Treatment of psychosis through administration of buntanetap and its analogues

Abstract

The present invention relates to methods and pharmaceutical compositions effective for treating, inhibiting, reducing, slowing, or delaying the onset of psychosis in mammals (e.g., humans) through the administration of an effective amount of a compound selected from the group consisting of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention is directed to methods and pharmaceutical compositions of an effective amount of a compound selected from the group consisting of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof, and an effective amount of an antipsychotic, antidepressant, hallucinogen, and combinations thereof. In certain embodiments, the psychosis is autism, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, or schizophrenia.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 440,890, filed January 24, 2023, which is incorporated herein by reference.

[0002] This patent application relates to methods of inhibiting, preventing, or treating psychosis in animals or mammals (e.g., human subjects or patients) through the administration of buntanetap or related compounds, including pharmaceutically acceptable salts thereof. [Background technology]

[0003] A protein called amyloid beta ("Abeta") has a notorious reputation as a possible trigger for the development of Alzheimer's disease and dementia. Clumps called plaques are found throughout the brain of individuals who develop the cognitive symptoms of Alzheimer's disease. For unknown reasons, "diseased" brains have high iron levels, which upregulate the synthesis of Abeta and other neurotoxic aggregating proteins, leading to the overproduction of Abeta and other neurotoxic aggregating proteins in the diseased brain. High iron levels increase the translation of neurotoxic proteins, resulting in impaired axonal transport, inflammation, and neuronal death.

[0004] Abeta is a known contributor to the development of Alzheimer's disease. Abeta plaques are found throughout the brain of people who develop the cognitive symptoms of Alzheimer's disease.

[0005] The five major psychiatric disorders—autism, attention-deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia—appear to share several commonalities. They all exhibit dysfunctional neuronal transmission and communication, dysregulation of Abeta protein synthesis similar to neurodegenerative diseases, and share genetic risk factors, according to a study of genetic data from over 60,000 individuals worldwide (Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: a Genome-Wide Analysis, The Lancet, Vol. 381, Issue 9875, pp. 1371-1379, published online February 28, 2013).

[0006] Prior to the present invention, buntanetap, compounds similar to buntanetap described herein, and pharmaceutically acceptable salts and complexes thereof have not been used to treat and prevent psychosis and psychiatric disorders. Summary of the Invention

[0007] It is an object of the present invention to provide a treatment for psychosis or psychiatric disorders in an animal or mammal (e.g., a human subject or patient), including major psychoses such as autism, attention deficit hyperactivity disorder, anxiety, phobia, obsessive-compulsive disorder, bipolar disorder, major depressive disorder, and schizophrenia.

[0008] A further object of the present invention is to prevent, slow or delay the onset of psychoses such as autism, attention deficit hyperactivity disorder, anxiety, fear, obsessive-compulsive disorder, bipolar disorder, major depressive disorder, and schizophrenia.

[0009] In accordance with the above objectives and others, the present invention is directed, in part, to methods for inhibiting, preventing, or treating psychoses or mental disorders, such as autism, attention deficit hyperactivity disorder, anxiety, fear, obsessive-compulsive disorder, bipolar disorder, major depressive disorder, and schizophrenia, via administration of buntanetap, compounds similar to buntanetap described herein, and pharmaceutically acceptable salts and complexes thereof. For example, as is evident from the examples of the present invention, buntanetap and pharmaceutically acceptable salts and complexes thereof are useful for inhibiting, preventing, and / or treating psychoses or mental disorders.

[0010] A further object of the present invention is to inhibit, delay, or slow the onset of neurological disorders, such as autism, attention deficit hyperactivity disorder, anxiety, phobia, obsessive-compulsive disorder, bipolar disorder, major depressive disorder, and schizophrenia, in a mammal (e.g., a human), comprising or consisting of administering to the human a therapeutically effective amount of buntanetap, an active metabolite of buntanetap, a therapeutically effective analog of buntanetap, a compound similar to buntanetap described herein, a pharmaceutically acceptable salt or complex thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, buntanetap is orally administered in an amount of about 1 mg to about 120 mg, preferably once daily. In certain embodiments, effective amounts of compounds that are antipsychotics, antidepressants, and hallucinogens, or any combination thereof, are administered simultaneously or in the same dosage form.

[0011] In certain preferred embodiments, buntanetap is administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47 mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg , 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99 The dose ranges from 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, and all integers between these values, up to about 120 mg. In certain preferred embodiments, buntanetap is administered orally, for example, at a dose of about 2 mg to about 80 mg. In other embodiments, buntanetap is administered intravenously in an amount of about 0.1 to about 25 mg per day. In other preferred embodiments, buntanetap is administered intraperitoneally / intramuscularly (IP / IM) at a dose of about 0.3 mg per day to about 70 mg per day. In certain preferred embodiments, buntanetap is administered in conjunction with a suitable antidiabetic agent, as further described herein in the following paragraphs.

[0012] In certain embodiments of each of the above methods, the oral pharmaceutical composition contains about 1 mg to about 120 mg of buntanetap or a pharmaceutically acceptable salt thereof, the IP / IM pharmaceutical composition contains about 0.3 to about 70 mg of buntanetap or a pharmaceutically acceptable salt thereof, and the intravenous (IV) pharmaceutical formulation contains about 0.1 to about 25 mg of buntanetap or a pharmaceutically acceptable salt thereof. Single oral doses of buntanetap greater than about 120 mg / day and multiple oral doses up to 240 mg / day are associated with an increased incidence of side effects (e.g., nausea and vomiting).

[0013] In certain preferred embodiments of the methods described herein, the peak plasma circulating level of buntanetap in humans is, for example, about 0.1 ng / mL to about 380 ng / mL, in certain embodiments, about 2 ng / mL to about 20 ng / mL, more preferably about 3.7 ng / mL to about 120 ng / mL, and any numeric or integer range therebetween. In certain preferred embodiments, the peak plasma circulating level is reached within about 1 to 3 hours after administration of buntanetap to a human. In certain embodiments, the plasma circulating level of buntanetap in the brain is greater than or equal to about 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL, 5 ng / mL, 6 ng / mL, 7 ng / mL, 8 ng / mL, 9 ng / mL, 10 ng / mL, 11 ng / mL, 12 ng / mL, 13 ng / mL, 14 ng / mL, 15 ng / mL, 16 ng / mL, 17 ng / mL, 18 ng / mL, 19 ng / mL, or 20 ng / mL for at least 9 hours, preferably at least 12 hours, after administration of buntanetap to a human. In certain embodiments, the steady-state plasma concentration of buntanetap in the brain is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 1, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, or 130 ng / mL.In certain embodiments, the half-life of buntanetap in cerebrospinal fluid after administration is about 12 hours, and the half-life of buntanetap in plasma after administration is about 5 hours. In certain embodiments, administration of buntanetap to humans results in brain levels of buntanetap that are in the range of about 4 to about 10 times the plasma levels of buntanetap in these patients. In certain embodiments, the concentration of buntanetap in the human brain is about 8 ng / g to about 3040 ng / g, and in certain embodiments, about 30 ng / g to about 960 ng / g.

[0014] For each of the above-described methods, buntanetap, a pharmaceutically acceptable salt thereof, an analog, or a similar compound described herein can be administered, for example, orally, parenterally, sublingually, via a suppository, nasally, topically, transdermally, or via a subcutaneous implant.

[0015] The present invention is further directed, in part, to a method for preventing, treating, inhibiting, delaying, or slowing neurological disorders such as autism, attention deficit hyperactivity disorder, anxiety, phobia, obsessive-compulsive disorder, bipolar disorder, major depressive disorder, and schizophrenia in a human at risk of developing such a neurological disorder, comprising administering to the human a compound selected from the group consisting of Formula (I), Formula (II), Formula (III), and Formula (IV).

[0016] [ka]

[0017] In formula (I) and formula (II), R1 and R2 are independently hydrogen, branched or straight chain C1-C8 alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R3 is branched or straight chain C1-C4 alkyl or heteroalkyl or C4-C8 alkyl or heteroalkyl, or substituted or unsubstituted aryl; X and Y are independently O, S, alkyl, a hydrocarbon moiety, C(H)R4, or NR5; R4 and R5 are independently hydrogen, oxygen, branched or straight chain C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, aralkyl, or substituted or unsubstituted aryl; R6 is hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C2-C8 alkynyl, aralkyl, or substituted or unsubstituted aryl, or (CH2) n R7, where R7 is hydroxy, alkoxy, cyano, ester, carboxylic acid, substituted or unsubstituted amino, and n is 1 to 4. In certain embodiments, the present invention is directed to preventing or slowing the ability of melanoma cells to supply themselves with Abeta by treatment (administration of buntanetap) as described in this section.

[0018] In certain embodiments, the compound of Formula (I) or Formula (II) is a substantially pure (+) enantiomer. In certain embodiments, the compound of Formula (I) is buntanetap or an active metabolite thereof.

[0019] In a preferred embodiment, the compound is a buntanetap of formula IV:

[0020] [ka]

[0021] In formula (III), R1 and R2 are independently hydrogen, branched or straight chain C1-C8 alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R3 is branched or straight chain C1-C4 alkyl or heteroalkyl or C4-C8 alkyl or heteroalkyl, or substituted or unsubstituted aryl; X is NR5; and R5 is C 2~8 Alkenyl, C 2~8 alkynyl, or aralkyl, and Y is selected from C(H)R or NR, where R and R are independently hydrogen, branched or straight chain C(H)R. 1~8 It is alkyl or heteroalkyl, alkenyl, or C2-C8 alkynyl, aralkyl.

[0022] The present invention is also directed, in part, to a method for preventing or treating anxiety in a human in need thereof, comprising administering a therapeutically effective dose of buntanetap or a pharmaceutically acceptable salt thereof to the human. Administration of a therapeutically effective dose of buntanetap or a pharmaceutically acceptable salt thereof to a human can, for example, prevent the onset of anxiety in the human, completely alleviate anxiety in the human, or result in a reduction in anxiety of at least about 20% in the human. The reduction in anxiety can be, for example, about 30% to about 100%, about 40% to about 80%, or about 40% to about 60%. The reduction in anxiety can last, for example, from about 1 minute to about 24 hours, from about 1 minute to about 22 hours, from about 1 minute to about 18 hours, or from about 1 minute to about 12 hours. The reduction in anxiety can last, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours.

[0023] The present invention is also directed, in part, to a method for preventing or treating obsessive-compulsive behavior in a human in need thereof, comprising administering a therapeutically effective dose of buntanetap or a pharmaceutically acceptable salt thereof to the human. Administration of a therapeutically effective dose of buntanetap or a pharmaceutically acceptable salt thereof to a human can, for example, prevent obsessive-compulsive behavior in the human, completely alleviate obsessive-compulsive behavior in the human, or result in at least about a 10% reduction in obsessive-compulsive behavior in the human. The reduction in obsessive-compulsive behavior can be, for example, about 10% to about 90%, about 40% to about 80%, or about 20% to about 60%. The reduction in obsessive-compulsive behavior can last, for example, from about 1 minute to about 24 hours, from about 1 minute to about 22 hours, from about 1 minute to about 18 hours, or from about 5 minutes to about 12 hours. The reduction in compulsive behavior can last, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours.

[0024] Additionally, the present invention is directed, in part, to a method for preventing or treating fear in a human in need thereof, comprising administering a therapeutically effective dose of buntanetap or a pharmaceutically acceptable salt thereof to the human. Administration of a therapeutically effective dose of buntanetap or a pharmaceutically acceptable salt thereof to a human can, for example, prevent fear in the human, completely alleviate fear in the human, or result in a reduction in fear of at least about 10% in the human. The reduction in fear can be, for example, about 10% to about 90%, about 40% to about 80%, or about 20% to about 60%. The reduction in fear can last, for example, from about 1 minute to about 24 hours, from about 1 minute to about 22 hours, from about 1 minute to about 18 hours, or from about 1 minute to about 12 hours. The reduction in fear can last, for example, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours.

[0025] In certain embodiments, buntanetap or a pharmaceutically acceptable salt thereof is (i) orally administered in an amount of about 1 mg to about 120 mg once daily, (ii) intravenously administered in an amount of about 0.1 mg to about 25 mg / day, or (iii) intraperitoneally / intramuscularly (IP / IM) administered in a dose of about 0.3 to about 70 mg / day. Buntanetap or a pharmaceutically acceptable salt thereof is orally administered, for example, in an amount of about 10 mg to about 80 mg once daily. Peak plasma circulating levels of buntanetap in humans range, for example, from about 1 ng / mL to about 380 ng / mL.

[0026] For methods for preventing or treating anxiety, obsessive-compulsive disorder, or phobia, buntanetap or a pharmaceutically acceptable salt thereof is generally orally administered in an amount of about 1 mg to about 120 mg once daily. Therefore, methods for preventing or treating anxiety, obsessive-compulsive disorder, or phobia according to the present invention include oral administration of buntanetap or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 100 mg once daily. Specifically, methods for preventing or treating anxiety, obsessive-compulsive disorder, or phobia according to the present invention include administering about 5 mg to about 80 mg of buntanetap or a pharmaceutically acceptable salt thereof as needed, up to a maximum daily dose of about 120 mg.

