Bicyclic compounds and their use in the treatment of Pitt-Hopkins syndrome

Abstract

This invention provides compounds and compositions for treating Pitt-Hopkins syndrome and its symptoms. [Solution] The present invention provides therapeutic diketopiperazine compounds comprising cyclic G-2-allylproline and other cyclic glycylproline compounds for treating Pitt-Hopkins syndrome and its symptoms. The present invention also provides compositions, methods and uses comprising these compounds, as well as methods for producing pharmaceuticals including compositions, tablets, capsules, liquid formulations, gels, injectable solutions and other formulations useful for treating such conditions.

Description

[Technical Field]

[0001] This PCT international patent application claims priority to U.S. Provisional Patent Application No. 62 / 924,452, filed on 22 October 2019, and relates to bicyclic compounds structurally related to diketopiperazine and their therapeutic use in the treatment of Pitt-Hopkins syndrome. For example, this disclosure relates to the use of cyclic glycylproline ("cGP") and its analogues, including cyclic glycyl-2-allylproline ("cyclic G-2-allyl P" or "cG-2-allyl P"), cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and / or related compounds and pharmaceutical compositions in the treatment of Pitt-Hopkins syndrome (PTHS). This Provisional Patent Application is incorporated herein in full by reference. [Background technology]

[0002] Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by heterozygous lower-order morphology or null mutations or deletions in the transcription factor 4 (TCF4) gene on human chromosome 18q21.1 (Sweatt, 2013). TCF4 haploinsufficiency has been proposed as the underlying mechanism of PTHS. TCF4 encodes a basic helix-loop-helix (bHLH) transcription factor, which is known to heterodimerize with several other bHLH transcription factors that play important roles in neurogenesis and neuronal migration in the brain. Currently, there are no specific drugs or treatments for PTHS.

[0003] Clinical picture Pitt-Hopkins syndrome (PTHS) is characterized by marked developmental delay with moderate to severe intellectual disability, behavioral differences, distinctive facial features, and sudden onset of hyperventilation and / or respiratory arrest while awake. Speech development is markedly delayed, and most individuals do not speak, with receptive language often superior to expressive language. Other common findings include symptoms of autism spectrum disorder, sleep disturbances, stereotyped hand movements, seizures, constipation, and severe myopia (Sweetser et al, 2012).

[0004] Because no formal prevalence surveys have been conducted, the true prevalence of PTHS has not been established. Rosenfeld et al, (2009) estimated the frequency of chromosome 18q21 deletions associated with PTHS to be between 1:34,000 and 1:41,000. Sweetser et al, (2012) stated that if the deletion is found in about one-third of individuals with PTHS, the frequency of the condition could be as high as 1:11,000. Based on the above estimated prevalence ranges, if the US population is currently at least 327,167,434 (US Census 2018), then between 8,000 and 30,000 US citizens may be affected by PTHS.

[0005] Pitt Hopkins syndrome affects both men and women and can occur in individuals of any ethnic or racial background. The Pitt Hopkins Foundation patient registry currently lists approximately 1,000 affected individuals.

[0006] Pitt-Hopkins syndrome is a severely limiting disorder in which individuals rarely acquire the functional abilities to perform self-care, protect themselves from harm, form normal adult relationships, or hold paid employment. This severe impairment results in significant medical and support costs. The disorder is also associated with provocative behaviors that cause acute and chronic stress to caregivers. There are currently no approved medications for the treatment of PTHS. [Overview of the project] [Problems that the invention aims to solve]

[0007] The inventors have identified a novel challenge in the field of this technology: how to effectively treat Pitt-Hopkins syndrome. To this end, the inventors studied the effects of certain diketopiperazine analogs in an animal model of Pitt-Hopkins syndrome (PTHS). Mice with and without mutations in the tcf4 (TCF4) gene were examined in a control study. Since tcf4 mutant mice exhibit characteristics of PTHS, the study of the effects of diketopiperazine, cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and related cyclic piperidines predicts their effects in humans with PTHS.

[0008] Therefore, the inventors treated PTHS patients with cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, or related cyclic piperidines to mimic the innate action of cGP while avoiding TCF4 deficiency by restoring abnormal dendritic morphology and stimulating protein synthesis in excitatory synapses through the following mechanisms (though not necessarily necessarily): 1. Suppression of neuroinflammation and pathological glial cell activation; 2. Normalization of AKT expression and activation upstream of mTOR in the PI3K-AKT-mTOR pathway; 3. Normalization of ERK expression and activation in the MAPK-ERK signaling pathway; and / or 4. Restoration of IGF-1 to normal levels and / or bioavailability.

[0009] As described later, oral administration of cG-2-allyl P for 6 weeks affected PTHS Tcf4 without affecting wild-type control mice. + / - The phenotype of the knockout mouse model can be recovered.

[0010] The cyclic GP is cG-2-allyl P, and the related compound is shown in formula 1.

Chem.

[0011] In some embodiments, the compound of formula 1 comprises the following substituents: X 1 is selected from the group consisting of NR′, O, and S; X 2 is selected from the group consisting of CH2, NR′, O, and S; R 1 、R 2 、R 3 、R 4 、and R 5 are independently selected from the group consisting of -H, -OR′, -SR′, -NR′R′, -NO2, -CN, -C(O)R′, -C(O)OR′, -C(O)NR′R′, -C(NR′)NR′R′, trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, and substituted heteroarylalkyl; each R′ is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; or R 4 and R 5 are -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; or R 2 and R 3 are -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; provided that when R 1 = methyl and R 2 = R 3 = R 4 = H, then R 5 ≠ benzyl; and provided that when R 1 = H, then at least one of R 2 and R 3 ≠ H.

[0012] In a further embodiment, the present invention provides compounds of formula 1 or pharmaceutically acceptable salts, stereoisomers or hydrates thereof, where R 1 = Allele, R 2 =R 3 =R 4 =R 5 =H, X 1 =NH_PilotX 2 =CH2 (cyclic glycyl-2-allylproline).

[0013] In yet another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of cyclic G-2-allyl P.

[0014] In a further embodiment, the present invention provides a method for treating an animal having cognitive impairment, the method comprising administering to the animal a composition containing an effective amount of cyclic G-2-allyl P. In a further embodiment, the animal being treated is a human.

[0015] This disclosure will be described with reference to specific embodiments thereof. Other aspects of the present invention can be understood with reference to the drawings. [Brief explanation of the drawing]

[0016] [Figure 1] This shows the chemical structure of cG-2-allyl P. [Figure 2] This graph shows the results of an open-field study comparing the effects of the tcf4+ / - mutation on reduced activity (travel distance) of cG-2-allyl P or vehicle in mice with the mutation with wild-type mice. [Figure 3] This graph shows the results of a study comparing the effects of cG-2-allyl P or vehicle on repetitive behavior (time spent on self-grooming) in mice with the tcf4+ / - mutation compared to wild-type mice. [Figure 4]This graph shows the results of a study comparing the effects of cG-2-allyl P or vehicle on fear conditioning (time spent freezing in place) in mice with the tcf4+ / - mutation compared to wild-type mice. [Figure 5] This graph shows the results of a study comparing the effects of cG-2-allyl P or vehicle on sociability (time spent with novel mice) in mice with the tcf4+ / - mutation, compared to wild-type mice. [Figure 6] This graph shows the results of a study comparing the effects of cG-2-allyl P or vehicle on daily life (nesting) in mice with the tcf4+ / - mutation compared to wild-type mice. [Figure 7] This graph shows the results of a study comparing the effects of cG-2-allyl P or vehicle on motor ability (hind limb strength) in mice with the tcf4+ / - mutation compared to wild-type mice. [Modes for carrying out the invention]

[0017] definition An "alkenyl" refers to an unsaturated branched, linear, or cyclic hydrocarbon radical having at least one carbon-carbon double bond. The radical may be in either a cis or trans conformation around the double bond(s). Exemplary alkenyl groups include allyl, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, and cyclopentenyl. In some embodiments, the alkenyl group is a (C2-C6) alkenyl, while in other embodiments, allyls may be particularly useful.

[0018] "Alkyl" refers to saturated branched, linear, or cyclic hydrocarbon radicals. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopropylmethyl, and hexyl. In some embodiments, the alkyl group is (C1-C6) alkyl.

[0019] "Alkynyl" refers to an unsaturated branched, linear, or cyclic hydrocarbon radical having at least one carbon-carbon triple bond. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, and isobutynyl. In some embodiments, the alkynyl group is a (C2-C6) alkynyl.

[0020] "Aryl" refers to an unsaturated cyclic hydrocarbon radical having a conjugated π-electron system. Exemplary aryl groups include phenyl and naphthyl. In some embodiments, the aryl group is (C5-C 20 ) It is Ariel.

[0021] "Arylalkyl" refers to a linear alkyl, alkenyl, or alkynyl group in which one of the hydrogen atoms bonded to the terminal carbon is replaced by an aryl group. Examples of arylalkyl groups include benzyl, naphthylmethyl, and benzylidene.

[0022] "Cognitive impairment" and "cognitive dysfunction" mean one or more signs or symptoms of memory loss, loss of spatial orientation, reduced learning ability, reduced ability to form short-term or long-term memory, reduced episodic memory, reduced ability to consolidate memory, reduced spatial memory, reduced receptive language and / or communication, reduced expressive language and / or communication, reduced synapse formation, reduced synaptic stability, executive function deficits, cognitive map and scene memory deficits, declarative and related memory deficits, reduced rapid acquisition of constructive or connective relationships, reduced coding and recall of context-specific specific events, reduced episodic and / or episodic-like memory, anxiety, abnormal fear conditioning, abnormal social behavior, repetitive behavior, inhibitory behavior, abnormal sleep behavior, aggressive behavior, self-injurious behavior, stereotyped hand movements, tantrums, seizure activity, abnormal spontaneous movement, abnormal expression or activation of ERK1 / 2 and / or Akt, and bradycardia.

[0023] "Comprising" and "Comprises" mean including but not being limited to the enumerated elements.

[0024] "Consists of" means that it includes the listed elements but does not include any other elements.

[0025] "To essentially become from" means to include the listed elements and their equivalents.

[0026] "Growth factors" refer to extracellularly active polypeptides that stimulate cells to grow or proliferate by interacting with receptors on the cell surface.

[0027] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by other atoms such as N, P, O, or S. Examples of heteroalkyl groups include pyrrolidine, morpholine, piperidine, piperazine, imidazolidine, pyrazolidine, tetrahydrofuran, (C1-C 10 Examples include substituted amines and (C2-C6) thioethers.

[0028] A "heteroaryl" refers to an aryl portion in which one or more carbon atoms are replaced by other atoms such as N, P, O, or S. Examples of heteroaryl groups include carbazole, furan, imidazole, indazole, indole, isoquinoline, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrrole, thiazole, thiophene, and triazole.

[0029] "Pharmacologically acceptable excipients" generally refer to excipients that are useful for preparing safe, non-toxic, and desirable pharmaceutical compositions, and include excipients that are acceptable for veterinary and human pharmaceutical use. Such excipients may be solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous.

[0030] A "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological properties. Such salts include those that can be formed when acidic protons present in a compound can react with inorganic or organic bases. Suitable inorganic salts include those formed with alkali metals, such as sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with amine bases, such as organic bases like ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine. Such salts also include acid addition salts formed with inorganic acids (e.g., hydrochloric acid and hydrobromic acid) and organic acids (e.g., acetic acid, citric acid, maleic acid, and alkanes and arenesulfonic acids such as methanesulfonic acid and benzenesulfonic acid). If two acidic groups are present, a pharmaceutically acceptable salt may be a mono-acid mono-salt or di-acid; similarly, if more than two acidic groups are present, some or all of these groups may exist as a salt.

[0031] In organic synthesis, the term "protecting group" has a conventionally related meaning: it is a group that selectively blocks one or more reaction sites in a polyfunctional compound so that a chemical reaction can be selectively carried out on another unprotected reaction site, and so that the group can be easily removed after the selective reaction is complete.

[0032] A "stereoisomer" is a molecule that has the structure of cyclic G-2-allylproline but possesses a chiral center. The term "cyclic G-2-allylproline" includes all stereoisomers.

[0033] "Substitutable" refers to a case where one or more hydrogen atoms on an alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, or arylalkyl radical are independently replaced by another substituent. Examples of substituents include -R', -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', -NR'-C(NR')-OR', -NR'-C(NR')-SR', NR'-C(NR')-NR'R', trihalomethyl, and halogen, where each R' is independently -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0034] "Symptoms(s)" means one or more signs or symptoms of cognitive impairment or cognitive dysfunction, which are one or more of the following: memory loss, loss of spatial orientation, reduced learning ability, reduced ability to form short-term or long-term memory, reduced episodic memory, reduced ability to consolidate memory, reduced spatial memory, reduced receptive language and / or communication, reduced expressive language and / or communication, reduced synapse formation, reduced synaptic stability, executive function deficits, cognitive map and scene memory deficits, declarative and related memory deficits, reduced rapid acquisition of constructive or connective relationships, reduced coding and recall of context-specific concrete events, reduced episodic and / or episodic-like memory, anxiety, abnormal fear conditioning, abnormal social behavior, repetitive behavior, inhibitory behavior, abnormal sleep behavior, aggressive behavior, self-injurious behavior, stereotyped hand movements, tantrums, seizure activity, abnormal spontaneous movement, abnormal expression or activation of ERK1 / 2 and / or Akt, and bradycardia.

[0035] "Therapeutic dose" means the amount administered to an animal to treat a disease that is sufficient to achieve treatment of the disease. "Therapeutic dose" means the amount that reduces adverse symptoms or findings, promotes desirable symptoms or findings, and / or treats the underlying disorder, and / or is curative.

[0036] "Treating" a disease or "treatment" of a disease includes prevention, which means inhibiting the symptoms of the disease, suppressing the disease (delaying or preventing its onset), reducing the symptoms or side effects of the disease (including palliative treatment), and alleviating the disease (bringing it into remission), in animals that may be susceptible to the disease but have not yet experienced or exhibited symptoms of the disease. Treatment does not include correcting the genetic abnormality of Pitt-Hopkins syndrome.

[0037] Potential hydrogen atoms (e.g., hydrogen on a pyrrole ring) are omitted from the formula for clarity, but should be understood as being present.

[0038] "ATF3" stands for Activated Transcription Factor 3.

[0039] "IL1-beta" refers to interleukin-1-beta.

[0040] "IL-6" stands for interleukin-6.

[0041] "BDNF" stands for brain-derived neurotrophic factor.

[0042] "Cdh2" stands for cadherin-2.

[0043] "Cebpb" stands for CCAAT / enhancer-binding protein beta.

[0044] "Crem" refers to the cyclic AMP response element coupling.

[0045] "Egr1" stands for Early Growth Response Protein 1.

[0046] "Gria 4" refers to the ion channel type glutamate receptor AMPA4.

[0047] "Grm5" stands for metabotropic glutamate receptor 5.

[0048] "Mapk 1" stands for Mitogen-Activated Protein Kinase 1.

[0049] "Nr4a1" refers to nuclear receptor subfamily 4A member 1, also known as nerve growth factor IB.

[0050] "Ntf3" stands for Neurotrophin 3.

[0051] "Ntf4" stands for Neurotrophin 4.

[0052] "Pcdh8" stands for protocadherin-8.

[0053] "Plm1" stands for mRNA precursor leak protein 1.

[0054] "Ppp3ca" stands for protein phosphatase 3, catalytic subunit, alpha.

[0055] "Tnf" stands for tumor necrosis factor.

[0056] PTHS stands for Pitt-Hopkins syndrome.

[0057] "cG-2-allyl P", "cyclic glycyl-2-allyl P", "NNZ2591", and "NNZ-2591" each refer to (8aS)-allyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione.

[0058] "Cyclic cyclohexyl-G-2-MeP" means (8aS)-methyl-spiro[cyclohexane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione.

[0059] "Cyclic cyclopentyl-G-2-MeP" means (8aS)-methyl-spiro[cyclopentane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione.

[0060] "tcf4" and "TCF4" refer to genes associated with PTHS.

[0061] "tcf4 + / - This refers to a heterozygous mutation in the TCF4 gene associated with PTHS.

