Methods for treating benzodiazepine misuse / use disorder

Abstract

Compositions and methods for treating benzodiazepine misuse and / or use disorders are disclosed. The methods for treating benzodiazepine misuse and / or use disorders include administering GABA A It involves administering to a subject in need thereof an effective amount of a compound that produces both a partial modulatory effect and a partial antagonist effect at the receptor.

Description

[Technical Field]

[0001] Statement regarding federally funded research

[0001] This invention was made with the support of the U.S. Government under grant number DA011792, awarded by the National Institute on Drug Abuse. The U.S. Government has certain rights in this invention. Technical field

[0002] This disclosure relates to compositions for use in treating benzodiazepine misuse and / or use disorders, and related methods for using such compounds to treat benzodiazepine misuse and / or use disorders. [Background technology]

[0002] Related technologies

[0003] Benzodiazepines were originally developed as anxiety-reducing ("anxiolytic") and sedatives to treat anxiety and sleep disorders. Commonly prescribed benzodiazepines include diazepam (trade name: Valium®), alprazolam (trade name: Xanax®), clonazepam (trade name: Klonopin®), lorazepam (trade name: Ativan®), midazolam (trade name: Versed®), and temazepam (trade name: Restoril®). The core of a benzodiazepine is a condensate of a benzene ring and a diazepine ring, with a phenyl group attached to the diazepine, sometimes substituted.

[0003]

[0004] Since their introduction in the 1960s, benzodiazepines have been associated with a tendency towards abuse and dependence. Benzodiazepine abuse can be characterized as “misuse” (use outside of prescription instructions) and “use disorder” (a mental disorder in which benzodiazepine intake is not controlled, is harmful to psychosocial functioning, and is usually accompanied by physical dependence, as defined by WHO guidelines).

[0004]

[0005] Recent epidemiological findings suggest that benzodiazepine abuse, along with misuse, appears to be increasing among U.S. adults, who account for nearly 20% of overall substance use. Benzodiazepine prescription rates remain relatively high in the U.S. (approximately 8% of the population), and are prescribed to women at roughly three times higher rates than men across all age groups. Hospitalizations in the U.S. due to benzodiazepine use increased 43% between 2006 and 2016. Of particular concern is the increase in deaths from overdoses caused by benzodiazepines combined with opioids. In addition, coupled with the COVID-19 pandemic, prescriptions for anxiolytics in the U.S. increased 34.1% between mid-February and mid-March 2020.

[0005]

[0006] Despite these issues, there are unapproved, generally effective drug therapies for the treatment of benzodiazepine misuse and / or use disorders. Currently, the options are off-label use of other benzodiazepines, such as gabapentin (a drug used to treat neuralgia) or phenobarbital sodium (an anesthetic barbiturate). These treatment options have minimal evidence to support their effectiveness in treating benzodiazepine misuse and / or use disorders. Furthermore, given the toxicity and abuse tendencies of such drugs, the use of barbiturates like phenobarbital sodium is a cause for concern. [Overview of the project] [Problems that the invention aims to solve]

[0006]

[0007] Therefore, there is a continuing need for improved therapies to treat benzodiazepine misuse and / or use disorders. Ideally, such therapies should effectively suppress the effects of conventional benzodiazepines without increasing the potential for abuse. Ideally, such therapies should also produce these effects without causing significant loss of motor coordination, appetite suppression, respiratory depression, or other undesirable physiological side effects. Ideally, such therapies should also produce these effects without causing benzodiazepine withdrawal symptoms. [Means for solving the problem]

[0007]

[0008] This disclosure relates to compositions and methods for treating benzodiazepine misuse and / or use disorder. The compounds disclosed herein combine partial modulator and partial antagonist profiles. These partial modulator / antagonist compounds reduce the potential for abuse of benzodiazepines while still retaining their anxiety-relieving ability. The compounds disclosed herein can directly inhibit the action of benzodiazepines (i.e., independently of the sedative or motility effects of the compounds). The compounds disclosed herein do not exhibit the ability to induce withdrawal symptoms following a bolus administration of benzodiazepines, suggesting that the transition to treatment is particularly easy.

[0008]

[0009] In one embodiment, a method for treating benzodiazepine misuse and / or use disorder involves GABA A This involves administering an effective amount of a compound that produces both partial modulator and partial antagonist effects at a receptor to a subject requiring it. The compound may be a compound of formula I, formula II, formula III (which are described in more detail below), or a combination or mixture thereof.

[0009]

[0010] In some embodiments, the treatment produces an anxiolytic effect, but the positive reinforcing effect of the compound is lower than that from conventional benzodiazepines. In some embodiments, the compound acts to suppress the effects of conventional benzodiazepines that are independent of the sedative or motor effects of the administered partial modulator / antagonist compound. In some embodiments, the suppression cannot be overridden and thus cannot be counteracted by increased benzodiazepine administration.

[0010]

[0011] In some embodiments, the compound is administered at a dose of about 0.01 mg / kg or more or greater than about 0.03 mg / kg. In some embodiments, the treatment produces both an anxiolytic effect and a benzodiazepine-suppressing effect when administered.

[0011]

[0012] In some embodiments, the treatment does not induce a substantial loss of motor coordination in the subject, does not induce substantial appetite suppression in the subject, and does not substantially affect the respiratory rate, tidal volume, or minute ventilation in the subject.

[0012]

[0013] In some embodiments, the treatment does not cause benzodiazepine withdrawal symptoms. For example, the compound may be administered without performing a prior or concurrent detoxification treatment on the subject or may be administered with less detoxification compared to conventional treatment options.

[0013]

[0014] This summary is provided to introduce, in a simplified form, a selected set of concepts that are further described in the following modes for carrying out the invention. This summary is not intended to identify key features or essential features of the subject matter recited in the claims, nor is it intended to be used as an indicator of the scope of the subject matter recited in the claims.

[0014]

[0015] Various objects, features, characteristics, and advantages of the present invention will become apparent and will be more readily understood from the following description of the embodiments in conjunction with the accompanying drawings and the appended claims, which form a part of this specification. In the drawings, the same reference numerals may be used to indicate corresponding or similar parts in the various figures, and the various elements are not necessarily drawn to scale.

Brief Description of the Drawings

[0015] [Figure 1]

[0016] Figure 1A is a diagram showing the GABAA receptor and its protein family subunits, and shows the enhancement of the allosteric binding to the GABAA receptor and the ability of GABA to increase chloride conductance. Figure 1B is a diagram showing the GABAA receptor and its protein family subunits, and shows the enhancement of the allosteric binding to the GABAA receptor and the ability of GABA to increase chloride conductance. [Figure 2]

[0017] It is a diagram showing exemplary compounds according to Formulas I, II, and III, respectively, which may be used for treating the misuse and / or use disorders of benzodiazepines. [Figure 3] It is a diagram showing exemplary compounds according to Formulas I, II, and III, respectively, which may be used for treating the misuse and / or use disorders of benzodiazepines. [Figure 4] It is a diagram showing exemplary compounds according to Formulas I, II, and III, respectively, which may be used for treating the misuse and / or use disorders of benzodiazepines. [Figure 5]

[0018] This figure shows the breakpoints (highest response requirements) for the maximum self-administered doses of lorazepam and TPA023B (doses are in parentheses on the x-axis and are mg / kg / injection). These values ​​were compared to the breakpoints obtained when the medium was available. Data are median and interquartile range for n=4 monkeys and were analyzed using repeated measures ANOVA based on Friedman's rank. *p<0.05, Dunnett's test based on rank. [Figure 6]

[0019] This figure shows the self-administration of midazolam (MZ, 0.018 and 0.056 mg / kg / injection) and feed (2 pellets / release) under a PR schedule after TPA023B pretreatment. Data are the mean number of reinforcers, ±SEM, where "reinforcer" consists of either a midazolam injection or the release of 2 pellets. V: Midazolam medium. N = 4 monkeys. [Figure 7]

[0020] Figure 7A shows the dose-response function for midazolam self-administration in a PR procedure (N=4 monkeys). Figure 7A: Data as mean number of injections / session ± SEM. For clarity, error bars have been removed from the lower panel. Figure 7B shows the dose-response function for midazolam self-administration in a PR procedure (N=4 monkeys). Figure 7B: Data as mean maximum % obtained as maximum number of injections / session for each individual monkey. For clarity, error bars have been removed from the lower panel. [Figure 8]

[0021] This figure compares the anti-conflict effect of TPA023B and the inhibition of midazolam self-administration in rhesus monkeys. The data represents the average of the maximum effect percentages for each individual monkey. N=8 monkeys (4 conflicted, 4 self-administered). [Figure 9]

[0022] This figure shows lung ventilation in adult male Sprague-Dawley rats (N=8) after administration of alprazolam and TPA023B. Respiratory parameters were measured via whole-body plethysmography and are presented as mean ± SEM for each measurement. *p<0.05 is for media treatment ("Veh"), and Bonferroni's t-test is used. TPA023B had no effect on any respiratory measurement in either ANOVA or Bonferroni's t-test. [Figure 10]