[0027] In certain embodiments, the psychosis is present as a disruption of the human genetic code at CACNA1C or CACNB2. In certain embodiments, the psychosis is selected from the group consisting of autism, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

[0028] The present invention is also directed to a compound selected from the group consisting of Formula (I), Formula (II) and Formula (III) for use in the treatment of psychosis.

[0029] The present invention is further directed to buntanetap or a pharmaceutically acceptable salt thereof for use in the treatment of psychosis.

[0030] Additionally, the present invention is directed to buntanetap or a pharmaceutically acceptable salt thereof for use in the treatment of anxiety.

[0031] The present invention is further directed to buntanetap or a pharmaceutically acceptable salt thereof for use in the treatment of fear.

[0032] The present invention is also directed to buntanetap or a pharmaceutically acceptable salt thereof for use in the treatment of obsessive-compulsive behavior.

[0033] The present invention is further directed to the use of a compound selected from the group consisting of Formula (I), Formula (II) and Formula (III) for the manufacture of a medicament for use in the treatment of psychosis.

[0034] The present invention is also directed to the use of buntanetap or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of psychosis.

[0035] The present invention is further directed to the use of a compound selected from the group consisting of Formula (I), Formula (II) and Formula (III) for the manufacture of a medicament for the treatment of anxiety.

[0036] The present invention is also directed to the use of buntanetap or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of anxiety.

[0037] The present invention is further directed to the use of a compound selected from the group consisting of Formula (I), Formula (II) and Formula (III) for the manufacture of a medicament for the treatment of phobia.

[0038] The present invention is also directed to the use of buntanetap or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of phobia.

[0039] The present invention is further directed to the use of a compound selected from the group consisting of Formula (I), Formula (II) and Formula (III) for the manufacture of a medicament for the treatment of obsessive-compulsive behavior.

[0040] The present invention is also directed to the use of buntanetap or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of obsessive-compulsive behavior.

[0041] The present invention is further directed, in part, to a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of Formula (I), Formula (II), and Formula (III); an effective amount of a compound that is an antipsychotic, an antidepressant, and a hallucinogen, or any combination thereof; and at least one pharmaceutically acceptable excipient.

[0042] In certain preferred embodiments, the compound of formula (III) is a substantially pure (-) enantiomer.

[0043] In certain preferred embodiments, the compound is buntanetap of formula (IV):

[0044] [ka] The compound of formula (IV) is the substantially pure (+) enantiomer, or a pharmaceutically acceptable salt thereof.

[0045] In certain embodiments, the buntanetap or pharmaceutically acceptable salt thereof is in an amount of about 1 mg to about 120 mg, and in certain preferred embodiments, the buntanetap or pharmaceutically acceptable salt thereof is in an amount of about 10 mg to about 120 mg.

[0046] In certain embodiments, the antipsychotic agent is a therapeutically effective amount of a typical antipsychotic agent, an atypical antipsychotic agent, a miscellaneous antipsychotic agent, a pharmaceutically acceptable salt thereof, or a combination of any of the foregoing. In certain embodiments, the antipsychotic agent is included in a sub-therapeutic amount.

[0047] In certain embodiments, the pharmaceutical composition comprises an antidepressant, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, and any combination of the foregoing. In certain embodiments, the antidepressant or hallucinogen or lithium is present in a sub-therapeutic amount.

[0048] In certain embodiments, the pharmaceutical composition comprises a hallucinogen or a pharmaceutically acceptable salt thereof, and any combination of the foregoing, hi certain embodiments, the hallucinogen is included in a sub-therapeutic amount.

[0049] In certain embodiments, a pharmaceutical composition comprises a therapeutically effective agent selected from Formula (I), Formula (II), Formula (III), or Formula (IV) together with two or more of an antipsychotic, an antidepressant, lithium, a hallucinogen, a pharmaceutically effective salt thereof, or a therapeutically effective combination of an antipsychotic, an antidepressant, lithium, a hallucinogen, a pharmaceutically effective salt thereof. The two or more of the antipsychotic, antidepressant, lithium, a hallucinogen, and a pharmaceutically effective salt thereof may be included in therapeutic or subtherapeutic amounts.

[0050] In certain preferred embodiments, the pharmaceutical composition is in an oral dosage form.

[0051] In certain preferred embodiments of the pharmaceutical composition, the amount of the compounds of Formula (I), (II), and (III), or pharmaceutically acceptable salts thereof, and the antipsychotic agent, antidepressant, hallucinogen, or any combination thereof, is effective to treat, inhibit, reduce, slow, or delay the symptoms of psychosis.

[0052] In certain embodiments, the psychosis is selected from the group consisting of autism, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

[0053] definition As used herein, each of the following terms has the meaning associated with it in this section.

[0054] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature and laboratory procedures used herein in biochemistry, analytical chemistry, and organic chemistry are those well known and commonly employed in the art. Standard techniques, or modifications thereof, are used for chemical synthesis and chemical analysis.

[0055] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0056] The term "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. In the context of this application, the term "about" means a value within 20% (±20%) of the value immediately following the term "about," including values ​​equal to the upper limit (i.e., +20%) and the lower limit (i.e., -20%) of this range. For example, the phrase "about 100" encompasses any numerical value between 80 and 120, inclusive.

[0057] As used herein, the terms "buntanetap" and "posifen" are used interchangeably to refer to (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate or a salt thereof.

[0058] As used herein, the term "APP" refers to amyloid precursor protein.

[0059] As used herein, the term "Aβ" refers to Abeta or amyloid beta or amyloid-β peptide. For purposes of the present invention, these terms are considered synonymous.

[0060] For purposes of this invention, "Buntanetap-type" drugs include those of formula (I), formula (II), formula (III) or formula (IV).

[0061] As used herein, "C9orf72" refers to the C9orf72 protein, which is found in many regions of the brain.

[0062] As used herein, the term "neurotoxic aggregating protein" refers to a protein or family of proteins that have neurotoxic effects when accumulated in brain tissue, such as brain tissue. Non-limiting examples of neurotoxic aggregating proteins include APP, Aβ, SOD1, SNCA, NAC, TSE amyloid plaques, HTT, tau, TDP43, and C9orf72.

[0063] As used herein, the terms "protein," "peptide," and "polypeptide" are used interchangeably and refer to compounds made up of amino acid residues covalently joined by peptide bonds.

[0064] The term "specifically binds," as used herein, means a molecule, such as an antibody or small molecule, that recognizes and binds to another molecule or feature in a sample, but does not substantially recognize or bind to other molecules or features.

[0065] The phrase "inhibit," as used herein, means to reduce by a measurable amount or to totally prevent the expression, stability, function, or activity of a molecule, reaction, interaction, gene, mRNA, and / or protein. Inhibitors are, for example, compounds that bind to, partially or completely block stimulation, reduce, prevent, delay activation, inactivate, desensitize, or downregulate protein, gene, and mRNA stability, expression, function, and activity, e.g., antagonists.

[0066] "Effective amount" or "therapeutically effective amount" are used interchangeably herein and refer to an amount of a compound, formulation, substance, or composition described herein that is effective to achieve a particular biological result. Such result may include, but is not limited to, the treatment of a disease or condition as determined by any method suitable in the art.

[0067] As used herein, the term "pharmaceutical composition" refers to a mixture of at least one compound of the present invention with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or additives. Pharmaceutical compositions facilitate administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0068] As used herein, the term "co-administering" refers to a compound of Formula (I), (II), and / or (III) administered to a mammal (e.g., a human subject or patient) in conjunction with an appropriate antidiabetic agent such that the two classes of agents provide an overlapping effect. While it is possible in certain cases to administer the two classes of agents in a single dosage form, it is contemplated that the agents may be administered separately via either the same or different routes of administration to achieve an overlapping effect, taking into account their different physical / chemical properties (including, but not limited to, solubility, bioavailability, half-life, metabolism, and clearance / excretion from the body).

[0069] "Pharmaceutically acceptable" refers to a substance that is compatible with the activity of the compounds useful within the present invention and physiologically acceptable to a patient (e.g., a human) from a pharmacological / toxicological standpoint, and to a manufacturing pharmacist from a physical / chemical standpoint with respect to composition, formulation, stability, patient acceptance, and bioavailability.

[0070] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, additive, thickener, solvent, or encapsulating substance, that is involved in carrying or transporting a compound useful within the invention into or to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances utilized in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include pharmaceutically acceptable salts of the compounds useful within the present invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0071] As used herein, the term "salt" includes the addition salt of a free acid or free base that is a compound useful in the present invention.Suitable acid addition salts can be prepared from inorganic or organic acids.Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, perchloric acid, and tetrafluoroboronic acid. Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid. Suitable base addition salts of compounds useful within the present invention include, for example, metal salts, including alkali metal, alkaline earth metal, and transition metal salts, such as lithium, calcium, magnesium, potassium, sodium, and zinc salts. Acceptable base addition salts also include organic salts formed from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. All of these salts can be prepared from the corresponding free base compound by conventional procedures, for example, by reacting the appropriate acid or base with the corresponding free base.

[0072] An "individual," "patient," or "subject," as these terms are used herein, includes members of any animal species, including, but not limited to, birds, humans and other primates, and other mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs. Preferably, the subject is a human.

[0073] The term "treat" or "treating," as used herein, means reducing the frequency with which a subject experiences a symptom, or administering a combination of drugs or compounds to reduce the frequency and / or severity of the symptoms. As used herein, "alleviating" is used interchangeably with the term "treating." Treating a disease, disorder, or condition may or may not include complete eradication or elimination of symptoms. Thus, the term "treating" encompasses preventing and slowing down the conditions described herein.

[0074] The term "therapeutic" as used herein means the treatment and / or prevention of a condition or disease state described herein.

[0075] The term "reduction," as used herein, means a statistically significant reduction. [Brief explanation of the drawings]

[0076] [Figure 1] 1 is a Western blot and graph showing that Buntanetap reduced APP in vitro in a dose-dependent manner in SH-SY-5Y human neuroblastoma cells. [Figure 2] 1 is a collection of tables, graphs, and Western blots showing that Buntanetab treatment of APP / PS1 transgenic AD mice reduced APP and its fragments in the hippocampus. [Figure 3] 1 is a table showing reductions in APP / Abeta, Tau / phosphotau and αSYN in spinal fluid of patients with mild cognitive impairment. [Figure 4] FIG. 1 shows normal axonal transport (retrograde 0.5 frames / sec) in a normal neuron, demonstrating the normal flow and velocity of vesicles carrying D+BDNF across the axon. [Figure 5]Neurons in Down syndrome contain high levels of Abeta, tau, and α-SYN, and exhibit abnormal transport. BDNF transport is significantly slowed and impaired across axons. [Figure 6] Treatment with Buntanetab for 48 hours shows complete restoration of axonal transport in Down syndrome neurons. [Figure 7] In Example 7, the number of sawdust-covered glass marbles for each group is summarized. [Figure 8-1] FIG. 8A shows a summary of the results of the elevated plus maze test of Example 8. [Figure 8-2] 8B and 8C show a summary of the results of the elevated plus maze test of Example 8. [Figure 8-3] 8D and 8E show a summary of the results of the elevated plus maze test of Example 8. [Figure 9] 1 shows a summary of the results of the fear conditioning test of Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0077] The present invention is directed, in part, to methods for inhibiting, preventing, or treating psychosis through the administration of buntanetap, compounds similar to buntanetap described herein (e.g., drugs comprising Formula (I), Formula (II), Formula (III), or Formula (IV)), pharmaceutically acceptable salts thereof, and complexes thereof, in combination with an effective amount of a compound that is an antipsychotic, an antidepressant, a hallucinogen, or any combination thereof, and one or more pharmaceutically acceptable excipients.

[0078] Mental health and neurological disorders are one of the major groups of non-communicable diseases (NCDs) and affect a person's thoughts, emotions, behavior, and relationships. These include a diverse range of diseases and conditions such as depression, schizophrenia, dementia, Alzheimer's disease, anxiety, and substance abuse disorders, among many others. An estimated 450 to 500 million people worldwide live with a mental condition.

[0079] Neurological and neuropsychiatric disorders all involve dysfunction of the nervous system accompanied by impaired neuronal communication. Neurological disorders include Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease. Neuronal communication disorders are associated with depression, behavioral problems, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and schizophrenia. These disorders can affect social interactions, mood, concentration, memory, and body control. Mental disorders are illnesses that affect the brain rather than just the mind and can affect an individual's function; disorders are disturbances of normal physical or mental health of the mind or body. A pathological condition of a body part, organ, or system resulting from various causes, such as infection, genetic defect, or environmental stress, and characterized by a identifiable group of signs or symptoms. Because "disease" specifies that the pathological condition is of a body part, people were unlikely to use the term "psychiatric illness" until it was understood that mental illness was a physical disorder. The difference between a "mental disorder" and a "mental illness" then is one in which the origin of the condition is considered. The main classes of mental illness include:

[0080] Neurodevelopmental Disorders: This class encompasses a wide range of problems that typically begin in infancy or childhood, often before children enter school. Examples include autism spectrum disorder, attention-deficit / hyperactivity disorder (ADHD), and learning disabilities. Autism spectrum disorders (ASDs) are conditions (neurological and developmental) related to brain development that affect how a person interacts with others, communicates, learns, and behaves. Autistic disorders typically include language delays, communication problems, social issues, and unusual interests and behaviors. While autism can be diagnosed at any age, it is described as a "developmental disorder" because symptoms generally emerge by age 2. An estimated 30–80 percent of children with autism also meet criteria for ADHD, and conversely, 20–50 percent of children with ADHD meet criteria for autism. Given the extent of overlap, scientists are beginning to reexamine the relationship between the two conditions and search for a common biological root. The idea that autism and ADHD are intrinsically intertwined arises not only from their frequent co-occurrence but also from the observation that they share behavioral characteristics. The core diagnostic criteria for the conditions remain distinct in DSM-5: social communication impairments and restricted and repetitive behaviors for autism; and apathy or hyperactivity and impulsivity, or a combination, for ADHD. However, both conditions may include language delays, heightened sensory response, oppositional behavior, problems regulating emotions, and difficulties planning and inhibiting behaviors. Both manifest in childhood and are more commonly diagnosed in boys.