[0062] "Tcf4 + / + " refers to the wild-type TCF4.

[0063] Genetic abnormalities in Pitt-Hopkins syndrome Impairment of synaptic structure and function is a fundamental characteristic of PTHS. TCF4 is a transcription factor that regulates neurogenesis and neuronal migration in the brain. In humans, loss of function of the TCF4 gene leads to PTHS, a rare neurodevelopmental disorder characterized by intellectual disability, developmental delay, and autistic behaviors. TCF4 is highly expressed during fetal and early postnatal development (de Pontual et al, 2009), particularly in the hippocampus (Brzozka et al, 2010; Sepp et al, 2011; Navarrete et al, 2013). It is also expressed in the adult brain, lymphocytes, fibroblasts, gut, muscles, and enteric myoplexus (Pscherer et al, 1996; Amiel et al, 2007; Brockschmidt et al, 2007; de Pontual et al, 2009). Recent cognitive and imaging studies have also shown that TCF4 is important for normal brain function (Blake et al, 2010; Navarrete et al, 2013).

[0064] Deletion and mutation of the TCF4 gene inhibit the ability of corresponding proteins to regulate the downstream activity of genes related to nervous system development and function (Sweatt, 2013). In particular, studies have shown that TCF4 interacts with a potentially broad repertoire of transcription factors, including preneurial gene products such as ASCL1, ATOH1, and NEUROD1, to regulate neurogenesis, cell differentiation, cell signaling, and survival in the developing brain (Flora et al, 2007; Blake et al, 2010; Brzozka et al, 2010; Bertrand et al, 2002; Forrest et al, 2013).

[0065] A study by Crux et al (2018) on the causal relationship between TCF4 loss of function and dendritic spines in mature neurons showed a decrease in the number of dendritic spines and morphological changes in both homozygous and heterozygous TCF4 loss. This study suggests that TCF4 plays an important role in synaptic plasticity in mature neurons, independently of its developmental function, and that TCF4 loss may contribute to the neurological symptoms of PTHS.

[0066] Furthermore, changes in TCF4 appear to alter the gene expression of components of the IGF signaling pathway, particularly downregulating the genes encoding IGF-binding proteins 3, 4, and 5 (Forrest et al, 2013). Cyclic glycine-proline has been reported to regulate the binding of IGF-1 to IGF-binding protein 3 in the brain, thereby regulating IGF-1 bioavailability (Guan et al, 2014). This autoregulatory mechanism maintains IGF-1 homeostasis, with bioavailability increasing when IGF-1 is deficient and decreasing when IGF-1 levels are excessive. In addition, both cGP and cG-2-allyl P inhibit neuroinflammation, which is part of the underlying pathogenesis of PTHS and contributes to the hyperactivation of microglia, which is crucial for synapse formation and maintenance. Across numerous animal models of neurodevelopmental disorders, cG-2-allyl P normalizes the microglial phenotype, which helps restore synaptic function and morphology.

[0067] Clinical methods for evaluating Pitt-Hopkins syndrome Pit Hopkins syndrome can be evaluated using one or more clinical tests, such as the Aberrant Behavior Checklist Community Edition (ABC), Aberrant Behavior Checklist (Stereotypy), Vineland, Clinical Global Impression of Severity (CGI-S), Caregiver Strain Questionnaire (CSQ), Children's Yale-Brown OC Scale (CYBOCS-PDD), Child Autism Rating Scale, Interview of Repetitive Behaviors, Nisonger Child Behavior Rating Scale, Pervasive Developmental Disorder Behavior Inventory, Stereotyped Behavior Scale, Repetitive Behavior Scale, Rossago Scale, Repetitive Behavior Questionnaire, PedQL (trademark) Measurement Model, and Stereotyped Behavior Scale, or one or more physiological tests selected from the group consisting of spike frequency of electroencephalogram (EEG), overall output in the frequency band of EEG, hand movement, QTc and heart rate variability (HRV), and irregular respiration, compared to control animals not suffering from the disorder.

[0068] Anxiety can be assessed using one or more scales, including the Anxiety, Depression and Mood Scale (ADAMS), Child and Adolescent Symptom Inventory (CASI), Child Behavior Checklist (CBCL), Multidimensional Anxiety Scale for Children (MASC), Pediatric Autism Rating Scale (PARS), Revised Child Anxiety and Depression Scale (RCAD), Screen for Child Anxiety Related Disorders (SCARED), Nisonger Child Behavior Rating Form, and Anxiety Diagnostic Interview Scale (ADIS).

[0069] Social communication is assessed using clinical tools such as ABAS-II Domain scores, Aberrant Behavior Checklist (ABC)-Lethargy / Social Withdrawal, ADI-R, Autism Diagnostic Observation Scale-Generic (ADOS-G)-new severity scores, Autism Impact Measure, Autism Spectrum Rating Scales, Autism Treatment Evaluation Checklist (ATEC), Ball Toss Game, Behavior Assessment Scale (BAS), Behavior Assessment System for Children 2nd Edition BASC-2 (social behavior subscale), Behavior Rating Inventory of Executive Function, California Verbal Learning Task-Children's Version (VLT-C) and Modified VLT-C (MVLT-C), Caregiver-Child Interaction, etc.Jahromi 2009, CGI, Childhood Autism Rating Scale (CARS), Children’s Social Behavior Questionnaire, Clinical Evaluation of Language Fundamentals (CELF-3 and 4) - Pragmatics Profile, Communication and Symbolic Behavior Scales (CSBS), Comprehension of Affective Speech Task, General Trust Scale, Gilliam Autism Rating Scale (GARS), Joint Attention Measure from the ESCS (JAMES), Let’s Face It!, Observational Assessment of Spontaneous Expressive Language (OSEL), Parent Questionnaire, Nagaraj et al. 2006, Parent´s Rating Questionnaire, Chan et al,In 2009, it can be evaluated using the Pervasive Developmental Disorder Behavior Inventory (PDD - BI) (Short Version available: PDD - BI - Screening Version), Reading the Mind in Films - Adult, Reading the Mind in Films - Child, Reading the Mind in the Eyes Task - Revised (RMET - R) - Adult, Reading the Mind in the Eyes Task - Revised (RMET - R) - Child, Reading the Mind in Voice - Adult, Social Communication Questionnaire (SCQ), Social Responsiveness Scale, Social Skills Improvement System (SSiS), Theory of Mind Test, and VABS - Socialization and Communication.,

[0070] The compound of the present invention Certain embodiments of the present disclosure include derivatives of cyclic glycylproline ("cGP") having a structure as described below. [Chemical formula]

[0071] In certain embodiments, the compound of formula 1 contains substituents, X 1 is selected from the group consisting of NR´, O, and S; X 2 is selected from the group consisting of CH2, NR´, O, and S; R 1 R 2 R 3 R 4 and R 5R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 4 and R 5 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; However, R 1 =methyl and R 2 =R 3 =R 4 If =H, then R 5 ≠ benzyl; Furthermore, R 1 If =H, then R 2 and R 3 The condition is that at least one of them is not equal to H.

[0072] In further embodiments, the compound of Formula 1 includes the following substituents: R 1 =methyl, R 2 =R 3 =R 4 =R 5 =H, X 1 =NH_PilotX 2 =CH2; R 1 = Allele, R 2 =R 3 =R 4=R 5 =H, X 1 =NH, X 2 =CH2; R 1 =R 2 =R 3 =H, R 4 =R 5 =methyl, X 1 =NH, X 2 =CH2; R 1 =R 4 =R 5 =H, R 2 =R 3 =methyl, X 1 =NH, X 2 =CH2.

[0073] In other embodiments of the present invention, the compound of formula 1 comprises the following substituents: R together with 4 and R 5 is -CH2-(CH2) n -CH2-; R 1 =methyl, R 2 =R 3 =H, n = 0, X 1 =NH, X 2 =CH2; R 1 =methyl, R 2 =R 3 =H, n = 2, X 1 =NH, X 2 =CH2; R 1 =allyl, R 2 =R 3 =H, n = 0, X 1 =NH, X 2 =CH2; R 1 =allyl, R 2 =R 3 =H, n = 2, X 1 =NH, X 2 =CH2; R 1 =methyl, R 2 =R 3 =H, n = 3, X 1 =NH, X 2 =CH2; R 1 = Allele, R 2 =R 3 =H, n=3, X 1 =NH_PilotX 2 =CH2.

[0074] In further embodiments of this disclosure, the compound of formula 1 comprises substituents, R 1 =methyl or allyl, R 2 =R 3 =R 4 =H and R 5 The amino acid is selected from the group consisting of side chains such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, serine, threonine, tryptophan, tyrosine, valine, norvaline, norleucine, citrulline, ornithine, homocysteine, homoserine, alloisoleucine, isovaline, sarcosine, etc.

[0075] In a further embodiment of the present invention, the compound of formula 1 comprises the following substituents: R 1 =methyl, R 2 =R 3 =methyl, R 4 =R 5 =H, X 1 =NH and X 2 =S; R 1 = Allele, R 2 =R 3 =methyl, R 4 =R 5 =H, X 1 =NH, and X 2 =S.

[0076] Those skilled in the art will understand that the above structural representation may contain chiral centers, the number of which depends on various substituents. The chirality may be either R or S at each center. The structural diagram may represent only one of the potential tautomers, stereoisomers, or enantiomers, and the present invention should be understood to encompass any tautomer, stereoisomer, or enantiomer exhibiting biological or pharmacological activity as described herein.

[0077] Pharmacology and utility Cyclic glycyl-2-allyl proline (cG-2-allyl P) is the subject of several patent applications: U.S. Utility Application No. 11 / 399,974, filed on April 7, 2006, titled "Cyclic G-2Allyl Proline in Treatment of Parkinson's Disease," now U.S. Patent No. 7,776,876, issued on August 17, 2010; U.S. Utility Application No. 10 / 570,395, filed on March 2, 2006, titled "Neuroprotective Bicyclic Compounds and Methods for Their Use," now U.S. Patent No. 8,067,425; PCT International Patent Application No. PCT / US2004 / 028308, also titled "Neuroprotective Bicyclic Compounds and Methods for Their Use," filed on September 3, 2003, also titled "Neuroprotective Bicyclic Compounds and Methods for Their This is described in U.S. Provisional Patent Application No. 60 / 499,956, titled "Use," and in U.S. Patent Application No. 13 / 043,215, filed on March 8, 2011, titled "Cyclic Glycyl-2-AllylProline Improves Cognitive Performance in Impaired Animals." Each of the above patent applications and patents is fully and expressly incorporated herein by reference.

[0078] Other active agents may be administered together with the compounds of the present invention. Such other active agents may be selected from the group consisting of, for example, growth factors and related derivatives, such as insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), tripeptide GPE, transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, and / or IGF-binding protein.

[0079] therapeutic use The compositions and methods of the present invention have been found to be used in the treatment of animals, such as human patients, who suffer from symptoms associated with cognitive impairment and Pitt-Hopkins syndrome. More generally, the compositions and methods of the present disclosure have been found to be used in the treatment of mammals, such as human patients, who suffer from memory impairment, intellectual disability, impairment of social interaction, impairment of language and communication, impairment of motor function, restricted and repetitive interests and behaviors, abnormal sleep behavior, other abnormal behaviors, and seizures.

[0080] Pharmaceutical composition and administration cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and related cyclic piperidines may be administered as part of a pharmaceutical or pharmaceutical preparation. This may involve combining the compounds of the present invention with any pharmaceutically appropriate carrier, adjuvant, or excipient. The choice of carrier, adjuvant, or excipient will, of course, depend on the route of administration typically used.

[0081] Generally, the compounds of the present disclosure will be administered in a therapeutically effective amount, either alone or in combination with other conventional therapeutic agents for the disease being treated, by any of the ordinary modes known in the art. The therapeutically effective amount can vary widely depending on the disease, its severity, the age and relative health of the animal being treated, the potency of the compound(s), as well as other factors. The therapeutically effective amount of cyclic G-2-allyl P can range from 0.001 to 600 milligrams per kilogram of animal body mass and is suitable for administration by methods such as oral, systemic (e.g., transdermal), intralesional, or parenteral (e.g., intravenous) administration. One of ordinary skill in the art will be able to determine the therapeutically effective amount of the compound, taking into account their skill and the present disclosure, without undue experimentation.

[0082] cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP and / or related cyclic piperidines and other cGP-related compounds may be administered peripherally via any peripheral route known in the art. These may include parenteral routes, such as injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intrathecal, intracisternal, topical, infusion (using a slow-release device such as an osmotic pump or skin patch or a minipump), implantation, aerosol, inhalation, intralesional, intraperitoneal, intra-articular, intramuscular, intranasal, oral, buccal, transdermal, transpulmonary, rectal or vaginal. The composition may be formulated for parenteral administration to humans or other mammals in a therapeutically effective amount (e.g., an amount that alleviates or reduces the patient's pathological condition) to provide therapy for the neurological diseases described above.

[0083] Preferably, cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP and / or related cyclic piperidines can be administered orally in an aqueous solution.

[0084] Another convenient route of administration includes subcutaneous injection (e.g., dissolved in a physiologically compatible carrier such as 0.9% sodium chloride).

[0085] With respect to “directly or indirectly via circulation,” the inventors mean the administration of cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, or related cyclic piperidines to any tissue having sufficient blood flow to deliver the active substance into circulation. Non-limiting examples include the skin, nose, pharynx, gastrointestinal tract, or other such tissues. When administered to such tissue, the active substance is absorbed by the tissue, entering the interstitial fluid of the tissue, and then absorbed by venules, capillaries, arterioles, or lymphatic vessels. The active substance is then transported into the systemic circulation throughout the body, in which case it may be delivered to the affected area, including the brain. When the active substance is administered subcutaneously or peritoneally, it is absorbed by adjacent tissue, then enters the circulation locally, and then is delivered into the systemic circulation, in which case it may be transported to the brain. When the active substance approaches the blood-brain barrier, it can then diffuse into either the nerve tissue or the cerebrospinal fluid within the brain, and in the process, it can be delivered to the nerve tissue.

[0086] The effective amount of the compound in the CNS may be increased by administration of a prodrug form of the compound comprising the compound of the present invention and a carrier, wherein the carrier is linked to the compound of the present invention by a linkage that is sensitive to cleavage or digestion in the patient's body. Any suitable linkage that will be cleaved or digested after administration may be used.

[0087] However, the applicant has no intention of excluding other forms of administration.

[0088] In further embodiments of this disclosure, restoring neurological function in animals involves administering therapeutic doses of cyclic G-2-allyl P, for example, growth factors and related derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGF-binding protein, IGFBP-3, basic fibroblast growth factor, acidic fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homologue). This may include administration in combination with other active agents selected from FHF-1 (FHF-1), FHF-2, FHF-3, and FHF-4, keratinocyte growth factor 2, glial cell activator, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia suppressor, oncostatin M, interleukin), α-interferon, β-interferon, γ-interferon, or consensus interferon, and TNF-α. Other forms of therapeutic agents include clomethiazole; kynurenic acid, Semax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adrenocorticotropic hormone-(4-9) analog (ORG 2766), disolcipine (MK-801), selegiline; glutamate antagonists, NPS1506, GV1505260, MK-801, GV150526; AMPA antagonists, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, anti-inflammatory agents against adresin MAdCAM-1 and / or its integrin α4 receptor (α4β1 and α4β7), anti-MAdCAM-1 mAb MECA-367 (ATCC accession number HB-9478) is one example.

[0089] cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP and / or related cyclic piperidines and other cGP-related compounds are preferably administered by a sustained-release system. Suitable examples of sustained-release compositions include semipermeable polymer matrices in molded form, such as films or microcapsules. Examples of sustained-release matrices include polylactide (U.S. Patent No. 3,773,919; EP 58,481), copolymer of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., 1983, Biopolymers: 22: 547-56), poly(2-hydroxyethyl methacrylate) (Langer et al., 1981, J. Biomed. Mater. Res.: 15: 267), ethylene vinyl acetate (Langer et al., 1981, J. Biomed. Mater. Res.: 15: 267), or poly-D-(-)-3-hydroxybutyrate (EP 133,988). Sustained-release compositions also include compounds encapsulated in liposomes. Liposomes containing the compound are prepared by methods known in themselves: DE 3,218,121, EP 52,322, EP 36,676, EP 88,046, EP 143,949, EP 142,641, Japanese Patent Application No. 83-118008, U.S. Patents No. 4,485,045 and No. 4,544,545, and EP 102,324. Typically, the liposomes are small (about 200-800 angstroms) monolayer type, in which the lipid content is greater than about 30 mol percent cholesterol, and the selected proportion is adjusted to suit the most effective therapy.