[0023] Figure 10A shows the effect of diazepam, a full modulator, on the diet-maintained response rate in rats (N=8). The data represent the mean ±% of the baseline response before the test session. Note that *p<0.05 vs. media (V), Bonferroni t-test. Figure 10B shows the effect of flumazenil, an antagonist, on the diet-maintained response rate in rats (N=8). The data represent the mean ±% of the baseline response before the test session. Note that *p<0.05 vs. media (V), Bonferroni t-test. Figure 10C shows the effect of TPA023B, a selective partial modulator, on the diet-maintained response rate in rats (N=8). The data represent the mean ±% of the baseline response before the test session. Note that *p<0.05 vs. media (V), Bonferroni t-test. [Figure 11]

[0024] Figure 11A shows the effect of flumazenil on the response rate after administration of 3.0 mg / kg diazepam 60 minutes prior to the session. V, media (i.e., diazepam alone). Note that *p<0.05 is Bonferroni's t-test for ligand-only administration. Figure 11B shows the effect of TPA023B on the response rate after administration of 3.0 mg / kg diazepam 60 minutes prior to the session. V, media (i.e., diazepam alone). Note that *p<0.05 is Bonferroni's t-test for ligand-only administration. [Figure 12]

[0025] Figure 12A shows the effects of diazepam (full modulator), flumazenil (Flu) (antagonist), and L-838,417 and MRK-623 (selective partial modulators) on the diet-maintained response rate in rats (N=5). Data represent mean ±% of the baseline response before the test session. *p<0.05 vs. media (Veh), Bonferroni's t-test. "ns" means not significant. Figure 12B shows the effects of diazepam (full modulator), flumazenil (Flu) (antagonist), and L-838,417 and MRK-623 (selective partial modulators) on the diet-maintained response rate in rats (N=5). Data represent mean ±% of the baseline response before the test session. *p<0.05 vs. media (Veh), Bonferroni's t-test. "ns" means not significant. [Modes for carrying out the invention]

[0016] Overview of Benzodiazepines

[0026] The embodiments described herein relate to compounds and methods for treating benzodiazepine misuse and / or use disorders. Benzodiazepines have the following general structure:

[0017] [ka]

[0018]

[0027] As shown, the core of a benzodiazepine is a condensate of a benzene ring and a diazepine ring, with an optionally substituted phenyl group bonded to the diazepine. R1 is typically H or CH3, R2 is typically O, or R1 and R2 together form an optionally substituted diazole or triazole ring condensed to the diazepine ring. R3 is typically Cl or F, or absent. R4 is typically Cl, F, or a nitro group. R5 is typically OH, or absent.

[0019]

[0028] Other benzodiazepine-like drugs, while not strictly benzodiazepines, are associated with similar therapeutic targets and mechanisms of action, and are therefore sometimes associated with benzodiazepines. For example, certain non-benzodiazepine hypnotics, often referred to as "Z drugs," are structurally different from benzodiazepines, but they are GABA-based. A They are similarly used to modulate receptors and are sometimes associated with misuse and / or use disorders. Z drugs include zopiclone, eszopiclone (trade name: Lunesta®), zaleplon (trade name: Sonata®), and zolpidem (trade name: Ambien®).

[0020]

[0029] The compositions and methods described herein may be used to treat misuse and / or use disorders of benzodiazepines, Z drugs, or both. For brevity, the term “benzodiazepine” will be used to refer to both conventional benzodiazepines (i.e., compounds having the benzodiazepine structure as exemplified above) and benzodiazepine-like drugs such as Z drugs. The term “conventional benzodiazepine” will be used to specify compounds having the benzodiazepine structure.

[0021]

[0030] Benzodiazepines are GABA A Benzodiazepines act by allosterically binding to receptors and by enhancing GABA's ability to increase chloride conductance. For this reason, benzodiazepines are positive allosteric modulators of GABA. As illustrated in Figures 1A and 1B, GABA in the central nervous system... A Receptors are pentamers containing structurally distinct proteins, and each protein family is composed of different subunits. Most GABA A The receptor, viewed from "above" the synapse (Figure 1B), consists of α, β, and γ subunit families arranged in the sequence αβαβγ.

[0022]

[0031] The action of benzodiazepines appears to be mainly determined by the presence of specific α subunits. Benzodiazepine drugs bind to a site on the native GABA A receptor that is located at the interface of the α1, α2, α3, or α5 subunit (i.e., α1GABA A , α2GABA A , α3GABA A , α5GABA A subtypes) and the γ2 subunit, whereas the majority of these drugs are inactive in receptors containing the corresponding α4- and α6-subunits (i.e., α4GABA A , α6GABA A subtypes). The embodiments described herein mainly regulate the GABA A , α2GABA A , and α3GABA A receptor through an interaction with the receptor subunits that is thought to be important for mediating the abuse-related and anxiolytic actions of benzodiazepines.

[0023] Exemplary partial modulator / antagonist compounds

[0032] GABA A The design and discovery of compounds in the region of positive modulators of the receptor are α2GABA A and α3GABA A ​​This has been hampered by the difficulty in addressing selectivity for subtypes (Atack 2011, Current Topics in Med Chem, 11:1176~202; Maramai et al. 2020, J Med Chem 63:3425~46). Success in identifying "selective affinity," i.e., compounds with different binding constants (titers) for different subtypes, has been rare. The alternative approach that has emerged is "selective efficacy," in which the intrinsic efficacy of a subtype or combination of subtypes representing the target ranges from complete to partial modulation, while subtypes or combinations of subtypes associated with side effects ideally have zero intrinsic efficacy (i.e., they are antagonists at these sites). Assuming that antagonists have no functional effect, the behavior induced at sites with efficacy greater than zero can be interpreted as being mediated by these sites.

[0024]

[0033] The concept of intermediate efficacy, or "partial agonism," has driven drug discovery based on the understanding that lower levels of in vitro efficacy are expected to correlate with weaker behavioral effects. The equivalent term for allosteric modulators is "partial modulator." The specific embodiments described herein function beneficially as both subtype-selective partial modulators and antagonists.

[0025]

[0034] Table 1 lists a series of compounds originally developed by Merck & Co. that do not exhibit clear differences in receptor subtype affinity, but act as partial positive modulators for specific subtype combinations while exhibiting zero efficacy (i.e., antagonism) for other subtypes. The chemical properties and basic pharmacology of these compounds have been discussed in the literature (discussed in Atack 2011). However, in particular, previous studies have not explored the potential use of such compounds for treating benzodiazepine misuse and / or use disorders.

[0026] [Table 1]

[0027]

[0035] The imidazotriazine TPA023B has been studied for its use as a non-sedating anxiolytic (Atack 2011). In Merck's preclinical program, TPA023B was found to be mildly sedative (rodent rotord and chain-pulling, squirrel monkey lever-pushing) and to have anxiolytic-like effects (rodent elevated plus maze, conditioned suppression of drinking, fear-potentiated startle; squirrel monkey conditioned emotional response; Atack et al. 2010, J Psychopharmacol 25:329~344). In anxiety relief assays in rodents and primates using both in vivo occupancy and imaging, the minimum effective dose of TPA023B was a dose occupying 61-88% of the CNS benzodiazepine binding sites (Atack et al. 2010).

[0028]

[0036] In a Phase I clinical trial (Atack et al., 2010), TPA023B was orally administered to males at a maximum dose of 3.0 mg / 70 kg. This dose caused fatigue and somnolence in some subjects (1-4 out of 8 subjects). However, no adverse effects were observed at a dose of 1.5 mg / 70 kg. This dose, as measured by PET, occupied 50-55% of the CNS benzodiazepine binding sites. No ataxia was observed at any dose. These mild sedative effects are consistent with our findings in monkeys.

[0029]

[0037] These past clinical trials focused on developing non-sedating anxiolytics, and therefore the compounds investigated were not considered in terms of treating benzodiazepine misuse and / or use disorder. While even slight drowsiness may be considered (or deemed harmful) in the development of anxiolytics, these effects are likely to be within acceptable limits in the application of benzodiazepine misuse and / or use disorder. In addition, these mild sedative effects are significantly lower than those typically observed with off-label drug therapies currently used to treat this disorder, such as phenobarbital, gabapentin, or other conventional benzodiazepines with tapered doses.

[0030]

[0038] Another undesirable side effect associated with benzodiazepine use is cognitive impairment, clinically described as anterograde amnesia. While there is relatively little data available on the effects of selectively effective compounds on cognitive function, a study by Soto et al. (2013, Neuropsychopharmacology 38:2315~25) evaluated the effects of TPA023B on cognition in rhesus monkeys compared to the conventional benzodiazepine triazolam. In the delayed matching task (DMTS) for visual cognitive memory and the self-ordered spatial search (SOSS) task for spatial working memory, triazolam significantly reduced accuracy in both methods, consistent with the cognitive impairment effects reported with conventional benzodiazepines. In contrast, TPA023B did not alter the accuracy or number of completed tests in either task, suggesting that this compound does not have an effect on visual / spatial memory.