[0081] Schizophrenia Spectrum and Other Psychotic Disorders: Psychotic disorders cause detachment from reality, such as delusions, hallucinations, and disorganized thinking and behavior. The most notable example is schizophrenia, but other classes of disorders can also sometimes be associated with detachment from reality. Research suggests that there may be a link between schizophrenia and ASD because they share common symptoms. While both disorders can differ greatly in their symptoms, both affect how the brain develops. ASD and schizophrenia may be genetically linked. Some disorders are caused by changes to our chromosomes, the molecules that carry our genetic code. A 2017 study, B. St. Pourcain et al., ASD and Schizophrenia show Distinct Developmental Profiles in Common Genetic Overlap with Population-Based Social Communication Difficulties, Molecular Psychiatry 23, 263-270 (2018), shows that deletion of chromosome 22 can lead to the development of certain disorders, including ASD and schizophrenia.

[0082] Bipolar disorder and related disorders: This class includes disorders with alternating episodes of mania (periods of excessive activity, energy, and excitement) and depression. Like other psychotic disorders, research suggests that bipolar disorder may be relatively common among children and adults with autism. Some studies have found that 27 percent of people with autism also have symptoms of bipolar disorder. A. Cardno, et al., Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder, Schizophr Bull., 40(3); 504-515 (2014) states that there is substantial evidence of overlapping genetic influences between schizophrenia and bipolar disorder.

[0083] Depressive disorders include disorders that affect how one feels emotionally, such as levels of sadness and happiness, and can disrupt one's ability to function. Examples include major depressive disorder and premenstrual dysphoric disorder. Depression occurs when a person experiences a low mood (feeling sad, irritable, and empty) or loss of pleasure or interest in activities for more than two weeks. Depression can significantly affect a person's ability to function and interact with others and society. It is estimated that approximately 264 million people, or approximately 5% of adults, are affected by depression. Autism and depression often occur together, and it is well documented that people diagnosed with autism have a high incidence of co-occurring mental health conditions, with depression being the most reported. Depression may have the same etiology as autism and / or share overlapping symptoms, which can be explained by a genetic predisposition. B. FC van Heijst, et al., Autism and Depression are Connected: A Report of Two Complimentary Network Studies, Autism. 2020 Apr; 24(3): 680-692.

[0084] Anxiety Disorders. Anxiety is an emotion characterized by the anticipation of future danger or misfortune, accompanied by excessive worry. It may involve behaviors aimed at avoiding anxiety-provoking situations. This class includes generalized anxiety disorder, panic disorder, and pathological phobias. Research suggests that autistic individuals are more prone to experience anxiety, and it is estimated that up to half of all autistic individuals experience high levels of anxiety on a regular basis.

[0085] Obsessive-compulsive disorder and related disorders. These disorders involve preoccupations or obsessions and repetitive thoughts and behaviors. Examples include obsessive-compulsive disorder, hoarding disorder, and trichotillomania (trichotillomania). There appears to be a relationship between obsessive-compulsive disorders. See S. Jacob, et al., Autism Spectrum and Obsessive-compulsive Disorders: OC Behaviors, Phenotypes and Genetics, Autism Res. 2(6):293-311 (209). However, it is concluded that autism spectrum disorders (ASD) are a phenotypically and etiologically heterogeneous set that includes obsessive-compulsive disorder (OCD).

[0086] Traumatic and stress-related disorders. These are adjustment disorders in which a person has problems coping during or after a stressful life event. Examples include post-traumatic stress disorder (PTSD) and acute stress disorder.

[0087] Dissociative disorders, which are disorders in which the sense of self is disrupted, such as dissociative identity disorder and dissociative amnesia.

[0088] Somatic symptom disorder and related disorders. People with one of these disorders may have somatic symptoms that cause major emotional distress and problems functioning. There may or may not be a separately diagnosed medical condition associated with these symptoms, but responses to the symptoms are not normal. These disorders include somatic symptom disorder, illness anxiety disorder, and factitious disorder.

[0089] Feeding disorders (eating disorders) These disorders include eating disorders that affect nutrition and health, such as anorexia nervosa and binge eating disorder.

[0090] Elimination disorders. These disorders involve the inappropriate elimination of urine or feces, either intentionally or unintentionally. Bedwetting (enuresis) is one example.

[0091] Sleep-wake disorders, which are disorders of sleep severe enough to require clinical attention, such as insomnia, sleep apnea, and restless legs syndrome.

[0092] Sexual dysfunction, which includes disorders of sexual response such as premature ejaculation and female orgasmic disorder.

[0093] Gender dysphoria, which refers to the distress associated with the desire to identify as another gender.

[0094] Disruptive disorders, impulse control disorders and conduct disorders. These disorders involve problems with emotional and behavioral self-control, such as kleptomania or intermittent explosive disorder.

[0095] Substance-related and addictive disorders. These include problems related to excessive use of alcohol, caffeine, tobacco, and drugs. This class also includes gambling disorders.

[0096] Personality disorders involve long-lasting patterns of emotional instability and unhealthy behavior that cause problems in life and relationships. Examples include borderline personality disorder, antisocial personality disorder, and narcissistic personality disorder.

[0097] Paraphilic disorders: These disorders involve sexual interests that cause personal distress or harm or result in potential or actual harm to others. Examples are sexual sadism disorder, voyeuristic disorder, and pedophilic disorder.

[0098] Other Mental Disorders. This class includes mental disorders that are due to other medical conditions or that do not fully meet the criteria for one of the above disorders. In certain embodiments, the mental illness is acute stress disorder, agoraphobia (anxiety about being in places from which escape may be impossible), amnesia, anorexia nervosa, attention-deficit / hyperactivity disorder (ADHD), body dysmorphic disorder (preoccupation with and belief in the existence of defects in one or more specific body parts), brief psychotic disorder, bulimia nervosa, conversion disorder (deficits in voluntary motor or sensory function that are not produced intentionally and cannot be better explained by another health condition), cyclothymic disorder (a milder variant of bipolar disorder), depersonalization disorder (a sense of unreality that one's own body does not belong to oneself or that one is constantly in an unreal state; dissociative identity disorder (DID)), dyspareunia (recurrent or persistent genital pain associated with sexual intercourse that is not better explained by another medical condition), dysthymic disorder (a condition that occurs most days of the day for more than two years), or depression), erectile dysfunction, exhibitionism, fetishism, kleptomania (touching or rubbing one's genitals in a sexual manner with another person without their consent to achieve sexual pleasure or orgasm), pathological gambling, generalized anxiety disorder, hypoactive sexual desire disorder, hypochondriasis (a frightening preoccupation with having a serious illness based on a misinterpretation of bodily sensations), impotence, intermittent explosive disorder, kleptomania, masochism, major depressive disorder, obsessive-compulsive disorder, orgasm The term further includes: sexual disorders, pain disorders, panic disorders, pedophilia, pathological phobias, post-traumatic stress disorder, premature ejaculation, pyromania, sadism, schizophrenia, schizoaffective disorder, sexual arousal disorder (female), sexual aversion disorder, shared delusions, somatization disorder, substance abuse, Tourette's syndrome, transvestism, trichotillomania, vaginismus (recurrent or voluntary spasms of the vaginal muscles that interfere with sexual intercourse not better explained by another medical condition), and voyeurism.

[0099] The connections between the disorders described above are presented merely to show that they exist and are not meant to be all-inclusive. For the purposes of this application, these connections are presented to show that many of these disorders exhibit abnormal patterns of neurotoxic aggregating proteins in the brain, always have abnormal axonal transport and synaptic transmission problems, and have at least partial overlap in etiology, including, but not limited to, a genetic component.

[0100] A serious mental illness is a severely impairing mental, behavioral, or emotional condition that substantially interferes with or limits one or more major life activities. Examples of serious mental illnesses include major depressive disorder, schizophrenia, and bipolar disorder.

[0101] Some of the most commonly used classes of psychiatric prescription medications include antidepressants (used to treat depression, anxiety, and sometimes other conditions), anti-anxiety medications, mood stabilizers (most commonly used to treat bipolar disorder), and antipsychotics (typically used to treat psychotic disorders such as schizophrenia and bipolar disorder, or used in conjunction with antidepressants to treat depression). Psychotherapy (which involves the patient talking with a healthcare provider about their condition) is also commonly used. Brain stimulation procedures are sometimes used for depression and other mental health disorders and are generally reserved for situations where medication and psychotherapy have failed. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, deep brain stimulation, and vagus nerve stimulation.

[0102] Antipsychotics can reduce or alleviate psychotic symptoms such as delusions (false beliefs) and hallucinations (seeing or hearing things that are not there). Formerly known as primary tranquilizers and neuroleptics, antipsychotics are the primary class of medication used to treat people with schizophrenia. They are also used to treat people with bipolar disorder, depression, and psychosis caused by Alzheimer's disease. Other uses of antipsychotics include stabilizing mood in bipolar disorder, reducing anxiety in anxiety disorders, and reducing tics in Tourette's syndrome. The primary difference between first- and second-generation antipsychotics is that first-generation drugs block dopamine, while second-generation drugs block dopamine and also affect serotonin levels. Evidence suggests that some second-generation drugs have milder movement-related side effects than first-generation drugs. Second-generation antipsychotics (referred to as "atypical antipsychotics") include, but are not limited to, risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), ziprasidone (Zeldox), paliperidone (Invega), aripiprazole (Abilify), and clozapine (Clozaril). Although they are not officially approved for this use, atypical antipsychotics are sometimes used to treat mood and anxiety disorders such as bipolar disorder, post-traumatic stress disorder, and obsessive-compulsive disorder. Various antipsychotics differ slightly from first- and second-generation antipsychotics and have different modes of action for treating mood disorders and schizophrenia. Various antipsychotics include, but are not limited to, haloperidol, pimozide, molindone, and loxapine. Phenothiazine antipsychotics are believed to act by blocking the actions of dopamine in the brain and include, but are not limited to, prochlorperazine, chlorpromazine, perphenazine, fluphenazine, thioridazine, and mesoridazine. Another class of antipsychotics is the thioxanthenes, which are dopamine-2 (D2) receptor antagonists, which block the actions of dopamine in the brain and include, but are not limited to, thiothixene.Additional antipsychotic agents useful in the treatments and formulations of the present invention include asenapine, benperidol, zuclopenthixol, flupenthixol, fluphenazine, lurasidone, levomepromazine, promazine, pericyazine, caripraine, amisulpride, trifluorperazine, sulpiride, acepromazine, acetophenazine, ziprasidone, iloperidone, and the like.

[0103] As reported in the American Psychological Associate, May 2013, Vol. 44, No. 5, the five major psychiatric disorders—autism, attention-deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia—appear to share several common genetic risk factors, according to a study of genetic data from more than 60,000 individuals worldwide (The Lancet, online, February 28, 2013). Researchers from 19 countries examined the genomes of more than 33,000 individuals with one of the disorders and nearly 28,000 controls. The researchers found four regions of the genetic code in which mutations are associated with all five disorders. Of particular interest are disruptions in two specific genes. One, CACNA1C, has already been linked to bipolar disorder and schizophrenia. The other, CACNB2, regulates calcium flow in brain cells and is important for helping neurons communicate with each other. These researchers believe that disruption of calcium channel function may be one early pathway that predisposes humans to developing any of the five disorders mentioned above.

[0104] In certain embodiments, the pharmaceutical composition comprises that the antipsychotic agent is selected from the group consisting of risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole, clozapine, haloperidol, pimozide, molindone, loxapine, prochlorperazine, chlorpromazine, perphenazine, fluphenazine, thioridazine, mesoridazine, thiothixene, asenapine, benperidol, zuclopenthixol, flupenthixol, fluphenazine, lurasidone, levomepromazine, promazine, pericyazine, cariprazine, amisulpride, trifluoperazine, sulpiride, acepromazine, acetophenazine, ziprasidone, iloperidone, pharmaceutically acceptable salts thereof, and combinations of any of the foregoing.

