WO2021231582A1

WO2021231582A1 - Nitro-aminoadamantane compounds for the treatment of negative symptoms and cognitive impairment associated with schizophrenia

Info

Publication number: WO2021231582A1
Application number: PCT/US2021/032006
Authority: WO
Inventors: Randall Dean MARSHALL
Original assignee: Eumentis Therapeutics, Inc.
Priority date: 2020-05-12
Filing date: 2021-05-12
Publication date: 2021-11-18

Abstract

The invention features the use of nitro-aminoadamantane compounds for the treatment of negative symptoms and cognitive impairment associated with schizophrenia. A method of treating cognitive impairment associated with schizophrenia (CIAS) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof.

Description

NITRO-AMINOADAMANTANE COMPOUNDS FOR THE TREATMENT OF NEGATIVE SYMPTOMS AND COGNITIVE IMPAIRMENT ASSOCIATED WITH SCHIZOPHRENIA

Background of the Invention

N-methyl-d-aspartate (NMDA) receptors (NMDAR) are postsynaptic, ionotropic receptors that are responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA. The NMDA receptor controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated ion channel. The NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience-dependent synaptic modifications. In addition, NMDA receptors are also thought to be involved in long term potentiation, synaptic plasticity, learning, memory, and a number of central nervous system disorders.

Schizophrenia is a chronic psychiatric disorder, characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation, communication behaviors, social drive and interest, adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition) (Blanchard et al, Schizophr Res. 185:137-143 (2017), and cognitive impairment, including problems with reasoning and executing complex behaviors needed for activities of daily living. Moreover, even patients exhibiting cognitive function within normal limits are likely to have impaired cognitive function relative to pre-morbid levels. Cognitive impairment contributes to overall disability in schizophrenia patients independently of positive and negative symptoms.

Likewise, negative symptoms in schizophrenia are poorly treated by current approved medications (antipsychotics) (Blanchard et al., Schizophr Bull. 37:291-299 (2011); Murphy et al., Schizophr Res. 88:5-25 (2006)). Negative symptoms are associated with poor social functioning and longitudinally predict social and occupational impairment (Milev et al Am J Psychiatry. 162:495-506 (2005)) and are factorially distinct from positive symptoms or comorbid disorders such as depression or anxiety (Blanchard et al., Schizophr Bull. 37:291-299 (2011)). Current approved medications for schizophrenia, such as dopamine antagonists or serotonergic partial agonists, are minimally effective for negative symptoms (Murphy et al., Schizophr Res. 88:5-25 (2006)).

Multiple lines of evidence demonstrate that negative symptoms, like cognitive symptoms, are related to l/E imbalance and glutamate dysregulation (Merritt et al., Schizophr Bull. 43(Suppl 1):S142- S143 (2017)). Pyramidal neurons, which are glutamatergic, are blunted in the prefrontal cortex in schizophrenia and contribute to negative symptoms (D.T. Balu Adv Pharmacol. 76:351-382 (2016)). Reduced plasma levels of glycine correlate with severity of negative symptoms (Kantrowitz et al., Clin Schizophr Relat Psychoses. 4:189-200 (2010)). Ketamine induces a surge of glutamate release, a mechanism confirmed in animal proton magnetic resonance spectroscopy (Kim et al., NMR Biomed. 24:1235-42 (2011)). In humans, ketamine induces a syndrome with negative as well as positive symptoms resembling schizophrenia. This is caused by ketamine’s preferential inhibition of GABA interneurons regulating limbic and cortical neuronal circuitry (Krystal et al., Psychopharmacology 179:303-309 (2005); Abdallah et al., Neuropsychopharmacology. 43:2154-2160 (2018)). Nitro- aminoadamantane compounds can function as NMDA receptor antagonists to correct some of the imbalances characteristic of this condition.

While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available anti psych otics are largely ineffective in treating cognitive impairments and negative symptoms in schizophrenia subjects.

Cognitive impairments in schizophrenia can involve both frontal and temporal lobe functions that include memory, attention, processing speed, and executive control. Altered brain activity/excitability in the medial temporal lobe memory system may contribute to cognitive impairment and may also play a role in augmenting psychotic symptoms due to disinhibition of dopaminergic neurons.

Cognitive deficits are increasingly recognized as a clinical feature that can be detected in a prodromal phase and in remission, as well as during full expression of schizophrenia, and cognitive and negative symptoms are not effectively treated by available antipsychotics. Because untreated features of schizophrenia, especially impaired cognition and negative symptoms, predict long-term disability in some subjects (Green et al., Schizophr. Res. 72:41-45 (2004); Milev et al Am J Psychiatry. 162:495-506 (2005)), it is critical to develop effective therapies for the cognitive impairments associated with schizophrenia.

Summary of the Invention

The invention features the use of nitro-aminoadamantane compounds for the treatment of negative symptoms and cognitive impairments associated with schizophrenia.

In a first aspect, the invention features a method of treating cognitive impairment associated with schizophrenia (CIAS) in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof. For example, the working memory, attention, reasoning and problem solving, and/or social cognition can be maintained or improved (e.g., by 10%, 20%, 30%, or 50%) relative to the cognitive performance of the subject prior to receiving the treatment of the invention. Alternatively, the cognitive impairment in working memory, attention, reasoning and problem solving, and/or social cognition can be reduced by 10%, 20%, 30%, or 50% relative to control subjects of the same age, severity of symptoms, and having the same comorbidities.

The invention also features a method of inhibiting the progression of cognitive decline associated with schizophrenia in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof. For example, the cognitive decline in working memory, attention, reasoning and problem solving, and/or social cognition can be reduced by 10%, 20%, 30%, or 50% relative to control subjects of the same age, severity of symptoms, and having the same comorbidities.

In some embodiments of the above aspects, the subject has schizophrenia under remission.

The invention also features a method of treating cognitive impairment in a subject suffering from prodromal schizophrenia, the method including administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof. For example, the working memory, attention, reasoning and problem solving, and/or social cognition can be maintained or improved (e.g., by 10%, 20%, 30%, or 50%) relative to the cognitive performance of the subject prior to receiving the treatment of the invention. Alternatively, the cognitive impairment in working memory, attention, reasoning and problem solving, and/or social cognition can be reduced by 10%, 20%, 30%, or 50% relative to control subjects of the same age, severity of symptoms, and having the same comorbidities.

The invention also features a method of improving cognitive function in a subject suffering from prodromal schizophrenia, the method including administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof. For example, the working memory, attention, reasoning and problem solving, and/or social cognition of the subject can be improved by 10%, 20%, 30%, or 50% relative to the cognitive performance of the subject prior to receiving the treatment of the invention.

In some embodiments of any of the above aspects, the working memory of the subject is maintained or improved in comparison to untreated subjects.

In certain embodiments of any of the above aspects, the attention of the subject is maintained or improved in comparison to untreated subjects.

In some embodiments of any of the above aspects, the reasoning and problem solving of the subject is maintained or improved in comparison to untreated subjects.

In certain embodiments of any of the above aspects, the social cognition of the subject is maintained or improved in comparison to untreated subjects.

In some embodiments of any of the above aspects, the subject is identified as being at least 0.5 SD (standard deviations), 1 .0 SD, 1 .5 SD, or 2.0 SD below normative scores on any validated measure of cognition. The validated measure of cognition can be any measure of cognition described herein.

In certain embodiments of any of the above aspects, the subject has retrospectively-assessed deterioration of cognition from pre-morbid levels of functioning as assessed by a physician.

In an embodiment of any of the above methods, the subject is over the age of 18 (e.g., 19, 20, 21 , or older). In still other embodiments of any of the above methods, the subject is not further suffering from autism spectrum disorder (ASD) as a comorbid condition.

In a related aspect the invention features a method of treating negative symptoms associated with schizophrenia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof. For example, the degree of negative symptoms (e.g., apathy, alogia, asociality, and/or avolition) can be reduced (e.g., by 10%, 20%, 30%, or 50%) relative to the degree of negative symptoms observed for the subject prior to receiving the treatment of the invention. Alternatively, the negative symptoms (e.g., apathy, alogia, asociality, and/or avolition) can be reduced by 10%, 20%, 30%, or 50% relative to control subjects of the same age, severity of symptoms, and having the same comorbidities. In particular embodiments, the subject has schizophrenia under remission.

The invention further features a method of treating negative symptoms in a subject suffering from prodromal schizophrenia, said method comprising administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof. For example, the degree of negative symptoms (e.g., apathy, alogia, asociality, and/or avolition) can be reduced (e.g., by 10%, 20%, 30%, or 50%) relative to the degree of negative symptoms observed for the subject prior to receiving the treatment of the invention. Alternatively, the negative symptoms (e.g., apathy, alogia, asociality, and/or avolition) cars be reduced by 10%, 20%, 30%, or 50% relative to control subjects of the same age, severity of symptoms, and having the same comorbidities.