[0090] For parenteral administration, in one embodiment, cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and / or related cyclic piperidines can generally be formulated by mixing each of them, generally to the desired purity, in unit dose injectable form (solution, suspension, or emulsion) with a pharmaceutically or parenterally acceptable carrier, i.e., one that is nontoxic to the recipient at the dose and concentration used and compatible with the other ingredients of the formulation.

[0091] To deliver the compounds of the present invention to mucosal tissue, the compounds can be incorporated into gel formulations. Upon delivery to the mucous membrane (e.g., oral cavity, gastrointestinal tract, rectum), the active substance may diffuse away from the gel or the gel may decompose, thereby releasing the active substance into the tissue, in which case it may be absorbed in circulation. Exemplary gel formulations include those made from carboxypolysaccharides such as carboxymethylcellulose, carboxyethylcellulose, chitin, chitosan, starch, and cellulose, proteins such as hyaluronic acid, or other polymers such as polyvinylpyrrolidine and polyvinyl alcohol, as well as other gel materials known in the art.

[0092] Generally, formulations are prepared by contacting cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and / or related cyclic piperidines with a liquid carrier, a micronized solid carrier, or both. The product is then formed into the desired formulation, if necessary. Preferably, the carrier is a parenteral carrier, more preferably a solution isotonic with the recipient's blood. Examples of such carrier vehicles include water, physiological saline, Ringer's solution, buffer solutions, and glucose solutions. Non-aqueous vehicles such as fixative oils and ethyl oleate are also useful herein.

[0093] The carrier preferably contains small amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are nontoxic to the recipient at the dosage and concentration used and include buffers such as phosphates, citrates, succinates, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides, e.g., polyarginine or tripeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, trehalose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; nonionic surfactants such as polysorbate, poloxamer, or polyethylene glycol (PEG); and / or neutral salts, e.g., NaCl, KCl, MgCl2, CaCl2, etc.

[0094] cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP and / or related cyclic piperidines and other cGP compounds are typically formulated in such vehicles at a pH of about 4.5–8. It will be understood that the formation of salts of the compounds is brought about by the certain use of the aforementioned excipients, carriers, or stabilizers. The final preparation may be a stable liquid or a lyophilized solid.

[0095] Formulations of cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and / or related cyclic piperidines in pharmaceutical compositions may also contain adjuvants. Typical adjuvants that can be incorporated into tablets, capsules, etc., include binders such as gum arabic, corn starch, or gelatin; excipients such as microcrystalline cellulose; disintegrants such as corn starch or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose or lactose; and flavoring agents such as peppermint, dwarf spicebush, or cherry. When the dosage form is a tablet, the cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and / or related cyclic piperidine compositions may contain binders and, optionally, smoothing agents. When the dosage form is a capsule, in addition to the above materials, a liquid carrier such as fatty oil may also be included. Various types of other materials may be used as coating agents or modifiers for the physical form of the dosage unit. The syrup or elixir may contain the active compound, sweeteners such as sucrose, preservatives such as propylparaben, colorants, and flavorings such as cherry. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, it may be desirable to dissolve or suspend the active compound in water, or in a vehicle such as a naturally occurring vegetable oil such as sesame, peanut, or cottonseed oil, or a synthetic fatty vehicle such as ethyl oleate. Buffers, preservatives, antioxidants, etc., may be incorporated according to accepted pharmaceutical practice.

[0096] Pharmaceutical preparations containing cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP, and / or related cyclic piperidines are typically stored in single-dose or multi-dose containers, for example, in sealed ampoules or vials, as aqueous solutions or as lyophilized preparations for reconstitution. As an example of a lyophilized preparation, a 10 mL vial is filled with 5 mL of a sterile-filtered 1% (w / v) aqueous solution of the compound, and the resulting mixture is lyophilized. The solution is prepared by reconstituting the lyophilized compound using bacteriostatic water for injection. Other dosage forms and types of preparations may be used, and it will be readily apparent that all of these are considered part of the present disclosure.

[0097] Preparation of compounds The starting materials and reagents used to prepare cG-2-allyl P, cyclic cyclohexyl-G-2-MeP, cyclic cyclopentyl-G-2-MeP and / or related cyclic piperidines are available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or Fieser and Fieser's Reagents for Organic Synthesis, vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supplements, Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, NY, 1991; March J; Advanced Organic Chemistry, 4 thThey are prepared either by methods well known to those skilled in the art, following the procedures described in references such as John Wiley and Sons, New York, NY, 1992; and Larock: Comprehensive Organic Transformations, VCH Publishers, 1989. In most cases, amino acids and their esters or amides, as well as protected amino acids, are widely available commercially, and the preparation of modified amino acids and their amides or esters is extensively described in the chemical and biochemical literature and is therefore well known to those skilled in the art.

[0098] The starting materials, intermediates, and final products of this disclosure may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, and chromatography. They may also be characterized using conventional methods, including physical constants and spectral data.

[0099] Cyclic G-2-allyl P is a cyclic dipeptide (bicyclic 2,5-diketopiperazine) and a member of the class of compounds known as cyclic GP ("cGP"). In general, cGP and cyclic G-2-allyl P can be prepared by methods already well known to those skilled in the art of peptide and modified peptide synthesis, in accordance with the reaction schemes specified herein, or by other methods well known to those skilled in the art of peptide and analogue synthesis. See, for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer-Verlag 1993.

[0100] The diketopiperazine compounds of this disclosure may be synthesized by liquid-phase synthesis or by solid-phase synthesis as exemplified by Merrifield et al. 1963 J. Amer. Chem. Soc.: 85, 2149-2156. Solid-phase synthesis can be carried out using commercially available peptide synthesizers such as the Applied Biosystems Model 430A, using protocols established for the instrument.

[0101] Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and the references therein. Those skilled in the art, considering their skills and available knowledge, as well as the present disclosure, would not have difficulty developing one or more suitable synthetic methods for the compounds of the present invention.

[0102] The selection of an appropriate protecting group for the chosen method (solid-phase or liquid-phase), and the selection of a suitable substrate if a solid-phase synthesis method is used, should be within the scope of the skills of those skilled in the art. Suitable protecting groups for peptide synthesis include t-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bzl), t-amyloxycarbonyl (Aoc), tosyl (Tos), benzyloxycarbonyl (Z or Cbz), and o-bromo-benzyloxycarbonyl (BrZ). Additional protecting groups have been identified in Goodman M. (ed.), “Synthesis of Peptides and Peptidomimetics” in Methods of organic chemistry (Houben-Weyl) (Workbench Edition, E22a,b,c,d,e; 2004; Georg Thieme Verlag, Stuttgart, New York).

[0103] The selection of coupling agents for the chosen method will also be within the scope of the skills of those skilled in the art. Suitable coupling agents include DCC (N,N'-dicyclohexylcarbodiimide), Bop (benzotriazole-1-yl-oxytris-(dimethylamino)-phosphonium hexafluorophosphate), PyBop (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), BopCl (bis(2-oxo-3-oxazolidinyl)phosphinate chloride), and 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP). In synthesis, other compounds such as HOBt (N-hydroxybenzotriazole) and HOAt (1-hydroxy-7-azabenzotriazole) may be used, for example, to prevent racemization.

[0104] Embodiment The specific embodiments described below are not intended to limit the scope of the invention. Those skilled in the art can create other embodiments by incorporating one or more of the elements listed below in combinations not specifically described herein. All such embodiments should be considered to fall within the scope of the invention.

[0105] Embodiment 1. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 It is selected from the group consisting of NR', O, and S; X 2 It is selected from the group consisting of CH2, NR', O, and S; R 1 , R 2 , R 3 , R 4 and R 5R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 4 and R 5 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; However, R 1 =methyl and R 2 =R 3 =R 4 If =H, then R 5 ≠ benzyl; Furthermore, R 1 If =H, then R 2 and R 3 The method comprising administering to an animal (provided that at least one of ≠ H).

[0106] Embodiment 2. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 It is selected from the group consisting of NR', O, and S; X2 It is selected from the group consisting of CH2, NR', O, and S; R 1 , R 2 and R 3 R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; The method comprising administering to an animal (provided that at least one R≠H).

[0107] Embodiment 3. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 It is selected from the group consisting of NR', O, and S; X 2 It is selected from the group consisting of CH2, NR', O, and S; R 1 , R 2 and R 3R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 2 and R 3 is -CH2-(CH2) n The method comprising administering -CH2- (where n is an integer from 0 to 6) to an animal.

[0108] Embodiment 4. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 , X 3 , and X 4 It is independently selected from the group consisting of S, O, and NH; X 2 It is selected from the group consisting of S, O, CH2, and NH; R 1 , R 2 , R 3 , R 4 and R 5R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 4 and R 5 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; However, at least one R≠H and X 3 and X 4 The method comprising administering to an animal (provided that both ≠ O).

[0109] Embodiment 5. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, R 1 and R 2R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 1 and R 2 is -CH2-(CH2) n The method comprising administering -CH2- (where n is an integer from 0 to 6) to an animal.

[0110] Embodiment 6. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, R 1 , R 2 and R 3R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 2 and R 3 is -CH2-(CH2) n The method comprising administering -CH2- (where n is an integer from 0 to 6) to an animal.

[0111] Embodiment 7. A method for treating the symptoms of PTHS in animals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, The method comprising administering to an animal a substance R selected from the group consisting of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl.

[0112] Embodiment 8.R 1 The method according to any one of embodiments 1 to 4 or 6, wherein =methyl.

[0113] Embodiment 9.R 1 The method according to any one of embodiments 1 to 4 or 6, wherein the allele is allele.

[0114] Embodiment 10.R 2 =R 3 =methyl, X 2 The method according to any one of embodiments 1 to 4, wherein =S.

[0115] Embodiment 11.R 1 = Allele, R 2 =R 3 =R 4 =R 5 =H, X 1 =NH_PilotX 2 The method according to Embodiment 1, wherein =CH2.

[0116] Embodiment 12.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)3-CH2-, X 1 =NH_PilotX 2 The method according to Embodiment 1, wherein =CH2.

[0117] Embodiment 13.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)2-CH2-, X 1 =NH_PilotX 2 The method according to Embodiment 1, wherein =CH2.

[0118] Embodiment 14. The method according to any one of Embodiments 1 to 13, further comprising administering a pharmaceutically acceptable excipient.

[0119] Embodiment 15. The method according to any one of Embodiments 1 to 13, further comprising administering pharmaceutically acceptable excipients and binders.

[0120] Embodiment 16. The method according to any one of Embodiments 1 to 13, further comprising administering a pharmaceutically acceptable excipient and a capsule.

[0121] Embodiment 17. The method according to any one of Embodiments 1 to 13, further comprising administering at least one other anti-apoptotic agent, anti-necrotic agent, or neuroprotective agent.

[0122] Embodiment 18. Neuroprotective agents include growth factors and related derivatives (insulin-like growth factor-I [IGF-I], insulin-like growth factor-II [IGF-II], transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGF-binding protein, IGFBP-3, basic fibroblast growth factor, acid fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homology-1 (FHF-1), FHF-2, FHF-3 and FHF-4, keratinocyte growth factor 2, glial cells) The method according to Embodiment 17, wherein the agent is selected from activators, FGF-10 and FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 [BMP-2], glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia suppressor, oncostatin M, interleukin), α-interferon, β-interferon, γ-interferon, consensus interferon, TNF-α, clomethiazole, kynurenic acid, Cemax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adrenocorticotropic hormone-(4-9) analog [ORG 2766], disolcipin [MK-801], selegiline, glutamate antagonists, AMPA antagonists, and anti-inflammatory agents.

[0123] Embodiment 19. The method according to Embodiment 18, wherein the glutamic acid and / or NMDA antagonist is selected from the group consisting of NPS1506, GV1505260, MK-801, and GV150526.

[0124] Embodiment 20. The method according to Embodiment 18, wherein the AMPA antagonist is selected from the group consisting of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, and LY300164.

[0125] Embodiment 21. The method according to Embodiment 18, wherein the anti-inflammatory agent is selected from the group consisting of anti-MAdCAM-1 antibodies and antibodies against integrin α4β1 receptors and integrin α4β7 receptors.

[0126] Embodiment 22. The method according to Embodiment 21, wherein the anti-MAdCAM-1 antibody is MECA-367.

[0127] Embodiment 23. The method according to Embodiment 1, wherein the compound is cyclic G-2-allyl P.

[0128] Embodiment 24. The method according to Embodiment 1, wherein the compound is cyclic cyclohexyl-G-2MeP.

[0129] Embodiment 25. The method according to Embodiment 1, wherein the compound is cyclic cyclopentyl-G-2MeP.

[0130] Embodiment 26. A method for treating the symptoms of PTHS in an animal suffering from such a disorder, comprising administering a pharmaceutically effective amount of cyclic glycyl-2-allylproline (cG-2-allyl P) to the animal.

[0131] Embodiment 27. The method according to Embodiment 26, wherein the cG-2-allyl P comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.

[0132] Embodiment 28. The method according to Embodiment 26, further comprising one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule.

[0133] Embodiment 29. The method according to any one of Embodiments 1 to 30, wherein the compound is administered directly or indirectly via circulation.

[0134] Embodiment 30. The method according to any one of Embodiments 1 to 29, wherein the compound is administered orally, intraperitoneally, intravascularly, peripherally, subcutaneously, intraorbitally, ophthalmoscopy, intrathecally, intracision, topically, by injection, transplantation, aerosol, inhalation, slit, intraperitoneally, intraarticularly, intramuscularly, intranasally, buccally, percutaneously, transpulmonaryly, transrectally, or transvaginally.

[0135] Embodiment 31. The method according to any one of Embodiments 1 to 30, wherein the effective amount has a lower limit of about 0.001 milligrams and an upper limit of about 200 mg / kg per kilogram (mg / kg) mass of the animal.

[0136] Embodiment 32. The method according to any one of Embodiments 1 to 31, wherein the effectiveness is evaluated by measuring phosphorylated ERK (pERK) or phosphorylated Akt (pAkt) in animal lymphocytes, and in this case, normalization of either pERK or pAkt indicates a decrease in the severity of the disorder.

[0137] Embodiment 33. The method according to any one of Embodiments 1 to 32, wherein the treatment improves the symptoms of PTHS while being evaluated using one or more clinical tests selected from the group consisting of Aberrant Behavior Checklist Community Edition (ABC), Vineland Adaptive Behavior Scales, Clinical Global Impression of Severity (CGI-S), Clinical Global Impression Improvement (CGI-I), and Caregiver Strain Questionnaire (CSQ), or one or more physiological tests selected from the group consisting of electroencephalogram (EEG) spike frequency, overall output in the EEG frequency band, hemispheric EEG frequency coherence, stereotyped hand movements, QTc and heart rate variability (HRV), abnormal expression or activation of ERK1 / 2 and Akt, abnormal expression of growth-related protein-43 (GAP-43), abnormal expression of synaptophysin (SYN), irregular respiration, and the correlation between cardiac and respiratory function, compared to a control animal not suffering from the disorder.

[0138] Embodiment 34. The method according to any one of Embodiments 1 to 33, wherein the symptoms of PTHS are cognitive impairment or cognitive dysfunction, characterized by one or more signs or symptoms of: memory loss, loss of spatial orientation, reduced learning ability, reduced ability to form short-term or long-term memories, reduced episodic memory, reduced ability to consolidate memories, reduced spatial memory, reduced synapse formation, reduced synaptic stability, executive function deficits, cognitive map and scene memory deficits, statement and relevance memory deficits, reduced rapid acquisition of constructive or connective relationships, reduced coding and recall of context-specific specific events, reduced episodic and / or episodic-like memory, anxiety, abnormal fear conditioning, abnormal social behavior, repetitive behavior, abnormal nocturnal behavior, seizure activity, abnormal spontaneous movement, abnormal expression or activation of ERK1 / 2 and Akt, and bradycardia.