[0105] In a further embodiment, the pharmaceutical composition comprises an antidepressant. Many common medications for depression fall into the following drug classes: selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram (Cipramil®), dapoxetine (Priligy®), escitalopram (Cipralex®), fluoxetine (Prozac® or Oxactin®), fluvoxamine (Faverin®), paroxetine (Seroxat®), sertraline (Lustral®), vortioxetine ( Brintellix®), serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., desvenlafaxine, venlafaxine, duloxetine, levomilnacipran); tricyclic antidepressants (TCAs) (e.g., amitriptyline, amoxapine, desipramine (Norpramin®), doxepin, imipramine (Tofranil®), nortriptyline (Pamelor®), protriptyline, trimipramine); tetracyclic antidepressants (amitriptyline, amoxapine, desipramine) dopamine reuptake blockers (e.g., Aplenzin®, bupropion (Wellbutrin®), bupropion / naltrexone (e.g., Contrave®, Forfivo® XL); 5-HT1A receptor antagonists (e.g., buspirone, flesinoxan, gepirone, flibanserin, nalutzotan) , lurasidone, aripiprazole); 5-HT2 receptor antagonists (e.g., clozapine, olanzapine, quetiapine, risperidone, and asenapine); 5-HT3 receptor antagonists (e.g., clozapine, olanzapine, quetiapine, risperidone, and asenapine); monoamine oxidase inhibitors (MAOIs) (e.g., isocarboxazid (Marplan®), phenelzine (Nardil®), selegiline (Emsam®), tranylcypromine (Parnate®);noradrenergic antagonists (e.g., propranolol, phentolamine); and atypical antidepressants (not included in these drug classes), and natural dietary supplements, such as St. John's wort; stimulants (e.g., cocaine, MDMA, khat, nicotine, caffeine, amphetamines (including but not limited to Adderall®), methamphetamine, dexamphetamine (Focalin®), methylphenidate (Ritalin®), atomoxetine hydrochloride (Strattera®), lisdexamfetamine dimesylate (Vyvanse®)); and lithium, including immediate-release and extended-release forms thereof;

[0106] In certain embodiments, the pharmaceutical composition comprises a hallucinogen. Hallucinogens (also known as psychedelics) are a group of drugs that alter the way a person sees and perceives reality, causing hallucinations. Hallucinogens are typically found in plants and fungi or synthetically produced. They are a large and diverse class of psychostimulants that can produce altered states of consciousness characterized by profound changes in thinking, mood, and perception, as well as other changes. Most hallucinogens can be classified as either psychedelics, dissociatives, or delirium-inducing drugs. Many hallucinogens have chemical structures similar to those of natural neurotransmitters such as acetylcholine, serotonin, or catecholamines. Typically, hallucinogens are divided into two categories: classical hallucinogens and dissociative drugs. Three major categories of hallucinogenic drugs include psychedelics, dissociatives, and delirium-inducing drugs. Psychedelics work by disrupting the function of neurotransmitters in the brain. Drugs in this category include DMT (dimethyltryptamine), peyote, mescaline, magic mushrooms, LSD (D-lysergic acid diethylamide), MDMA (methylenedioxymethamphetamine), psilocybin, psilocin, THC (tetrahydrocannabinol), ketamine, and other therapeutically active cannabinoid molecules found in marijuana. Mescaline is the primary component of the peyote cactus. Psilocybin and psilocin are natural products found in hallucinogenic mushrooms. MDMA is a synthetic drug derived from amphetamine that acts by increasing the activity of the neurotransmitters dopamine, serotonin, and norepinephrine.

[0107] Mental disorders result from brain dysfunction, whereas neurological disorders often correlate strongly with psychological and social factors and result in psychological symptoms. The International Classification of Diseases (ICD) and Diagnostic and Statistical Manual (DSM) 1, 2, which remain the dominant classifications of mental disorders, continue to distinguish clearly between mental disorders, a psychiatric domain, and brain disorders, a neurological domain. Some have proposed that mental disorders should be reclassified as disorders of the (central) nervous system. Advances in structural and functional brain imaging, neuropharmacology, and genetics are changing the biological research on psychiatric disorders. Meta-analyses show that structural brain abnormalities are present in schizophrenia, bipolar affective disorder, recurrent depressive disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Functional brain imaging demonstrates that both normal and abnormal emotions have neural representations.

[0108] Buntanetap, developed by QR Pharma, Inc. (now Annovis Bio, Inc.), is a small molecule that reduces soluble APP protein levels through a post-transcriptional mechanism. Buntanetap is also known as (+)-phenserine. Buntanetap is a stereoisomer of phenserine (-)-N-phenylcarbamoyl eseroline, and has achieved clinical evaluation for AD as an anticholinesterase inhibitor. Phenserine is an AChE inhibitor that is being investigated as a potential therapeutic agent for cognitive impairment associated with aging and Alzheimer's disease (U.S. Patent No. 5,409,948). Due to its highly cholinomimetic side effects, phenserine has failed three phase 3 clinical trials.

[0109] Buntanetap is a selective inhibitor of amyloid precursor protein (APP) production and is potentially useful as a disease-modifying treatment for AD (Cullen 2006; Utsuki 2006; Lahiri 2007). Buntanetap was discovered at the National Institute on Aging and selected from a series of structurally related compounds designed specifically for APP, with no or minimal acetylcholinesterase inhibitory activity. Buntanetap has been shown to reduce APP and, consequently, beta-amyloid (Aβ) production in relevant preclinical in vitro and in vivo studies. Maccecchini, et al., "Buntanetap as a Candidate Drug to Lower CSF Amyloid Precursor Protein, Amyloid-β Peptide and τ Levels: Target Engagement, Tolerability and Pharmacokinetics in Humans," J. Neurosurg. Psychiatry 2012;83:894-902, incorporated herein by reference, reported the results of a single and multiple ascending dose, phase 1, randomized, double-blind, placebo-controlled, safety, tolerability, and pharmacokinetic study of buntanetap conducted in 120 healthy human volunteers, followed by a small non-randomized study of five MCI subjects. Doses of buntanetap up to 4 x 60 mg daily for 10 days were well tolerated. In plasma, buntanetap was rapidly absorbed (Tmax = 1.2-1.7 hours) and biphasically eliminated from the circulation (terminal half-life of 4.3-4.7 hours) at all doses. Buntanetap was well tolerated and significantly reduced CSF levels of sAPPα, sAPPβ, t-tau, p-tau, and specific inflammatory markers, and CSF Aβ. 42The activity of buntanetap was also described in the applicant's U.S. Patent No. 10,383,851, which is incorporated herein by reference. Phase II data for buntanetap was published in C. Fang et al., "Buntanetap, a Novel Translational Inhibitor of Multiple Neurotoxic Proteins, Proves to Be Safe and Promising in Both Alzheimer's and Parkinson's Patients," J Prev Alzheimers Dis (2022). https: / / doi.org / 10.14283 / jpad.2022.84, published October 10, 2022, and incorporated herein by reference in its entirety. This publication reported the results of a Phase 2a clinical trial, a double-blind, placebo-controlled, multicenter study of 14 patients with early-stage AD and 54 patients with early-stage PD. Patients with AD received either 80 mg of buntanetap or a placebo QD. PD patients received buntanetap at 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg QD or placebo. The primary endpoints were safety and tolerability, and the secondary endpoint was plasma pharmacokinetics of buntanetap. Buntanetap was safely and well tolerated in both AD and PD patients at doses up to 80 mg. Cmax and AUC increased with dose, without any plateau observed up to 80 mg QD. Biomarker data demonstrated reduced levels of neurotoxic proteins and inflammatory factors and trends toward improved axonal integrity and synaptic function in both AD and PD cohorts. Psychometric testing demonstrated statistically significant improvements in the ADAS-Cog11 and WAIS coding scores in AD patients and the MDS-UPDRS and WAIS coding scores in PD patients.

[0110] As used herein, the term "buntanetap" refers to (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate having the chemical structure shown in Formula IV below, in a chemical purity of at least 90%, preferably at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.9% or 100%.

[0111] [ka]

[0112] The term "chemical purity," as applied to a pharmaceutically acceptable salt of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate or buntanetap, means the weight percent of the pharmaceutically acceptable salt of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate or buntanetap relative to the pharmaceutically acceptable salt of (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate or buntanetap and other chemical impurities that may be present, e.g., its (-) enantiomer.

[0113] The present invention also encompasses active metabolites of Buntanetap. Active metabolites have been previously identified and are known, for example, as "N 1 -nor-buntanetap" (referred to as (3aR)-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate) or a salt thereof; 8 -nor-buntanetap" (referred to as (3aR)-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate) or a salt thereof; and "N 1 ,N8 -nor-buntanetap" (referred to as (3aR)-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ylphenylcarbamate) or a salt thereof.

[0114] In other embodiments, the methods of the invention are practiced using phenserine or phenserine-like compounds, metabolites, enantiomers, or derivatives thereof known to those of skill in the art, such as those described in U.S. Pat. Nos. 5,171,750, 6,410,747, 6,683,105, 7,153,882, 7,786,162, 7,973,057, 8,258,172, 8,546,430, 8,691,864, and 8,853,253, all of which are incorporated by reference in their entireties.

[0115] In a broader sense, the present invention is directed, in part, to the administration of a buntanetap-type compound as defined by Formula (I), Formula (II), Formula (III) or Formula (IV) in combination with an effective amount of a compound that is an antipsychotic, an antidepressant, and a hallucinogen, or any combination thereof.

[0116] The Buntanetape type compounds have the following formula I or II or III:

[0117] [ka] wherein R1 and R2 are independently hydrogen, branched or straight chain C1-C8 alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R3 is branched or straight chain C1-C4 alkyl or heteroalkyl or C4-C8 alkyl or heteroalkyl, or substituted or unsubstituted aryl; X and Y are independently O, S, alkyl, a hydrocarbon moiety, C(H)R4, or NR5; R4 and R5 are independently hydrogen, oxygen, branched or straight chain C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, aralkyl, or substituted or unsubstituted aryl; R6 is hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C2-C8 alkynyl, aralkyl, or substituted or unsubstituted aryl, or (CH2) n R7, where R7 is hydroxy, alkoxy, cyano, ester, carboxylic acid, substituted or unsubstituted amino, and n is 1 to 4. in combination with an effective amount of an (appropriate) antidiabetic agent.

[0118] The chiral center of the compounds of Formula I and II is the carbon atom having R3 bonded thereto. As depicted herein, the (+) enantiomer has R3 pointing away from the plane of the page. While only the (+) isomer is depicted to conserve space, in other embodiments, the compounds having Formula I or II can be any (+) isomer, (-) isomer, or mixtures of both isomers (e.g., racemic mixtures, including 1:1 racemic mixtures) of compounds encompassed by the present invention.

[0119] In certain embodiments, the compound having Formula I or II has an enantiomeric purity for the (+) enantiomer of 55-100%, preferably 75-100%, more preferably 85-100%, more preferably 95-100%, and even more preferably 100%.

[0120] In certain preferred embodiments, the compound having Formula I or II is a substantially pure (+) enantiomer.

[0121] In one embodiment, when the compound is of Formula I, R3 is methyl and X is NCH3.

[0122] In one embodiment, when the compound is of Formula I or II, R3 is not methyl. In certain embodiments, R3 is a branched or straight chain alkyl or heteroalkyl group of 2, 3, 4, 5, 6, 7, or 8 carbons, or a substituted or unsubstituted aryl.

[0123] In another embodiment, when the compound is of Formula I or II, Y is C(H)R4 or X is O, S, or C(H)R4.

[0124] In another embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is NCH3. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is NCH3, R1 is a C1-C8 straight chain alkyl or benzyl, and R2 is hydrogen. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is NCH3, R1 is a substituted or unsubstituted phenyl, and R2 is hydrogen. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is NCH3, and R1 and R2 are independently methyl or ethyl.

[0125] In another embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is O. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is O, R1 is a C1-C8 straight chain alkyl or benzyl, and R2 is hydrogen. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is O, and R1 and R2 are independently methyl or ethyl. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is O, R1 is a substituted or unsubstituted phenyl, and R2 is hydrogen.

[0126] In another embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is S. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is S, R1 is a C1-C8 straight chain alkyl or benzyl, and R2 is hydrogen. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is S, and R1 and R2 are independently methyl or ethyl. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is S, R1 is a substituted or unsubstituted phenyl, and R2 is hydrogen.

[0127] In another embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, and Y is NR5. In one embodiment, when the compound has Formula I, R3 is methyl, X is NCH3, Y is NR5, and R5 is -CH2CH=CH2, -CH2CH2Ph, benzyl, or hydrogen.

[0128] In another embodiment, when the compound has Formula I, R3 is methyl, Y is NCH3, X is NCH3, and R4 is benzyl or hydrogen.

[0129] In another embodiment, when the compound is of Formula I, R3 is methyl, X is NCH3, Y is NR5, and each R4 and R5 is independently hydrogen or benzyl.

[0130] In another embodiment, when the compound is of Formula I, R3 is phenyl, X is NCH3, and Y is NCH3.

[0131] In another embodiment, when the compound is of Formula I, R3 is methyl, X is NCH3, and Y is not NH or NHCH2Ph.

[0132] In some embodiments, when the compound is of Formula I, R1 and R2 are independently hydrogen, substituted or unsubstituted aryl, R3 is a straight chain C1-C8 alkyl, X and Y are independently NR5, and R5 is independently hydrogen or a straight chain C1-C8.