In the above methods for treating negative symptoms, the negative symptoms can include ( i) a degree of apathy and the degree of apathy in the subject is reduced in comparison to untreated subjects; (ii) a degree of alogia and the degree of alogia in the subject is reduced in comparison to untreated subjects; (iii) a degree of asociality and the degree of asociality in the subject Is reduced In comparison to untreated subjects; and/or (iv) a degree of avolition and the degree of avolition in the subject is reduced in comparison to untreated subjects.

In some embodiments of the above methods for treating negative symptoms, the social impairment (i e., impaired social performance) of the subject Is reduced in comparison to untreated subjects or reduced in comparison to the subject prior to receiving the treatment of the invention.

In particular embodiments of the above methods for treating negative symptoms, the occupational impairment (i e., Impaired job performance) of the subject is reduced In comparison to untreated subjects or reduced in comparison to the subject prior to receiving the treatment of the Invention.

In embodiments of any of !he above methods, the administration occurs between once per week to three times per day. For example, the administration can be once per day or twice per day.

In embodiments of any of the above methods, the nitro-aminoadamantane compound is administered orally, intravenously, or by any other route of administration described herein.

In one embodiment of any of the above methods, the nitro-aminoadamantane compound is a compound of any one of formulas (l)-(V) (described herein). in one particular embodiment of any of the above methods, the nitro-aminoadamantane compound is selected from:

, and pharmaceutically acceptable salts thereof.

Definitions

As used herein, the term “about" means +/- 10% of the recited value.

As used herein, by “administration” or “administering” Is meant a method of giving a dosage of a nitro-ammoadamantane compound to a subject. The nitro-aminoadamantane compounds utilized in the methods described herein can be administered, for example, orally, or by another other route described herein.

As used herein, the term "cognitive impairment" refers to a functional deficit in any higher order intellectual brain process or brain state, respectively, involved in learning and/or memory including, but not limited to, atention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, Inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, the temporal integration of voluntary behavior, expressing an interest in one's surroundings and self-care, speed of processing, reasoning and problem solving and social cognition In humans, cognitive function may be measured, for example and without limitation, by the clinical global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Batery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschk c Selective Reminding Test (Buschke and Fu!d, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual Reproduction subtest of the We chsler Memory Scale- Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test, or the explicit 3-alternative forced choice task, or MATRlCS consensus neuropsychological test battery (see Folsteln et al., J Psychiatric Res 12: 189-98, (1975); Robbins et al,, Dementia 5: 268-81 , (1994); Rey, L'examen Clinique en psychologic, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. Also see Buchanan, R.W., Keefe, R.S E., Umbncht, D„ Green, M.F , Laughren, T„ and Marder, S R (2011), The FDA-NIMH-MATRlCS guidelines for clinical trial design of cognitive- enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217). Cognitive function may also be measured using imaging techniques such as Positron Emission Tomography (PET), functional magnetic resonance Imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function. In animals, cognitive function may also be measured with electrophysioiogicai techniques. As used herein, "preserving" cognitive function refers to affecting normal or impaired cognitive function such that it does not decline or does not fall below that observed In the subject upon first presentation or diagnosis, or delays such decline The methods of the invention can be used to preserve cognitive function in a subject with schizophrenia or in the prodromal phase of schizophrenia. As used herein, the term "schizophrenia" refers to a chronic debilitating disorder, characterized by a spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and in some cases cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics arc largely ineffective in treating cognitive impairments and negative symptoms in subjects.

As used herein, a "therapeutically effective amount" refers to an amount of a nitro- aminoadamantane compound required to treat, ameliorate the symptoms of, inhibit the progression of cognitive impairment in subjects suffering from schizophrenia or in the prodromal phase of schizophrenia. The effective amount of a nitro-aminoadamantane compound used to practice the invention for therapeutic treatment cognitive impairment can vary depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician will decide the appropriate amount and dosage regimen. Such amount is referred to as a "therapeutically effective amount."

As used herein, the term “cognitive impairment associated with schizophrenia” or “CIAS” refers to a subject with schizophrenia or prodromal schizophrenia and (i) identified as being at least 0.5 SD below normative scores on any validated measure of cognition; and (ii) subjects with retrospectively-assessed deterioration of cognition from pre-morbid levels of functioning as assessed by a physician. In certain embodiments, the subject has schizophrenia under remission.

As used herein, the term “negative symptoms associated with schizophrenia” refers to a diminution or lack of a normal function including one or more of: (a) affective experience, either focused on reduced pleasure (i.e., anhedonia) or on a broader reduction in the range and intensity of both positive and negative emotions; (b) interest in and motivation for productive activities or sense of purpose (relating to avolition or apathy); (c) social drive or interest and desire for affiliation (relating to asociality); and (d) expressive or communicative behaviors, including diminished facial expression, decreased gestures, and decreased vocal intonation (all aspects of flat or blunted affect), as well as diminished verbal production or reduced spontaneous speech (i.e., alogia) in a subject with schizophrenia or prodromal schizophrenia. The severity of the negative symptoms can be assessed using testing/rating scales known in the art.

By “pharmaceutical composition” is meant any composition that contains a nitro- aminoadamantane compound combined with a pharmaceutically acceptable carrier that together is suitable for administration to a subject and that treats cognitive impairment in subjects suffering from schizophrenia or in the prodromal phase of schizophrenia. Pharmaceutical compositions useful in the methods of the invention can take the form of tablets, gelcaps, capsules, pills, powders, granulates, suspensions, and/or emulsions.

As used herein, the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active ingredients (e.g., a nitro-aminoadamantane compound). The pharmaceutically acceptable carrier can be compatible with the other ingredients of the formulation and not deleterious to the recipient. For oral administration, a solid carrier may be preferred.

As used herein, the term "treat" or "treating" includes administration of a nitro-aminoadamantane compound to a subject by any route, e.g., orally. The subject, e.g., a subject, can be one having a disorder (e.g., a disease or condition described herein), a symptom of a disorder, or a predisposition toward a disorder. Treatment is not limited to curing or complete healing, but can result in one or more of alleviating, relieving, altering, partially remedying, ameliorating, improving or affecting the cognitive impairment and/or negative symptoms of subjects suffering from schizophrenia or in the prodromal phase of schizophrenia. The effect is beyond what is seen in the absence of treatment.

As used herein, the term “pharmaceutically acceptable salt” refers to salt forms (e.g., acid addition salts or metal salts) of the nitro-aminoadamantane compounds suitable for therapeutic use according to the methods of the invention.

As used herein, the term "nitro-aminoadamantane compound" refers to compounds including an adamantane moiety substituted by at least one amino group and at least one terminal nitrate group. The nitro-aminoadamantane compound used in the methods of the invention can be any nitro- aminoadamantane compound of formulas (l)-(V), or subgenera thereof.

The terms “halogen”, “halide” and “halo” refer to fluorine/fluoride, chlorine/chloride, bromine/bromide and iodine/iodide.

The term “alkyl” refers to a linear or branched, saturated monovalent hydrocarbon radical, wherein the alkyl group can optionally be substituted with one or more substituents as described herein.

In certain embodiments, an alkyl group is a linear saturated monovalent hydrocarbon radical that has 1 to 10 (C_1-10) or 1 to 6 (C_1-6) carbon atoms, or is a branched saturated monovalent hydrocarbon radical that has 3 to 10 (C_3-10) or 3 to 6 (C_3-6) carbon atoms. As an example, the term “C_1-6 alkyl” refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Linear C_1-6 and branched C_3-6 alkyl groups may also be referred to as “lower alkyl”. Non-limiting examples of alkyl groups include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including all isomeric forms, such as n-butyl, isobutyl, sec-butyl and tert- butyl), pentyl (including all isomeric forms, such as n-pentyl), and hexyl (including all isomeric forms, such as n-hexyl).

The terms “alkylene” and “-alkyl-” refer to a divalent alkyl group, which can optionally be substituted with one or more substituents as described herein.

The term “heteroalkyl” refers to a linear or branched, saturated monovalent hydrocarbon group containing one or more heteroatoms independently selected from O, N and S. In some embodiments, one or more heteroatoms are in the main chain of the linear or branched hydrocarbon group. The terms “heteroalkylene” and “-heteroalkyl-” refer to a divalent heteroalkyl group. A heteroalkyl group and a - heteroalkyl- group can optionally be substituted with one or more substituents as described herein. Examples of heteroalkyl and -heteroalkyl- groups include without limitation -(CH₂)_m-(O or S)-(CH₂)_nCH₃ and -(CH₂)_m-(O or S)-(CH₂)_P-, wherein m is 1 , 2 or 3, n is 0, 1 or 2, and p is 1 , 2 or 3.

The term “alkoxy” refers to an -O-alkyl group, which can optionally be substituted with one or more substituents as described herein.