[0139] Embodiment 35. A method for detecting the presence, degree, or evaluation of a therapeutic effect according to any one of the prior embodiments, comprising measuring the expression level of phosphorylated ERK1 / 2 or phosphorylated Akt in peripheral lymphocytes of a subject having PTHS compared with the expression level of phosphorylated ERK1 / 2 or phosphorylated Akt in peripheral lymphocytes of a control group not having PTHS, or the expression level of phosphorylated ERK1 / 2 or phosphorylated Akt in peripheral lymphocytes of a subject before treatment.

[0140] Embodiment 36. Use of a compound in the manufacture of a medicament for treating symptoms of Pitt-Hopkins syndrome, wherein the compound is a pharmaceutically effective amount of a compound comprising cyclic glycyl-2-allylproline (cG-2-allyl P), cyclic cyclohexyl-G-2MeP, or cyclic cyclopentyl-G-2MeP.

[0141] Embodiment 37. The use described in Embodiment 36, wherein the compound is cyclic cyclohexyl-G-2MeP.

[0142] Embodiment 38. The use described in Embodiment 36, wherein the compound is cyclic G-2-allyl P.

[0143] Embodiment 39. The use described in Embodiment 36, wherein the compound is cyclic cyclopentyl-G-2MeP.

[0144] Embodiment 40. Use of a compound in the manufacture of a pharmaceutical for treating the symptoms of Pitt-Hopkins syndrome in mammals suffering from such a disorder, wherein the compound has the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 It is selected from the group consisting of NR', O, and S; X 2 It is selected from the group consisting of CH2, NR', O, and S; R 1 , R 2, R 3 , R 4 and R 5 R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 4 and R 5 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; However, R 1 =methyl and R 2 =R 3 =R 4 If =H, then R 5 ≠ benzyl; and R 1 If =H, then R 2 and R 3 The use described above is provided that at least one of the conditions is ≠ H.

[0145] Embodiment 41.R 1 =methyl, as described in Embodiment 40.

[0146] Embodiment 42.R 1 = Allyl, as described in Embodiment 40

[0147] Embodiment 43.R2 =R 3 =methyl, X 2 The use described in Embodiment 40, where =S.

[0148] Embodiment 44.R 1 = Allele, R 2 =R 3 =R 4 =R 5 =H, X 1 =NH_PilotX 2 The use described in Embodiment 40, where =CH2.

[0149] Embodiment 45.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)3-CH2-, X 1 =NH_PilotX 2 The use described in Embodiment 40, where =CH2.

[0150] Embodiment 46.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)2-CH2-, X 1 =NH_PilotX 2 The use described in Embodiment 40, where =CH2.

[0151] Embodiment 47. The use according to any one of Embodiments 40 to 46, further comprising the compound in a pharmaceutically acceptable excipient or in a gel.

[0152] Embodiment 48. The use according to any one of Embodiments 40 to 47, further comprising the compound with pharmaceutically acceptable excipients and binders.

[0153] Embodiment 49. The use according to any one of Embodiments 40 to 48, further comprising the compound with a pharmaceutically acceptable excipient or in a capsule.

[0154] Embodiment 50. The use according to any one of Embodiments 40 to 49, further comprising at least one anti-apoptotic compound, anti-necrotic compound, neuroprotective agent, or anti-inflammatory agent.

[0155] Embodiment 51. Anti-apoptotic compounds, anti-necrotic compounds, or neuroprotective agents include insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGFBP-3, basic fibroblast growth factor, acid fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homolog-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial cell activity Sexualization factors, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia suppressor, oncostatin M, interleukin, α-interferon, β-interferon, γ-interferon, consensus interferon, TNF-α, clomethiazole, kynurenic acid, Cemax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adrenocorticotropic hormone-(4-9) analog (ORG The use described in Embodiment 50, selected from the group consisting of 2766), disolcipine (MK-801), selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and the anti-MAdCAM-1 antibody MECA-367.

[0156] Embodiment 52. The use according to any one of Embodiments 40 to 50, wherein the compound is cyclic G-2-allyl P.

[0157] Embodiment 53. The use according to any one of Embodiments 40 to 50, wherein the compound is cyclic cyclohexyl-G-2MeP.

[0158] Embodiment 54. The use according to any one of Embodiments 40 to 53, wherein the compound is cyclic cyclopentyl-G-2MeP.

[0159] Embodiment 55. The use according to Embodiment 40, further comprising one or more excipients, carriers, additives, adjuvants or binders in the tablet.

[0160] Embodiment 56. The use according to Embodiment 40, further comprising a microemulsion, a coarse emulsion, or a liquid crystal in the capsule.

[0161] Embodiment 57. A method for treating a mammal having Pitt-Hopkins syndrome, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 It is selected from the group consisting of NR', O, and S; X 2 It is selected from the group consisting of CH2, NR', O, and S; R 1 , R 2 , R 3 , R 4 and R 5R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 4 and R 5 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; However, R 1 =methyl and R 2 =R 3 =R 4 If =H, then R 5 ≠ benzyl; and R 1 If =H, then R 2 and R 3 The method comprising administering to a mammal (provided that at least one of the is ≠ H).

[0162] Embodiment 58.R 1 The method according to embodiment 57, wherein =methyl.

[0163] Embodiment 59.R 1 The method according to embodiment 57, wherein the allele is allele.

[0164] Embodiment 60.R 2 =R 3 =methyl, X2 The method according to embodiment 57, wherein =S.

[0165] Embodiment 61.R 1 = Allele, R 2 =R 3 =R 4 =R 5 =H, X 1 =NH_PilotX 2 The method according to embodiment 57, wherein =CH2.

[0166] Embodiment 62.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)3-CH2-, X 1 =NH_PilotX 2 The method according to embodiment 57, wherein =CH2.

[0167] Embodiment 63.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)2-CH2-, X 1 =NH_PilotX 2 The method according to embodiment 57, wherein =CH2.

[0168] Embodiment 64. The method according to Embodiment 57, further comprising administering the compound together with a pharmaceutically acceptable excipient or in a gel.

[0169] Embodiment 65. The method according to Embodiment 57, further comprising administering the compound together with pharmaceutically acceptable excipients and binders.

[0170] Embodiment 66. The method according to Embodiment 57, further comprising administering the compound together with a pharmaceutically acceptable excipient or in a capsule.

[0171] Embodiment 67. The method according to Embodiment 57, further comprising administering at least one anti-apoptotic compound, anti-necrotic compound, neuroprotective agent, or anti-inflammatory agent.

[0172] Embodiment 68. Anti-apoptotic compounds, anti-necrotic compounds, or neuroprotective agents include insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGFBP-3, basic fibroblast growth factor, acid fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homolog-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial cell activity Sexualization factors, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia suppressor, oncostatin M, interleukin, α-interferon, β-interferon, γ-interferon, consensus interferon, TNF-α, clomethiazole, kynurenic acid, Cemax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adrenocorticotropic hormone-(4-9) analog (ORG The method according to Embodiment 67, selected from the group consisting of 2766), disolcipine [MK-801], selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and the anti-MAdCAM-1 antibody MECA-367.

[0173] Embodiment 69. The method according to Embodiment 57, wherein the compound is cG-2-allyl P.

[0174] Embodiment 70. The method according to Embodiment 57, wherein the compound is cyclic cyclohexyl-G-2MeP.

[0175] Embodiment 71. The method according to Embodiment 57, wherein the compound is cyclic cyclopentyl-G-2MeP.

[0176] Embodiment 72. A composition for treating the symptoms of Pitt-Hopkins syndrome, comprising a pharmaceutically effective amount of a compound including cyclic glycyl-2-allylproline (cG-2-allyl P), cyclic cyclohexyl-G-2MeP, or cyclic cyclopentyl-G-2MeP.

[0177] Embodiment 73. The composition according to Embodiment 72, wherein the compound is cyclic cyclohexyl-G-2MeP.

[0178] Embodiment 74. The composition according to Embodiment 72, wherein the compound is cyclic G-2-allyl P.

[0179] Embodiment 75. The composition according to Embodiment 72, wherein the compound is cyclic cyclopentyl-G-2MeP.

[0180] Embodiment 76. A composition for treating the symptoms of Pitt-Hopkins syndrome in mammals suffering from such a disorder, comprising the formula: [ka] Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X 1 It is selected from the group consisting of NR', O, and S; X 2 It is selected from the group consisting of CH2, NR', O, and S; R 1 , R 2 , R 3 , R 4 and R 5R' is independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, combined R 4 and R 5 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; Or, combined R 2 and R 3 is -CH2-(CH2) n -CH2-, where n is an integer from 0 to 6; However, R 1 =methyl and R 2 =R 3 =R 4 If =H, then R 5 ≠ benzyl; and R 1 If =H, then R 2 and R 3 The composition comprising (provided that at least one of the elements is ≠H).

[0181] Embodiment 77.R 1 =methyl, the composition according to embodiment 76.

[0182] Embodiment 78.R 1 = Allyl, the composition according to embodiment 76.

[0183] Embodiment 79.R 2 =R 3 =methyl, X 2The composition according to embodiment 76, wherein =S.

[0184] Embodiment 80.R 1 = Allele, R 2 =R 3 =R 4 =R 5 =H, X 1 =NH_PilotX 2 The composition according to embodiment 76, wherein =CH2.

[0185] Embodiment 81.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)3-CH2-, X 1 =NH_PilotX 2 The composition according to embodiment 76, wherein =CH2.

[0186] Embodiment 82.R 1 =methyl, R 2 =R 3 =H, combined R 4 and R 5 is -CH2-(CH2)2-CH2-, X 1 =NH_PilotX 2 The composition according to embodiment 76, wherein =CH2.

[0187] Embodiment 83. The composition according to any one of Embodiments 76 to 82, further comprising the compound in a pharmaceutically acceptable excipient or in a gel.

[0188] Embodiment 84. The composition according to any one of Embodiments 76 to 83, further comprising the compound with pharmaceutically acceptable excipients and binders.

[0189] Embodiment 85. The composition according to any one of Embodiments 76 to 84, wherein use further comprises the compound in a pharmaceutically acceptable excipient or in a capsule.

[0190] Embodiment 86. The composition according to any one of Embodiments 76 to 85, further comprising at least one anti-apoptotic compound, an anti-necrotic compound, a neuroprotective agent, or an anti-inflammatory agent.

[0191] Embodiment 87. Anti-apoptotic compounds, anti-necrotic compounds, or neuroprotective agents include insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGFBP-3, basic fibroblast growth factor, acid fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homolog-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial cell activity Sexualization factors, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia suppressor, oncostatin M, interleukin, α-interferon, β-interferon, γ-interferon, consensus interferon, TNF-α, clomethiazole, kynurenic acid, Cemax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adrenocorticotropic hormone-(4-9) analog (ORG The composition according to Embodiment 86, selected from the group consisting of 2766), disolcipin [MK-801], selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and the anti-MAdCAM-1 antibody MECA-367.

[0192] Embodiment 88. The composition according to any one of Embodiments 76 to 87, wherein the compound is cyclic G-2-allyl P.

[0193] Embodiment 89. The composition according to any one of Embodiments 76 to 87, wherein the compound is cyclic cyclohexyl-G-2MeP.

[0194] Embodiment 90. The composition according to any one of Embodiments 76 to 87, wherein the compound is cyclic cyclopentyl-G-2MeP.

[0195] Embodiment 91. The composition according to Embodiment 76, further comprising one or more excipients, carriers, additives, adjuvants or binders in the tablet.

[0196] Embodiment 92. The composition according to Embodiment 76, further comprising a microemulsion, a coarse emulsion, or a liquid crystal in the capsule.

[0197] Embodiment 93. The method according to any one of Embodiments 57 to 71, wherein the treatment improves the symptoms of PTHS while being evaluated using one or more clinical tests selected from the group consisting of the Aberrant Behavior Checklist Community Edition (ABC), Vineland Adaptive Behavior Scales, Clinical Global Impression of Severity (CGI-S), Clinical Global Impression Improvement (CGI-I), and Caregiver Strain Questionnaire (CSQ), or one or more physiological tests selected from the group consisting of electroencephalogram (EEG) spike frequency, overall output in the EEG frequency band, hemispheric EEG frequency coherence, stereotyped hand movements, QTc and heart rate variability (HRV), abnormal expression or activation of ERK1 / 2 and Akt, abnormal expression of growth-related protein-43 (GAP-43), abnormal expression of synaptophysin (SYN), irregular respiration, and the correlation between cardiac and respiratory function, compared to a control animal not suffering from the disorder.

[0198] Embodiment 94. The method according to any one of Embodiments 57-71 or 93, wherein the symptoms of PTHS are cognitive impairment or cognitive dysfunction, characterized by one or more signs or symptoms of: memory loss, loss of spatial orientation, reduced learning ability, reduced ability to form short-term or long-term memories, reduced episodic memory, reduced ability to consolidate memories, reduced spatial memory, reduced synapse formation, reduced synaptic stability, executive function deficits, cognitive map and scene memory deficits, statement and relevance memory deficits, reduced rapid acquisition of constructive or connective relationships, reduced coding and recall of context-specific specific events, reduced episodic and / or episodic-like memory, anxiety, abnormal fear conditioning, abnormal social behavior, repetitive behavior, abnormal nocturnal behavior, seizure activity, abnormal spontaneous movement, abnormal expression or activation of ERK1 / 2 and Akt, and bradycardia.

[0199] Embodiment 95. The method according to any one of Embodiments 1 to 71 or 93 to 94, wherein the dose of the compound is about 0.001 mg / kg to about 600 mg / kg.

[0200] Embodiment 96. The composition according to any one of Embodiments 72 to 92, wherein the amount of the compound is sufficient to produce a dosage of the compound in the range of about 0.001 mg / kg to about 600 mg / kg.

[0201] Embodiment 97. The animal or mammal is a human, as described in one or more of Embodiments 1 to 96. [Examples]

[0202] The present disclosure will be further illustrated by the following embodiments. These embodiments are provided merely as examples and are not intended to limit the scope of the present invention.

[0203] Example 1: General method for synthesizing compounds Flash chromatography was performed using Scharlau 60 (40-60 μm mesh) silica gel. Thin-layer chromatography for analysis was performed on 0.20 mm pre-coated silica gel plates (ALUGRAM® SIL G / UV). 254 The procedure was performed on a surface, and the compounds were visualized using UV fluorescence or by heating a plate immersed in potassium permanganate in an alkaline solution.

[0204] The melting point in degrees Celsius (°C) was measured using an Electrothermal® melting point analyzer without correction.

[0205] Optical rotation was measured using a Perkin Elmer 341 polarimeter with a 10 cm path length cell at 20°C, and the unit is 10 -1 degcm 2 g -1 The sample is prepared in the required solvent at the specified concentration (g / 100cm³). 3 The samples were prepared using (measured at ). The IR spectra were recorded with a Perkin Elmer Spectrum One FT-IR spectrometer. The samples were prepared as thin films on sodium chloride disks or as solids in potassium bromide disks. Broadband signals are indicated by br. The frequency (ν) of the absorption maximum is the wavenumber (cm). -1 This is shown by ).

[0206] The NMR spectrum was obtained using a Bruker AVANCE DRX400. 1 H, 400MHz; 13 C, 100MHz) or Bruker AVANCE300 1 H, 300MHz; 13 The temperature was recorded at ambient temperature using a 75MHz spectrometer (C). 1 For H NMR data, the chemical shift values ​​are listed as parts per million (ppm) from SiMe4 to the low magnetic field, and the position (δ H The integral ratio, multiplicity (s=single line, d=double line, t=triple line, dd=double line of double lines, m=multiple lines, br=broad line), coupling constant (J / Hz), and attribution are reported sequentially. 13For 13C NMR data, chemical shift values ​​are expressed in ppm compared to CDCl3, and the position (δ) is specified. C The degree of hybridization and its attribution, as determined by the DEPT method, will be reported sequentially. 1 For the 1H NMR spectra, SiMe4 (δ0.00) or CDCl3 (δ7.26) was used as the internal reference. 13 In the 13C NMR spectrum, CDCl3 (δ77.0) was used as the internal reference. When two sets of peaks appear in the NMR spectrum due to different stereostructures around the glycine-prolineamide bond, the chemical shifts for a few cis-stereostructural isomers are marked with an asterisk (*).