[0031]

[0039] In some embodiments, a compound for treating benzodiazepine misuse and / or use disorder is given by formula I:

[0032] [ka]

[0033] That is correct.

[0040] In formula I, R1 and R2 are independently H, Cl, F, CF3, CN, alkyl (e.g., C1-C5), alkoxy (e.g., C1-C5), OCF3, or isopropanol group:

[0034] [ka]

[0035] In certain preferred embodiments, one of R1 and R2 is H, and the other is a CH3, CF3, or isopropanol group. For example, in some embodiments, R1 is a CH3, CF3, or isopropanol group, and R2 is H.

[0036]

[0041] Q1 and Q2 are independently C or N. In a preferred embodiment, one or both of Q1 or Q2 are N, resulting in an imidazopyrimidine or imidazotriazine core in the compound.

[0037]

[0042] Ar1 and Ar2 are each six-membered aromatic rings, each of which is optionally substituted with one or two substituents. Each of Ar1 and Ar2 may independently contain one or more heteroatoms selected from O or N.

[0038]

[0043] In some embodiments, Ar1 and Ar2 are independently phenyl, pyridine, pyridazine, pyrimidine, or pyrazine. In embodiments where one or both of Ar1 or Ar2 are substituted, the substituent includes one or more of Cl, F, CF3, CN, alkyl (e.g., C1-C5), alkoxy (e.g., C1-C5), or OCF3. In preferred embodiments, the substituent is F and / or CN.

[0039]

[0044] In some embodiments, Ar1 and Ar2 are biphenyl groups:

[0040] [ka]

[0041] The phenyl groups are formed, and one or both of the phenyl groups are optionally substituted with F and / or CN.

[0042]

[0045] In some embodiments, the compound of formula I may be completely or partially deuterated.

[0043]

[0046] Figure 2 shows a few exemplary compounds described in Formula I. Sequential addition of nitrogen atoms of imidazopyridine to the benzimidazole core improves bioavailability and half-life without affecting binding and efficacy properties (Maramai et al., 2020), resulting in imidazopyrimidine and imidazotriazine as important analogs. TPA023B, a preferred compound for the embodiments described herein, is an imidazotriazine having a fluorinated biphenyl structure. MRK-968 and MRK-973 are notable variants of TPA023B. Analogues of imidazopyrimidine, important intermediates, have improved plasma half-lives by fluorination; for example, MRK-898 has a viable half-life, bioavailability, and selectivity (49% bioavailability and 13-hour half-life in rhesus monkeys; α1 / α5GABA). A Antagonist in subtypes; Atack, 2011). MRK-623 in this series has reasonable bioavailability but an extremely short half-life (0.5 hours in rhesus monkeys). However, deuterated formulations of such compounds may improve the half-life.

[0044]

[0047] In some embodiments, a compound for treating benzodiazepine misuse and / or use disorder is given by formula II:

[0045] [ka]

[0046] Contains the triazolopyridazine core described above.

[0048] In Formula II, R1 is H, Cl, F, CF3, CN, alkyl (e.g., C1-C5), or cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl). In some preferred embodiments, R1 is isopropyl or cyclobutyl.

[0047]

[0049] R2 is H, Cl, F, CF3, CN, alkyl (e.g., C1-C5), alkoxy (e.g., C1-C5), or OCF3, and n is 1 or 2. In some preferred embodiments, R2 is F.

[0048]

[0050] Q is C, N, O, S, sulfone, or sulfoxide. In some preferred embodiments, Q is O.

[0051] Ar is optionally substituted with a diazole, triazole, or pyridine. In some preferred embodiments, Ar is a substituted triazole:

[0049] [ka]

[0050] (In the formula, R3 is H or C1-C2 alkyl).

[0052] Figure 3 shows a few exemplary compounds described in Formula II. Triazolopyridazine, including TPA023, progressed to Phase II clinical trials but was discontinued due to cataract development. Post-hoc analyses of three clinical trials showed significant anxiety relief in patients with generalized anxiety disorder (Atack 2009, Adv Pharmacol 57:137~85). As shown, substitution of the bicyclic group of the starting triazolopyridazine molecule enhances efficacy. The poor PK of MRK-067 is corrected by fluorination of its phenyl group. Substitution of the bicyclic group of triazolopyridazine with t-butyl substitution results in L-838,417 and TPA023, all of which are α1GABAA Ineffective in certain subtypes. Poor PK was addressed by the development of deuterated L-838,417 (also known as "C21191" or "CTP-354").

[0051]

[0053] In some embodiments, a compound for treating benzodiazepine misuse and / or use disorder is given by formula III:

[0052] [ka]

[0053] Contains the pyridazine core described above.

[0054] In formula III, each of Q1, Q2, and Q3 is independently C or N. In some preferred embodiments, at least one of Q1 or Q2 is N, and Q3 is N.

[0054]

[0055] Each R1 (where n is 1 or 2) is H, Cl, F, CF3, CN, C1-C5 alkyl, C1-C5 alkoxy, or OCF3. Similarly, each R2 (where n is 1 or 2) is H, Cl, F, CF3, CN, C1-C5 alkyl, C1-C5 alkoxy, or OCF3, and each R3 (where n is 1 or 2) is H, Cl, F, CF3, CN, C1-C5 alkyl, C1-C5 alkoxy, or OCF3. In some preferred embodiments, R1, R2, and R3 are F.

[0055]

[0056] Figure 4 shows a few exemplary compounds of formula III. These compounds are α5GABA A-Although initially developed as a selective ligand, it instead exhibited an efficacy profile as a selective partial positive modulator, where fluorination techniques were used to address metabolic instability. The initial PKs of all three compounds were relatively good, and although MRK-547 could be excluded, their in vitro results did not correlate with in vivo findings (Atack, 2011). The three compounds had different selectivity, with MRK-100 being α3GABA A This shows only partial regulation of α3GABA. A Compounds that exhibit complete positive regulation of the receptor may have a relatively low potential for abuse, which is noteworthy (Meng et al. 2020; J sychopharmacol 34:348~357).

[0056] Treatment of benzodiazepine misuse and / or use disorder

[0057] The compounds described herein may be effectively used to treat benzodiazepine misuse and / or use disorders. When administered to subjects in need, such compounds, at effective doses, will produce beneficial anxiolytic effects as a result of their partial modulator function, but the positive reinforcement effect will be lower than that of benzodiazepines (including those from "conventional benzodiazepines") to prevent a shift from the abuse of one compound to the abuse of another.

[0057]

[0058] The compounds described herein also provide beneficial functions for antagonistic activity and for inhibiting the action of benzodiazepines (including "conventional benzodiazepines"). As demonstrated herein, the inhibitory effect is not merely a side effect such as the sedative and / or motility effects of the compounds, but rather, GABA A This is directly related to receptor antagonism. As further demonstrated herein, in at least some circumstances, the suppression of benzodiazepine action is irreversible; that is, the suppression cannot be completely abolished simply by increasing the dose of benzodiazepine.

[0058]

[0059] In some embodiments, the compounds are administered in doses of about 0.005 mg / kg to about 10 mg / kg, or more preferably, about 0.01 mg / kg to about 1 mg / kg. For example, the compounds described herein may be administered in doses of about 0.01, 0.02, 0.03, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg / kg, or within a dose range with any two of the aforementioned values ​​as endpoints. The preferred dosage for humans may be approximately 0.5 mg / 70 kg (0.007 mg / kg) to 5.0 mg / 70 kg (0.07 mg / kg), or approximately 1.0 mg / 70 kg (0.01 mg / kg) to 2.0 mg / 70 kg (0.03 mg / kg). Higher doses are possible, but considering that low doses of approximately 0.3 mg / kg to 1.0 mg / kg occupy about 90-95% of the benzodiazepine binding site, this is not considered an efficient use of the compound (for example, intravenous administration of 0.32 mg / kg in baboons results in an occupancy rate of over 95%, and oral administration to Sprague Dawley rats results in occupancy rates of 0.3 mg / kg = 87%, 1.0 mg / kg = 96%, and 3.0 mg / kg = 99%).

[0059]

[0060] Beneficially, the compounds described herein have the ability to simultaneously produce both anxiolytic effects (as a result of partial modulator functionality) and benzodiazepine inhibitory effects (as a result of antagonist functionality). These effects allow the compounds to be used effectively to treat benzodiazepine misuse and / or use disorders.

[0060]

[0061] As demonstrated herein, the beneficial effects of administering the disclosed compounds are obtained without inducing substantial loss of motor coordination or appetite suppression in the subjects. As further demonstrated herein, the beneficial effects are obtained without substantially affecting the respiratory rate, tidal volume, or minute ventilation in the subjects.