Examples of -O-heteroalkyl and -O-heteroalkyl- groups include without limitation ethylene glycol groups and polyethylene glycol (PEG) groups, including but not limited to - (OCH₂CH₂)_n-OR and - (OCH₂CH₂)_n-O-, wherein R is hydrogen or alkyl and n is 1 , 2 or 3. It is understood that for a -O- heteroalkyl-ONO₂ group, when the -O-heteroalkyl- group is an ethylene glycol or PEG group, the terminal oxygen atom of the ethylene glycol or PEG group is part of the nitrate (-ONO₂) group. An -O-heteroalkyl group and an -O-heteroalkyl- group can optionally be substituted with one or more substituents as described herein.

The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogen/halide atoms. A haloalkyl group can optionally be substituted with one or more additional substituents as described herein. Examples of haloalkyl groups include without limitation fluoroalkyl groups such as - CH₂F, -CHF₂ and -(CH₂)_nCF₃, and perfluoroalkyl groups such as -CF₃ and -(CF₂)_nCF₃, wherein n is 1 , 2,

3, 4 or 5.

The term “-alkylaryl” refers to an alkyl group that is substituted with one or more aryl groups. An - alkylaryl group can optionally be substituted with one or more additional substituents as described herein.

The term “cycloalkyl” refers to a cyclic saturated, bridged or non-bridged monovalent hydrocarbon radical, which can optionally be substituted with one or more substituents as described herein. In certain embodiments, a cycloalkyl group has from 3 to 10 (C_3-10), or from 3 to 8 (C_3-8), or from 3 to 6 (C_3-6) carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl and adamantyl. The term “-cycloalkyl-” refers to a divalent cycloalkyl group, which can optionally be substituted with one or more substituents as described herein.

The terms “heterocyclyl” and “heterocyclic” refer to a monocyclic non-aromatic group or a multicyclic group that contains at least one non-aromatic ring, wherein at least one non-aromatic ring contains one or more heteroatoms independently selected from O, N and S. The non-aromatic ring containing one or more heteroatoms may be attached or fused to one or more saturated, partially unsaturated or aromatic rings. In certain embodiments, a heterocyclyl or heterocyclic group has from 3 to 10, or 3 to 8, or 3 to 6 ring atoms. In some embodiments, a heterocyclyl or heterocyclic group is a monocyclic, bicyclic or tricyclic ring system, which may include a fused or bridged ring system, and in which nitrogen or sulfur atoms can optionally be oxidized, nitrogen atoms can optionally be quaternized, and one or more rings may be fully or partially saturated, or aromatic. A heterocyclyl or heterocyclic group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyl or heterocyclic groups include without limitation azepinyl, azetidinyl, aziridinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, b-carbolinyl, chromanyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, indolizinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl (oxolanyl), tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl (tetrahydrothiophenyl, thiolanyl), thiamorpholinyl (thiomorpholinyl), thiazolidinyl and 1 ,3,5-trithianyl. The term “-heterocyclyl-” refers to a divalent heterocyclyl group. A heterocyclyl or heterocyclic group, and a -heterocyclyl- group, can optionally be substituted with one or more substituents as described herein.

The term “aryl” refers to a monocyclic aromatic hydrocarbon group or a multicyclic group that contains at least one aromatic hydrocarbon ring. In certain embodiments, an aryl group has from 6 to 10 ring atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, biphenyl and terphenyl. The aromatic hydrocarbon ring of an aryl group may be attached or fused to one or more saturated, partially unsaturated or aromatic rings - e.g., dihydronaphthyl, indenyl, indanyl and tetrahydronaphthyl (tetralinyl). The term “-aryl-” refers to a divalent aryl group. An aryl group and an -aryl- group can optionally be substituted with one or more substituents as described herein.

The term “heteroaryl” refers to a monocyclic aromatic group or a multicyclic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, N and S. The heteroaromatic ring may be attached or fused to one or more saturated, partially unsaturated or aromatic rings that may contain only carbon atoms or that may contain one or more heteroatoms. A heteroaryl group may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, a heteroaryl group has from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include without limitation pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridonyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridazinonyl and triazinyl. Non-limiting examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzothienyl (benzothiophenyl), quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzotriazolyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indazolyl, naphthyridinyl, phthalazinyl, quinazolinyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include without limitation carbazolyl, benzindolyl, dibenzofuranyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and phenothiazinyl. The term “-heteroaryl-” refers to a divalent heteroaryl group. A heteroaryl group and a -heteroaryl- group can optionally be substituted with one or more substituents as described herein.

Each group described herein (including without limitation monovalent and divalent alkyl, heteroalkyl, -O-alkyl, -O-heteroalkyl, alkylaryl, cycloalkyl, heterocyclyl, aryl and heteroaryl), whether as a primary group or as a substituent group, can optionally be substituted with one or more substituents. In certain embodiments, each group described herein can optionally be substituted with 1 , 2, 3, 4, 5 or 6 substituents independently selected from halide, cyano, nitro, nitrate, hydroxyl, sulfhydryl (-SH), -NH ₂, - OR¹¹, -SR¹¹, -NR¹²R¹³, -C(= O)R¹¹, -C(= O) OR¹¹, - OC(= O)R¹¹, -C(= O)NR¹²R¹³, -NR¹²C(= O)R¹¹, - OC(= O)OR¹¹, -OC(= O)NR¹²R¹³, -NR¹²C(= O) OR¹¹, -NR¹¹C(= O)NR¹²R¹³, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein:

R¹¹ in each occurrence independently is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and

R¹² and R¹³ in each occurrence independently are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R¹² and R¹³ and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring.

Other features and advantages of the invention will be apparent from the following Detailed Description, and the claims. Detailed Description of the Invention

The invention features methods for treating negative symptoms and cognitive impairments associated with schizophrenia or prodromal schizophrenia. The methods include administering a nitro- aminoadamantane compound to the subject with schizophrenia or prodromal schizophrenia suffering, or at risk of, cognitive impairment.

Negative symptoms and cognitive impairments can be associated with schizophrenia. They can precede the onset of psychosis and can be present in non-affected relatives. The negative symptoms and cognitive impairments associated with schizophrenia reflect dysfunction in frontal cortical and hippocampal circuits. Subjects with schizophrenia may also present hippocampal pathologies such as reductions in hippocampal volume, reductions in neuronal size and dysfunctional hyperactivity. An imbalance in excitation and inhibition in these brain regions has also been documented in schizophrenic subjects. Cognitive impairments in schizophrenia can produce deficits in memory, attention, processing speed, and executive control. Negative symptoms in schizophrenia can produce social and occupational impairment. Altered brain activity/excitability in the medial temporal lobe memory system may contribute to cognitive impairment and may also play a role in augmenting psychotic symptoms due to disinhibition of dopaminergic neurons.

Considerable research has shown that schizophrenia is a disorder of hyperexcitability (i.e., the ratio of inhibitory to excitatory cortical activity, or “l/E imbalance”) (Stare et al., Schizophr Res. 181 : 107- 116 (2017)), particularly in brain regions associated with cognition and executive function (Merritt, JAMA Psychiatry. 73:665-74 (2016)). Nitro-aminoadamantane compounds can function as NMDA receptor antagonists to correct some of the imbalances characteristic of this condition.

Using the methods of the invention, the nitro-aminoadamantane compound, or a pharmaceutically acceptable salt thereof, can be administered to treat, maintain or improve the working memory, attention, reasoning and problem solving, and/or social cognition of the subject.

Provided herein are methods of using nitro-aminoadamantane compounds for treating, ameliorating symptoms of, or inhibiting progression of negative symptoms and/or cognitive decline in a subject with schizophrenia or prodromal schizophrenia.

The nitro-aminoadamantane compound used in the methods of the invention can be a compound of any of formulas (l)-(V):

wherein in formulas (l)-(IV), Y is a nitrate-containing group and R1 , R2, R3, R4, R5, X, p, and m are as defined elsewhere herein. In formula (V) each of Y¹, Y², and Y³, is optionally a nitrate-containing group and Y¹, Y², Y³, X¹, X², X³, R³, and R⁴ m are as defined elsewhere herein

Nitro-aminoadamantane compounds

The nitro-aminoadamantane compounds used in the methods of the invention can be synthesized using methods analogous to those described in U.S. Patent No. 7,326.730 and PCT Publication No. WO2019104020, each of which is incorporated herein in its entirety.

Compounds of Formula (l)-(IV)

The nitro-aminoadamantane compound used in the methods of the invention can be a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² independently are hydrogen, halide, linear or branched alkyl, linear or branched heteroalkyl, linear or branched alkoxy, linear or branched -O-heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which can optionally be substituted;

R³ and R⁴ independently are hydrogen or linear or branched C₁-C₆ alkyl, or R³, R⁴ and the nitrogen atom to which they are attached form a 3-8-membered heterocyclic ring;

R⁵ is hydrogen or linear or branched C₁-C₆ alkyl;

X is bond, linear or branched -alkyl-, linear or branched -heteroalkyl-, linear or branched -O-alkyl-, linear or branched -O-heteroalkyl-, -(CH₂)_j-cycloalkyl-(CH₂)_k-, -(CH₂)_j-heterocyclyl-(CH₂)_k-, -(CH₂)_j-aryl- (O)_h-(CH₂)_k- or -(CH₂)_j-heteroaryl-(O)h-(CH₂)_k-, each of which can optionally be substituted;

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (la):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², X and Y are as defined for formula (I); and n is 1 , 2, 3, 4, 5 or 6. In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IA):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, X and m are as defined for formula (I).

