M. Harwood (Blackwell Science, M.A., 1999); Experimental Analysis Of Behavior by I. H. Iversen and K. A. Lattal (Elsevier, N.Y., 1991); A Practical Guide To Behavioral Research: Tools And Techniques by R. Sommer and B. Sommer (Oxford University Press, N.Y., 2002); Advances In Drug Discovery Techniques by A. L. Harvey (Chichester, N.Y., 1998); Quantitative Calculations In Pharmaceutical Practice And Research by T. P. Hadjiioannou (VCH, N.Y., 1993); Drug Fate And Metabolism: Methods And Techniques by E. R. Garrett and J. L. Hirtz (M. Dekker, N.Y., 1977); Behavioral Science Techniques: An Annotated Bibliography For Health Professionals by M. K. Tichy (Praeger Publishers, N.Y., 1975).
USPTO Backgrounds
USPTO Backgrounds