[0207] The exact mass was measured and recorded using a VG-70SE mass spectrometer.

[0208] Hexane and dichloromethane were distilled before use. Methanol was dried using magnesium shavings and iodine and distilled under nitrogen. Triethylamine was dried on calcium hydride and distilled under nitrogen.

[0209] Example 2: Synthesis of (8aS)-methyl-hexahydropyrrolo[1,2-a]pyrazine-1,-dione (cyclic G-2MeP) [ka] Scheme 1: Reagents, conditions and yield: (i) LDA, THF, -78°C, iodomethane, -78->-50°C, 2 hours (63%); (ii) SOCl2, CH3OH, reflux, N2, 2.5 hours (98%); (iii) Et3N, BoPCl, CH2Cl2, room temperature, N2, 20.5 hours (78%); (iv) 10% Pd / C, CH3OH, room temperature, 15 hours (98%).

[0210] (2R,5S)-4-methyl-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one 9 n-BuLi(1.31M, 4.68cm) 3 (6.14 mmol) dry tetrahydrofuran (10 cm3 ) Diisopropylamine (0.86 cm) 3 The solution was then added dropwise to a 6.14 mmol (6.14 mmol) stirred solution under a nitrogen atmosphere at -78°C. The solution was stirred for 5 minutes, warmed to 0°C, and stirred for 15 minutes. The solution was then added to a dry tetrahydrofuran (20 cm³). 3 To a solution of oxazolidinone 8 (1.00 g, 4.09 mmol) in ) the solution was added dropwise over 20 minutes at -78°C (until it turned dark brown), and the mixture was stirred for another 30 minutes. Then, iodomethane (0.76 cm³) was added. 3 (12.3 mmol) was added dropwise over 5 minutes. The solution was heated to -50°C over 2 hours. Water (15 cm 3 Add ) and warm the solution to room temperature, then add chloroform (3 x 40 cm 3 Extraction was performed using ). The combined organic extracts were dried (MgSO4), filtered, and evaporated under reduced pressure to a dry state to obtain a dark brown semi-solid. The residue was purified by flash column chromatography (15% ethyl acetate-hexane) to obtain oxazolidinone 9 (0.67 g, 63%) as a pale yellow solid: melting point 55-57°C (literature value, 57-60°C); δ H (300MHz,CDCl3) 1.53 (3H,s,CH3), 1.72-2.02 (3H,m,Proβ-H and Proγ-H2), 2.18-2.26 (1H,m,Proβ-H), 3.15-3.22 (1H,m,Proδ-H), 3.35-3.44 (1H,m,Proδ-H) and 4.99 (1H,s,NCH).

[0211] L-2-methylprophosphate methyl hydrochloride 10 a) Use of acetyl chloride Oxazolidinone 9 (0.60 g, 2.33 mmol) was dissolved in dry methanol (15 cm³) under a nitrogen atmosphere. 3 ) dissolved in acetyl chloride (0.33 cm 3(4.66 mmol) was added dropwise to an ice-cold solution. The solution was heated under reflux for 4.5 hours, and then the solvent was removed under reduced pressure to obtain a brown oil. This was purified by flash column chromatography (10% CH3OH-CH2Cl2) to obtain hydrochloride 10 (0.2 g, 48%) as a scaly white solid: melting point 107-109°C (literature value, 106-108°C); δ H (300MHz,CDCl3)1.81(3H,s,CH3),1.93-2.14(3H,m,Proβ-H A H B and Proγ-H2), 2.33-2.39(1H, m, Proβ-H A H B ), 3.52-3.56(2H,m,Proδ-H2) and 3.82(3H,s,CO2CH3).

[0212] b) Use of thionyl chloride Dry methanol (1 cm 3 A cold solution of oxazolidinone 9 (53 mg, 0.21 mmol) in ) was mixed with thionyl chloride (0.045 cm³). 3 The solution was treated dropwise with 0.62 mmol of toluene. The solution was heated under reflux for 2.5 hours, cooled, and the solvent was removed under reduced pressure to obtain brown oil. The oil was then dissolved in toluene (5 cm³). 3 The solution was dissolved in ) and concentrated to a dry state to remove residual thionyl chloride and methanol. Then, it was purified by flash column chromatography (10% CH3OH-CH2Cl2) to obtain hydrochloride 10 (16 mg, 43%) as a scaly white solid. 1 The assignment of the 1H NMR spectrum was consistent with that reported above.

[0213] Methyl-N-benzyloxycarbonyl-glycyl-L-2-prophosphate methyl 12 Dried triethylamine (0.27 cm) 3 (1.96 mmol) dry dichloromethane (35 cm 3To a solution of hydrochloride salt 10 (0.11 g, 0.61 mmol) and N-benzyloxycarbonyl-glycine 11 (98.5%) (0.17 g, 0.79 mmol), the mixture was added dropwise at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred for 10 minutes. Bis(2-oxo-3-oxazolidinyl)phosphinate chloride (BoPCl, 97%) (0.196 g, 0.77 mmol) was added, and the resulting colorless solution was stirred for 20.5 hours. The solution was then cooled in a 10% hydrochloric acid aqueous solution (30 cm³). 3 ) and saturated sodium carbonate solution (30cm³) 3 The mixture was then washed with (MgSO4), dried, filtered, and evaporated under reduced pressure until dry. The resulting residue was purified by flash column chromatography (50-80% ethyl acetate-hexane; gradient elution) to obtain dipeptide 12 (0.18 g, 92%) as a colorless oil. Amide 12 was, 13 ¹¹C NMR analysis revealed that trans:cis exists as a 98:2 mixture of stereoisomers (the ratio was estimated from the relative resonance intensities at δ20.8 and 23.5, respectively, attributed to the Proγ-C atoms of the minority and majority of stereoisomers):[α] D -33.0 (c1.0 in MeOH); ν max (Film) / cm -1 3406,2952,1732,1651,1521,1434,1373,1329,1310,1284,1257,1220,1195,1172,1135,1107,1082,1052,1029,986,965,907,876,829,775,738 and 699;δ H (300MHz, CDCl3)1.49(3H,s,CH3),1.77-2.11(4H,m,Proβ-H2 and Proγ-H2),3.43-3.48(2H,m,Proδ-H2),3.61 (3H,s,OCH3),3.85-3.89(2H,m,Glyα-H2),5.04(2H,s,PhCH2),5.76(1H,brs,NH) and 7.21-7.28(5H,s,ArH);δ C (75MHz, CDCl3) 13.8 * (CH3,Proα-CH3),21.1(CH3,Proα-CH3),20.8* (CH2,Proγ-C),23.5(CH2,Proγ-C),38.0(CH2,Proβ-C),40.8 * (CH2,Proβ-C),43.3(CH2,Glyα-C),45.5 * (CH2,Glyα-C),46.6(CH2,Proδ-C),48.7 * (CH2,Proδ-C), 51.9 * (CH3,OCH3),52.1(CH3,OCH3),60.0 * (Quadruple, Proα-C),66.0(Quadruple,Proα-C),66.3(CH2,PhCH2),68.6 * (CH2,PhCH2),127.5(CH,Ph),127.6(CH,Ph),127.9 * (CH,Ph),128.1(CH,Ph),128.3 * (CH,Ph),136.2(quartet,Ph),155.9(quartet,NCO2),166.0(quartet,Gly-CON),169.4 * (Quadruple, Gly-CON) and 173.6 (Quadruple, CO2CH3); m / z (EI+) 334.1535 (M + .C 17 H 22 Calculated value for N2O5: 334.1529.

[0214] (8aS)-methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (cyclic G-2MeP) Methanol (8.0 cm³) 3 To a solution of dipeptide 12 (0.167 g, 0.51 mmol) in ) , 10% Pd (8.1 mg, 0.076 mmol) on activated carbon was added, and hydrogen gas was passed through the container. The resulting suspension was vigorously stirred under a hydrogen atmosphere for 15 hours. The mixture was then filtered through a Celite pad and a short silica gel plug with methanol, and the solvent was removed under reduced pressure to obtain cyclic G-2MeP (83 mg, 98%) as a yellow solid: melting point 133-135°C; [α] D -128.1 (c0.52 in MeOH); δ H(300MHz,CDCl3)1.36(3H,s,CH3),1.87-2.01(3H,m,Proβ-H A H B and Proγ-H2), 2.07-2.21(1H, m, Proβ-H A H B ), 3.45-3.64 (2H, m, Proδ-H2), 3.82 (1H, dd, J17.1 and 4.1, CH A H B NH), 3.99 (1H, d, J17.1, CH A H B NH) and 7.66(1H,brs,NH);δ C (75MHz,CDCl3) 20.2 (CH2,Proγ-C), 23.2 (CH3,Proα-CH3), 35.0 (CH2,Proβ-C), 44.7 (CH2,Proδ-C), 45.9 (CH2,CH2NH), 63.8 (quadruple,Proα-C), 163.3 (quadruple,NCO) and 173.3 (quadruple,CONH); m / z (EI+) 168.08986 (M + . C8H 12 The calculated value for N2O2 is 168.08988.

[0215] Example 3: (8aS)-methyl-spiro[cyclohexane-1,3(4H)- Synthesis of tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione (cyclic cyclohexyl-G-2-MeP) [ka] Scheme 2: Reagents, conditions and yield: (i) BnO2CCl, Na2CO3, H2O-dioxane (3:1), 19 hours, 96%; (ii) Et3N, HOAt, CIP, 1,2-dichloroethane, reflux, N2, 19 hours (23%); (iii) 10% Pd / C, CH3OH, room temperature, 17 hours (65%).

[0216] N-benzyloxycarbonyl-1-aminocyclohexane-1-carboxylic acid (14) Water-Dioxane (21cm) 3A suspension of 1-aminocyclohexanecarboxylic acid 13 (0.72 g, 5.02 mmol) and sodium carbonate (1.6 g, 15.1 mmol) dissolved in a 3:1 ratio is prepared, and benzyl chloroformate (0.79 cm³) is added to the suspension. 3 Add 5.52 mmol of diethyl ether dropwise and stir the solution at room temperature for 19.5 hours. The aqueous layer was separated from the aqueous layer by diethyl ether (60 cm³). 3 Wash with ) and acidify with 2M HCl, then ethyl acetate (2 x 60 cm 3 Extracted using ). The organic layers were combined, dried (MgSO4), filtered, evaporated under reduced pressure, and allowed to stand, yielding a colorless oil that solidified as a white solid crude carbamate 14 (1.23g, 88%): melting point 152-154℃ (literature value, 148-150℃); δ H (400MHz,CDCl3) 1.27-1.56 (3H,m,3x cyclohexyl-H), 1.59-1.73 (3H,m,3x cyclohexyl-H), 1.85-1.91 (2H,m,2x cyclopentyl-H), 2.05-2.09 (2H,m,2x cyclopentyl-H), 5.02 (1H,brs,NH), 5.12 (2H,s,OCH2Ph) and 7.27-7.36 (5H,s,Ph);δ C (100MHz,CDCl3) 21.1 (CH2, 2x cyclohexyl-C), 25.1 (CH2, 2x cyclohexyl-C), 32.3 (CH2, cyclohexyl-C), 59.0 (quadruplets, 1-C), 67.1 (CH2, OCH2Ph), 128.1 (CH, Ph), 128.2 (CH, Ph), 128.5 (CH, Ph), 136.1 (quadruplets, Ph), 155.7 (quadruplets, NCO2) and 178.7 (quadruplets, CO2H).

[0217] Methyl-N-benzyloxycarbonyl-cyclohexyl-glycyl-L-2-prophosphate methyl(15) Dried triethylamine (0.21 cm) 3 (1.5 mmol) dried 1,2-dichloroethane (26 cm 3To a solution of hydrochloride 10 (84.0 mg, 0.47 mmol), carboxylic acid 14 (0.17 g, 0.61 mmol), and 1-hydroxy-7-azabenzotriazole (16 mg, 0.12 mmol) in ) (in a nitrogen atmosphere), the mixture was added dropwise at room temperature, and the reaction mixture was stirred for 10 minutes. 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (0.13 g, 0.47 mmol) was added, and the resulting solution was heated under reflux for 21 hours, and then 10% hydrochloric acid aqueous solution (30 cm³) was added. 3 ) and saturated sodium carbonate solution (30cm³) 3 The mixture was then washed with ) and dried (MgSO4), filtered, and evaporated under reduced pressure to a dry state. The resulting residue was purified by flash column chromatography (40-50% ethyl acetate-hexane; gradient elution) to obtain amide 15 (16 mg, 9%) as a white solid. Amide 15 is, 13 ¹¹C NMR analysis revealed that trans:cis exists as a mixture of 11:1 stereoisomers (the ratio was estimated from the relative resonance intensities at δ 41.3 and 48.2, attributed to the Proδ-C atoms of the minority and majority of stereoisomers): melting point 219–222°C; [α] D -44.9(c1.31 in CH2Cl2);ν max (Film) / cm -1 3239,2927,1736,1707,1617,1530,1450,1403,1371,1281,1241,1208,1194,1165,1150,1132,1089,1071,1028,984,912,796,749,739 and 699;δ H (400MHz, CDCl3) 1.24-2.10 (17H, m, Proα-CH3, Proβ-H2, Proγ-H2 and 5x cyclohexyl-H2), 3.25-3.48 (1H, brm, Proδ-H A H B ),3.61-3.87(4H,brm,OCH3 and Proδ-H A H B ),4.92-5.19(3H,m,NH and OCH2Ph) and 7.35-7.37(5H,s,Ph);δ C(100MHz, CDCl3) 21.26 (CH2, cyclohexyl-C), 21.33 (CH2, cyclohexyl-C), 21.7 (CH3, Proα-CH3), 24.8 (CH2, cyclohexyl-C), 25.0 (CH2, Proγ-C), 29.4 * (CH2, Cyclohexyl-C), 29.7 * (CH2,cyclohexyl-C),31.1(CH2,cyclohexyl-C),31.6(CH2,cyclohexyl-C),31.9 * (CH2,Cyclohexyl-C),32.2 * (CH2,Cyclohexyl-C),32.8 * (CH2,Cyclohexyl-C),37.3(CH2,Proβ-C),41.4 * (CH2,Proδ-C),48.2(CH2,Proδ-C),52.1(CH3,OCH3),59.1(quartet,Glyα-C),66.7(CH2,OCH2Ph),67.3 * (CH2,OCH2Ph),67.4(quartet,Proα-C),128.0 * (CH,Ph),128.1 * (CH,Ph), 128.3(CH,Ph), 128.5(CH,Ph), 128.7(CH,Ph), 136.6(quadruplets,Ph), 153.7(quadruplets,NCO2), 171.0(quadruplets,Gly-CO) and 174.8(quadruplets,CO2CH3); m / z(EI+) 402.2151(M + .C 22 H 30 The calculated value for N2O5 is 402.2155.

[0218] (8aS)-methyl-spiro[cyclohexane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione(cyclic cyclohexyl-G-2MeP) Methanol (3.3 cm 3To a solution of amide 15 (40 mg, 0.01 mmol) in ) , 10% Pd (1.6 mg, 0.015 mmol) on activated carbon was added, and hydrogen gas was passed through the container. The resulting suspension was vigorously stirred under a hydrogen atmosphere for 61.5 hours, and then passed through a Celite® pad with methanol (15 cm³). 3 The filtrate was filtered using a 3D filter. The filtrate was concentrated under reduced pressure to a dry state to obtain a yellow semi-solid, which was purified by reverse-phase C18 flash column chromatography (0-10% CH3CN / H2O; gradient elution) to obtain cyclic cyclohexyl-G-2MeP (19 mg, 81%) as a white solid: melting point 174-177°C; [α] D -63.8(c1.13 in CH2Cl2);ν max (Film) / cm -1 3215,2925,2854,1667,1646,1463,1427,1276,1232,1171,1085,1014,900,868,818,783,726 and 715;δ H (400MHz, CDCl3) 1.31-1.89 (12H, m, 9x cyclohexyl-H and 8a-CH3), 1.94-2.15 (4H, m, 7-H2 and 8-H2), 2.26 (1H, td, J13.7 and 4.5, 1x cyclohexyl-H), 3.44-3.51 (1H, m, 6-H A H B ),3.79-3.86(1H,m,6-H A H B ) and 6.40(1H,brs,NH);δ C (100MHz,CDCl3) 19.5 (CH2,7-C), 20.6 (CH2,cyclohexyl-C), 20.8 (CH2,cyclohexyl-C), 24.5 (CH2,cyclohexyl-C), 25.0 (CH3,8a-CH3), 33.7 (CH2,cyclohexyl-C), 36.3 (CH2,8-C), 36.5 (CH2,cyclohexyl-C), 44.7 (CH2,6-C), 59.5 (quadruplets,8a-C), 64.0 (quadruplets,3-C), 168.1 (quadruplets,4-C) and 171.6 (quadruplets,1-C); m / z (EI+) 236.15 246 (M + .C 13 H 20The calculated value for N2O2 is 236.15248.