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (lA-a):

or a pharmaceutically acceptable salt thereof, wherein R¹, R² and X are as defined for formula (I); and n is 1 , 2, 3, 4, 5 or 6.

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IB):

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IB-a):

In some embodiments, X of the compounds of formula (I) and subgenera thereof is bond, linear or branched C₁-C₆ or C₁-C₃ -alkyl-, or linear or branched C₁-C₆ or C₁-C₃ -O-alkyl-. In certain embodiments, X of the compounds of Formula I and subgenuses thereof is bond or linear or branched C₁-C₃ -alkyl- [e.g., -CH₂-, -(CH₂)₂-, -CHCH₃, -(CH₂)₃-, -CHCH₂CH₃, -CH₂CHCH₃ or - CH(CH₃)CH₂-].

The nitro-aminoadamantane compound used in the methods of the invention can be a compound of formula (II) or formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R⁵ is hydrogen or linear or branched C₁-C₆ alkyl;

X is bond, linear or branched -alkyl-, linear or branched -heteroalkyl-, linear or branched -O-alkyl-, linear or branched -O-heteroalkyl-, -(CH₂)_j-cycloalkyl-(CH₂)_k-, -(CH₂)_j-heterocyclyl-(CH₂)_k-, -(CH₂)_j-aryl- (O)_h-(CH₂)_k- or -(CH₂)_j-heteroaryl- (O)_h-(CH₂)_k-, each of which can optionally be substituted;

The nitro-aminoadamantane compound used in the methods of the invention can be a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², X and Y are as defined for formulas (II) and (III); and p is 0, 1 , 2, 3, 4, 5 or 6.

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula

or a pharmaceutically acceptable salt thereof, wherein X and Y are as defined for formulas (II) and (III); and p is 0, 1 , 2, 3, 4, 5 or 6. In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (ll-a) or formula (lll-a):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, X and m are as defined for formulas (II) and (III).

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IVA):

or a pharmaceutically acceptable salt thereof, wherein R¹, R² and X are as defined for formulas (II) and (III); and p is 0, 1 , 2, 3, 4, 5 or 6.

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IVA-a):

or a pharmaceutically acceptable salt thereof, wherein X is as defined for formulas (II) and (III); and p is O, 1 , 2, 3, 4, 5 or 6.

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (I IB) or formula (I IIB):

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IVB):

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (IVB-a):

For the compounds of formulas (II) and (III), and subgenera thereof, the compounds of Formula III and subgenuses thereof, and the compounds of Formula IV and subgenuses thereof, the -X-Y, -X-ONO₂ or -X-CH(ONO₂)CH₂-ONO₂ moiety can be attached to an ortho position, a meta position or the para position of the phenyl ring. In certain embodiments, the -X-Y, -X-ONO₂ or -X- CH(0N0₂)CH₂-0NC>₂ moiety is attached to a meta position of the phenyl ring.

For the compounds of formulas (II), (III), (IV), and subgenera thereof, in some embodiments X is bond, linear or branched C₁-C₆ or C₁-C₃ -alkyl-, or linear or branched C₁-C₆ or C₁-C₃ -O-alkyl-. In certain embodiments, X is bond or linear or branched C₁-C₃ -O-alkyl- [e.g., -O-CH₂-, -0-(CH₂)₂-, -O- CHCH₃, -0-(CH₂)3-, -O-CHCH₂CH₃, -O-CH₂CHCH₃ or -0-CH(CH₃)CH₂-].

For the compounds of formulas (I), (II) and (III), and subgenera thereof, examples of 3-8- membered, nitrogen-containing heterocyclic rings include without limitation aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl and azocanyl, where the second ring nitrogen atom of a piperazinyl group can optionally be substituted with a linear C₁-C₃ alkyl group or a -(C=O)R group, wherein R is hydrogen or linear C₁-C₃ alkyl. In certain embodiments, R³, R⁴ and the nitrogen atom to which they are attached form a 3-6-membered heterocyclic ring.

For the compounds of formulas (I), (III) and (IV), and subgenera thereof, in certain embodiments m is 0, 1 or 2; n is 1 , 2 or 3; and p is 0, 1 , 2 or 3.

For the compounds of formulas (I), (II) and (III), and subgenera thereof, in some embodiments both R³ and R⁴ are hydrogen. In other embodiments, one of R³ and R⁴ is hydrogen, and the other is linear or branched C₁-C₃ alkyl. In certain embodiments, one of R³ and R⁴ is hydrogen, and the other is methyl or ethyl. In yet other embodiments, R³ and R⁴ independently are linear C₁-C₃ alkyl (e.g., methyl or ethyl), optionally the same alkyl group.

For the compounds of formulas (I) and (III), and subgenera thereof, in some embodiments R⁵ is hydrogen. In other embodiments, R⁵ is linear or branched C₁-C₃ alkyl. In certain embodiments, R⁵ is methyl or ethyl.

For the compounds of formulas (I), (II), (III), and (IV), and subgenera thereof, in some embodiments R¹ and R² independently are hydrogen or linear or branched C₁-C₆ or C₁-C₃ alkyl. In certain embodiments, both R¹ and R² are hydrogen. In other embodiments, R¹ is hydrogen and R² is linear or branched C₁-C₆ or C₁-C₃ alkyl, or R² is hydrogen and R¹ is linear or branched C₁-C₆ or C₁-C₃ alkyl. In certain embodiments, R¹ is hydrogen and R² is methyl, ethyl or n-propyl, or R² is hydrogen and R¹ is methyl, ethyl or n-propyl. In yet other embodiments, R¹ and R² independently are linear or branched C₁-C₆ or C₁-C₃ alkyl, optionally the same alkyl group. In certain embodiments, R¹ and R² independently are methyl, ethyl or n-propyl, optionally the same alkyl group. In some embodiments, R¹ is hydrogen and R² is methyl or ethyl, or R² is hydrogen and R¹ is methyl or ethyl. In other embodiments, both R¹ and R² are methyl or ethyl.

For the compounds of formulas (I), (II), (III), and (IV), and subgenera thereof, in some embodiments the R¹ group, the R² group or the X group, or any combination or all thereof, independently are substituted with 1 , 2 or 3 substituents selected from linear or branched C₁-C₆ or Ci- C₃ alkyl, haloalkyl, -OR⁶, -NR⁷R⁸, -ONO₂, -CN, -C(=O)R⁶, -C(=O)OR⁶, -OC(=O)R⁶, -C(=O)NR⁷R⁸, - NR⁷C(=O)R⁶, -OC(=O)OR⁶, -OC(=O)NR⁷R⁸, -NR⁷C(=O)OR⁶, -NR⁶C(=O)NR⁷R⁸, aryl and heteroaryl, or/and are substituted with 1 to 6 halogen (e.g., fluorine) or have all available hydrogen atoms replaced with halogen (e.g., fluorine), wherein R⁶ in each occurrence independently is hydrogen or linear or branched C₁-C₆ or C₁-C₃ alkyl; and R⁷ and R⁸ in each occurrence independently are hydrogen or linear or branched C₁-C₆ or C₁-C₃ alkyl, or R⁷, R⁸ and the nitrogen atom to which they are attached form a 3-6-membered ring. In certain embodiments, the R¹ group, the R² group or the X group, or any combination or all thereof, independently are monovalent or divalent fluoroalkyl or alkyl- ONO₂.

For the compounds of formulas (I), (II), (III), and (IV), and subgenera thereof, non-limiting examples of linear or branched C₁-C₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter t-butyl, n-pentyl and n-hexyl. Examples of linear or branched C₁-C₃ alkyl groups include methyl, ethyl, n-propyl and isopropyl.

For the compounds of formulas (I), (II), (III), and (IV), and subgenera thereof, in some embodiments X has 0, 1 , 2, 3, 4, 5 or 6 carbon atoms. In certain embodiments, X has 0, 1 , 2 or 3 carbon atoms.

Table 1 depicts representative compounds of formula (IA-a-i) to (IA-a-xx):

lAa-v lAa-vi lAa-vii lAa-viii

lAa-xvii lAa-xviii lAa-xix lAa-xx

Table 1

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by a subgenus of formula (IA-a-i) to (IA-a-xx), or a pharmaceutically acceptable salt thereof. In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is selected from:

IBa-i IBa-ii IBa-iii IBa-iv

Table 2

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by a subgenus of formula (IB-a-i) to (IB-a-vii), or a pharmaceutically acceptable salt thereof. In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is selected from:

and pharmaceutically acceptable salts thereof. Table 3 depicts representative compounds of formula (IVA-i) to (IVA-vii):

Table 3

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by a subgenus of formula (IVA-i) to (IVA-vii), or a pharmaceutically acceptable salt thereof. In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is selected from:

and pharmaceutically acceptable salts thereof.