[0061]

[0062] In addition, the compounds described herein enable partial modulator and antagonist effects without causing benzodiazepine withdrawal symptoms. This allows for beneficial treatment of subjects who are physically dependent on benzodiazepines, without (or at least significantly less than) the need for prior or concurrent detoxification treatment, which can be difficult and time-consuming.

[0062] Pharmaceutical composition

[0063] The compounds described herein may be administered individually, but it may be preferable to formulate the compounds as a pharmaceutical composition (e.g., a formulation). Therefore, in yet another embodiment, pharmaceutical compositions useful in the methods and uses of the disclosed embodiments are provided. A pharmaceutical composition is any composition that may be administered to a subject in vitro, in vivo, or both, to treat, prevent, or induce remission of a condition, or otherwise, prophylactically, to improve or maintain the health of the subject. In a preferred embodiment, the pharmaceutical composition may be administered in vivo. While the subject will most often be human, this disclosure also takes into account situations in which the compounds are administered to mammals (e.g., as part of a test protocol).

[0063]

[0064] The compositions of the present invention may be in the form of injectable suspensions, solutions, sprays, lyophilized powders, syrups, elixirs, etc. Any suitable form of the composition may be used. To prepare such compositions, a composition of the present disclosure having a desired degree of purity is mixed with one or more pharmaceutically acceptable carriers and / or excipients.

[0064]

[0065] As used herein, the terms “pharmaceutically acceptable” and “physiologically acceptable” mean a biocompatible gaseous, liquid, or solid formulation, or mixture thereof, suitable for one or more routes of administration, in vivo delivery, or contact. A formulation is acceptable if it does not induce any adverse side effects that are more significant than any prophylactic effect or benefit, or therapeutic effect or benefit.

[0065]

[0066] In some embodiments, the pharmaceutical composition may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, and diluents, depending on the specific mode of administration and dosage form. The pharmaceutical composition should generally be formulated to obtain a physiologically suitable pH, which may be in the range of about 3 to about 11, preferably about 3 to about 7, depending on the formulation and route of administration. In alternative embodiments, the pH may be preferably adjusted to the range of about 5 to about 8. More specifically, the pharmaceutical composition may contain at least one of the compounds described herein in a therapeutically or prophylactically effective amount, together with one or more pharmaceutically acceptable excipients.

[0066]

[0067] For example, formulations for parenteral or oral administration are most typically solids, solutions, emulsions, or suspensions, while inhalable formulations for intranasal or pulmonary administration are generally liquids or powders. Exemplary pharmaceutical compositions may be formulated as lyophilized solids that are reconstituted with a physiologically suitable solvent or carrier before administration. Other suitable carriers or diluents may be water or buffered saline with or without preservatives.

[0067]

[0068] Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dose and concentration used and include, but are not limited to, water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol, or combinations thereof, buffers such as phosphoric acid, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides ( This includes less than approximately 10 residues; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0068]

[0069] Pharmacologically acceptable excipients are determined to some extent by the specific composition being administered, and similarly by the specific method used to administer the composition. Therefore, a wide variety of suitable formulations of pharmaceutical compositions exist (see, for example, Remington's Pharmaceutical Sciences).

[0069]

[0070] Suitable excipients may be carrier molecules containing large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, and amino acid copolymers. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting agents or emulsifiers; and pH buffering agents. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

[0070]

[0071] For example, pharmaceutically acceptable excipients particularly suitable for use in conjunction with tablets include, for example, inert diluents such as cellulose, calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; disintegrants such as cross-linked povidone, corn starch or alginate; binders such as povidone, starch, gelatin or acacia gum; and lubricants such as magnesium stearate, stearic acid or talc. Pharmaceutical compositions may be formulated as dispersible powders and granules suitable for the preparation of suspensions by the addition of appropriate excipients.

[0071]

[0072] As another example, a pharmaceutical composition may be formulated as a suspension containing the compounds disclosed herein in a mixture, together with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. Excipients suitable for use in conjunction with suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), alkylene oxide condensates with fatty acids (e.g., polyoxyethylene stearate), ethylene oxide condensates with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and ethylene oxide condensates with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate); polysaccharides and polysaccharide-like compounds (e.g., dextran sulfate); glycosaminoglycans and glycosaminoglycan-like compounds (e.g., hyaluronic acid); and thickeners such as carbomers, beeswax, solid paraffins, or cetyl alcohol. The suspension may contain one or more preservatives such as acetic acid, methyl and / or n-propyl p-hydroxybenzoic acid; one or more coloring agents; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

[0072]

[0073] Compositions can be designed to introduce a compound to a desired site of action and release it at an appropriate and controllable rate. For example, controlled-release preparations can be produced by using polymers to complex or incorporate the compound. Controlled-release formulations can be prepared using suitable macromolecules (e.g., polyesters, polyamino acids, polyvinyl, pyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, or protamine sulfate) known to yield desired controlled-release properties or release profiles. Another way in which the duration of action can be controlled by controlled-release preparations is to incorporate the active ingredient into particles of polymer materials such as polyesters, polyamino acids, hydrogels, polylactic acid, polyglycolic acid, copolymers of these acids, or ethylene vinyl acetate copolymers.

[0073]

[0074] Alternatively, instead of incorporating these active ingredients into polymer particles, these materials can be encapsulated in microcapsules. Microencapsulation has been applied to the injection of microencapsulated pharmaceuticals to provide controlled release. Many factors contribute to the selection of specific polymers for microencapsulation. The reproducibility of the polymer synthesis and microencapsulation processes, the cost of the microencapsulation materials and processes, their toxicity profiles, the variable release dynamics of the polymer and compound, and the requirements for physicochemical compatibility are all factors that must be considered. Examples of useful polymers include polycarbonates, polyesters, polyurethanes, polyorthoesters, and polyamides, especially those that are biodegradable.

[0074]

[0075] Microcapsules can be prepared, for example, by coacervation technology or interfacial polymerization, as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, respectively. Such techniques are disclosed in *New Trends and Developments in Vaccines*, Voller et al. (eds.), University Park Press, Baltimore, Md., 1978, and *Remington's Pharmaceutical Sciences*, 16th edition.

[0075]

[0076] A frequently chosen carrier for pharmaceuticals is poly(d,l-lactide-co-glycolide) (PLGA). This is a biodegradable polyester with a long history of medical use in erosive sutures, bone plates, and other temporary prostheses, and has shown no toxicity in its use. A wide variety of pharmaceuticals, including peptides and antigens, have been formulated into PLGA microcapsules. For example, as outlined by Eldridge, JH et al., Current Topics in Microbiology and Immunology, 1989, 146:59-66, a great deal of data has been accumulated regarding the application of PLGA for the controlled release of compounds. Encapsulation of compounds in PLGA microspheres with a diameter of 1-10 microns has been shown to have a remarkable adjuvant effect when administered orally. The PLGA microencapsulation process uses phase separation of a water-in-oil emulsion. The compound of interest is prepared as an aqueous solution, and the PLGA is dissolved in a suitable organic solvent such as methylene chloride and ethyl acetate. These two immiscible solutions were co-emulsified by high-speed stirring. Next, a non-solvent for the polymer was added, which caused the polymer to precipitate around the aqueous droplets, forming initial microcapsules. The microcapsules were collected and stabilized with one of the following combinations of agents (polyvinyl alcohol (PVA), gelatin, alginate, polyvinylpyrrolidone (PVP), methylcellulose), and the solvent was removed by drying under reduced pressure or by solvent extraction.

[0076]

[0077] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. This oil-in-water emulsion may be based on, for example, light liquid paraffin oil (European Pharmacopoeia type); isoprenoid oils such as squalane, squalene, EICOSANE®, or tetratetracontane; oils obtained from the oligomerization of alkenes, such as isobutene or decene; vegetable oils; esters of acids or alcohols containing linear alkyl groups, such as ethyl oleate, dicaprylic / capric acid propylene glycol, tricaprylic / capric acid glyceryl, or propylene glycol dioleate; or esters of branched fatty acids or alcohols, such as isostearate esters. Conveniently, the oil is used in combination with an emulsifier to form an emulsion. The emulsifier may be a nonionic surfactant such as sorbitan, mannides (e.g., mannitol oleate anhydride), glycerol, polyglycerol, propylene glycol, and optionally ethoxylated oleic acid, isostearic acid, ricinoleic acid, or hydroxystearic acid esters, and a polyoxypropylene-polyoxyethylene copolymer block such as Pluronic® products, e.g., L121. The adjuvant may be a mixture of emulsifiers, micelle-forming agents, and oils, such as those marketed under the name Provax® (IDEC Pharmaceuticals, San Diego, Calif.). The emulsion may contain sweeteners and flavorings. The syrup and elixir may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may contain lubricants, preservatives, flavorings, or colorings.

[0077]

[0078] Furthermore, the pharmaceutical composition may be in the form of a sterile injection preparation, such as a sterile aqueous emulsion or oily suspension for sterile injection. This emulsion or suspension may be formulated according to known techniques using the appropriate dispersants or wetting agents and suspending agents described above. The sterile injection preparation may also be a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a 1,2-propane-diol solution.