[0133] In some embodiments, when the compound is of Formula I, R1 and R2 are independently hydrogen or unsubstituted aryl, R3 is a straight chain C1-C8 alkyl, X and Y are independently NR5, and R5 is independently hydrogen or a straight chain C1-C8.

[0134] In some embodiments, when the compound is of Formula I, R1 is hydrogen, R2 is unsubstituted aryl, R3 is methyl, X and Y are independently NR5, and R5 is independently hydrogen or methyl.

[0135] In certain preferred embodiments, when the compound is of Formula I, R1 is hydrogen, R2 is phenyl, R3 is methyl, X is NCH3, and Y is NCH3.

[0136] In another embodiment, when the compound is of Formula I, R1 is hydrogen, R2 is phenyl, R3 is methyl, X is NCH3, and Y is NH.

[0137] In certain preferred embodiments, when the compound is of Formula I, R1 is hydrogen, R2 is phenyl, R3 is methyl, X is NH, and Y is NCH3.

[0138] In certain preferred embodiments, when the compound is of Formula I, R1 is hydrogen, R2 is phenyl, R3 is methyl, X is NH, and Y is NH.

[0139] In another embodiment, when the compound is of Formula II, R3 is methyl, X is C(H)CH3, R6 is (CH2)2R7, and R7 is a substituted or unsubstituted amino group.

[0140] In certain preferred embodiments, when the compound is of Formula II, R3 is methyl, X is NCH3, R6 is (CH2)2R7, and R7 is a substituted or unsubstituted amino group.

[0141] In certain preferred embodiments, the compound having formula II is a substantially pure (+) enantiomer.

[0142] The present invention also relates to the use of compounds having formula (III):

[0143] [ka] wherein R1 and R2 are independently hydrogen, branched or straight chain C1-C8 alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R3 is branched or straight chain C1-C4 alkyl or heteroalkyl or C4-C8 alkyl or heteroalkyl, or substituted or unsubstituted aryl; X is NR5; and R5 is C 2~8 Alkenyl, C 2~8 alkynyl, or aralkyl, and Y is selected from C(H)R or NR, where R and R are independently hydrogen, branched or straight chain C(H)R. 1~8 It is alkyl or heteroalkyl, alkenyl, or C2-C8 alkynyl, aralkyl.

[0144] As depicted herein, the (-) enantiomer has R3 facing towards you relative to the plane of the page. Although only the (-) isomer is depicted to conserve space, in other embodiments, compounds having formula (III) can be all (+) isomers, (-) isomers, and mixtures of both isomers (e.g., racemic mixtures, including 1:1 racemic mixtures) of compounds encompassed by the present invention.

[0145] In certain preferred embodiments, the compound having formula (III) is a substantially pure (-) enantiomer.

[0146] In one embodiment, when the compound is of Formula (III), X is NR5 and R5 is aralkyl.

[0147] In one embodiment, when the compound is of Formula (III), X and Y are NR5 and R5 is aralkyl.

[0148] In one embodiment, when the compound has Formula (III), X is NR5, R5 is aralkyl, Y is NR5, and R5 is branched or linear C 1~8 It is alkyl or heteroalkyl.

[0149] In one embodiment, when the compound is of Formula (III), R1 is branched or straight chain C1-C8 alkyl, aralkyl, or aryl; R2 is hydrogen, branched or straight chain C1-C8 alkyl, substituted or unsubstituted aryl, or aralkyl; Y is NR5; R5 is aralkyl; X is NR5; and R5 is hydrogen, branched or straight chain C 1~8 It is alkyl or heteroalkyl.

[0150] In one embodiment, when the compound is of Formula (III), R1 is branched or straight chain C1-C8 alkyl, aralkyl, or aryl; R2 is hydrogen, branched or straight chain C1-C8 alkyl; Y is NR5; R5 is benzyl; X is NR5; R5 is hydrogen, branched or straight chain C 1~8 It is alkyl or heteroalkyl.

[0151] In one embodiment, when the compound is of formula (III), R1 is branched or straight chain C1-C8 alkyl, aralkyl, or aryl, R2 is hydrogen, branched or straight chain C1-C8 alkyl, Y is NR5, R5 is benzyl, X is NR5, and R5 is hydrogen.

[0152] In one embodiment, when the compound is of formula (III), R1 is para-halophenyl, Y is NCH3, X is NR5, R5 is alkyl or aralkyl, and when R5 is benzyl, R1 is not para-phenylbromophenyl.

[0153] In one embodiment, when the compound is of formula (III), R1 is para-isopropylphenyl, R2 is hydrogen, R3 is methyl, Y is NR5, R5 is benzyl, X is NR5, and R5 is hydrogen.

[0154] Included in the formulations of the present invention are all (+) isomers, (-) isomers, and mixtures of both isomers (e.g., 1:1 racemic mixtures) of the compounds of the present invention, unless such compounds are specifically excluded.

[0155] Throughout this specification, variables such as R1-R7, n, X and Y are the same variables as previously defined unless stated to the contrary.

[0156] The term "alkyl," as used herein, refers to a branched or unbranched saturated hydrocarbon group of 1 to 4, 1 to 8, or 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Examples of cycloalkyl groups include cyclopentyl and cyclohexyl.

[0157] The term "alkenyl," as used herein, refers to a hydrocarbon group of 2 to 4, 2 to 8, or 2 to 20 carbon atoms and a structural formula containing a carbon-carbon double bond.

[0158] The term "alkynyl," as used herein, refers to a hydrocarbon group of 2 to 4, 2 to 8, or 2 to 20 carbon atoms and a structural formula containing a carbon-carbon triple bond.

[0159] The term "aryl" is defined as any carbon-based aromatic group, including, but not limited to, phenyl, benzene, naphthalene, anthracene, phenanthrene, pyrene, and benzo[a]pyrene.

[0160] The term "substituted aryl" is defined as an aryl group having at least one group attached to the aryl group that is not hydrogen. Examples of groups that can be attached to the aryl group include, but are not limited to, alkyl, alkynyl, alkenyl, aryl, heterocycle, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, alkoxy, cyano, alkoxy, thioalkyl, haloalkyl, hydroxyalkyl, alkylamino, diakylamino, or acyl. In various embodiments, a substituent is attached to carbon 2, 3, 4, 5, or 6 of one of these moieties. Examples of alkoxy substituents include, but are not limited to, methoxy, ethoxy, and isopropoxy groups. Examples of acyl substituents include acetyl and benzoyl groups.

[0161] The term "aralkyl" is defined as an aryl group having an alkyl, alkynyl, or alkenyl group attached to the aryl group. An example of an aralkyl group is the benzyl group.

[0162] The term "heteroaryl" is defined as an aryl group having at least one heteroatom such as nitrogen, sulfur, or oxygen incorporated into the ring of the aryl group.

[0163] The term "heteroalkyl" is defined as an alkyl group having at least one heteroatom, such as nitrogen, sulfur, oxygen, or phosphate, incorporated within or attached to the alkyl group.

[0164] The compounds described herein can form salts with acids or bases, and such salts are included in the present invention. In one embodiment, the salts are pharmaceutically acceptable salts. The term "salt" encompasses addition salts of free acids or free bases that are compounds of the present invention. The term "pharmaceutically acceptable salts" refers to salts that have toxicity profiles within a range that is useful for pharmaceutical use. Nevertheless, pharmaceutically unacceptable salts may have properties such as high crystallinity and are useful in the practice of the present invention, for example, in the synthesis, purification, or formulation process of the compounds of the present invention.

[0165] Examples of pharmaceutically acceptable salts of Buntanetap include acid addition salts prepared from suitable acids, such as hydrobromic acid, hydrochloric acid, hydroiodic acid, sulfuric acid, carbonic acid, nitric acid, phosphoric acid, tetrafluoroboronic acid, perchloric acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, acetic acid, phenylacetic acid, propionic acid, The pharmaceutically acceptable salt may be formic acid, succinic acid, glycolic acid, gluconic acid, malic acid, lactic acid, tartaric acid, citric acid, glucuronic acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, 4-hydroxybenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, mandelic acid, pamoic acid, pantothenic acid, sulfanilic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid. Preferably, the pharmaceutically acceptable salt is buntanetap tartrate, i.e., an acid addition salt of tartaric acid.

[0166] Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal, alkaline earth metal, and transition metal salts, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts formed from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. All of these salts can be prepared from the corresponding compounds, for example, by reacting with an appropriate acid or base.

[0167] Administration and Dosage In the methods of the present invention, buntanetap, its analogs, metabolites, or pharmaceutically acceptable salts thereof (with or without antipsychotics, antidepressants, hallucinogens, or any combination thereof) can be administered parenterally or enterally. Examples of routes of administration for buntanetap, or its analogs, metabolites (and antipsychotics, antidepressants, hallucinogens, or any combination thereof) or pharmaceutically acceptable salts thereof include intravenous, intraocular, intramuscular, subcutaneous, topical, oral, sublingual, and buccal. Preferably, for purposes of the present invention, buntanetap (with or without one of antipsychotics, antidepressants, hallucinogens, or any combination thereof) is administered orally.

[0168] In the present invention, buntanetap or a pharmaceutically acceptable salt thereof can be administered once, twice, three times, or four times daily. Buntanetap is preferably administered once daily. Depending on the route of administration, buntanetap is administered in different dosage ranges.

[0169] In certain embodiments, (buntanetap) is orally administered in an amount of about 1 mg to about 120 mg, preferably on a once-daily basis. In certain preferred embodiments, buntanetap is administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47 mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg , 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99 The dose ranges from about 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, and all integers between these values ​​and up to about 120 mg. In certain preferred embodiments, buntanetap is administered orally at a dose of about 10 mg to about 80 mg. In other embodiments, buntanetap is administered intravenously at a dose of about 0.1 to about 25 mg per day. In other preferred embodiments, buntanetap is administered intraperitoneally / intramuscularly (IP / IM) at a dose of about 0.3 to about 70 mg per day.

[0170] Doses for humans that are believed to be effective and safe are listed below in Table 1 for oral, IP / IM, and IV routes of administration.

[0171] [Table 1]

[0172] In certain embodiments of each of the methods of the present invention described above, the oral pharmaceutical composition contains about 1 mg to about 120 mg of buntanetap or a pharmaceutically acceptable salt thereof, the IP / IM pharmaceutical composition contains about 0.3 to about 70 mg of buntanetap or a pharmaceutically acceptable salt thereof, and the intravenous (IV) pharmaceutical formulation contains about 0.1 to about 25 mg of buntanetap or a pharmaceutically acceptable salt thereof.

[0173] Generally, a preferred dose of buntanetap to administer to an animal or human patient is a tolerated dose, i.e., a dose that does not cause adverse side effects in most human patients, and which is also effective for the prophylactic treatment of healthy humans, e.g., with respect to neurodegenerative diseases, cancer, cardiovascular homeostasis, diseases or conditions of vital organs, cardiovascular disease, etc.

[0174] In certain preferred embodiments of the methods described herein, peak plasma circulating levels of buntanetap in humans range, for example, from about 1 ng / mL to about 380 ng / mL, in certain embodiments, from about 2 ng / mL to about 20 ng / mL, and more preferably from about 3.7 ng / mL to about 120 ng / mL. In certain preferred embodiments, peak plasma circulating levels are reached within about 6 hours after administration of buntanetap to humans. In certain embodiments, peak plasma circulating levels are reached within about 3 hours after administration of buntanetap to humans. In certain embodiments, the plasma circulating level of buntanetap is greater than or equal to about 0.1 ng / mL, 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL, 5 ng / mL, 6 ng / mL, 7 ng / mL, 8 ng / mL, 9 ng / mL, 10 ng / mL, 11 ng / mL, 12 ng / mL, 13 ng / mL, 14 ng / mL, 15 ng / mL, 16 ng / mL, 17 ng / mL, 18 ng / mL, 19 ng / mL, or 20 ng / mL for at least 9 hours, preferably at least 12 hours, after administration of buntanetap to a human. In certain embodiments, the steady-state plasma concentration of buntanetap in the brain is at least about 0.01, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 , 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, or 130 ng / mL, and values ​​between these values.In certain embodiments, the half-life of buntanetap in cerebrospinal fluid after administration is about 12 hours, and the half-life of buntanetap in plasma after administration is about 5 hours. In certain embodiments, administration of buntanetap to humans results in brain levels of buntanetap that are in the range of about 4 to about 10 times the plasma levels of buntanetap in these patients. In certain embodiments, the concentration of buntanetap in the human brain is about 8 ng / g to about 3040 ng / g, and in certain embodiments, about 30 ng / g to about 960 ng / g.

[0175] Table 2 shows plasma levels calculated and extrapolated from animals (mouse data) and brain levels to humans.

[0176] [Table 2]

[0177] Therapeutic agents used as buntanetap-type drugs are preferably administered in therapeutically effective amounts known to those skilled in the art. In certain embodiments, a therapeutically effective amount is an amount that produces a maximum therapeutic effect. In other embodiments, a therapeutically effective amount produces a therapeutic effect that is less than the maximum therapeutic effect. For example, a therapeutically effective amount may be an amount that produces a therapeutic effect while avoiding one or more side effects associated with the dose that produces the maximum therapeutic effect. Those skilled in the clinical and pharmacological fields can determine a therapeutically effective amount through routine experimentation, i.e., by monitoring the subject's response to administration of the drug and adjusting the dosage accordingly. In certain embodiments, buntanetap-type drugs are preferably administered via an appropriate administration route (e.g., oral, subcutaneous, intravenous, intramuscular).