Table 4 depicts representative compounds of formula (IVB-i) to (IVB-vi):

IVB-iv IVB-v IVB-vi

Table 4

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by a subgenus of formula (IVB-i) to (IVB-vi), or a pharmaceutically acceptable salt thereof. In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is selected from:

and pharmaceutically acceptable salts thereof.

In particular embodiments, instead of being an amine group, the amine group indirectly or directly connected to the C-1 or C-2 position of the nitro-aminoadamantane compounds described herein can be an amide, carbamate or urea (e.g., an -NH(C=O)R amide, -NH(C=O)OR carbamate or -NHC(=O)NR^aR^b urea group)s. In some embodiments, the -NR³R⁴ moiety of nitro-aminoadamantane compounds is -NH(C=O)R⁶, -NH(C=O)OR⁶ or -NHC(=O)NR⁷R⁸, wherein R⁶ is hydrogen (for formamide) or linear or branched C₁-C₆ alkyl, and R⁷ and R⁸ independently are hydrogen or linear or branched C₁-C₆ alkyl, or R⁷, R⁸ and the nitrogen atom to which they are attached form a 3-6- membered ring. In certain embodiments, R⁶ is hydrogen (for formamide) or linear or branched C₁-C₃ alkyl (e.g., methyl or ethyl), and R⁷ and R⁸ independently are hydrogen or linear or branched C₁-C₃ alkyl (e.g., methyl or ethyl).

Compounds of Formula (V)

The nitro-aminoadamantane compound used in the methods of the invention can be a compound of formula (V):

NR 3³DR4'

Y¹— X¹

X² — Y²

X³

I

Y³ (V) or a pharmaceutically acceptable salt thereof, wherein:

R⁵ is hydrogen or linear or branched C₁-C₆ alkyl; each of X¹, X², and X³ is, independently, selected from a bond, linear or branched -alkyl-, linear or branched -heteroalkyl-, linear or branched -O-alkyl-, linear or branched -O-heteroalkyl-, -(CH₂)_j-cycloalkyl- (CH₂)_k-, -(CH₂)_j-heterocyclyl-(CH₂)_k-, -(CH₂)_j-aryl-(O)_h-(CH₂)_k- or -(CH₂)_j-heteroaryl-(O)_h-(CH₂)_k-, each of which can optionally be substituted; each of Y¹, Y², and Y³ is, independently, selected from -ONO₂,

, hydroxy, or a hydrogen atom, provided that at least one of Y¹, Y², and Y³ is -ONO₂ or

_; j is 0, 1 , 2 or 3; k is 0, 1 , 2 or 3; and h is 0 or 1 .

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is further described by formula (VA):

or a pharmaceutically acceptable salt thereof, wherein each of Y¹, Y², and Y³ is, independently, selected from -ONO₂, hydroxy, or a hydrogen atom; p is 0, 1 , 2, 3, 4, 5 or 6; q is 0, 1 , 2, 3, 4, 5 or 6; and r is 0, 1 , 2, 3, 4, 5 or 6, provided that at least one of Y¹, Y², and Y³ is -ONO₂.

In certain embodiments, the nitro-aminoadamantane compound used in the methods of the invention is selected from: , , , , and and pharmaceutically acceptable salts thereof. Dosing Regimens The therapeutically effective amount and the frequency of administration of a nitro- aminoadamantane compound to treat cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia may depend on various factors, including the type of disorder, the severity of the condition, the potency of the compound, the mode of administration, the age, body weight, general health, gender and diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician. In some embodiments, the effective dose of a nitro-aminoadamantane compound per day can be from about 1, 5 or 10 mg to about 100 mg, or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the effective dose of a nitro-aminoadamantane compound per day is from about 5 or 10 mg to about 50 mg or about 50-100 mg, or is about 5-10 mg, 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, or 100-250 mg. In further embodiments, the effective dose of a nitro-aminoadamantane compound per day is about 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225 mg, or more. In certain embodiments, the effective dose of a nitro-aminoadamantane compound per day is about 10-30 mg, or about 10, 15, 20, 25 or 30 mg. The dosage of a nitro-aminoadamantane compound can be adjusted during the course of the treatment regimen, which can be determined by the treating physician. For example, a nitro- aminoadamantane compound can be administered in an initial daily dose for the first week of treatment, and then the daily dose of the compound can be gradually or step-wise increased for every subsequent week of treatment until a target or suitable daily maintenance dose is administered for, e.g., the fourth week of treatment and thereafter for the duration of treatment. Increasing the dose of a drug gradually or step-wise during the initial phase of treatment would allow the treating physician to determine the optimum therapeutic dose for the particular subject while avoiding or minimizing any potential side effect. For example, a first daily initial dose can be about 4 times smaller than a target daily maintenance dose and can be taken for the first week, a second daily initial dose can be about 2 times larger than the first initial dose and can be taken for the second week, a third daily initial dose can be about 3 times larger than the first initial dose and can be taken for the third week, and the target or a suitable daily maintenance dose can be taken for the fourth week and thereafter for the duration of treatment. The initial doses and the maintenance dose can be any effective dose described herein. As a non-limiting example, a first initial dose of about 5-10 mg of a nitro- aminoadamantane compound can be administered once daily for the first week, a second initial dose of about 10-20 mg can be administered once daily for the second week, a third initial dose of about 15-30 mg can be administered once daily for the third week, and a maintenance dose of about 20-40 mg can be administered once daily for the fourth week and thereafter for the duration of therapy.

Alternatively, if it is desired to establish a therapeutic level of a nitro-aminoadamantane compound quickly for the treatment of cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia, a first loading dose of the compound can be administered on, e.g., day 1 , an optional second loading dose can be administered on, e.g., day 2, an optional third loading dose can be administered on, e.g., day 3, and a maintenance dose of the compound can be administered daily thereafter for the duration of treatment. A loading dose can be, e.g., about 5, 4, 3, 2.5, 2 or 1.5 times larger than the maintenance dose, and the optional second and third loading doses can be, e.g., smaller than the previous loading dose. For example, relative to the maintenance dose the first loading dose can be about 4 times larger, the second loading dose can be about 3 times larger, and the third loading dose can be about 2 times larger. The maintenance dose can be any effective dose described herein. In certain embodiments, the loading dose(s) can be any effective dose described herein.

A nitro-aminoadamantane compound can be administered in any suitable frequency to treat cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia, which can be determined by the treating physician. In some embodiments, a nitro- aminoadamantane compound is administered daily (including one, two, three or more times daily), once every two days, once every three days, twice weekly or once weekly, or as deemed appropriate by the treating physician. In certain embodiments, a nitro-aminoadamantane compound is administered once daily.

A nitro-aminoadamantane compound can be administered for any suitable period of time to treat cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia, which can be determined by the treating physician. For the treatment of cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia, in some embodiments a nitro-aminoadamantane compound is administered for a period of at least about 1 week, 2 weeks, 1 month, 3 months, or longer.

A nitro-aminoadamantane compound can be administered via any suitable route, and can be administered locally or systemically, for the treatment of cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia, which can be determined by the treating physician. Potential routes of administration of a nitro-aminoadamantane compound include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular/intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]). In certain embodiments, a nitro-aminoadamantane compound is administered orally (e.g., as a tablet or capsule). In other embodiments, a nitro-aminoadamantane compound is administered parenterally (e.g., intravenously, intramuscularly or subcutaneously, whether by injection or infusion).

Pharmaceutical Compositions

Additional embodiments of the disclosure relate to pharmaceutical compositions including a nitro-aminoadamantane compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers. The compositions can optionally contain an additional therapeutic agent. A pharmaceutical composition contains a therapeutically effective amount, or any appropriate fraction thereof, of a nitro-aminoadamantane compound, one or more pharmaceutically acceptable excipients or carriers and optionally an additional therapeutic agent, and is formulated for administration to a subject for therapeutic use.

A pharmaceutical composition contains a nitro-aminoadamantane compound and optionally an additional therapeutic agent in substantially pure form. In some embodiments, the purity of the nitro-aminoadamantane compound and the optional additional therapeutic agent independently is at least about 95%, 96%, 97%, 98% or 99%. In certain embodiments, the purity of the nitro- aminoadamantane compound and the optional additional therapeutic agent independently can be at least about 98% or 99%. In addition, a pharmaceutical composition can be substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inactive ingredients. In certain embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 2% or 1% relative to the combined weight of the intended active and inactive ingredients. Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act §501 (a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.

Pharmaceutical compositions/formulations can be prepared in sterile form. For example, pharmaceutical compositions/formulations for parenteral administration by injection or infusion generally are sterile. Sterile pharmaceutical compositions/formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards known to those of skill in the art, such as those disclosed in or required by the United States Pharmacopeia Chapters 797, 1072 and 1211 , and 21 Code of Federal Regulations 211.

Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials and vehicles. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils, such as olive oil and sesame oil), aqueous solvents {e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution)}, and organic solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional excipient or carrier is incompatible with the active ingredient, the disclosure encompasses the use of conventional excipients and carriers in formulations containing nitro- aminoadamantane compounds. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et ai, Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida) (2004).