[0078]

[0079] Sterile injectable preparations may be prepared as lyophilized powders. Among the acceptable media and solvents, those that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils may be used as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids such as oleic acid may be used in injectable preparations.

[0079]

[0080] In some embodiments, cyclodextrins may be added as water solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, and maltotriosyl derivatives of cyclodextrins. An exemplary cyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC), which may be added to any of the above compositions to further improve the water solubility properties of the compound of the embodiment. In one embodiment, the composition contains about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% to about 15% hydroxypropyl-o-cyclodextrin, and even more preferably about 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount of solubility enhancer used will depend on the amount of the compound of the embodiment in the composition.

[0080]

[0081] Cosolvents and adjuvants may be added to the formulation. Non-limiting examples of cosolvents include hydroxyl groups or other polar groups, such as alcohols like isopropyl alcohol; glycols like propylene glycol, polyethylene glycol, polypropylene glycol, and glycol ethers; glycerol; polyoxyethylene alcohol; and polyoxyethylene fatty acid esters. Adjuvants include, but are not limited to, inorganic salts (e.g., AlK(SO4)2, AlNa(SO4)2, AlNH(SO4)2, silica, alum, Al(OH)3, Ca3(PO4)2, kaolin, or carbon).

[0081]

[0082] Generally, pharmaceutical compositions are prepared by homogeneously and thoroughly associating an active ingredient with a liquid carrier, a micronized solid carrier, or both, and, if necessary, by molding the product. For example, tablets may be made by compression or molding. Compressed tablets may be prepared by compressing an active ingredient in a free-flowing form, such as a powder or granules, which is optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in appropriate equipment. Molded tablets may be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent, in appropriate equipment. Tablets may optionally be coated or scored, and may be formulated to provide sustained or controlled release of the active ingredient within them.

[0082]

[0083] Compounds containing the disclosed pharmaceutical compositions may be packaged in unit dose forms for ease of administration and uniformity of dosage. As used herein, “unit dose form” refers to a physically discontinuous unit suitable as a consolidated dose for the subject to be treated, each unit containing, optionally, a predetermined amount of the compound, calculated to produce a desired effect (e.g., prophylactic effect or prophylactic benefit or therapeutic effect or therapeutic benefit) when administered in one or more doses, together with a pharmaceutical carrier (e.g., excipients, diluents, media, or fillers). Unit dose forms may contain a once-weekly or once-monthly dose of the compound to be administered, or an appropriate portion thereof. Unit dose forms also include, for example, capsules, lozenges, tablets, ampoules, and vials, which may contain the composition in a lyophilized or freeze-dried state, for example, a sterile liquid carrier that may be added before in vivo administration or delivery. Unit dosage forms include, for example, ampoules and vials, further including ampoules and vials containing a liquid composition. Individual unit dosage forms may be contained in multi-dose kits or containers. Pharmaceutical preparations may be packaged in one or more unit dosage forms for ease of administration and uniformity of dosage.

[0083]

[0084] The compositions disclosed herein may be administered as a single bolus or multiple doses at any frequency over an appropriate period of time, according to the present method. Exemplary frequencies are typically 1 to 5 times, 1 to 3 times, 2 times, or once per month. In some embodiments, the compounds may be administered for the duration of sustained therapy, for example, for a week or longer, or for several months or years. Long-acting pharmaceutical compositions may be administered twice a week, every 3 to 4 days, or weekly, depending on the half-life and clearance rate of the particular formulation. [Examples]

[0084] Example 1: Conflict Model for Anxiety Relief

[0085] The conflict procedure methods include two-component multiple fixed-rate reinforcement, fixed-rate reinforcement, and punishment schedules (mult FR, FR+PUN). A key feature of this model is its high predictability of clinically active doses in human subjects (Rowlett et al. 2006, Psychopharmacology 184:201~11). One component of this schedule was associated with a characteristic visual stimulus (e.g., red light), and the other component was associated with a different stimulus (e.g., green light). In each component, after 10 responses were completed (FR10), a feed pellet was released, followed by a short (10-second) time-out period. This component ended after either 5 feed pellet releases or 5 minutes had elapsed, whichever came first. There was a 10-minute time-out period before each of the four cycles, each having two components (red 1, green 1). When performance in both components of the multiple schedule stabilized, the response in one component was suppressed by superimposing an FR schedule of electric shocks generated by the response. Under this overlapping schedule, a shock was administered every n responses (n=15-25, adjusted for each monkey according to individual performance). Once the response stabilized (in at least three sessions, the suppressed response was less than 50% of the unsuppressed response, and there was no increasing or decreasing trend in response rates for either component), the test compound was administered intravenously using a cumulative dosing technique during an extended time-out period. This technique allows for the determination of four dose-response functions in a single session.

[0085]

[0086] Table 2 summarizes the data for TPA023B in a conflict procedure using alprazolam as a positive control (n = 4 monkeys, 2 females and 2 males). The mean response to administration of the medium in the unsuppressed component was 2.2, which decreased by approximately 98% with the presentation of shock in the suppressed component (mean = 0.05 response). In the unsuppressed response, TPA023B had no effect on the mean response rate or control percentage over a 100-fold dose range (0.01–1.0 mg / kg, intravenously). The control drug, alprazolam, significantly reduced the unsuppressed response at an intravenous dose of 0.3 mg / kg. In the suppressed response, TPA023B significantly increased the proportion of suppressed responses, reaching the level of an unsuppressed response at an intravenous dose of 0.1 mg / kg. That is, this compound showed an anti-conflict effect. This effect was comparable to that observed with intravenous 0.03 mg / kg of alprazolam. An impressive characteristic of TPA023B in this procedure is the absence of a decrease in response rate at higher doses. In contrast, ratio-inhibitory effects are observed here with alprazolam and have also been demonstrated with a range of other conventional benzodiazepines (Rowlett et al. 2006).

[0086] [Table 2]

[0087]

[0087] In summary, TPA023B exhibited some anti-conflict effects similar to those of conventional anxiolytic benzodiazepines, but unlike benzodiazepines, it did not tend to impair the ability of the target to complete a response, i.e., it did not induce a lack of motor coordination.

[0088] Example 2: Observation / Sedation

[0088] The behavior of each monkey (n = 4 in total) was scored for the data presented here using a previously described individual tracking method (Duke et al. 2018, J Pharmacol Exp Ther 366:145~57). Briefly, a blinded, trained observer observed a specific monkey for 5 minutes and recorded each instance in which a specific behavior occurred within a 15-second interval. A score for each behavior was calculated as the numerical value for the 15-second interval in which the behavior occurred (for example, the maximum score would be 20). Planned exposure to stimuli was included in the observation session as a sedation assessment criterion (Duke et al., 2018). The responsiveness of the animal to the stimulus was assessed if it was observed that the monkey closed its eyes for more than 3 seconds. Specifically, the observer presented three stimuli: 1) walking towards the cage at a normal pace, 2) calling the animal's name, and 3) moving the key used to secure the cage door. If the monkey responded immediately (i.e., opened its eyes and turned towards the observer), it was scored as "resting / sleeping posture." If the monkey showed interest more slowly (i.e., for more than 3 seconds after the stimulus), the observer scored it as "moderate sedation." If the monkey did not open its eyes for 15 seconds between / throughout all three stimuli, the observer recorded a loss of the ability to respond to external stimuli and scored it as "deep sedation."

[0089]

[0089] When scored as moderate or deep sedation, the monkey may be observed to be in an abnormal posture different from a characteristic resting / sleeping posture (e.g., unable to maintain an upright posture). Sedation assessments were initiated during a 5-minute sampling period if the animal closed its eyes for longer than 3 seconds at any point during that period. The results of this assessment were recorded for each remaining 15-second interval of the 60-second epoch, unless the eyes were opened. If the eyes closed again, the assessment was then initiated. If the eyes remained closed, the assessment was repeated at the start of each 15-second interval of the next 60-second epoch. Thus, the maximum score for sedation during a 5-minute period was 20 (4 possible scores per minute for 15-second intervals, total for 5 minutes; i.e., 4 possible scores per minute for 5 minutes = 20). The order in which the animals were observed and the observers performing the scoring each day were randomized. Four observers participated in scoring throughout the entire duration of the trial, each receiving a minimum of 20 hours of training and meeting the inter-observer reliability criterion of agreement with more than 90% of all other observers.

[0090]

[0090] The 5-minute sampling period was repeated multiple times after intravenous injection of TPA023B or the medium (a few minutes after injection): 5, 10, 20, 40, 80, 160, 320. The scores were accumulated over the entire period, and the maximum cumulative score obtainable was 140. TPA023B was compared with alprazolam, and the results have been published by Duke et al. (2018). Key results are summarized in Table 3. However, among other things, Duke et al. 2018 did not consider the potential use of TPA023B as a treatment for benzodiazepine misuse and / or use disorder.