[0219] Example 4: Synthesis of (8aS)-allyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (cyclic G-2-allyl P) [ka] Scheme 3: Reagents, conditions and yield: (i) LDA, THF, -78°C, allyl bromide, -78->-30°C, N2, 4 hours (60%); (ii) Acetyl chloride, CH3OH, reflux, N2, 24 hours (63%); (iii) Et3N, BoPCl, CH2Cl2, room temperature, N2, 19.5 hours (45%); (iv) TFA, CH2Cl2, 1 hour, then Et3N, CH2Cl2, 23 hours (37%).

[0220] (2R,5S)-4-allyl-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one 17 n-BuLi(1.31M, 9.93cm) 3 (13.0 mmol) dry tetrahydrofuran (20 cm 3 ) Diisopropylamine (1.82 cm) 3 The solution (13.0 mmol) was added dropwise under a nitrogen atmosphere at -78°C. The solution was stirred for 5 minutes, warmed to 0°C, stirred for 15 minutes, and then dried tetrahydrofuran (40 cm³) was added. 3 Add the prooxazolidinone 16 (2.12 g, 8.68 mmol) solution to the mixture dropwise over 20 minutes at -78°C, stir the reaction mixture for a further 30 minutes, and then add allyl bromide (2.25 cm³). 3 Add 26.0 mmol of H2O (30 cm³) dropwise over 5 minutes. Slowly warm the solution to -30°C over 4 hours. 3 Quench with ) and warm the mixture to room temperature, then add chloroform (3 x 80 cm 3Extraction was performed using ). The combined organic extract was dried (MgSO4), filtered, and evaporated under reduced pressure to a dry state to obtain a dark brown semi-solid, which was purified by flash column chromatography (10-20% ethyl acetate-hexane; gradient elution) to obtain oxazolidinone 17 (1.48 g, 60%) as an orange oil that solidifies at 0°C. The NMR data for this was consistent with those reported in the literature:δ H (400MHz,CDCl3)1.58-1.92(2H,m,Proγ-H2),1.96-2.14(2H,m,Proβ-H2),2.50-2.63(2H,m,Proδ-H2),3. 12-3.23(2H,m,CH2-CH=CH2),4.97(1H,s,NCH),5.13-5.18(2H,m,CH=CH2) and 5.82-5.92(1H,m,CH=CH2);δ C (100MHz,CDCl3)25.1(CH2,Proγ-C),35.1(CH2,Proβ-C),41.5(CH2,Proδ-C),58.3(CH2,CH2CH=CH2),71.2(quadruplets,Proα-C),100.4(quadruplets,CCl3),102.3(CH,NCH),119.8(CH2,CH2CH=CH2),131.9(CH,CH2CH=CH2) and 176.1(quadruplets,C=O);m / z(CI+)284.0009[(M+H) + .C 10 H 13 35 Calculated values ​​for Cl3NO2: 284.0012, 285.9980 [(M+H)] + .C 10 H 13 35 Cl2 37 Calculated values ​​for ClNO2: 285.9982, 287.9951 [(M+H)] + .C 10 H 13 35 Cl 37 Calculated values ​​for Cl2NO2: 287.9953 and 289.9932 [(M+H) + .C 10 H 13 37 The calculated value for Cl3NO2 is 289.9923.

[0221] L-2-Prophosphate Allylmethyl Hydrochloride 18 Dry methanol (15cm 3 ) A cold solution of oxazolidinone 17 (0.64 g, 2.24 mmol) in methanol (5 cm) 3 ) Acetyl chloride (0.36 cm) 3 The solution was added dropwise with a 5.0 mmol solution. The solution was heated under reflux for 24 hours, then cooled and the solvent was removed under reduced pressure. The resulting brown oil was thawed with toluene (40 cm³). 3 The solution was dissolved in ( ), concentrated to a dry state, and residual thionyl chloride and methanol were removed. Then, it was purified by flash column chromatography (5-10% CH3OH-CH2Cl2; gradient elution) to obtain hydrochloride 18 (0.29 g, 63%) as a green solid. The NMR data for this was consistent with those reported in the literature:δ H (300MHz, CDCl3)1.72-2.25(3H,m,Proβ-H A H B and Proγ-H2), 2.32-2.52(1H, m, Proβ-H A H B ),2.72-3.10(2H,m,Proδ-H2),3.31-3.78(2H,m,CH2CH=CH2),3.84(3H,s,CO2CH3),5.20-5. 33(2H,m,CH=CH2),5.75-5.98(1H,m,CH=CH2) and 8.06(1H,brs,NH);m / z(CI+)170.1183[(M+H) + .C9H 16 [Calculated value for NO2: 170.1181]

[0222] Methyl-N-tert-butyloxycarbonyl-glycyl-L-2-prophosphate allyl 20 Dried triethylamine (0.28 cm) 3 (2.02 mmol) dry dichloromethane (35 cm 3To a solution of hydrochloride salt 18 (0.13 g, 0.63 mmol) and N-tert-butyloxycarbonyl-glycine 19 (0.14 g, 0.82 mmol) in )), the mixture was added dropwise at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred for 10 minutes. Bis(2-oxo-3-oxazolidinyl)phosphinate chloride (BoPCl, 97%) (0.20 g, 0.80 mmol) was added, and the solution was stirred for 19.5 hours. Then, a 10% hydrochloric acid aqueous solution (35 cm³) was added. 3 The mixture was then washed with a saturated aqueous solution of sodium bicarbonate (35 cm³), dried (MgSO4), filtered, and evaporated under reduced pressure to a dry state. The resulting residue was purified by flash column chromatography (40% ethyl acetate-hexane) to obtain dipeptide 20 (0.09 g, 45%) as a pale yellow oil:[α] D +33.8(c0.83 in CH2Cl2);ν max (Film) / cm -1 3419,3075,2977,2930,2874,1739,1715,1656,1499,1434,1392,1366,1332,1268,1248,1212,1168,1122,1051,1026,1003,943,919,867,830,779,739,699 and 679;δ H (300MHz, CDCl3)1.42[9H,s,C(CH3)3],1.93-2.08(4H,m,Proβ-H2 and Proγ-H2),2.59-2.67(1H,m,CH A H B CH=CH2),3.09-3.16(1H,m,CH A H B CH=CH2),3.35-3.44(1H,m,Proδ-H A H B ),3.56-3.62(1H,m,Proδ-H A H B ),3.70(3H,s,OCH3),3.89(2H,d,J4.2,Glyα-H2),5.06-5.11(2H,m,CH=CH2),5.42(1H,brs,Gly-NH) and 5.58-5.72(1H,m,CH=CH2);δ C(75MHz,CDCl3) 23.7(CH2,Proγ-C), 28.3[CH3,C(CH3)3], 35.0(CH2,Proβ-C), 37.6(CH2,CH2CH=CH2), 43.3(CH2,Glyα-C), 47.5(CH2,Proδ-C), 52.5(CH3,OCH3), 68.8(Quadratic,Proα-C), 79.5[Quadratic,C(CH3)3], 119.4(CH2,CH=CH2), 132.9(CH,CH=CH2), 155.7(Quadratic,NCO2), 166.9(Quadratic,Gly-CON) and 173.8(Quadratic,CO2CH3); m / z(EI+) 326.1845(M + .C 16 H 26 The calculated value for N2O5 is 326.1842.

[0223] (8aS)-allyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (cyclic G-2 allyl P) Dichloromethane (9cm 3 ) Dipeptide 20 (0.09 g, 0.28 mmol) solution in trifluoroacetic acid (1 cm 3 Add 0.013 mmol of chloromethane dropwise at room temperature, and stir the reaction mixture under a nitrogen atmosphere for 1 hour. Evaporate the solution under reduced pressure to obtain a colorless oil, which is then dissolved in dichloromethane (10 cm³). 3 ) dissolved in dry triethylamine (0.096 cm) 3 Add triethylamine (0.69 mmol), stir the reaction mixture for 4.5 hours, and then add triethylamine (0.096 cm³). 3 (0.69 mmol) was added. The reaction mixture was stirred overnight and concentrated to a dry state to obtain a green oil, which was purified by flash column chromatography (10% CH3OH-CH2Cl2) to obtain cyclic G-2 allyl P (20 mg, 37%) as an off-white solid: melting point 10⁶–10⁹°C; [α] D -102.7(c0.95 in CH2Cl2);ν max (CH2Cl2) / cm -13456,3226,2920,1666,1454,1325,1306,1299,1210,1133,1109,1028,1010,949,928,882,793,761 and 733;δ H (400MHz,CDCl3)1.92-2.01(2H,m,Proγ-H2),2.09-2.16(2H,m,Proβ-H2),2.39-2.56(2H,m,CH2CH2=CH2),3.46-3.53(1H,m,Proδ-H A H B ),3.78-3.87(2H,m,Proδ-H A H B and Glyα-H A H B ),4.09(1H,d,J17.2,Glyα-H A H B ),5.16-5.20(2H,m,CH=CH2),5.73-5.84(1H,m,CH=CH2) and 7.17(1H,brs,NH);δ C (100MHz,CDCl3) 20.1 (CH2,Proγ-C), 34.1 (CH2,Proβ-C), 41.7 (CH2,CH2CH2=CH2), 44.9 (CH2,Proδ-C), 46.4 (CH2,Glyα-C), 67.2 (Quadruple,Proα-C), 120.9 (CH2,CH=CH2), 131.0 (CH,CH=CH2), 163.4 (Quadruple,NCO) and 171.7 (Quadruple,CONH); m / z (EI+) 195.1132 (M + .C 10 H 15 Calculated value for N2O2: 195.1134.

[0224] Example 5: (8aS)-methyl-spiro[cyclopentane-1,3(4H)- Synthesis of tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione (cyclic cyclopentyl-G-2-MeP) [ka] Scheme 4: Reagents, conditions and yield: (i) Et3N, HOAt, CIP, 1,2-dichloroethane, 83°C, N2, 19 hours (23%); (ii) 10% Pd / C, CH3OH, room temperature, 17 hours (65%).

[0225] N-benzyloxycarbonyl-1-aminocyclopentane-1-carboxylic acid 21 Dioxane (2.5cm 3 ) A solution of benzyl chloroformate (0.290 g, 1.1 mmol) in water (5 cm) 3 To a solution of 1-aminocyclopentanecarboxylic acid (Fluka) (0.2 g, 1.54 mmol) and sodium carbonate (0.490 g, 4.64 mmol) in ), the mixture was added dropwise at 0°C. The mixture was stirred overnight at room temperature, and the reaction mixture was washed with ether. The aqueous layer was acidified with 2 M hydrochloric acid, extracted with ethyl acetate, dried to ((Na2SO4), filtered, and the solvent was removed to obtain carbamate 21 (0.253 g, 62%) as an oil that solidified upon standing. Carbamate 21 is, 1 1H NMR analysis revealed a 70:30 mixture of stereoisomers (the ratio was estimated from the integral of resonances at δ5.31 and 7.29–7.40, attributed to the NH protons of the majority and minority stereoisomers respectively): melting point 70–80°C (literature value) 1 82-86°C, ethyl acetate, petroleum ether); δ H (400MHz;CDCl3;Me4Si) 1.83 (4H,brs,2xcyclopentyl-H2), 2.04 (2H,brs,cyclopentyl-H2), 2.20-2.40 (2H,m,cyclopentyl-H2), 5.13 (2H,brs,OCH2Ph), 5.31 (0.7H,brs,NH) and 7.29-7.40 (5.3H,m,Ph and NH) * );δ C(100MHz;CDCl3) 24.6 (CH2, cyclopentyl-C), 37.5 (CH2, cyclopentyl-C), 66.0 (quadruplicate, cyclopentyl-C), 66.8 (CH2, OCH2Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quadruplicate, Ph), 155.8 (quadruplicate, NCO2), and 179.5 (quadruplicate, CO2H). * This represents resonances attributed to a small number of stereoisomers.

[0226] N-benzyloxycarbonylcyclopentyl-glycyl-L-2-methylprophosphate methyl 22 Dried triethylamine (0.19 cm) 3 (1.4 mmol) dried 1,2-dichloroethane (24 cm 3 To a solution of hydrochloride 10 (78 mg, 0.43 mmol), carboxylic acid 21 (0.15 g, 0.56 mmol), and 1-hydroxy-7-azabenzotriazole (Acros) (15 mg, 0.11 mmol), the mixture was added dropwise at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred for 10 minutes. 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) (Aldrich) (0.12 g, 0.43 mmol) was added, and the resulting solution was heated under reflux for 19 hours. Then, a 10% hydrochloric acid aqueous solution (30 cm³) was added. 3 ) and saturated sodium carbonate solution (30cm³) 3 The mixture was then washed with (MgSO4), dried, filtered, and evaporated under reduced pressure until dry. The resulting residue was purified by flash column chromatography (60% ethyl acetate-hexane) to obtain amide 22 (39 mg, 23%) as a white solid. Amide 22 is, 13 ¹¹C NMR analysis revealed that trans:cis exists as a 3:1 stereoisomer mixture of carbamate salts (the ratio was estimated from the relative resonance intensities at δ154.1 and δ155.7, which are attributed to the carbonyl-C atoms of the majority and minority stereoisomers, respectively): melting point 200–203°C; [α] D -54.5(c1.52 in CH2Cl2);νmax (Film) / cm -1 3432,3239,3042,2953,1736,1712,1627,1540,1455,1417,1439,1374,1282,1256,1216,1194,1171,1156,1136,1100,1081,1042,1020,107,953,917,876,756 and 701;δ H (400MHz, CDCl3) 1.33-1.53 ​​(3H, brm, Proα-CH3), 1.62-2.20 (11H, m, Proβ-H2, Proγ-H2 and 7x cyclopentyl-H), 2.59-2.71 (1H, brm, 1x cyclopentyl-H), 3.31-3.42 (1H, brm, Proδ-H A H B ), 3.58-3.79 (4H,brm,OCH3 and Proδ-H A H B ),4.92-5.17(3H,m,NH and OCH2Ph) and 7.27-7.42(5H,s,Ph);δ C (100MHz, CDCl3)21.7(CH3,Proα-CH3),24.1 * (CH2,cyclopentyl-C),24.2(CH2,cyclopentyl-C),24.4(CH2,Proγ-C),24.5(CH2,cyclopentyl-C),36.4(CH2,cyclopentyl-C),37.1(CH2,cyclopentyl-C),37.2 * (CH2,cyclopentyl-C),37.7(CH2,Proβ-C),38.2 * (CH2,cyclopentyl-C),48.5(CH2,Proδ-C),52.1(CH3,OCH3),66.6(CH2,OCH2Ph),66.9(quartet,Proα-C),67.2 (Quadruple, Glyα-C),127.8(CH,Ph),128.2(CH,Ph),128.4(CH,Ph),136.6(Quartet,Ph),154.1(Quadruple, NCO2),155.7 * (Quadruple, NCO2), 170.5 (Quadruple, Gly-CO) and 174.7 (Quadruple, CO2CH3); m / z (EI+) 388.1991 (M + .C 21 H 28Calculated value for N2O5: 388.1998)

[0227] (8aS)-methyl-spiro[cyclopentane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione(cyclic cyclopentyl-G-2MeP) Methanol (4.6 cm 3 To a solution of amide 22 (54 mg, 0.14 mmol) in ) , 10% Pd (2.2 mg, 0.021 mmol) on activated carbon was added, and hydrogen gas was passed through the container. The resulting suspension was vigorously stirred under a hydrogen atmosphere for 17 hours, and then passed through a Celite® pad and sterilized with methanol (15 cm³). 3 The solution was filtered using a filtration apparatus. The filtrate was concentrated under reduced pressure to a dry state to obtain a yellow semi-solid, which was purified by reverse-phase C18 flash column chromatography (0-10% CH3CN / H2O; gradient elution) to obtain cyclic cyclopentyl-G-2MeP (20 mg, 65%) as a yellow solid: melting point 160-163°C; [α] D -97.9(c1.61 in CH2Cl2);ν max (Film) / cm -1 3429,2956,2928,2856,1667,1643,1463,1432,1373,1339,1254,1224,1175,1086,1048,976,835,774 and 730;δ H (300MHz, CDCl3) 1.47 (3H, brs, 8a-CH3), 1.56-2.19 (11H, m, 8-H2, 7-H2 and 7x cyclopentyl), 2.58-2.67 (1H, brm, 1x cyclopentyl), 3.48-3.56 (1H, m, 6-H A H B ),3.72-3.82(1H,m,6-H A H B ) and 6.56(1H,brs,NH);δ C(75MHz,CDCl3) 19.9 (CH2,7-C), 24.6 (CH2,cyclopentyl), 24.92 (CH3,8a-CH3), 24.93 (CH2,cyclopentyl), 36.0 (CH2,8-C), 38.7 (CH2,cyclopentyl), 41.9 (CH2,cyclopentyl), 44.8 (CH2,6-C), 64.3 (quadruplets,8a-C), 66.8 (quadruplets,3-C), 168.3 (quadruplets,4-C) and 172.2 (quadruplets,1-C); m / z (EI+) 222.1369 (M + .C 12 H 18 Calculated value for N2O2: 222.1368.