[0178] Pharmaceutical Compositions and Therapies Administration of the compounds useful within the present invention can be achieved in several different ways, using methods known in the art. Thus, the therapeutic and prophylactic methods of the present invention encompass the use of pharmaceutical compositions containing the compounds useful within the present invention to practice the methods of the present invention.

[0179] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in the pharmaceutical compositions of the present invention will vary depending on the identity, size, and condition of the subject being treated, as well as the route by which the composition is administered. For example, the composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0180] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to result in compositions suitable for administration to a variety of animals are well understood, and an ordinarily skilled veterinary pharmacologist can design and implement such modifications with no more than routine experimentation, if any. Subjects contemplated for administration of the pharmaceutical compositions of the present invention include, but are not limited to, mammals, including humans and other primates, non-human primates, commercially relevant mammals such as cows, pigs, horses, sheep, cats, and dogs.

[0181] Typically, the dosage of buntanetap administered to an animal, preferably a human, in the methods of the present invention ranges from 0.5 μg to about 50 mg per kilogram of animal body weight. While the exact dosage administered will vary depending on any number of factors, including, but not limited to, the type of animal and disease state being treated, the animal's age, and the route of administration, the dosage of the compound preferably ranges from about 1 μg to about 10 mg per kilogram of animal body weight. More preferably, the dosage ranges from about 3 μg to about 30 mg per kilogram of animal body weight.

[0182] Pharmaceutical compositions useful in the methods of the invention may be prepared, packaged, or sold in a formulation suitable for oral, parenteral, topical, buccal, or another route of administration. Other contemplated formulations include engineered nanoparticles, liposomal preparations, resealed red blood cells containing the active ingredient, and immune system formulations.

[0183] The pharmaceutical compositions of the present invention can be prepared, packaged, or sold in bulk, for example, as a single unit dose of buntanetap and (optionally) additional drugs, such as antipsychotics, antidepressants, hallucinogens, or any combination thereof, or as multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient administered to a subject, or a convenient fraction of such a dosage, such as, for example, half or one-third of such a dosage.

[0184] The compositions of the present invention may consist solely of the active ingredient in a form suitable for administration to a (human) subject or patient, or the compositions may comprise at least one active ingredient and one or more pharmaceutically acceptable excipients.

[0185] In one embodiment, the compositions of the present invention are formulated using one or more pharmaceutically acceptable carriers.Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions, such as phosphates and organic acid salts.Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), a suitable mixture thereof, and vegetable oil.

[0186] The formulations can be utilized in admixture with conventional additives, i.e., pharmaceutically acceptable organic or inorganic carrier substances, suitable for oral, vaginal, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. Pharmaceutical preparations can be sterilized and, if desired, adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic buffers, coloring agents, flavoring and / or aromatic substances, etc. These can also be combined with other active agents, if desired.

[0187] As used herein, "additional ingredients" includes, but is not limited to, one or more of the following: additives; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binders; lubricants; sweeteners; flavoring agents; coloring agents; preservatives; physiologically degradable compositions, such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifiers; antioxidants; antibiotics; antifungal agents; stabilizers; and pharmaceutically acceptable polymeric or hydrophobic substances. Other "additional ingredients" that can be included in the pharmaceutical compositions of the present invention are known in the art and are described, for example, in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

[0188] The compositions of the present invention may contain a preservative at about 0.005% to 2.0% by weight of the total composition. Preservatives are used to prevent spoilage when exposed to environmental contaminants. Examples of preservatives useful in accordance with the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea, and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

[0189] The compositions may contain antioxidants and chelating agents that inhibit compound degradation. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol, and ascorbic acid in a preferred range of about 0.01% to 0.3%, more preferably BHT in a range of 0.03% to 0.1% by weight based on the total weight of the composition. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight based on the total weight of the composition. Particularly preferred chelating agents include edetate (e.g., disodium edetate) and citric acid in a weight range of about 0.01% to 0.20%, more preferably in a range of 0.02% to 0.10% by weight based on the total weight of the composition. Chelating agents are useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, for some compounds, although other suitable and equivalent antioxidants and chelating agents may be substituted as known to those skilled in the art.

[0190] Liquid suspensions can be prepared using conventional methods to suspend active ingredients in aqueous or oily vehicles.Aqueous vehicles include, for example, water and isotonic saline.Oil vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, refined vegetable oils, and mineral oils such as liquid paraffin.Liquid suspensions may further contain one or more additional ingredients, including but not limited to, suspending agents, dispersing agents, or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavoring agents, coloring agents, and sweeteners.Oil suspensions may further contain thickening agents.Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, tragacanth gum, gum arabic, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, and hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally occurring phosphatides, such as lecithin, condensation products of alkylene oxides with fatty acids, condensation products of long-chain fatty alcohols, condensation products of fatty acids with partial esters derived from hexitols, or condensation products of fatty acids with partial esters derived from hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0191] Liquid solutions of active ingredients in aqueous or oily solvents can be prepared in essentially the same way as liquid suspensions, with the main difference being that the active ingredient is dissolved in the solvent rather than suspended. As used herein, "oily" liquids are those that contain carbon-containing liquid molecules and exhibit less polarity than water. Liquid solutions of the pharmaceutical compositions of the present invention may contain each of the components described for liquid suspending agents, and it is understood that the suspending agent does not necessarily aid in the dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0192] The powder or granular preparation of the pharmaceutical preparation of the present invention can be prepared by known methods.This preparation is directly administered to the subject, for example, by forming tablets, filling into capsules, or by adding aqueous or oily vehicles to prepare aqueous or oily suspension or solution.Each of these preparations can further comprise one or more of dispersing or wetting agents, suspending agents, and preservatives.Additional additives such as fillers and sweeteners, flavoring agents, or coloring agents can also be included in these preparations.

[0193] The controlled release or sustained release formulation of the composition of the present invention can be prepared by using conventional technology in addition to the disclosure described elsewhere herein.In some cases, the dosage form used can be provided as a slow release or controlled release of one or more active ingredients thereof, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, or microspheres or their combinations, to provide desired release profiles at various rates.Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use with the composition of the present invention.

[0194] The controlled release of an active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled release ingredient" in the context of the present invention is defined herein as one or more compounds that facilitate the controlled release of an active ingredient, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, nanoparticles, or microspheres, or combinations thereof.

[0195] Routes of administration of any of the compositions of the present invention include oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., intravaginal and perivaginal), (intravaginal) nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0196] Particularly suitable for oral administration are tablets, dragees, liquids, drops, capsules, caplets, and gel caps. Other formulations suitable for oral administration include, but are not limited to, powdered or granular preparations, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, dentifrices, mouthwashes, coatings, oral rinses, or emulsions. Compositions intended for oral use can be prepared by any method known in the art, and such compositions may contain one or more inert, non-toxic pharmaceutical additives. Such additives include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricants such as magnesium stearate. The oral compositions of the present invention in the form of tablets or capsules are prepared by conventional methods and contain pharmaceutically acceptable additives such as binding agents, fillers, lubricants, disintegrants, or wetting agents.

[0197] Tablets can be uncoated, or can be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of the subject, thereby resulting in sustained release and absorption of active ingredients.For example, tablets can be coated using materials such as glyceryl monostearate or glyceryl distearate.For another example, tablets can be coated using the methods described in U.S. Patent No. 4,256,108; U.S. Patent No. 4,160,452; and U.S. Patent No. 4,265,874 to form osmotically controlled release tablets.Tablets can further comprise sweeteners, flavoring agents, coloring agents, preservatives, or some combination thereof, to provide pharmaceutically elegant and tasty preparations. For oral administration, tablets may optionally be coated using suitable methods and coating materials such as OPADRY® film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY® OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type, and OPADRY® White, 32K18400).

[0198] Hard capsules containing active ingredients can be made using physiologically degradable compositions such as gelatin.Such hard capsules contain active ingredients and can further contain additional ingredients, including inert solid diluents such as calcium carbonate, calcium phosphate, or kaolin.Soft gelatin capsules containing active ingredients can be made using physiologically degradable compositions such as gelatin.Such soft capsules contain active ingredients and can be mixed with water or oily medium such as peanut oil, liquid paraffin, or olive oil.

[0199] The liquid preparation for oral administration can be in the form of solution, syrup or suspension.Liquid preparation can be prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (for example, sorbitol syrup, methylcellulose or hydrogenated edible fat); emulsifiers (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters or ethyl alcohol); and preservatives (for example, methyl or propyl para-hydroxybenzoate or sorbic acid).The liquid preparation of the pharmaceutical composition of the present invention suitable for oral administration can be prepared, packaged and sold either in liquid form or in the form of a dry product, which is intended to be reconstituted with water or another suitable vehicle before use.

[0200] Tablets containing an active ingredient can be made, for example, by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form, such as a powdered or granular preparation, optionally with one or more binders, lubricants, additives, surfactants, and dispersants. Molded tablets can be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable additives used in tablet manufacture include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricants. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surfactants include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pregelatinized corn starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

[0201] As used herein, "parenteral administration" of a pharmaceutical composition includes any administration route characterized by physical penetration of the target tissue, and administration of the pharmaceutical composition through the penetration in the tissue. Thus, parenteral administration includes, but is not limited to, administration of the pharmaceutical composition by injection of the composition, application of the composition through a surgical incision, application of the composition through a non-surgical wound passing through the tissue, etc. In particular, parenteral administration is intended to include, but is not limited to, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, intratumoral, and kidney dialysis infusion techniques.

[0202] Pharmaceutical compositions suitable for parenteral administration include the active ingredient in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage forms, such as ampoules, or in multidose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients, including, but not limited to, suspending agents, stabilizers, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powdered or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0203] The pharmaceutical composition of the present invention can be prepared, packaged or sold in a formulation suitable for topical administration.There are several advantages to delivering compounds, including drugs or other therapeutic agents, to the skin (dermal drug delivery) or through the skin to the body (transdermal drug delivery).Transdermal compound delivery often provides an attractive alternative to injections and oral medications.

[0204] Additional dosage forms of the present invention include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837 and 5,007,790. Additional dosage forms of the present invention also include those described in U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Further dosage forms of the present invention also include those described in PCT Publication Nos. WO 03 / 35041, WO 03 / 35040, WO 03 / 35029, WO 03 / 35177, WO 03 / 35039, WO 02 / 96404, WO 02 / 32416, WO 01 / 97783, WO 01 / 56544, WO 01 / 32217, WO 98 / 55107, WO 98 / 11879, WO 97 / 47285, WO 93 / 18755, and WO 90 / 11757.

[0205] Whenever values ​​and ranges are provided herein, it should be understood that all values ​​and ranges encompassed within those values ​​and ranges are meant to be encompassed within the scope of the invention. Moreover, all values ​​that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated in this application.

[0206] Detailed Description of the Preferred Embodiments The following examples further illustrate aspects of the present invention, which are provided for illustrative purposes only, and the invention is not limited to these examples, but rather encompasses all variations that become apparent as a result of the teachings provided herein. [Example]

[0207] [Example 1] Three Phase I clinical trials established the safety of Buntanetap. Pharmacokinetic analysis showed that the lipophilic small molecule readily enters the brain, where its concentration is approximately eight times higher than in plasma. Importantly, Buntanetap normalized APP, tau, and α-SYN levels in the cerebrospinal fluid (CSF) of MCI subjects at a dose of 4 × 60 mg / day. Buntanetap had a half-life of more than 12 hours in the CSF of MCI subjects, and its effect in reducing these neurotoxic proteins and inflammation extended throughout the 12-hour sampling period after the final dose (Maccecchini, et al., "Buntanetap (buntanetap) as a Candidate Drug to Lower CSF Amyloid Precursor Protein, Amyloid-β Peptide, and τ Levels: Target Engagement, Tolerability, and Pharmacokinetics in Humans," J. Neurosurg. Psychiatry 2012; 83:894-902). Therefore, we conclude that a single daily dose of buntanetap would be effective in the proposed study. Indeed, a significantly lower dose was tested in a Phase 2 Alzheimer's / Parkinson's dual trial conducted and completed in 2021 (active IND #72,654). The Phase 2 dual trial enrolled 14 AD (Alzheimer's disease) and 54 patients, with more than 25 treated with a once-daily dose of buntanetap. The 14 AD patients received either 80 mg QD or placebo, and the 54 PD (Parkinson's disease) patients received 5, 10, 20, 40, or 80 mg QD or placebo. In short, the data show that in patients with AD and PD, Buntanetap (a) crosses the blood-brain barrier, (b) reduces neurotoxic protein biomarkers, (c) reduces inflammatory markers, and (d) improves axonal and synaptic function, and most importantly, improved affected function in both patient populations. In AD patients, Buntanetap improved cognition as measured by ADAS-Cog11 and WAIS coding speed (achieving statistical significance vs. baseline at the 80 mg dose, but not placebo).In PD patients, Buntanetap improved motor function as measured by the MDS-UPDRS (parts II, III, IV, and overall) at all doses, with maximal improvement at 10 and 20 mg, and improved WAIS speed and accuracy (achieving statistical significance vs. placebo in the 5 mg, 20 mg, and 80 mg dose arms [p<0.05] in the broader study population [n=54], with statistically significant improvements reported across all doses [p<0.001]). Data demonstrate potential benefits of reducing the overexpression of neurotoxic aggregation proteins in inflammation, axonal and synaptic function, and cognitive and functional health. We anticipate that larger sample sizes will enable Buntanetap to fully demonstrate statistically significant cognitive and functional improvements attributable to normalization of toxic protein levels in ongoing Phase 3 Parkinson's and Phase 2 / 3 Alzheimer's trials.