[0091] [Table 3]

[0092]

[0091] Consistent with findings from studies in human patients (Atack et al. 2010), TPA023B was well tolerated by rhesus monkeys, reaching intravenous doses of up to 1.0 mg / kg (30 times higher than the minimum dose that induces rest / sleep posture). At intravenous doses of 0.03–1.0 mg / kg, TPA023B induces a rest / sleep posture equivalent to a mild form of sedation, in which the subject can be easily awakened by stimulation.

[0093] Example 3: Self-administration

[0092] The potential for abuse of a novel compound can be determined by the use of an intravenous self-administration procedure in which the compound is made available to a subject who has been pre-trained to press a lever to obtain a known abuse drug. Our standard procedure is to use a progressive ratio (PR) schedule in which a succession of responses is required to obtain the injection. The final response requirement that is met is called a “breakpoint” (BP) and represents the maximum amount of “work” the subject will perform to obtain the drug or compound.

[0094]

[0093] In this embodiment, eight rhesus monkeys (four females and four males) were trained to respond to a schedule of intravenous midazolam (a conventional benzodiazepine) injections at a dose of 0.03 mg / kg / injection. Once self-administration was mastered (more than 20 injections / daily 2-hour sessions), the monkeys were trained under the PR schedule as described by Shinday et al. (2013). Each daily experimental session consisted of five components, each consisting of four trials (i.e., a total of 20 trials). Each trial within a component had the same response requirements and was separated by a timeout (30 minutes of lights off or lever unavailability) to minimize drug accumulation from repeated injections in a single session. The session ended when the response requirements were not met within the 30-minute time limit in two consecutive trials, or when all 20 trials were completed. The PR sequence had 40 initial response requirements per injection, with the response requirements doubling at the start of each component (i.e., 40, 80, 160, 320, and 640 response requirements). Training sessions alternated between the drug and saline according to the following five-session cycle: DSSDD, SDDSS (S=saline or D=drug). Response under the PR schedule was considered stable over the cycle if the number of injections / session did not show a consistent increasing or decreasing trend and remained below 5 during at least three sessions in which saline was available, or above 11 during at least three sessions in which the drug was available. Test sessions were inserted into the sequence every three sessions, e.g., DSTSDTD, STDDTSS (T=test). Test conditions included TPA023B compared to lorazepam, a conventional benzodiazepine with a similar duration of action to the test compound.

[0095]

[0094] A range of doses of lorazepam (0.001-0.03 mg / kg / injection) and TPA023B (0.003-0.03 mg / kg / injection) were tested, and both 2+ doses maintained significantly higher average injections / session than those maintained with the medium alone (the medium generally resulted in 3-4 injections / session due to the lack of a signal indicating drug availability). To directly compare self-administration of lorazepam and TPA023B, we here analyzed BP values ​​at the doses that maintained the highest level of average injections / session and compared these BP values ​​to BP values ​​obtained after testing the medium.

[0096]

[0095] As shown in Figure 5, the median BP for lorazepam at the dose with the most self-administrations was 320, compared to the highest response requirement maintained by TPA023B at 160. These values ​​were significantly different (Dunnett's rank test, p<0.05). As expected, both lorazepam and TPA023B maintained significantly higher median BP values ​​than those maintained by the medium (Dunnett's rank test, p<0.05). These findings suggest that TPA023B is a reinforcer, but has a significantly lower reinforcing effect than the conventional benzodiazepine lorazepam. These findings suggest that TPA023B is a GABA A This is consistent with the fact that, in terms of receptor subtypes, they are primarily partially positive modulators / antagonists.

[0097] Example 4: Specific suppression of benzodiazepine self-administration

[0096] TPA023B exhibited anti-conflict effects consistent with this compound having anxiolytic-like effects comparable to those of conventional benzodiazepines. When comparing its sedative-motor effects with those of the conventional benzodiazepine alprazolam (Xanax®), TPA023B showed only mild sedation and no motor impairment. Furthermore, when evaluating the potential for abuse, TPA023B demonstrated a lower potential for abuse than lorazepam (Ativan®), which was self-administered to the same extent as all conventional benzodiazepines in our PR procedure. A key question in evaluating this compound as a potential pharmacotherapy is the extent to which TPA023B attenuates the reinforcing effect of conventional benzodiazepines under conditions where TPA023B is a weak reinforcer.

[0098]

[0097] To test this, we trained monkeys to self-administer midazolam (0.056 mg / kg / intravenous injection), a short-acting conventional benzodiazepine, in a PR procedure as described above. Throughout the test sessions, we kept the training dose of midazolam constant initially, and immediately before the start of each session, we administered it intravenously as a pretreatment for TPA023B (0.003, 0.01, 0.03, 0.1, 0.3 mg / kg in the medium). In general, in addition to interpreting the inhibition of the reinforcing effect, an important consideration for any pharmacotherapy is the degree to which the inhibition is specific to the purpose of the drug, and not a general inhibition of behavior, for example, due to a sedative-motor effect that inhibits the monkey's ability to press a lever. Another possible confounding factor that may lead to inhibition of drug intake is systemic malaise or altered perception. In particular, appetite suppression would be an undesirable side effect in the pharmacotherapy of benzodiazepine dependence.

[0099]

[0098] To evaluate the extent to which the suppression of lever-pushing behavior by TPA023B exhibited nonspecific inhibition, we also tested self-administration of feed under a PR schedule. In these experiments, the test sessions were scheduled similarly to those with midazolam dose / medium, except that two feed pellets (1-g BioServ flavored feed pellets) were available as reinforcers instead of midazolam dose. All other aspects of the test were the same, including response requirements and TPA023B pretreatment conditions.

[0100]

[0099] Figure 6 shows the effect of pretreatment with TPA023B on self-administration of two doses of midazolam and feed pellets in four rhesus monkeys. Dots on "V" (medium) indicate that the release of both doses of midazolam and feed pellets was maintained between 11 and 15 of the 20 expected reinforcer releases per session, which was essentially the same as the baseline response. Dose increases of TPA023B reduced the midazolam maintenance response at both doses, decreasing by more than 50% at 0.03 mg / kg. In contrast, TPA023B did not alter the feed maintenance response up to 0.3 mg / kg. These findings clearly demonstrate that TPA023B inhibits the self-administration of the benzodiazepine midazolam without altering the self-administration of feed, suggesting that TPA023B exhibits desirable specificity and that the suppression of its response is not due to attenuation of the sedative-motor effect and / or overall enhancement process.

[0101] Example 5: Dosage evaluation for benzodiazepine inhibitory and anxiety-relieving effects

[0100] To further evaluate the extent to which the attenuation of the response was due to pharmacological antagonism, and to assess an exemplary range of effective doses, we evaluated single doses of TPA023B administered before sessions in which different doses of midazolam were tested.

[0102]

[0101] Figures 7A and 7B both show raw data (Figure 7A, number of injections / session) and maximum percentage (Figure 7B, maximum number of injections % / session for each monkey). These figures show that midazolam alone resulted in dose-dependent self-administration at 0.018, 0.056, and 0.18 mg / kg / injection, but not at 0.0056 mg / kg / injection, with the maximum self-administration occurring at a dose of 0.018 mg / kg / injection. Pretreatment with 0.003 mg / kg of TPA023B did not attenuate midazolam self-administration, but an increased TPA023B dose of 0.01 mg / kg shifted the midazolam dose-response function to the right. That is, TPA023B suppressed midazolam self-administration at 0.018 mg / kg / injection, but the response returned to the maximum level when the midazolam dose was increased (see Figure 4, lower panel).

[0103]

[0102] At higher doses of TPA023B, the dose-response function of midazolam shifts downwards to the right, and self-administration generally does not reach 50% of its maximum, even at relatively high midazolam doses. In other words, the suppression of midazolam self-administration by TPA023B is not completely reversed, meaning that resuming midazolam intake cannot be achieved simply by taking a higher dose of the benzodiazepine. These data further support TPA023B's ability to block the effects of conventional benzodiazepines, regardless of their sedative and / or motility effects, revealing a remarkable and irreversible profile.

[0104]

[0103] To illustrate the causal relationship between anxiety relief and prevention of benzodiazepine self-administration, Figure 8 plots the three highest doses of midazolam self-administration together with conflict data from Table 2 as the mean percentage of maximum effect. When plotted as maximum percentage, increased TPA023B suppressed the response in a dose-dependent manner ("anti-conflict effect"). As described above, TPA023B dose-dependently reduced midazolam self-administration to below 50% across all doses of midazolam, with the highest TPA023B dose consistently showing a reduction to below 25%. In terms of both conflict and prevention of self-administration, TPA023B doses of 0.03 mg / kg and above had an anti-conflict effect and prevented midazolam self-administration. Therefore, TPA023B attenuates the reinforcing effect of midazolam at the same dose that causes an enhancement of anxiolytic-like effects, suggesting that TPA023B maintains anxiety relief along with its ability to prevent benzodiazepine self-administration.