[0228] In Vitro and In Vivo trials The following pharmacological studies demonstrate the efficacy of cyclic G-2-allyl P in reducing the symptoms of PTHS. These are not intended to limit the scope of the present invention, and other compositions and methods may be developed without excessive experimentation. All such compositions and methods are considered part of this disclosure. All of the following experiments were conducted using protocols developed under guidelines approved by the University of Chile Animal Ethics Committee or an equivalent regulatory body.

[0229] Example 6: Delivery of cG2-allyl P into the brain after oral administration In an in vivo study, male Sprague Dawley rats (14 weeks old) were administered a single oral dose of cG-2-allyl P (either 100 mg / kg or 200 mg / kg). Cerebrospinal fluid (CSF) and whole blood were collected at 1.5 hours and 4 hours post-administration, and brain tissue was collected at 4 hours post-administration to assess cG-2-allyl P exposure. Table 1 below shows the levels of cG-2-allyl P in CSF and blood at 1.5 hours post-administration, and in CSF, blood, and brain at 4 hours post-administration.

[0230] [Table 1]

[0231] The concentrations of cG-2-allyl P in blood and CSF 1.5 hours after a single oral administration, and in blood, CSF, and brain 4 hours after administration, increased almost proportionally. The concentrations of cG-2-allyl P in blood and brain tissue 4 hours after administration were almost the same.

[0232] Example 7: Tcf4 in Pitt-Hopkins syndrome + / - Effects of cG-2-allyl P in mouse models A. Relevance of mouse models Several genetically modified PTHS rodent models have been created (Thaxton et al, 2018; Sweatt, 2013). These models are heterozygous Tcf4 (Tcf4 + / - They share a common base around them. Haploinsufficient mice (Tcf4 + / - ) has been characterized as a model system for PTHS (Kennedy et al, 2016). In the study by Kennedy et al (2016), Tcf4 + / - The mice were found to exhibit behaviors consistent with cognitive and motor dysregulation disorders associated with PTHS, including aversion to social interaction, lack of learning ability, and impaired overall motor control.

[0233] B. Experimental Design In vivo behavioral studies were conducted by Gen.DDI (Santiago, Chile) at Tcf4 + / - The experiment was conducted using mutant mice and wild-type litter control (WT) mice. The litter control was Tcf4 + / +The Tcf4 mutants consist of the following genotypes. Since homozygous Tcf4 mutants are lethal from the embryonic stage to the first day after birth, all Tcf4 mutant mice used were heterozygous Tcf4 mutants. Ten 14-week-old mice were used per treatment group for behavioral experiments. The experiments were conducted in accordance with the requirements of the UK Animals (Scientific Procedures) Act, 1986. Five mice were housed in plastic cages (35 × 30 × 12 cm) and acclimated to the animal facility for at least one week before the start of the experiment. Room temperature (21°C ± 2°C), relative humidity (55% ± 5%), a 12-hour light-dark cycle (lights on from 7 AM to 7 PM), and air exchange were automatically controlled. The animals had free access to commercially available solid feed and water. The experiments were conducted during the light phase of the circadian cycle, and the order of the experiments was determined by the principle of performing the most stressful experiment last. The assay was performed using Tcf4 + / - It was designed to reproduce and extend the original behavioral characteristics of mice. Tcf4 + / - WT control mice were treated for 6 weeks prior to the experiment and tested 30 minutes after administration of cG-2-allyl P, as shown in Table 2 below.

[0234] [Table 2]

[0235] Example 8: Reduced activity in open fields The open-field (OF) test is a combined test used to assess anxiety / hyperactivity and to evaluate habituation to novel environments, one of the most rudimentary forms of learning. In this test, the reduction in exploration due to repeated exposure to the same environment is considered an indicator of memory. This test is typically studied using two open-field exposure sessions, consisting of 10-minute and 24-hour habituation sessions.

[0236] The device used in this study is a 50 x 30 cm gray PVC enclosed activity area divided into 10 cm squares. Mice are placed in the laboratory 5 to 20 minutes before the experiment. Mice are placed in a corner section facing a corner and observed for 3 minutes. The number of sections (entire body) entered and the number of times they stand up (both forelegs off the ground, excluding grooming) are counted. The latency to the first stand-up is also noted. The movement of the mice within the field is recorded for 300 seconds using a video tracking device (vNT4.0, Viewpoint). The latency to the mouse entering the brightest central area of ​​the field, the time spent in this central area, and the total activity (in centimeters) are recorded.

[0237] The open field (OF) test is used to characterize exploratory behavior, anxiety, and / or reduced activity and hyperactivity in animals accustomed to daily handling under novel and familiar conditions. During exposure to the open field, mice become accustomed to the environment, and over time, their exploratory behavior decreases and their movement decreases.

[0238] In this experiment, movement and standing were recorded at the time of the first exposure (T1), the second exposure 10 minutes later (T2), and the third exposure 24 hours later (T3). If spontaneous movement or standing did not decrease at 10 minutes and 24 hours, it indicated short-term memory and long-term memory deficits, respectively.

[0239] An open-field study was conducted to evaluate whether cG-2-allyl P is effective in treating the reduced activity of PTHS. Over 30-minute trial sessions, Tcf4 + / - Compared to WT littermates, lower scores were detected in the measurement of open-field spontaneous movement.

[0240] The results are shown in Figure 2.

[0241] The vertical axis shows the relative distance traveled, and the horizontal axis shows the animals and their treatment methods. Wild-type (WT) mice treated with vehicle alone (left column) are considered to have traveled 100%. Tcf4 mice treated with vehicle alone + / - The mice (second column from the left) showed only about 60% of the mobility of the wild-type (WT) mice, indicating reduced activity. WT mice treated with NNZ-2591 (cG-2-allyl P) (third column from the left) showed slightly higher mobility than WT mice treated with vehicle alone, but this difference was small and not statistically significant. Tcf4 treated with vehicle alone + / - In contrast to mice, Tcf4 treated with 100 mg / kg of NNZ-2591 (cG-2-allyl P) + / - Surprisingly, the mice (fourth column from the left) showed almost the same mobility as WT mice treated with vehicle alone. WT mice treated with 200 mg / kg of NNZ-2591 (cG-2-allyl P) (fifth column from the left) showed almost the same mobility as WT mice treated with either vehicle alone or 100 mg / kg of NNZ-2591 (cG-2-allyl P). The effect of NNZ-2591 (cG-2-allyl P) was statistically significant. The inventors found that NNZ-2591 (cG-2-allyl P) at either 100 mg / kg or 200 mg / kg improved Tcf4 + / - We conclude that this mild to moderate decrease in activity in mice was normalized.

[0242] Open field (reduced activity) ANOVA = Analysis of Variance; ns = Not statistically significant; WT = Wild-type littermate control; **** =p<0.00001

[0243] [Table 3]

[0244] [Table 4]

[0245] Example 9: Self-grooming Repetitive self-grooming is a characteristic of mice. Tcf4 + / - In mice, the frequency of self-grooming has been shown to increase compared to wild-type mice. NNZ-2591 (cG-2-allyl P) is used to treat Tcf4 + / - To determine whether self-grooming behavior in mice could be normalized, a series of studies were conducted, as shown in Figure 3.

[0246] The vertical axis shows the time spent grooming during a 10-minute test (in seconds), and the horizontal axis shows the animal and treatment method. Wild-type (WT) mice treated with vehicle alone (left column) groomed themselves for approximately 110 seconds. Tcf4 mice treated with vehicle alone + / - Mice (second column from the left) performed more self-grooming compared to WT mice treated with vehicle alone. WT mice treated with 100 mg / kg of NNZ-2591 (cG-2-allyl P) (third column from the left) performed self-grooming for almost the same amount of time as WT mice treated with vehicle alone. This difference was not statistically significant. Unexpectedly, Tcf4 treated with 100 mg / kg of NNZ-2591 (cG-2-allyl P; fourth column from the left) or 200 mg / kg (right column) showed a significant difference. + / - In mice, the self-grooming time was almost the same as that of mice treated with a WT vehicle, and Tcf4 treated with vehicle alone + / - It was observed that the time spent by the mice on self-grooming was shorter than the time spent on self-grooming. This statistically significant finding was observed in Tcf4. + / - This was completely unexpected in mice.

[0247] Self-grooming / repetitive behavior ANOVA = Analysis of Variance; ns = Not statistically significant; WT = Wild-type littermate control **** =p<0.0001

[0248] [Table 5]

[0249] [Table 6]

[0250] The inventors of the present invention have identified Tcf4 + / - We conclude that the increased repetitive behavior (self-grooming) resulting from the mutation was corrected by treatment with cG-2-allyl P at either a dose of 100 mg / kg or 200 mg / kg.

[0251] Example 10: Fear Conditioning Fear conditioning to either an event or a context is a well-studied form of associative learning in many species. In mice, fear is often expressed by stopping movement, also known as freezing. Freezing is adaptive for predators, as they often locate moving prey. The dependent indicator used in contextual (delayed) fear conditioning is the freezing response that occurs after pairing an unconditioned stimulus (foot shock) with a conditioned stimulus (CS; e.g., an audible sound), a specific context, and / or cues. If a foot shock paired with a sound is administered in the context being conditioned, not only the sound but also the context will be learned.

[0252] Contextual fear conditioning is a fundamental method of conditioning. This method involves placing an animal in a novel environment, introducing an aversive stimulus, and then removing it. If the animal has memorized and associated the environment with the aversive stimulus, it will generally exhibit a freezing response when returned to the same environment. Freezing is a response to fear and is defined as "being unable to move except breathing." This freezing behavior can last from a few seconds to several minutes, depending on the intensity of the aversive stimulus, the number of times it has been presented, and the degree of learning achieved by the subject.

[0253] TCF4 + / -Animals with the mutation have been shown to exhibit less freezing behavior than wild-type mice. This maladaptive behavior can have serious consequences. Therefore, NNZ-2591 (cG-2-allyl P) is used to treat Tcf4 + / - A series of studies were conducted to determine whether normal fear conditioning could be restored in mice. Figure 4 shows the results of these studies.

[0254] The vertical axis of Figure 4 shows the percentage of time spent in freezing over a 5-minute test period. The horizontal axis shows the animals and their treatment methods.

[0255] Wild-type mice treated with vehicle alone (left column) spent approximately 50% of their time freezing. In contrast, Tcf4 + / - In mice (second column from the left), a significant reduction was observed in the time spent in freezing behavior. This was statistically significant.

[0256] Wild-type mice treated with either 100 mg / kg (third column from the left) or 200 mg / kg (fifth column from the left) of NNZ-2591 (cG-2-allyl P) exhibited freezing behavior for almost the same duration as wild-type mice treated with vehicle alone.

[0257] Tcf4 treated with vehicle + / - In contrast to wild mice, mice treated with either 100 mg / kg (fourth column from the left) or 200 mg / kg (right column) spent similar amounts of time freezing as wild-type mice. The difference between wild-type and 200 mg / kg treated animals was not statistically significant. However, mice treated with NNZ-2591 (cG-2-allyl P) spent less time freezing than Tcf4 treated with the vehicle. + / - It was significantly and statistically more long than that of mice.

[0258] Fear conditioning ANOVA = Analysis of Variance; ns = Not statistically significant; WT = Wild-type littermate control; **** =p<0.0001: *** =p<0.001;* =p<0.05

[0259] [Table 7]

[0260] [Table 8]

[0261] Example 11: Social Interaction Social cognition and social memory are extremely important in humans. Studies have shown that individuals with PTHS have less social cognition and social memory compared to individuals without PTHS. Similarly, Tcf4 + / - Studies have shown that mice exhibit significantly reduced social interaction compared to wild-type mice. Therefore, a series of studies were conducted in mice to determine whether NNZ-2591(cG-2-allyl P) could be effective in normalizing this condition. In these studies, the time spent by mice sniffing novel mice was measured.

[0262] To conduct these studies, exposures were repeatedly induced to induce intimacy and restore olfactory behavior to a high level upon introduction of novel stimulus animals. Mice were evaluated based on the time spent olfactorying the novel mice. The number of olfactory behavior occurrences in each group of animals was measured. The results of these studies are shown in Figure 5. The vertical axis represents the time spent olfactorying the novel mice, and the horizontal axis represents the animals and treatment methods.

[0263] The time spent by WT mice treated with vehicle alone (left column) sniffing novel mice was used as the control in the experiment. + / -In mice (second column from the left), the time spent smelling novel mice was significantly reduced. In WT mice treated with either 100 mg / kg (third column from the left) or 200 mg / kg (fifth column from the left), the time spent smelling novel mice was nearly the same. Tcf4 treated with either 100 mg / kg (fourth column from the left) or 200 mg / kg (right column) of cG-2-allyl P + / - In mice, Tcf4 treated with vehicle alone + / - Compared to mice, the amount of time spent with novel mice increased significantly and statistically.

[0264] sociability ANOVA = Analysis of Variance; ns = Not statistically significant; WT = Wild-type littermate control; **** =p<0.0001

[0265] [Table 9]

[0266] Example 12: Nest building Nest building is an activity necessary for mice to raise their offspring and serves as an indicator of social adaptation and daily living activities. Tcf4 + / - Mice build nests of significantly lower quality than wild-type mice. Therefore, a series of studies were conducted to determine whether NNZ-2591 (cG-2-allyl P) could restore nest-building quality. The results are shown in Figure 6. The vertical axis shows nest-building quality on a scale of 1 to 5, and the horizontal axis shows the animals and treatments.

[0267] Wild-type mice treated with vehicle alone showed a nest-building quality of approximately 5. In contrast, Tcf4 mice treated with vehicle alone showed a different level of nest-building quality. + / -Mice (second column from the left) produced nests of significantly lower quality. WT mice treated with either 100 mg / kg (third column from the left) or 200 mg / kg (fifth column from the left) of NNZ-2591 (cG-2-allyl P) produced nests of nearly the same quality as WT mice treated with vehicle. Tcf4 treated with either 100 mg / kg (fourth column from the left) or 200 mg / kg (right column) of NNZ-2591 (cG-2-allyl P) produced nests of nearly the same quality as those of WT mice treated with vehicle. + / - In mice, nest quality was normalized to almost the same level as that of WT mice. Tcf4 treated with NNZ-2591 + / - Regarding the differences in the quality of nests made by mice, Tcf4 treated with vehicle alone was used. + / - The results were significantly and statistically more favorable than those created by mice.