Appropriate formulation can depend on various factors, such as the route of administration chosen. Potential routes of administration of pharmaceutical compositions including nitro- aminoadamantane compounds include without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, intramedullary, intrathecal and topical), and topical (including dermal/epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], ocular/intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]). Topical formulations can be designed to produce a local or systemic therapeutic effect.

As an example, formulations of nitro-aminoadamantane compounds suitable for oral administration can be presented as, e.g., boluses; capsules (including push-fit capsules and soft capsules), tablets, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Push-fit capsules or two-piece hard gelatin capsules can contain a nitro-aminoadamantane compound in admixture with, e.g., a filler or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or/and a preservative.

For soft capsules or single-piece gelatin capsules, a nitro-aminoadamantane compound can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or more other liquid excipients or/and semi-solid excipients, such as a stabilizer or/and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol). In certain embodiments, a capsule (e.g., a hard gelatin capsule) includes a nitro-aminoadamantane compound and sugar spheres, polyvinylpyrrolidone, hypromellose, talc, polyethylene glycol, ethylcellulose, ammonium hydroxide, oleic acid, and medium-chain triglycerides.

Tablets can contain a nitro-aminoadamantane compound in admixture with, e.g., a filler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate). The tablets can be uncoated or can be coated with, e.g., an enteric coating that protects the active ingredient from the acidic environment of the stomach, or with a material that delays disintegration and absorption of the active ingredient in the gastrointestinal (Gl) tract and thereby provides a sustained action over a longer time period. In certain embodiments, a tablet includes a nitro-aminoadamantane compound and lactose monohydrate, microcrystalline cellulose, silica colloidal anhydrous, talc and magnesium stearate, and is film-coated (e.g., a film-coating containing hypromellose, titanium dioxide and macrogol 400).

Compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid or/and a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. Dispersible powder or granules of a nitro-aminoadamantane compound can be mixed with any suitable combination of an aqueous liquid, an organic solvent or/and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or/and a preservative) to form a solution, suspension or emulsion.

Nitro-aminoadamantane compounds can also be formulated for parenteral administration by injection or infusion to circumvent Gl absorption and first-pass metabolism. An exemplary parenteral route is intravenous. Additional advantages of intravenous administration include direct administration of a therapeutic agent into systemic circulation to achieve a rapid systemic effect, and the ability to administer the agent continuously or/and in a large volume if desired. Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or/and stabilizing agents. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain a nitro-aminoadamantane compound along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject. Aqueous or non-aqueous sterile suspensions can contain a nitro-aminoadamantane compound along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the nitro-aminoadamantane compound to allow for the preparation of a more concentrated solution or suspension. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneously or intravenously) can contain a nitro- aminoadamantane compound, sodium chloride, a buffering agent (e.g., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HCI) to adjust pH.

For topical administration, a nitro-aminoadamantane compound can be formulated as, e.g., a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of Gl absorption and first-pass metabolism, and rapid absorption into systemic circulation. A buccal or sublingual tablet or pill can be designed to provide faster release of the nitro- aminoadamantane compound for more rapid uptake of it into systemic circulation. In addition to a therapeutically effective amount of a nitro-aminoadamantane compound, the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol), binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

For topical administration, nitro-aminoadamantane compounds can also be formulated for intranasal administration. The nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability. An intranasal formulation can include a nitro-aminoadamantane compound along with excipients, such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethylcellulose) or/and a penetration enhancer. An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or spray using, e.g., a metering atomizing spray pump. Table 5 shows exemplary excipients of nasal-spray formulations.

An additional mode of topical administration of a nitro-aminoadamantane compound is pulmonary, including by oral inhalation and nasal inhalation. The lungs serve as a portal to the systemic circulation. Advantages of pulmonary drug delivery include, for example: 1) avoidance of first-pass metabolism; 2) fast drug action; 3) large surface area of the alveolar region for absorption, high permeability of the lungs (thin air-blood barrier), and profuse vasculature of the airways;

4) reduced extracellular enzyme levels compared to the Gl tract due to the large alveolar surface area; and 5) smaller doses to achieve equivalent therapeutic effect compared to other oral routes, and hence reduced systemic side effects. An advantage of oral inhalation over nasal inhalation includes deeper penetration/deposition of the drug into the lungs. Oral or nasal inhalation can be achieved by means of, e.g., a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a nebulizer, as is known in the art. In certain embodiments, a sterile aqueous solution for oral inhalation contains a nitro-aminoadamantane compound, sodium chloride, a buffering agent (e.g., sodium citrate), optionally a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or/and an acid (e.g., HCI) to adjust pH.

Topical formulations for application to the skin or mucosa can be useful fortransdermal or transmucosal administration of a drug into the blood for systemic distribution. Advantages of topical administration can include circumvention of the Gl tract (including enzymes and acid in the Gl tract and absorption through it) and first-pass metabolism; delivery of a drug with a short half-life, a small therapeutic index or/and low oral bioavailability; controlled, continuous and sustained release of the drug; a more uniform plasma level or delivery profile of the drug; lower dose and less frequent dosing of the drug; reduction of systemic side effects (e.g., side effects caused by a temporary overdose or an overly high peak plasma drug concentration); minimal or no invasiveness; ease of selfadministration; and increased subject compliance.

In general, compositions suitable for topical administration include without limitation liquid or semi-liquid preparations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, foams, ointments and pastes, and solutions or suspensions such as drops (e.g., eye drops, nose drops and ear drops). Various excipients can be included in a topical formulation. For example, solvents, including a suitable amount of an alcohol, can be used to solubilize the drug. Other optional excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, buffers, stabilizers, antioxidants, preservatives, cooling agents, opacifiers, colorants and fragrances. For a drug having a low rate of permeation through the skin or mucosal tissue, a topical formulation can contain a chemical permeation enhancer (CPE, such as a surfactant) to increase permeation of the drug through the skin or mucosal tissue. A topical formulation can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the drug, the CPE or any other component of the formulation.

In some embodiments, a topical composition includes a nitro-aminoadamantane compound dissolved, dispersed or suspended in a carrier. The carrier can be in the form of, e.g., a solution, a suspension, an emulsion, an ointment or a gel base, and can contain, e.g., petrolatum, lanolin, a wax (e.g., bee wax), mineral oil, a long-chain alcohol, polyethylene glycol or polypropylene glycol, a diluent (e.g., water or/and an alcohol [e.g., ethanol or propylene glycol]), a gel, an emulsifier, a thickening agent, a stabilizer or a preservative, or any combination thereof.

A topical composition can include, or a topical formulation can be administered by means of, e.g., a transdermal or transmucosal delivery device, such as a transdermal patch, a microneedle patch or an iontophoresis device. A topical composition can deliver a nitro-aminoadamantane compound transdermally or transmucosally via a concentration gradient (with or without the use of a CPE) or an active mechanism (e.g., iontophoresis or microneedles).

In some embodiments, a nitro-aminoadamantane compound is administered via a transdermal patch. In certain embodiments, a transdermal patch is a reservoir-type patch including an impermeable backing layer/film, a liquid- or gel-based drug reservoir, a semi-permeable membrane that serves as a rate-limiting or rate-controlling diffusion barrier, and a skin-contacting adhesive layer. The semi-permeable membrane can be composed of, e.g., a suitable polymeric material such as cellulose nitrate or acetate, polyisobutene, polypropylene, polyvinyl acetate or a polycarbonate. In other embodiments, a transdermal patch is a drug-in-adhesive patch including an impermeable backing layer/film and a skin-contacting adhesive layer incorporating the drug in a polymeric or viscous adhesive. The adhesive of the drug-loaded, skin-contacting adhesive layer can be, e.g., a pressure-sensitive adhesive (PSA), such as a PSA composed of an acrylic polymer (e.g., polyacrylate), a polyalkylene (e.g., polyisobutylene) or a silicone-based polymer (e.g., silicone-2675 or silicone-2920). Transdermal drug-delivery systems, including patches, can be designed to provide controlled and prolonged release of a drug over a period of about 1 week, 2 weeks, 3 weeks, 1 month or longer.

In some embodiments, a nitro-aminoadamantane compound is delivered from a sustained- release composition. As used herein, the term “sustained-release composition” encompasses sustained-release, prolonged-release, extended-release, delayed-release, slow-release and controlled-release compositions, systems and devices. Advantages of a sustained-release composition include without limitation a more uniform blood level of the drug (e.g., avoidance of wide peak-to-trough fluctuations), delivery of a therapeutically effective amount of the drug over a prolonged time period, reduced frequency of administration, and reduced side effects (e.g., avoidance of a drug overdose). In certain embodiments, the sustained-release composition delivers the nitro- aminoadamantane compound over a period of at least about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer. In some embodiments, the sustained-release composition is a drug-encapsulation system, such as nanoparticles, microparticles or a capsule made of, e.g., a biodegradable polymer or/and a hydrogel. In certain embodiments, the sustained-release composition includes a hydrogel. Non- limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium polyacrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or/and carboxylate groups). In other embodiments, the sustained-release drug-encapsulation system includes a membrane-enclosed reservoir, wherein the reservoir contains a drug and the membrane is permeable to the drug. Such a drug-delivery system can be in the form of, e.g., a transdermal patch.