[0208] The effect of Buntanetap on neurotoxic proteins: The drug reduces APP levels in neuroblastoma cells in vitro (Mikillineni et al: Parkinson's Disease; Volume 2012, Article ID 142372, 13 pages. The Anticholinesterase Phenserine and Its Enantiomer Buntanetap as 5' Untranslated-Region-Directed Translation Blockers of the Parkinson's Alpha Synuclein Expression). It also reduces the levels of APP and its fragments in APP / PS1 transgenic mice (AF Teich, et al., Alzheimer's & Dementia: Translational Research & Clinical Interventions 4 (2018) 37-45).

[0209] Buntanetap also reduces tau in vitro (Peter Davies Laboratory, Hofstra University, unpublished observations) and reduces human tau in vivo in mice (Peter Davies Laboratory, Hofstra University, unpublished observations). Buntanetap also reduces α-syn in neuroblastoma cells in vitro and in the brain and gastrointestinal tract of transgenic Parkinson's mice in vivo (Kuo et. al. Am J Neurodegener Dis 2019;8(1):1-15 www.AJND.us / ISSN:216 591X / AJND0086080: Translational inhibition of α-synuclein by Buntanetap (buntanetap) normalizes distal colon motility in transgenic Parkinson's mice).

[0210] Reversal of the neurotoxic cascade by buntanetap: The mechanism of action of buntanetap involves RP1- and iron-regulated expression of APP, tau, and αSYN, and how these proteins contribute to neurodegeneration by accumulating as toxic aggregates that impair axonal transport and synaptic transmission, leading to inflammation and ultimately to neuronal death (as previously described). By reducing APP, tau, and αSYN levels, buntanetap treatment prevented this toxic cascade. In support of this hypothesis, we show that buntanetap normalizes anterograde and retrograde vesicle transport in fully differentiated Down syndrome neurons [W. Mobley; USCD]; normalizes synaptic transmission deficits in the rat striatum after traumatic brain injury (TBI) [M.F. Chesselet; UCLA] and the hippocampus of APP / PS1 tg mice; reduces inflammation in human CSF of MCI subjects and in rat brain after TBI; and protects neurons in the rat substantia nigra after TBI and in a rat acute glaucoma model (J. Sundstrom; Hershey Medical School).

[0211] The AD field has largely focused on preventing APP processing or clearing Aβ in one of its many forms. These are downstream targets, and because buntanetap prevents the translational synthesis of APP and tau, two key proteins involved in AD, it should eliminate all downstream consequences of these proteins. Similarly, the PD field has mostly focused on inhibiting the accumulation of αSYN aggregates and the action of other proteins in this pathway, including LRRK or Parkin. Again, buntanetap prevents the synthesis of αSYN, thus halting the pathological cascade at the first step. Our data show that by normalizing APP / Aβ, tau / phosphotau, and αSYN levels, buntanetap normalizes axonal transport, reduces inflammation, and protects neurons from death (Mobley 2020, submitted for publication; Chesselet 2020, submitted for publication).

[0212] [Example 2] Figure 1. APP in vitro. Buntanetap reduces APP in SH-SY-5Y human neuroblastoma cells in a dose-dependent manner. On the left is a Western blot showing Buntanetap inhibition of APP relative to actin control at concentrations of 0, 0.1, 1, 5, and 10 μM, as well as a graph showing the same data plotted for statistical analysis.

[0213] Figure 2. APP in vivo. This study was conducted to demonstrate the effect of buntanetap in inhibiting the translation of APP and its fragments in an in vivo AD model. The table in Figure 2 shows that buntanetap treatment of APP / PS1 transgenic AD mice reduced APP and its fragments in the hippocampus. GAPDH and synaptophysin were loading controls. Figure 2 also includes a set of graphs showing the relative density of APP plotted against control and time after buntanetap treatment; the relative density of CTFβ plotted against control and time after buntanetap treatment; the relative density of CTFα plotted against control and time after buntanetap treatment; Aβ42 levels in brain tissue plotted against control and time after buntanetap treatment; and Aβ40 levels in brain tissue plotted against control and time after buntanetap treatment. Finally, Figure 2 also includes Western blots showing the levels of APP, NSB, CTFβ, and CTFα after buntanetap treatment over time (minutes). In APP / PS1 mice expressing a human mutation associated with familial AD, data show that buntanetap treatment reduced APP and all related peptides in the hippocampus for at least 9 hours after the final dose.

[0214] [Example 3] Figure 3 shows an initial proof-of-mechanism (POM) study of subjects with mild cognitive impairment (MCI) using a well-tolerated dose of buntanetap. Before and 10 days after administration of buntanetap to MCI subjects, plasma and cerebrospinal fluid (CSF) samples were collected for analysis of secreted APPα and APPβ, as well as Aβ42, tau (total and phosphorylated), and inflammatory marker levels. Figure 3 shows a reduction in APP / Aβ, tau / phospho-tau, and αSYN in the spinal fluid of patients with mild cognitive impairment. In this study, buntanetap normalized these aggregating proteins in the CSF of MCI subjects, consistent with data observed in animals.

[0215] [Example 4] Table 3 below provides useful doses for humans and mice. Doses are provided in mg / kg; mg dose for a 70 kg human; mouse and human plasma levels (ng / mL); human plasma levels (nM); mouse and human brain levels (ng / gram); oral human effective and safe dose (mg / day); IP / IP human effective and safe dose (mg / day); and IV human effective and safe dose (mg / day). Effective IP / IM dosing is believed to be in the middle of these ranges (e.g., approximately 60 mg / day based on an oral dose; approximately 35 mg / day based on an IP / IP human dose; and approximately 12.5 mg / day based on an IV dose). At approximately 120 mg / day to 200 mg / day, buntanap becomes toxic. A dose of 1 nM buntanap was found to be effective, as were (extrapolated) plasma levels of approximately 10 to approximately 10,000 nM in tissue culture.

[0216] [Table 3]

[0217] [Example 5] Neurodegeneration is an axonal transport disorder Example 5 demonstrates that disruption of axonal transport is implicated in human neurological conditions (Nature Review, September 2019). Axonal transport is responsible for several human neurological conditions, including, but not limited to, the neurotransmitters GABA (anxiety), Ach (cognition), dopamine (movement), and serotonin (mood); neurotrophic factors (NGF, BDBF); and all communication within and between neurons. Therefore, chronic and acute brain injury leads to high levels of neurotoxic proteins, impaired axonal transport, inflammation, and neurodegeneration. Butanetap simultaneously inhibits the production of multiple neurotoxic proteins.

[0218] Figure 4 shows normal axonal transport (retrograde 0.5 frames per second), demonstrating normal flow and velocity of vesicles carrying D+BDNF across the axon. Figure 5 demonstrates abnormal transport by showing blockage and slowing of BDNF across the axon. Black areas indicate slowed transport due to high levels of neurotoxic proteins. Finally, Figure 6 shows axonal transport with treatment with butanatap. APP, Ab42, C99 - Mobley, UCSD; αSYN - Isacson, Harvard; Lee, U. Penn; Tau - U. Muenich & Zuerich; Htt - Mobley, UCSD; TDP43 - Taylor, Northwestern. As can be easily seen in Figure 6, butanatap improves the flow and velocity of axonal transport (Chen XQ et al. Alzheimer's & Dementia 08 / 2020). On the other hand, high levels of neurotoxic proteins have been shown to lead to impaired axonal transport, slowed synaptic transmission, inflammation and neuronal death, and loss of cognitive and motor function. In a traumatic brain injury model, buntanetap improves dopaminergic neuropathology and working memory, and protects neurons from death in the eyes of glaucoma-affected rats. By reducing the levels of neurotoxic proteins, buntanetap improves axonal transport, increases synaptic transmission, reduces or eliminates inflammation, provides healthy neurons, and prevents the toxic cascade.

[0219] In Example 5, studies in eight animal and human models showed the following:

[0220] [Table 4]

[0221] [Example 6] AD (Alzheimer's disease) and DS (Down's syndrome) share several characteristic symptoms. DS results from trisomy of all or part of chromosome 21, which contains approximately 233 protein-coding genes, including APP. Recent evidence points to a regulatory role for dysregulation of the endosomal / lysosomal system and increased expression of the gene for APP and its 99 amino acid C-terminal fragment (C99, also known as β-CTF).

[0222] The latter is important for normal cellular function and, in neurons, for the transmission of neurotrophic signals. Chen X, et al., DOI 10.1002 / alz.12185, J. Alzeimer's & Dementia (2020), reported that reducing the levels of fl-APP protein and its products in models of DS prevents or reduces endosomal dysfunction and acts to restore trophic signaling. We begin by detailing our studies on buntanetap. buntanetap negatively regulates APP translation. 53,58 The proposed mechanism of action of buntanetap supports the regulatory role of iron in APP expression. The APP 5'-UTR contains an iron-responsive element (IRE) stem-loop that mediates translational control of APP expression. 60 The IRE is a 30-nucleotide RNA motif containing the classic 5'-CAGUGX-3' (X = U, C, or A) sequence. The APP IRE, containing a 5'-CAGAGC motif, shares homology with the canonical IRE RNA stem-loop, which binds to iron regulatory proteins (IRP1 and IRP2) and controls iron-dependent translation. 61,62 Among these, IRP1, but not IRP2, binds to the APP IRE. 63 IRP binding to the IRE prevents the release of messenger RNA (mRNA) and its subsequent association with ribosomes, thereby inhibiting translation. In the presence of high cellular iron levels, iron binds to the IRP and induces a conformational change, leading to the dissociation of IRP1 from the APP mRNA and thereby promoting translation. 62,64 Examination of the 5'-UTR IRE stem-loop in the mRNA of SNCA, which encodes α-synuclein, supports the Buntaneta-peptide model, in which compounds increase the affinity of the IRP for the IRE, resulting in reduced translation of APP mRNA. 54 Buntaneta-peptide treatment results in reduced levels of fl-APP and its products.

[0223] In this study, the 5'-UTR of App mRNA was amplified from the brains of both 2N and Ts65Dn mice and aligned with the corresponding sequences of mouse and human APP mRNA from the National Center for Biotechnology Information Entrez database. The predicted IRE sequences and conserved CAGAGC loop from 2N and Ts65Dn mice were identical to the mouse sequences in the database (Supplementary Figure S1), providing a theoretical basis for manipulating APP expression with buntanetap in Ts65Dn mice. The authors' hypothesis is that normalizing fl-APP and its products in DS using buntanetap would also normalize the structure and function of early endosomes, resulting in the phenotypic decline associated with AD-DS. This was addressed through testing buntanetap in a DS mouse model. However, the authors showed that buntanetap rescued the deficit in retrograde axonal transport of BDNF in cortical neurons. (A) Experimental design. Primary cultures of 2N and Ts65Dn cortical neurons were treated with buntanetap (5 μM) for 48 hours at day 5, followed by live imaging. Primary cultures of N and Ts65Dn neurons were maintained in microfluidic chambers, where neuronal axon terminals were fluidically isolated. A second series of studies was initiated, testing aged Ts65Dn mice with 50 mg / kg / d i.p. during an additional 5-day behavioral study to investigate the effects at 3 weeks and 16 months, at which age dysfunction and degeneration occur from neuronal cell bodies. QD-BDNF was added to the axonal chamber in preparation for tracking axonal transport of BDNF by live cell imaging. In vitro, treatment of Ts65Dn mice with buntanetap significantly reduced fl-APP. Two bands were detected and quantified together. No statistically significant differences were detected compared with Ts65Dn and 2N, or with vehicle, with Buntanetab treatment, although there was a clear decrease in the intensity of the high band with Buntanetab. This change was not evident in vitro, and cannot be explained, but may reflect differences in the levels of phosphorylated tau species.Consistent with this suggestion, the authors found that buntanetap reduced tau phosphorylation in Ts65Dn mice, as assessed by immunoblotting for tau phosphorylation at Thr231 and PHF1 epitopes, and that buntanetap-mediated normalization of fl-APP and its products restored normal Rab5 activity in vivo. The authors also determined that buntanetap treatment restored levels of pTrkB, pAkt, pERK, and pCREB in Ts65EN brains.

[0224] [Example 7] Mice were subjected to the marble-burying test described by Broekkamp et al. (Eur. J. Pharmacol., 126, 223-229, 1986). This test is based on the premise that mice exposed to novel objects (i.e., marbles) will bury them in sawdust bedding. Reduction of obsessive-compulsive behavior was evidenced by a decrease in the number of marbles buried by mice after treatment with the treatment agent compared to placebo. This test is sensitive to clinically used antidepressants and anxiolytics, such as benzodiazepines, SSRIs, and 5-HT1A compounds.

[0225] Mice were placed individually into a testing arena (32 × 21 cm) containing 25 black glass marbles evenly distributed in five rows on the floor for a 30-minute testing session. The testing protocol and groups used are shown in Table A.

[0226] [Table 5]

[0227] Buntanetap was the treatment agent. Saline did not contain any treatment agent and was used as a control. The study was validated using clobazam, a treatment agent with confirmed anti-obsessive-compulsive activity.

[0228] A summary of the number of sawdust-covered marbles for each group is shown in Figure 7.

[0229] Based on the results of the study, it was concluded that compared to saline, buntanetap reduced obsessive-compulsive behavior by 20-60%, confirming the anti-compulsive effectiveness of buntanetap.

[0230] [Example 8] Mice were subjected to several elevated plus maze tests as described by Handley and Mithani (Naunyn. Schmied. Arch. Pharmacol., 327, 1-5, 1984). This test is based on the premise that mice avoid open spaces (open arms of the elevated plus maze). Anxiolytics increase exploratory activity in the open arms, as indicated by an increase in the time spent in the open arms and / or an increase in the percentage of open arm entries.

[0231] The maze consisted of four arms (14 x 5 cm) of equal length and width arranged in the shape of a cross (+). Two opposing arms were enclosed by 12 cm high walls (closed arms). The other two arms had no walls (open arms). The maze was elevated approximately 60 cm above the floor. Mice were placed in the center of the plus maze and allowed to explore for 5 minutes. The test protocol and groups used for one test are shown in Table B.

[0232] [Table 6]

[0233] Buntanetap was the treatment agent. Saline did not contain any treatment agent and was used as a control. The test was validated using clobazam, a treatment agent with confirmed anxiolytic activity.

[0234] A summary of the test results is shown in Figures 8A-8E. Mice administered buntanetap entered the high open arms of the maze more frequently, stayed there longer, and traveled greater distances.

[0235] Based on the results of the test, it was concluded that compared to saline, Buntaneta Pap reduced anxiety associated with being in an elevated maze by 40-80%, confirming Buntaneta Pap's effectiveness in eliminating anxiety.

[0236] [Example 9] The sensory perception of electric foot shock was investigated in different groups of mice through a threshold assessment test. APP / PS1 mice (i.e., heterozygous double transgenic mice expressing both human APP (K670N:M671L) and human PS1 (M146L)) and WT mice (i.e., wild-type, normal healthy mice without defects) were used.

[0237] Animals were placed in the conditioning chamber, and the current (0.1 mA per second) was increased from 0.1 mA to 0.7 mA at 30-second intervals. Thresholds for flinching (the first visible response to the shock), jumping (the first extreme motor response), and vocalization were quantified for each animal by averaging the shock intensities at which each animal exhibited a behavioral response to the shock type. This test is based on the premise that if the combined treatment does not affect the animal's sensory threshold, no differences in threshold assessments should be found within different groups of mice.

[0238] Fear conditioning (FC) training was then performed. Mice were placed in the conditioning chamber for 2 min before the onset of a tone (conditioned stimulus (CS), 30 s, 2800 Hz, 85 dB). 2 s after the end of the CS, mice received a 2 s, 0.7 mA mild foot shock (unconditioned stimulus (US)) delivered through the floor bars. After the US, mice were left in the chamber for an additional 30 s. Freezing behavior, defined as the absence of movement except for behaviors required for breathing, was scored using Freezeview software (Med Associates, St. Albans, VT). Contextual fear learning, a type of memory that requires hippocampal function, was assessed 24 h after training by measuring freezing responses for 5 min in the same chamber in which mice were trained. Cued fear learning, a type of memory that depends on amygdala function, was assessed 24 h after contextual testing. Mice were placed in a novel context for 2 min (pre-CS test), followed by a 3 min CS (CS test). Freezing behavior was measured during the first 30 s, mimicking CS-US conditioning, and for the remaining 2.5 min. A decrease in % freezing between shocked and non-shocked animals is evidence of the effectiveness of fear reduction.

[0239] The groups tested were as follows: 1.APP / PS1+vehicle; 2.APP / PS1+Buntanetap(1mg / Kg); 3.APP / PS1+Buntanetap (10mg / Kg); and 4. WT+vehicle.

[0240] Mice that received the buntane tap were less fearful than mice that did not receive it.

[0241] A summary of the results is shown in Figure 9.

[0242] Based on the results of the test, we conclude that compared to WT vehicle, Buntaneta-pup reduces the fear response to learning to receive an electric shock in the dark box by 40-90%, confirming the fear reduction effectiveness of Buntaneta-pup.

[0243] While the present invention has been disclosed with reference to specific embodiments, it will be apparent that other embodiments and variations of the present invention may be devised by those skilled in the art without departing from the true spirit and scope of the present invention. All patents and publications mentioned herein are incorporated by reference in their entirety. It is intended that the appended claims be construed to include all such embodiments and equivalent variations.

Claims

1. A method for treating, inhibiting, reducing, slowing, or delaying the symptoms of psychosis, comprising administering to a patient a compound represented by Formula (I), Formula (II), and Formula (III): 【Chemistry 1】 [In the formula, In formula (I) and formula (II), R １ and R ２ are independently hydrogen, branched or linear C １ ~C ８ alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R ３ is a branched or linear C １ ~C ４ Alkyl or heteroalkyl or C ４ ~C ８ alkyl or heteroalkyl, or substituted or unsubstituted aryl; X and Y are independently O, S, alkyl, a hydrocarbon moiety, C(H)R ４ , or NR ５ and R ４ and R ５ are independently hydrogen, oxygen, branched or linear C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ alkynyl, aralkyl, or substituted or unsubstituted aryl; R ６ is hydrogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, aralkyl, or substituted or unsubstituted aryl, or (CH ２ ) ｎ R ７ and R ７ is hydroxy, alkoxy, cyano, ester, carboxylic acid, substituted or unsubstituted amino, and n is 1 to 4; In formula (III), R １ and R ２ are independently hydrogen, branched or linear C １ ~C ８ alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R ３ is a branched or linear C １ ~C ４ Alkyl or heteroalkyl or C ４ ~C ８ alkyl or heteroalkyl, or substituted or unsubstituted aryl; X is NR ５ and R ５ is C ２～８ Alkenyl, C ２～８ alkynyl, or aralkyl; Y is C(H)R ４ or NR ５ and R ４ and R ５ are independently hydrogen, branched or linear C １～８ Alkyl or heteroalkyl, alkenyl, or C ２ ~C ８ alkynyl, aralkyl] administering to the animal a therapeutically effective amount of a compound selected from the group consisting of: wherein the compound having formula (I), formula (II) or formula (III) is a substantially pure (-) enantiomer, a substantially pure (+) enantiomer, or a racemic mixture of the (-) enantiomer and the (+)-enantiomer, or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein the compound of formula (I) or formula (II) is a substantially pure (+) enantiomer.

3. 2. The method of claim 1, wherein said compound of formula (III) is a substantially pure (-) enantiomer.

4. The compound is a buntanetap of formula (IV), 【Chemistry 2】 10. The method of claim 1, wherein said compound of formula (IV) is a substantially pure (+) enantiomer, or a pharmaceutically acceptable salt thereof.

5. 10. The method of claim 1, wherein the compound is administered via a route selected from the group consisting of oral, parenteral, sublingual, via a suppository, nasal, topical, transdermal, and via a subcutaneous implant.

6. 10. The method of claim 1, wherein the compound is administered chronically to a human experiencing a psychosis selected from the group consisting of autism, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

7. 5. The method of claim 4, wherein buntanetap or a pharmaceutically acceptable salt thereof is (i) orally administered in an amount of about 1 mg to about 120 mg on a once-daily basis, (ii) intravenously administered in an amount of about 0.1 mg to about 25 mg / day, or (iii) administered intraperitoneally / intramuscularly (IP / IM) at a dose of about 0.3 to about 70 mg / day.

8. 8. The method of claim 7, wherein buntanetap or a pharmaceutically acceptable salt thereof is orally administered in an amount of about 10 mg to about 80 mg on a once-daily basis.

9. The method of claim 7, wherein the peak plasma circulating level of Buntanetab in humans ranges from about 1 ng / mL to about 380 ng / mL.

10. 10. The method of claim 1, wherein the compound is administered in a pharmaceutical formulation in combination with one or more pharmaceutically acceptable excipients.

11. The method of claim 6, wherein the compound is buntanetap.

12. (i) Formula (I), Formula (II) and Formula (III): 【Transformation 3】 [In the formula, In formula (I) and formula (II), R １ and R ２ are independently hydrogen, branched or linear C １ ~C ８ alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R ３ is a branched or linear C １ ~C ４ Alkyl or heteroalkyl or C ４ ~C ８ alkyl or heteroalkyl, or substituted or unsubstituted aryl; X and Y are independently O, S, alkyl, a hydrocarbon moiety, C(H)R ４ , or NR ５ and R ４ and R ５ are independently hydrogen, oxygen, branched or linear C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl or C ２ ~C ８ alkynyl, aralkyl, or substituted or unsubstituted aryl; R ６ is hydrogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, aralkyl, or substituted or unsubstituted aryl, or (CH ２ ) ｎ R ７ and R ７ is hydroxy, alkoxy, cyano, ester, carboxylic acid, substituted or unsubstituted amino, and n is 1 to 4; In formula (III), R １ and R ２ are independently hydrogen, branched or linear C １ ~C ８ alkyl, substituted or unsubstituted aryl, heteroaryl, or aralkyl; R ３ is a branched or linear C １ ~C ４ Alkyl or heteroalkyl or C ４ ~C ８ alkyl or heteroalkyl, or substituted or unsubstituted aryl; X is NR ５ and R ５ is C ２～８ Alkenyl, C ２～８ alkynyl, or aralkyl; Y is C(H)R ４ or NR ５ and R ４ and R ５ are independently hydrogen, branched or linear C １～８ alkyl or heteroalkyl, alkenyl, or C ２ ~C ８ alkynyl, aralkyl] a therapeutically effective amount of a compound selected from the group consisting of: wherein said compound having formula (I), formula (II), or formula (III) is a substantially pure (-) enantiomer, a substantially pure (+) enantiomer, or a racemic mixture of the (-) and (+) enantiomers, or a pharmaceutically acceptable salt thereof; (ii) an effective amount of a compound selected from the group consisting of antipsychotics, antidepressants, hallucinogens, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

1. A neuropsychotic pharmaceutical composition comprising:

13. 13. The pharmaceutical composition of claim 12, wherein said compound of formula (III) is a substantially pure (-) enantiomer.

14. The compound is a buntanetap of formula (IV), 【Chemistry 4】 wherein said compound of formula (IV) is the substantially pure (+) enantiomer, or a pharmaceutically acceptable salt thereof; The pharmaceutical composition of claim 12.

15. 15. The pharmaceutical composition of claim 14, wherein the buntanetap or a pharmaceutically acceptable salt thereof is in an amount of about 1 mg to about 120 mg.

16. 15. The pharmaceutical composition of claim 14, wherein the buntanetap or a pharmaceutically acceptable salt thereof is in an amount of about 10 mg to about 120 mg.

17. 13. The pharmaceutical composition of claim 12, wherein the antipsychotic agent is a therapeutically effective amount of a typical antipsychotic agent, an atypical antipsychotic agent, a miscellaneous antipsychotic agent, a pharmaceutically acceptable salt thereof, and a combination of any of the foregoing.

18. 13. The pharmaceutical composition of claim 12, wherein the antipsychotic, antidepressant, or hallucinogen is present in a sub-therapeutic amount.

19. 13. The pharmaceutical composition of claim 12, wherein the antipsychotic agent is selected from the group consisting of risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole, clozapine, haloperidol, pimozide, molindone, loxapine, prochlorperazine, chlorpromazine, perphenazine, fluphenazine, thioridazine, mesoridazine, thiothixene, asenapine, benperidol, zuclopenthixol, flupenthixol, fluphenazine, lurasidone, levomepromazine, promazine, pericyazine, cariprazine, amisulpride, trifluoperazine, sulpiride, acepromazine, acetophenazine, ziprasidone, iloperidone, pharmaceutically acceptable salts thereof, and any combination of the foregoing.

20. 13. The pharmaceutical composition of claim 12, in oral dosage form.

21. 13. The pharmaceutical composition of claim 12, wherein the amount of the compound of Formula (I), (II), and (III), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent selected from an antipsychotic, an antidepressant, and a hallucinogen is effective to treat, inhibit, reduce, slow, or delay the symptoms of psychosis.

22. 22. The pharmaceutical composition of claim 21, wherein the psychosis is selected from the group consisting of autism, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

23. 2. The method of claim 1, wherein the psychosis is present as a disruption in the genetic code of the human genetic code at CACNA1C or CACNB2.

24. 10. The method of claim 1, further comprising co-administering an effective amount of a compound selected from the group consisting of antipsychotics, antidepressants, hallucinogens, and pharmaceutically acceptable salts thereof.

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