[0268] Daily Life Test ANOVA = Analysis of Variance; ns = Not statistically significant; WT = Wild-type littermate control; **** = p < 0.0001.

[0269] [Table 10]

[0270] [Table 11]

[0271] Example 13: Hind limb strength Hindlimb strength is important for measuring a mouse's ability to jump away from predators. However, Tcf4 + / - In animals with the mutation, the ability to jump away from predators is significantly reduced, making this mutation very serious and potentially life-threatening. Furthermore, hind limb strength is considered a substitute for human motor function. A series of studies measuring hind limb strength were conducted to determine whether NNZ-2591 (cG-2-allyl P) could provide a useful treatment for this condition. These results are shown in Figure 7. The vertical axis represents force in Newtons (N), and the horizontal axis represents the animal and treatment.

[0272] Wild-type mice treated with the vehicle alone were able to generate a force of approximately 0.8 N. In contrast, Tcf4 mice treated with the vehicle... + / - The mice (second column from the left) were only able to generate approximately 0.3 N. This is a significant and statistically important deficit. WT mice treated with either 100 mg / kg (third column from the left) or 200 mg / kg (fifth column from the left) of NNZ-2591 were able to generate nearly the same level of force as WT mice treated with the vehicle. Tcf4 treated with either 100 mg / kg (fourth column from the left) or 200 mg / kg (right column) of NNZ-2591 + / - In mice, the force generated was nearly the same as that generated by wild-type mice. In contrast, Tcf4 treated with either 100 mg / kg (fourth column from the left) or 200 mg / kg of NNZ-2591 was also shown. + / - The mice were treated with Tcf4 in a vehicle. + / - The mice were able to generate significantly greater and statistically more force than mice. Therefore, the inventors conclude that weakness and motor dysfunction caused by PTHS can be normalized by treatment with cG-2-allyl P.

[0273] Strength test (hind limbs) ANOVA = Analysis of Variance; ns = Not statistically significant; WT = Wild-type littermate control; **** =p<0.00001.

[0274] [Table 12]

[0275] [Table 13]

[0276] overview As summarized in Table 3, Tcf4 + / -In a mouse model, treatment with 200 mg / kg of cG-2-allyl P for 6 weeks resulted in the recovery of all tested PTHS phenotypic behaviors. Treatment with 100 mg / kg of cG-2-allyl P resulted in the recovery of all tested behaviors except fear conditioning. Although fear conditioning improved, a significant difference from the wild type remained.

[0277] [Table 14]

[0278] References: All patents and patent applications referenced, as well as the following references, are incorporated herein in full by reference.

[0279] Amiel J, Rio M, de Pontual L, et al. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet. 2007;80(5):988-993. Bertrand N, Castro DS, Guillemot F. Proneural genes and the specification of neural cell types. Nat Rev Neurosci. 2002;3(7):517-530. Blake DJ, Forrest M, Chapman RM, et al. TCF4, schizophrenia, and Pitt-Hopkins Syndrome. Schizophr Bull. 2010;36(3):443-447. doi: https: / / doi. org / 10. 1093 / schbul / sbq035. Brockschmidt A, Todt U, Ryu S, et al. Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum Mol Genet. 2007;16(12):1488-1494. Brzozka MM, Radyushkin K, Wichert SP, Ehrenreich H, Rossner MJ. Cognitive and Sensorimotor Gating Impairments in Transgenic Mice Overexpressing the Schizophrenia Susceptibility GeneTcf4in the Brain. Biol Psychiatry. 2010;68(1):33-40. https: / / doi.org / 10. 1016 / j .biopsych. 2010. 03.015. Crux S, Herms J, Dorostkar MM. Tcf4 regulates dendritic spine density and morphology in the adult brain. PLoS ONE. 2018;13(6):e0199359. https: / / doi. org / 10.1371 / journal. pone. 0199359. de Pontual L, Mathieu Y, Golzio C, et al. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins Syndrome. Hum Mutat. 2009;30(4):669-676. Flora A, Garcia JJ, Thaller C, Zoghbi HY. The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc Nat Acad Sci U.S.A. 2007;104(39):15382-15387. DOI:10.1073 / pnas.0707456104. Forrest MP, Waite AJ, Martin-Rendon E, Blake DJ. Knockdown of humanTCF4affects multiple signaling pathways involved in cell survival, epithelial to mesenchymal transition and neuronal differentiation. PLoS One. 2013;8(8):e73169. https: / / doi.org / 10.1371 / journal.pone. 0073169. Guan J, Mathai S, Harris P, et al. Peripheral administration of a novel diketopiperazine, NNZ2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats. Neuropharmacology. 2007;53(6):749-762. https: / / doi.org / 10.1016 / j.neuropharm. 2007.08.010. Guan J, Zhang R, Dale-Gandar L, Hodgkinson S, Vickers MH. NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat. Behav Brain Res. 2010;210(2):221-228. https: / / doi.org / 10.1016 / j.bbr.2010.02.039 Guan J, Gluckman P, Yang P et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1.Sci Rep. 2014;4:4388. DOI:10.1038 / srep04388. Kennedy AJ et al. Tcf4Regulates Synaptic Plasticity, DNA Methylation, and Memory Function. Cell Rep. 2016 Sep 6;16(10): 2666-2685.10.1016 / j.celrep.2016. 08.004. Krishnamurthi RV, Mathai S, Kim AH, Zhang R, Guan J. A novel diketopiperazine improves functional recovery given after the onset of 6-OHDA-induced motor deficit in rats. Br J Pharmacol. 2009;156(4):662-672. Navarrete K, Pedroso I, De Jong S, et al. TCF4 (e2-2;ITF2): A schizophrenia-associated gene with pleiotropic effects on human disease. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(1):1-16. doi:https: / / doi.org / 10.1002 / ajmg.b. 32109. Pscherer A, Dorflinger U, Kirfel J, et al. The helix‐loop‐helix transcription factor SEF‐2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene. EMBO J. 1996;15(23):6680-6690. https: / / doi.org / 10.1002 / j.1460-2075. 1996. tb01058.x Rosenfeld JA, Leppig K, Ballif BC, et al. Genotype-phenotype analysis ofTCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet Med. 2009;11(11):797-805. Sepp M, Kanike K, Eesmaa A, Urb M, Timmusk T. Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5’ exon usage and splicing. PLoS One. 2011;6(7):e22138. doi:10.1371 / journal.pone.0022138. Sweatt JD. Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med. 2013;45:e21. doi:10.1038 / emm.2013.32. Sweetser DA, Elsharkawi I, Yonker L, et al. Pitt-Hopkins Syndrome. 2012 Aug 30 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews(Registered Trademark) [Internet]. Seattle (WA): University of Washington, Seattle;1993-2019. Thaxton C, Kloth AD, Clark EP, Moy SS, Chitwood RA, Philpot BD. Common Pathophysiology in Multiple Mouse Models of Pitt-Hopkins Syndrome. JNeurosci.2018;24;38(4):918-936. doi: 10.1523 / JNEUROSCI.1305-17.2017. Epub 2017 Dec 8. UK Animals (Scientific Procedures) Act, 1986. United States Census Bureau, Population Clock;July 12th 2019;0.045 UTC. www. census.gov / popclock. [Industrial applicability]

[0280] The embodiments of this disclosure are useful in medical and veterinary technologies and can be used industrially.

Claims

1. A method for treating mammals with Pitt-Hopkins syndrome, comprising the formula: 【Chemistry 1】 Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X １ It is selected from the group consisting of NR', O, and S; X ２ CH ２ Selected from the group consisting of NR', O, and S; R １ 、R ２ 、R ３ 、R ４ and R ５ are independently selected from the group consisting of -H, -OR', -SR', -NR'R', -NO ２ , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, R together ４ and R ５ is, -CH ２ - (CH ２ ) ｎ -CH ２ - where n is an integer from 0 to 6; Or, R together ２ and R ３ is, -CH ２ - (CH ２ ) ｎ -CH ２ - where n is an integer from 0 to 6; However, R １ = Methyl and R ２ = R ３ = R ４ If = H, then R ５ ≠ benzyl; and R １ If = H, then R ２ and R ３ The method comprising administering to the mammal (provided that at least one of the is ≠ H).

2. R １ The method according to claim 1, wherein the result is methyl.

3. R １ The method according to claim 1, wherein the allyl is used.

4. R ２ = R ３ = Methyl, X ２ The method according to claim 1, wherein = S.

5. R １ = Allele, R ２ = R ３ = R ４ = R ５ = H, X １ =NH, X ２ =CH ２ The method according to claim 1.

6. R １ = Methyl, R ２ = R ３ = H, R which became one ４ and R ５ is, -CH ２ - (CH ２ ) ３ -CH ２ -, X １ =NH, X ２ =CH ２ The method according to claim 1.

7. R １ = Methyl, R ２ = R ３ = H, R which became one ４ and R ５ is, -CH ２ - (CH ２ ) ２ -CH ２ -, X １ =NH, X ２ =CH ２ The method according to claim 1.

8. The method according to any one of claims 1 to 7, further comprising administering the compound together with a pharmaceutically acceptable excipient or in a gel.

9. The method according to any one of claims 1 to 8, further comprising administering the compound together with pharmaceutically acceptable excipients and binders.

10. The method according to any one of claims 1 to 9, further comprising administering the compound together with a pharmaceutically acceptable excipient or in a capsule.

11. The method according to any one of claims 1 to 10, further comprising administering at least one anti-apoptotic compound, anti-necrotic compound, neuroprotective agent, or anti-inflammatory agent.

12. The aforementioned anti-apoptotic compounds, anti-necrotic compounds, or neuroprotective agents include insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGFBP-3, basic fibroblast growth factor, acid fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homolog-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial cell activator, F GF-10, FGF-16, Ciliary Neurotrophic Factor, Brain-Derived Growth Factor, Neurotrophin 3, Neurotrophin 4, Bone Morphogenic Protein 2 (BMP-2), Glial Cell-Derived Neurotrophic Factor, Activity-Dependent Neurotrophic Factor, Cytokine Leukemia Suppressor Factor, Oncostatin M, Interleukin, α-Interferon, β-Interferon, γ-Interferon, Consensus Interferon, TNF-α, Clomethiazole, Kynurenic Acid, Semax, Tacrolimus, L-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, Adrenocorticotropic Hormone-(4-9) Analogue (ORG) The method according to claim 11, comprising a selection from the group consisting of 2766), disolcipin [MK-801], selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and the anti-MAdCAM-1 antibody MECA-367.

13. The method according to claim 1, wherein the compound is cG-2-allyl P.

14. The method according to claim 1, wherein the compound is cyclic cyclohexyl-G-2MeP.

15. The method according to claim 1, wherein the compound is cyclic cyclopentyl-G-2MeP.

16. The aforementioned procedures include Aberrant Behavior Checklist Community Edition (ABC), Vineland Adaptive Behavior Scales, Clinical Global Impression of Severity (CGI-S), Clinical Global Impression Improvement (CGI-I), and Caregiver Strain. The method according to any one of claims 1 to 15, which improves the symptoms of the disorder while evaluating using one or more clinical tests selected from the group consisting of Questionnaire (CSQ), electroencephalogram (EEG) spike frequencies, overall output in the EEG frequency band, hemispheric EEG frequency coherence, stereotyped hand movements, eye tracking, QTc variability, heart rate variability (HRV), irregular breathing, and abnormal correlations between cardiac and respiratory function, compared to a control animal without the disorder.

17. The method according to any one of claims 1 to 16, wherein the treatment reduces at least one symptom selected from the group consisting of anxiety, depression, cognitive impairment, cognitive dysfunction, memory loss, loss of spatial orientation, reduced learning ability, reduced ability to form short-term or long-term memories, reduced episodic memory, reduced ability to consolidate memories, reduced spatial memory, reduced synapse formation, reduced synaptic stability, executive function deficits, cognitive map and scene memory deficits, statement and related memory deficits, reduced rapid acquisition of constructive or connective relationships, reduced coding and recall of context-specific specific events, reduced episodic and / or episodic-like memory, abnormal fear conditioning, abnormal social behavior, repetitive behavior, abnormal nocturnal behavior, seizure activity, abnormal spontaneous movement, abnormal expression of phosphorylated ERK1 / 2, abnormal expression of phosphorylated Akt, and bradycardia.

18. A composition for treating the symptoms of Pitt-Hopkins syndrome in mammals suffering from such a disorder, comprising the formula: 【Chemistry 2】 Compounds of or pharmaceutically acceptable salts or hydrates thereof (where, X １ It is selected from the group consisting of NR', O, and S; X ２ CH ２ Selected from the group consisting of NR', O, and S; R １ , R ２ , R ３ , R ４ and R ５ -H, -OR', -SR', -NR'R', -NO ２ Each R' is independently selected from the group consisting of -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', trihalomethyl, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl; each R' is independently selected from the group consisting of -H, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Or, R together ４ and R ５ is, -CH ２ - (CH ２ ) ｎ -CH ２ - where n is an integer from 0 to 6; Or, R together ２ and R ３ is, -CH ２ - (CH ２ ) ｎ -CH ２ - where n is an integer from 0 to 6; However, when R １ = methyl and R ２ = R ３ = R ４ = H, then R ５ ≠ benzyl; and R １ If = H, then R ２ and R ３ The composition comprising (provided that at least one of the is not equal to H).

19. R １ The composition according to claim 18, wherein the methyl

20. R １ The composition according to claim 18, wherein R is allyl.

21. R ２ = R ３ = Methyl, X ２ The composition according to claim 18, wherein = S.

22. R １ = Allele, R ２ = R ３ = R ４ = R ５ = H, X １ =NH, X ２ =CH ２ The composition according to claim 18.

23. R １ = Methyl, R ２ = R ３ = H, R which became one ４ and R ５ is, -CH ２ - (CH ２ ) ３ -CH ２ -, X １ =NH, X ２ =CH ２ The composition according to claim 18.

24. R １ = Methyl, R ２ = R ３ = H, R which became one ４ and R ５ is, -CH ２ - (CH ２ ) ２ -CH ２ -, X １ =NH, X ２ =CH ２ The composition according to claim 18.

25. The composition according to any one of claims 18 to 24, further comprising the compound in a pharmaceutically acceptable excipient or in a gel.

26. The composition according to any one of claims 18 to 25, further comprising the compound with pharmaceutically acceptable excipients and binders.

27. The composition according to any one of claims 18 to 26, wherein use further comprises the compound in a pharmaceutically acceptable excipient or in a capsule.

28. The composition according to any one of claims 18 to 27, further comprising at least one anti-apoptotic compound, anti-necrotic compound, neuroprotective agent, or anti-inflammatory agent.

29. The aforementioned anti-apoptotic compounds, anti-necrotic compounds, or neuroprotective agents include insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGFBP-3, basic fibroblast growth factor, acid fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-inducible growth factor, int-2, fibroblast growth factor homolog-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, and glial cell activator. Child, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia suppressor, oncostatin M, interleukin, α-interferon, β-interferon, γ-interferon, consensus interferon, TNF-α, clomethiazole, kynurenic acid, Cemax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, adrenocorticotropic hormone-(4-9) analog (ORG The composition according to claim 28, selected from the group consisting of 2766), disolcipin [MK-801], selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and the anti-MAdCAM-1 antibody MECA-367.

30. The composition according to any one of claims 18 to 29, wherein the compound is cyclic G-2-allyl P.

31. The composition according to any one of claims 18 to 29, wherein the compound is cyclic cyclohexyl-G-2MeP.

32. The composition according to any one of claims 18 to 29, wherein the compound is cyclic cyclopentyl-G-2MeP.

33. The composition according to any one of claims 18 to 32, further comprising one or more excipients, carriers, additives, adjuvants or binders in the tablet.

34. The composition according to any one of claims 18 to 33, further comprising a microemulsion, a coarse emulsion, or a liquid crystal in a capsule.

35. The method according to any one of claims 1 to 17, wherein the dose of the compound is about 0.001 mg / kg to about 600 mg / kg.

36. The composition according to any one of claims 18 to 34, wherein the amount of the compound is sufficient to produce a dosage of the compound in the range of about 0.001 mg / kg to about 600 mg / kg.

37. The animal or mammal is a human, as described in any one or more of claims 1 to 36.

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