In certain embodiments, the sustained-release composition is formulated as polymeric nanoparticles or microparticles, wherein the polymeric particles can be delivered, e.g., by injection or from an implant. In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of a biodegradable polymer. In certain embodiments, the biodegradable polymer includes lactic acid or/and glycolic acid [e.g., an L-lactic acid-based copolymer, such as poly(L-lactide-co-glycolide) or poly(L-lactic acid-co-D,L-2-hydroxyoctanoic acid)]. For example, biodegradable polymeric microspheres composed of polylactic acid or/and polyglycolic acid can serve as sustained-release pulmonary drug-delivery systems. The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer’s degradation, like the polymer, are biocompatible.

In further embodiments, a sustained-release composition includes a dendrimer. In certain embodiments, the dendrimer is a water-soluble dendrimer, such as a poly(amidoamine) (PAMAM) dendrimer. In some embodiments, a dendrimer encapsulates a drug through the formation of a dendrimer-drug supramolecular assembly. In other embodiments, a sustained-release composition includes a water-soluble polymer [e.g., poly(DL-lactide)] or a liposome encapsulating a drug complexed with a dendrimer.

In other embodiments, the sustained-release composition is an oral dosage form, such as a tablet or capsule. For example, a drug can be embedded in an insoluble porous matrix such that the dissolving drug must make its way out of the matrix before it can be absorbed through the Gl tract. Alternatively, a drug can be embedded in a matrix that swells to form a gel through which the drug exits. Sustained release can also be achieved by way of a single-layer or multi-layer osmotic controlled-release oral delivery system (OROS). An OROS is a tablet with a semi-permeable outer membrane and one or more small laser-drilled holes in it. As the tablet passes through the body, water is absorbed through the semi-permeable membrane via osmosis, and the resulting osmotic pressure pushes the drug out through the hole(s) in the tablet and into the Gl tract where it can be absorbed.

For a delayed or sustained release of a nitro-aminoadamantane compound, a composition can also be formulated as, e.g., a depot that can be implanted in or injected into a subject, e.g., intramuscularly or subcutaneously. A depot formulation can be designed to deliver the nitro- aminoadamantane compound over an extended period of time, e.g., over a period of at least about 1 week, 2 weeks, 3 weeks, 1 month, 6 weeks, 2 months, or longer. For example, a nitro- aminoadamantane compound can be formulated with a polymeric material (e.g., polyethylene glycol [PEG], polylactic acid [PLA] or polyglycolic acid [PGA], or a copolymer thereof [e.g., PLGA]), a hydrophobic material (e.g., as an emulsion in an oil) or/and an ion-exchange resin, or as a sparingly soluble derivative (e.g., a sparingly soluble salt). As an illustrative example, a nitro- aminoadamantane compound can be incorporated or embedded in sustained-release microparticles composed of PLGA and formulated as a monthly depot.

A nitro-aminoadamantane compound can also be contained or dispersed in a matrix material. The matrix material can include a polymer (e.g., ethylene-vinyl acetate) and controls the release of the compound by controlling dissolution or/and diffusion of the compound from, e.g., a reservoir, and can enhance the stability of the compound while contained in the reservoir. Such a “release system” can be designed as a sustained-release system, can be configured as, e.g., a transdermal or transmucosal patch, and can contain an excipient that can accelerate the compound’s release, such as a water-swellable material (e.g., a hydrogel) that aids in expelling the compound out of the reservoir. US Pat. Nos. 4,144,317 and 5,797,898 describe examples of such a release system.

The release system can provide a temporally modulated release profile (e.g., pulsatile release) when time variation in plasma levels is desired, or a more continuous or consistent release profile when a constant plasma level is desired. Pulsatile release can be achieved from an individual reservoir or from a plurality of reservoirs. For example, where each reservoir provides a single pulse, multiple pulses (“pulsatile” release) are achieved by temporally staggering the single pulse release from each of multiple reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of a compound through it over an extended time period. In addition, continuous release can be approximated by releasing several pulses of a compound in rapid succession (“digital” release). An active release system can be used alone or in conjunction with a passive release system, as described in US Pat. 5,797,898.

In addition, pharmaceutical compositions including a nitro-aminoadamantane compound can be formulated as, e.g., liposomes, micelles (e.g., those composed of biodegradable natural or/and synthetic polymers, such as lactosomes), nanoparticles (e.g., lipid nanoparticles such as solid lipid nanoparticles), microparticles or microspheres, whether or not designed for sustained release. For example, liposomes can be used as sustained-release pulmonary drug-delivery systems that deliver a drug to the alveolar surface and then the circulation. As another example, lipid nanoparticles containing a lipophilic drug can be delivered into the lungs and then the circulation by oral inhalation.

In some embodiments, liposomes or micelles are composed of one or more phospholipids. Phospholipids include without limitation phosphatidic acids (e.g., DEPA, DLPA, DMPA, DOPA, DPPA and DSPA), phosphatidylcholines (e.g., DDPC, DEPC, DLPC, DLOPC, DMPC, DOPC, DPPC, DSPC, MPPC, MSPC, PLPC, PMPC, POPC, PSPC, SMPC, SOPC and SPPC), phosphatidylethanolamines (e.g., DEPE, DLPE, DMPE, DOPE, DPPE, DSPE and POPE), phosphatidylglycerols (e.g., DEPG, DLPG, DMPG, DOPG, DPPG, DSPG and POPG), phosphatidylserines (e.g., DLPS, DMPS, DOPS, DPPS and DSPS), and salts (e.g., sodium and ammonium salts) thereof. In certain embodiments, liposomes or micelles are composed of one or more phosphatidylcholines. Liposomes have a hydrophilic core, so liposomes are particularly suited for delivery of hydrophilic drugs, whereas micelles have a hydrophobic core, so micelles are particularly suited for delivery of hydrophobic drugs. The salt group of a salt form of a nitro-aminoadamantane compound provides hydrophilicity, while the adamantyl scaffold provides hydrophobicity. Liposomes and micelles can permeate across biological membranes. Liposomes and micelles can provide sustained release of a drug based in part on the rate of degradation of the liposomes and micelles.

The pharmaceutical compositions can be manufactured in any suitable manner known in the art, e.g., by means of conventional mixing, dissolving, suspending, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

The compositions can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. A unit dosage form generally contains a therapeutically effective dose of the drug, but can contain an appropriate fraction thereof. A representative example of a unit dosage form is a tablet, capsule or pill for oral uptake.

Alternatively, the compositions can be presented as a kit, wherein the active ingredient, excipients and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected intravenously).

A kit can contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers, and can contain instructions for administering or using the pharmaceutical composition to treat cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia.

In some embodiments, a kit contains a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, and instructions for administering the compound or the pharmaceutical composition to treat cognitive impairment and negative symptoms in subjects with schizophrenia or prodromal schizophrenia.

Assessing Cognitive Impairment

There are various tests known in the art for assessing cognitive function in humans, for example and without limitation, the clinical global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment- Geriatric (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test, or MATRICS consensus neuropsychological test battery which includes tests of working memory, speed of processing, attention, verbal learning, visual learning, reasoning and problem solving and social cognition. See Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81 , (1994); Rey, L'examen Clinique en psychologic, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. Also see Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (2011) The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217. Another example of a cognitive test in humans is the explicit 3-alternative forced choice task. In this test, subjects are presented with color photographs of common objects consisting of a mix of three types of image pairs: similar pairs, identical pairs and unrelated foils. The second of the pair of similar objects is referred to as the "lure". These image pairs are fully randomized and presented individually as a series of images. Subjects are instructed to make a judgment as to whether the objects seen are new, old or similar. A "similar" response to the presentation of a lure stimulus indicates successful memory retrieval by the subject. By contrast, calling the lure stimulus "old" or "new" indicates that correct memory retrieval did not occur. Any method for assessing cognitive function (e.g., working memory, attention, reasoning and problem solving, and/or social cognition) can be used to assess the maintenance or improvement in cognitive function achieved using the methods of the invention.

Assessing Negative symptoms

There are various tests known in the art for assessing negative symptoms associated with schizophrenia, for example and without limitation, the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), and the Negative Symptom Assessment (NSA), the Clinical Asssessment Interview for Negative Symptoms(CAINS), the Brief Negative Symptom Scale (BNSS), the Negative symptom Assessment-16 (NSA-16), and the (Clinical Global Impression Schizophrenia (CGI-SCH) (see, e.g., Blanchard et al., Schizophr Bull. 37:291-299 (2011); and Kumari et al., J Addict Res Ther. 8:324 (2017)). Any method for assessing negative symptoms (e.g., asociality, apathy, alogia, and avolition) can be used to assess the maintenance or improvement in negative symptoms (or reduction in the degree of symptom severity) achieved using the methods of the invention.