[0105] Example 6: Evaluation of respiratory depression

[0104] Although considered safer than some other drugs in psychiatry, benzodiazepines are known respiratory depressants. While the effect of benzodiazepines on lung ventilation is considered mild, they carry a risk of aspiration, and their use is contraindicated for sleep apnea. Importantly, when benzodiazepines are combined with alcohol and / or opioids, there is an increased risk of death from overdose. Therefore, we initiated a trial to evaluate the potential respiratory depressant effects of our partially positive modulator.

[0106]

[0105] We first evaluated the effects of TPA023B compared to alprazolam using whole-body plethysmography (WBP; DSI systems). In these studies, adult male Sprague-Dawley rats (n=8) were acclimated in a chamber for 30 minutes. The chamber was then filled with 21% oxygen, closed, and pressure fluctuations were measured for 1 minute. Next, the chamber was opened, and the rats were injected intraperitoneally with either alprazolam or TPA023B, and the rats were placed in the closed chamber during a 15-minute pre-treatment period. The chamber was refilled with 21% oxygen, and fluctuating pressures were recorded for 1 minute to obtain tidal volume (vital capacity), respiration / min, and minute ventilation (vital capacity per unit time).

[0107]

[0106] Figure 9 shows the results from tests conducted once or twice per week on eight rats using alprazolam and TPA023B. Alprazolam significantly reduced respiratory rate and minute ventilation at 3.0 mg / kg, but did not reduce tidal volume. In contrast, TPA023B did not alter any ventilation parameters across the tested doses. Importantly, the doses were selected to occupy 95% of the benzodiazepine binding site (1.0 and 3.0 mg / kg, Atack et al. 2010). These findings demonstrate low toxicity to a partially positive modulator, which is an important characteristic considering that benzodiazepine-dependent patients are likely to abuse other substances as well.

[0108] Example 7: Evaluation of physical dependence and withdrawal symptoms

[0107] A well-documented consequence of benzodiazepine exposure and a significant contributing factor to the abuse of these drugs is physical dependence (Licata & Rowlett 2008, Pharmacol Biochem Behav 90:74-89). Physical dependence occurs when exposure to a drug leads to adverse, or even fatal, consequences upon discontinuation of the drug exposure. Discontinuation can occur as a result of either "spontaneous withdrawal symptoms" (abrupt removal of drug treatment) or induced withdrawal symptoms (administration of a drug with antagonist properties). Signs of benzodiazepine withdrawal symptoms include gastrointestinal disturbances (e.g., nausea, vomiting), anxiety, insomnia, tremors, and, in severe cases, seizures. Relief of withdrawal symptoms may be a major factor in the resumption of benzodiazepine use.

[0109]

[0108] Mild withdrawal symptoms can occur with a single dose of benzodiazepines, even after relatively large bolus exposure. This effect may be an earlier contributing factor to benzodiazepine dependence, especially in vulnerable patients (for example, the induction of mild anxiety may cause anxious patients to seek out more benzodiazepines). Acute dependence can be demonstrated in non-human animals, providing a means to study early events in the dependence cycle, but also providing methods to mitigate the risks to subjects.

[0110]

[0109] Acute addiction can occur after a single exposure to the benzodiazepine chlordiazepoxide, but α2 / 3GABA A This cannot occur after exposure to a selective ligand (Fischer et al., 2013, Psychopharmacology 227:347-54). Here, we tested to what extent TPA023B could induce withdrawal symptoms in rats after a single, large bolus dose of diazepam. For these tests, adult Sprague-Dawley rats (N=8) were trained to press a lever 10 times to receive a food pellet during a 10-minute session once daily (FR10 schedule). Once the response rate stabilized, doses of diazepam, the non-selective benzodiazepine antagonist flumazenil, and TPA023B were administered before each session.

[0111]

[0110] Figures 10A-10C show that the mean response rate (expressed as a percentage of the baseline control) was significantly reduced with diazepam, but not with flumazenil or TPA023B. Next, we varied the time between the injection of 3.0 mg / kg of diazepam and the test, and observed the strongest effect with 30 minutes of pretreatment before the session, and no effect with 60 minutes of pretreatment.

[0112]

[0111] To evaluate the extent to which flumazenil and TPA023B induce withdrawal symptoms, we evaluated the effects of pretreatment with both compounds prior to diazepam, using a 60-minute pretreatment period during which the effects of diazepam had worn off. As shown in Figure 11A, when the flumazenil dose was retested, the response was reliably suppressed at all doses tested compared to the ratio after flumazenil alone. Specifically, flumazenil interrupted lever-pushing behavior 60 minutes after a bolus injection of diazepam, which was an indication of the withdrawal state.

[0113]

[0112] In contrast, as shown in Figure 11B, TPA023B did not alter the response rate at any of the doses tested (doses that were shown to occupy approximately 95% of benzodiazepine binding sites in the brain (3.0 and 10 mg / kg)). These findings suggest that TPA023B and similar compounds are not expected to cause withdrawal symptoms in dependent subjects, which would represent a significant leap at the start of treatment, as patients with benzodiazepine dependence do not appear to need to be detoxified from benzodiazepines before therapy.

[0114] Example 8: Representative imidazopyrimidine and triazolopyridazine compounds

[0113] TPA023B contains an imidazotriazine core. Compounds MRK-623 and L-838,417 were also evaluated as exemplary compounds having an imidazopyrimidine core and a triazolopyridazine core, respectively.

[0115]

[0114] Triazolopyradizine L-838,417 is α2 / 3 / 5GABA A It has functional selectivity for the receptor, and α1GABA A It is an antagonist. This profile is remarkably similar to that of TPA023B, despite its structural differences. Imidazopyrimidine, MRK-623, is an α2 / 3GABA A It has a different selectivity profile from TPA023B in that it is subtype-selective. For both compounds, based on published literature or pilot studies in our laboratory, we selected intraperitoneal administration at a dose of 3.0 mg / kg to rats.

[0116]

[0115] Figures 12A and 12B show the results of acute dependence tests using these compounds. As shown, in addition to the non-selective antagonist flumazenil, doses of 3.0 mg / kg of L-838,417 and MRK-623 blocked the ability of diazepam to suppress the response rate (30-minute pretreatment; Figure 12A). When these same doses of ligand were administered to rats after 60-minute diazepam pretreatment (when the effects of diazepam had worn off; Figure 12B), flumazenil induced a significant decrease in the response rate, which is consistent with withdrawal-like symptoms and acute dependence. However, since none of L-838,417 and MRK-623 altered the response rate, it is suggested that these compounds, like TPA023B, do not induce acute physical dependence.

[0117] Exemplary Embodiments

[0116] Embodiments of the present disclosure may include, but are not limited to, the features enumerated in the following clauses.

[0118]

[0117] Clause 1: A method for treating benzodiazepine misuse and / or use disorder, wherein GABA A A method comprising administering an effective amount of a compound that produces both partial modulator and partial antagonist effects at a receptor to a subject requiring it.

[0119]

[0118] Clause 2: The method according to Clause 1, wherein the compound is a compound of Formula I, Formula II, Formula III, or a combination or mixture thereof.

[0119] Clause 3: The method according to Clause 1 or 2, wherein the compound produces an anxiolytic effect.

[0120]

[0120] Clause 4: The method according to Clause 3, wherein the anxiolytic effect is lower than that of benzodiazepines.

[0121] Clause 5: The method according to any one of Clauses 1 to 4, wherein the positive reinforcing effect of the compound is lower than that of the benzodiazepine.

[0121]

[0122] Clause 6: The method according to any one of Clauses 1 to 5, wherein the compound works to inhibit the action of a benzodiazepine.

[0123] Clause 7: The method according to Clause 6, wherein the inhibition is unrelated to the sedative effect of the compound.

[0122]

[0124] Clause 8: The method according to Clause 6 or Clause 7, wherein the inhibition is independent of the kinetic activity of the compound.

[0125] Clause 9: The method described in any one of Clauses 6-8, wherein the suppression is irreversible and therefore cannot be counteracted by increased benzodiazepine administration.

[0123]

[0126] Clause 10: The method according to any one of Clauses 1 to 9, wherein the compound is administered in a dose of approximately 0.01 mg / kg or more.

[0127] Clause 11: The method according to any one of Clauses 1 to 9, wherein the compound is administered in a dose of approximately 0.03 mg / kg or more.

[0124]

[0128] Clause 12: The method according to Clause 11, wherein the compound, when administered, produces both an anxiolytic effect and a benzodiazepine inhibitory effect.

[0129] Clause 13: The method according to any one of Clauses 1 to 12, wherein the compound does not induce a substantial loss of motor coordination in the subject.

[0125]

[0130] Clause 14: The method according to any one of Clauses 1 to 13, wherein the compound does not induce substantial appetite suppression in the subject.

[0131] Clause 15: The method described in any one of Clauses 1 to 14, wherein the compound does not substantially affect the respiratory rate, tidal volume, or minute ventilation in the subject.

[0126]

[0132] Clause 16: The method according to any one of Clauses 1 to 15, wherein the compound does not cause benzodiazepine withdrawal symptoms.

[0133] Clause 17: The method according to any one of Clauses 1 to 16, wherein the compound is administered without prior or concurrent detoxification treatment of the subject.

[0127]

[0134] Clause 18: The method described in any one of Clauses 1 to 17, wherein the compound is partially or completely deuterated.

[0135] Clause 19: Compounds for use in treating benzodiazepine misuse and / or use disorders in accordance with the method described in any one of Clauses 1 to 18.

[0128] Additional terms and definitions

[0136] Specific embodiments of this disclosure are described in detail with reference to specific arrangements, parameters, components, elements, etc., but this description is illustrative and should not be construed as limiting the scope of the invention as described in the claims.

[0129]

[0137] Furthermore, with respect to all of the specified elements of the components of the embodiments described, it should be understood that any of the possible alternatives listed for that element or component may generally be used individually or in combination with each other, unless otherwise stated implicitly or explicitly.

[0130]

[0138] Furthermore, unless otherwise indicated, any quantities, components, distances, or other measured numbers used herein and in the claims should be understood to be optionally modified by the term “about” or its synonyms. When the terms “about,” “approximately,” “substantially,” or similar terms are used with any quantity, value, or condition described herein, they should be understood to mean a quantity, value, or condition that deviates by less than 20%, less than 10%, less than 5%, less than 1%, less than 0.1%, or less than 0.01% from the described quantity, value, or condition. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted in light of the reported number of significant figures and by applying common rounding techniques.

[0131]

[0139] All titles and subtitles used herein are for structural purposes only and are not intended to limit the scope of the specification or claims.

[0140] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” do not exclude multiple references unless the context clearly indicates otherwise. For example, an embodiment referring to a singular reference (e.g., “miniatures”) may include two or more such references.

[0132]

[0141] The embodiments described herein may include properties and / or features (e.g., materials, components, members, elements, parts, and / or components) described in one or more individual embodiments, and will not necessarily be strictly limited to the features explicitly described for that particular embodiment. Therefore, various features of a given embodiment can be combined with and / or incorporated into other embodiments of the Disclosure. For this reason, the disclosure of specific features related to a particular embodiment of the Disclosure should not be interpreted as limiting the application or inclusion of such features to that particular embodiment. Rather, it will be understood that other embodiments may also include such features. Non-limitingly, the present invention includes the following embodiments. [Aspect 1] A method for treating benzodiazepine misuse and / or use disorder, GABA A Administering an effective amount of a compound that produces both partial modulator and partial antagonist effects at the receptor to the target that requires it. A method that includes this. [Aspect 2] The compound is, Formula I: [ka] (In the formula: R1 and R2 are independently H, Cl, F, CF3, CN, alkyl (e.g., C1-C5), alkoxy (e.g., C1-C5), OCF3, or isopropanol group [ka] And, Q1 and Q2 are independently either C or N. Ar1 and Ar2 are each six-membered aromatic rings, each of which is optionally substituted with one or two substituents. The method according to embodiment 1, wherein the compound is [the compound]. [Aspect 3] The method according to embodiment 2, wherein one of R1 and R2 is H and the other is CH3, CF3, or an isopropanol group. [Aspect 4] The method according to embodiment 2, wherein R1 is a CH3, CF3, or isopropanol group, and R2 is H. [Aspect 5] The method according to embodiment 2, wherein one or both of Q1 or Q2 are N. [Aspect 6] The method according to embodiment 2, wherein Ar1, Ar2, or both thereof contain one or more heteroatoms selected from O or N. [Aspect 7] The method according to embodiment 2, wherein Ar1 and Ar2 are each independently phenyl, pyridine, pyridazine, pyrimidine, or pyrazine. [Aspect 8] The method according to embodiment 2, wherein Ar1, Ar2, or both are substituted, and the substituent includes one or more of Cl, F, CF3, CN, alkyl, alkoxy, or OCF3. [Aspect 9] The method according to embodiment 8, wherein the substituent is F and / or CN. [Aspect 10] The method according to embodiment 2, wherein the compound is TPA023B. [Aspect 11] The compound is, Formula II: [ka] (In the formula: R1 is H, Cl, F, CF3, CN, alkyl, or cycloalkyl. R2 is H, Cl, F, CF3, CN, alkyl, alkoxy, or OCF3, and n is 1 or 2. Q is C, N, O, S, sulfone, or sulfoxide. The method according to embodiment 1, wherein Ar is a compound of a diazole, triazole, or pyridine that is optionally substituted. [Aspect 12] The method according to embodiment 11, wherein R1 is isopropyl or cyclobutyl. [Aspect 13] The method according to embodiment 11, wherein R2 is F. [Aspect 14] The method according to embodiment 11, wherein Q is O. [Aspect 15] Ar-substituted triazoles: [ka] (In the formula, R3 is H or a C1-C2 alkyl group.) The method according to embodiment 11. [Aspect 16] The compound is, Formula III: [ka] (In the formula: Each of Q1, Q2, and Q3 is independently either C or N. Each of R1, R2, and R3 is independently H, Cl, F, CF3, CN, C1-C5 alkyl, C1-C5 alkoxy, or OCF3. (Each n is either 1 or 2) The method according to embodiment 1, wherein the compound is [the compound]. [Aspect 17] The method according to embodiment 16, wherein at least one of Q1 or Q2 is N, and Q3 is N. [Aspect 18] The method according to embodiment 16, wherein R1, R2, and R3 are F. [Aspect 19] The method according to any one of embodiments 1 to 18, wherein the compound produces an anxiolytic effect. [Aspect 20] The method according to embodiment 19, wherein the anxiolytic effect is lower than that of benzodiazepines. [Aspect 21] The method according to any one of embodiments 1 to 18, wherein the positive reinforcing effect of the compound is lower than that of the benzodiazepine. [Aspect 22] The method according to any one of embodiments 1 to 18, wherein the compound works to suppress the action of benzodiazepines. [Aspect 23] The method according to embodiment 22, wherein the inhibition is unrelated to the sedative effect of the compound. [Aspect 24] The method according to embodiment 22, wherein the inhibition is independent of the kinetic activity of the compound. [Pattern 25] The method according to embodiment 22, wherein the suppression is irreversible and therefore cannot be counteracted by increased benzodiazepine administration. [Aspect 26] The method according to any one of embodiments 1 to 18, wherein the compound is administered in a dose of approximately 0.01 mg / kg or more. [Aspect 27] The method according to any one of embodiments 1 to 18, wherein the compound is administered in a dose of approximately 0.03 mg / kg or more. [Aspect 28] The method according to embodiment 27, wherein the compound provides both an anxiolytic effect and a benzodiazepine inhibitory effect. [Aspect 29] The method according to any one of embodiments 1 to 18, wherein the compound does not induce a substantial loss of motor coordination in the subject. [Aspect 30] The method according to any one of embodiments 1 to 18, wherein the compound does not induce substantial appetite suppression in the subject. [Aspect 31] The method according to any one of embodiments 1 to 18, wherein the compound does not substantially affect the respiratory rate, tidal volume, or minute ventilation in the subject. [Aspect 32] The method according to any one of embodiments 1 to 18, wherein the compound does not cause benzodiazepine withdrawal symptoms. [Aspect 33] The method according to any one of embodiments 1 to 18, wherein the compound is administered without prior or simultaneous detoxification treatment of the subject. [Aspect 34] The method according to any one of embodiments 1 to 18, wherein the compound is partially or completely deuterated. [Aspect 35] Compounds for use in treating benzodiazepine misuse and / or use disorders according to the method described in any one of embodiments 1 to 18.

Claims

1. A pharmaceutical composition comprising a compound for treating benzodiazepine misuse and / or use disorder, The compound has the following structure: 【Chemistry 1】 Includes TPA023B, The compound is administered at a dose of 0.03 mg / kg or more, and The administration of the aforementioned compound follows: (i) The compound inhibits the action of benzodiazepines and benzodiazepine self-administration, wherein the inhibition is irreversible and cannot be counteracted by increased benzodiazepine administration. (ii) The compound does not cause benzodiazepine withdrawal symptoms in the subject. It results in one or both outcomes. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the compound provides an anxiolytic effect.

3. The pharmaceutical composition according to claim 2, wherein the anxiolytic effect is lower than that of benzodiazepines.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the positive reinforcing effect of the compound is lower than that of the benzodiazepine.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound acts to suppress the action of a benzodiazepine independently of the sedative effect of the compound and / or independently of the kinetic effect of the compound.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the compound does not induce a loss of motor coordination in the subject and / or induce appetite suppression in the subject.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the compound does not affect the respiratory rate, tidal volume, or minute ventilation in the subject.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is administered without prior or simultaneous detoxification treatment of the subject.

9. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a pharmaceutical for treating benzodiazepine misuse and / or use disorder.

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