Examples

The following examples are put forth to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

Example 1. Effect of Nitro-aminoadamantane compounds on cognitive impairment associated with schizophrenia (CIAS).

Subjects identified as suffering from CIAS are treated with oral doses (in the range of 5 to 75 mg BID) of compound A (structure below) for a period of up to 3 months to assess the effect of the treatment on cognitive function in the subjects.

Cognitive ability in the subjects is assessed using one or more of the methods briefly described below.

Primary Outcome Measures :

(1) MATRICS Consensus Cognitive Battery (MCCB) [Time Frame: at Baseline and every 4 weeks]. Assessment of cognitive effects overtime measured suing the MCCB battery. Secondary Outcome Measures :

(2) Continuous Performance Test-AX Version (CPT-AX) [Time Frame: at Baseline and every 4 weeks]. Assessment of Cognitive effects overtime measured using the Continuous Performance Test (AX version).

(3) N-Back [Time Frame: at Baseline and every 4 weeks]. Assessment of Cognitive effects over time measured using the N-Back Working Memory Test.

(4) Brief Psychiatric Rating Scale (BPRS) [Time Frame: at Baseline and every 2 weeks]

(5) Calgary Depression Scale (CDS) [Time Frame: at Baseline and every 2 weeks]

(6) Scale for Assessment of Negative Symptoms (SANS) [Time Frame: at Baseline and every 2 weeks]

(7) Simpson-Angus Extra pyramid a I Symptom Rating Scale (SAS) [Time Frame: at Baseline and every 2 weeks]

(8) Abnormal Involuntary Movement Scale (AIMS) [Time Frame: at Baseline and every 2 weeks]

(9) Change from Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment to Week 12 [Time Frame: Baseline, Week 12].

(10) The UPSA-Bi, international version, an abbreviated version of the UPSA-Validation of Intermediate Measures, is a measure of functional capacity and assesses skills used in community tasks. This assessment measures 2 general skills that were previously identified as essential to functioning in the community: financial skills and communication skills.

(11) Change from Baseline in Schizophrenia Cognition Rating Scale (SCoRS) assessment to Week 12 [Time Frame: Baseline, Week 12] The SCoRS is an interview-based assessment of cognition that involves interviews with participants and informants. The SCoRS includes 20 items designed to specifically assess aspects of cognitive functioning found in each of the seven MCCB cognitive domains including the following: Memory: 4 items, Learning: 2 items, Attention: 3 items, Working Memory: 2 items, Problem Solving: 3 items, Processing/Motor speed: 2 items, Social cognition: 3 items, Language: 1 item. Score ranges from 1 to 10 with a higher score indicating a greater degree of impairment.

(12) Change from Baseline in MCCB Composite and Individual Domain Scores (Excluding Working Memory Domain) to Week 12 [Time Frame: Baseline, Week 12] The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). Scores for the individual tests will be calculated according to the developer's recommended scoring algorithms.

(13) Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score and Subscale Scores to Week 12 [Time Frame: Baseline, Week 12] The PANSS includes 3 scales and 30 items: 7 items that make up the Positive Scale (e.g., delusions, conceptual disorganization, hallucinatory behavior); 7 items that make up the Negative Scale (e.g., blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal); and 16 items that make up the General Psychopathology Scale (e.g., somatic concern, anxiety, guilt feelings, mannerisms and posturing, motor retardation, uncooperativeness, disorientation, poor impulse control, preoccupation). The positive and negative subscale each consist of 7 items rated from 1 (absent) - 7(extreme) with a minimum score = 7, maximum score = 49. The general subscale consists of 16 items with a minimum score = 16, maximum score = 112. A Total PANSS score (positive·!· negative + general scores) has a minimum of 30 and maximum of 210. Higher scores represent more severity in symptoms.

(14) Change from Baseline in Clinical Global Impression-Severity (CGl-S) to Week 12 [Time Frame: Baseline, Week 12], The CGl-S consists of a single 7-point rating score of illness severity

Raters select one response based on the following question: "Considering your total clinical experience with this particular population, how mentally ill is your participant at this time?" Scores are as follows: 1 , Normal, not ill at all: 2, Borderline mentally ill; 3, Mildly ill: 4, Moderately ill: 5, Markedly III; 8, Severely III; or 7, Among the most severely ill subjects,

(15) Change from Baseline in Clinical Global impression-improvement (CGI-I) at Week 12 [Time Frame: Week 12], The CGI-I consists of a single 7-point rating score total improvement, regardless of whether or not the change is due entirely to drug treatment. Raters select one response based on the following question: "Compared to your participant's condition at the beginning of treatment, how much has your participant changed?" Scores are as follows: 1 , Very much improved: 2, Much improved: 3,

Minimally improved; 4, No change; 5, Minimally worse; 6, Much worse; or 7, Very much worse For the CGI-I scale, the participant's condition at the Baseline/Day 1 Visit will be the criterion forjudging improvement at subsequent visits.

(16) Scale for the Assessment and Rating of Ataxia (SARA) Score [Time Frame: Up to Week 14j. The SARA is a clinical scale that is based on a semlquantitative assessment of cerebellar ataxia on an impairment level and will complement the brief neurological examination. The SARA scale is an eight-item clinical rating scale (gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test) with a total score range of 0-40, where 0 is the best neurological status and 40 the worst,

(17) Columbia-Suicide Severity Rating Scale (C-SSRS) score [Time Frame: Up to Week 14].

The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Suicidal Ideation Is classified on a 5-iterrs scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). Suicidal behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt)

(compound A).

At the end of the study, the cognitive performance of the subjects (e g., working memory, attention, reasoning and problem solving, and/or social cognition) is maintained or improved relative to the subject's initial baseline test scores, and/or maintained or improved relative to the test scores of untreated control subjects. Other Embodiments

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

What is claimed is: Claims

1. A method of treating cognitive impairment associated with schizophrenia (CIAS) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof.

2. A method of inhibiting the progression of cognitive decline associated with schizophrenia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a nitro-aminoadamantane compound or a pharmaceutically acceptable salt thereof.

3. A method of treating cognitive impairment in a subject suffering from prodromal schizophrenia, said method comprising administering to the subject a therapeutically effective amount of a nitro- aminoadamantane compound or a pharmaceutically acceptable salt thereof.

4. A method of improving cognitive function in a subject suffering from prodromal schizophrenia, said method comprising administering to the subject a therapeutically effective amount of a nitro- aminoadamantane compound or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1-2, wherein the subject has schizophrenia under remission.

6. The method of any one of claims 1 -5, wherein the working memory of the subject is maintained or improved in comparison to untreated subjects.

7. The method of any one of claims 1-5, wherein the attention of the subject is maintained or improved in comparison to untreated subjects.

8. The method of any one of claims 1-5, wherein the reasoning and problem solving of the subject is maintained or improved in comparison to untreated subjects.

9. The method of any one of claims 1 -5, wherein the social cognition of the subject is maintained or improved in comparison to untreated subjects.

10. The method of any one of claims 1-9, wherein the subject is identified as being at least 0.5 SD below normative scores on any validated measure of cognition.

11. The method of any one of claims 1 -9, wherein the subject has retrospectively-assessed deterioration of cognition from pre-morbid levels of functioning as assessed by a physician.

12. A method of treating negative symptoms associated with schizophrenia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a nitro- aminoadamantane compound or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein the subject has schizophrenia under remission .

14. A method of treating negative symptoms in a subject suffering from prodromal schizophrenia, said method comprising administering to the subject a therapeutically effective amount of a nitro- aminoadamantane compound or a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 12-14, wherein the negative symptoms include a degree of apathy and the degree of apathy in the subject is reduced in comparison to untreated subjects.

16. The method of any one of claims 12-14, wherein the negative symptoms include a degree of alogia and the degree of alogia in the subject is reduced in comparison to untreated subjects.

17. The method of any one of claims 12-14, wherein the negative symptoms include a degree of asociality and the degree of asociality in the subject is reduced in comparison to untreated subjects.

18. The method of any one of claims 12-14, wherein the negative symptoms include a degree of avolition and the degree of avolition in the subject is reduced in comparison to untreated subjects.

19. The method of any one of claims 12-18, wherein social impairment of the subject is reduced in comparison to untreated subjects.

20. The method of any one of claims 12-18, wherein occupational impairment of the subject is reduced in comparison to untreated subjects.

21. The method of any one of claims 1-20, wherein the administering occurs between once per week to three times per day.

22. The method of any one of claims 1-20, wherein the administering occurs once per day.

23. The method of any one of claims 1 -20, wherein the administering is twice per day.

24. The method of any one of claims 1-23, wherein the nitro-aminoadamantane compound is administered orally.

25. The method of any one of claims 1-24, wherein the nitro-aminoadamantane compound is a compound of any one of formulas (l)-(V).

26. The method of any one of claims 1-24, wherein the nitro-aminoadamantane compound is selected from: