Use of a monoterpene derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of obsessive-compulsive disorder

Abstract

The application discloses application of a monoterpenoid derivative or pharmaceutically acceptable salt thereof in preparation of a drug for preventing or treating obsessive-compulsive disorder. The monoterpenoid derivative has a structural formula as shown in the specification, wherein X is hydrogen or an acyl group. The monoterpenoid derivative can effectively relieve and improve obsessive-compulsive symptoms of a mouse model of obsessive-compulsive disorder, and can be used for preparing the drug for preventing or treating obsessive-compulsive disorder, thereby providing a new drug selection for treatment of obsessive-compulsive disorder.

Description

Technical Field

[0001] This invention belongs to the field of obsessive-compulsive disorder (OCD) treatment drugs, and relates to the use of a class of monoterpene derivatives or their pharmaceutically acceptable salts in the preparation of drugs for the prevention or treatment of OCD. Background Technology

[0002] Obsessive-compulsive disorder (OCD) is a chronic, disabling mental illness characterized by recurrent, unwanted, persistent, and intrusive thoughts, impulses, or images (obsessive thoughts) and repetitive behaviors (compulsive behaviors) that an individual attempts to ignore or suppress these thoughts, impulses, or images. OCD patients are constantly troubled by obsessive thoughts and compulsive behaviors, knowing that the persistence of these symptoms is meaningless and irrational, yet unable to control their recurring occurrence. Patients experience recurring obsessive thoughts and compulsive behaviors in their daily lives. In addition to obsessive symptoms, OCD patients often have cognitive deficits. Cognitive deficits are considered a significant cause of the development and maintenance of obsessive symptoms. The cognitive impairment in OCD patients is widespread, involving multiple aspects such as executive function, attention, and memory. Numerous studies have shown that OCD patients have deficits in various executive functions, including inhibitory control, cognitive flexibility, and working memory.

[0003] Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder after depression, alcohol / substance abuse, and social phobia. Globally, the prevalence of OCD is approximately 2-3%. OCD typically develops at a young age and often leads to severe impairment of social functioning, resulting in a significant socioeconomic burden. In terms of quality of life, compared to healthy individuals, people with OCD experience a decline in quality of life in almost all areas.

[0004] Obsessive-compulsive disorder (OCD) is characterized by repetitive intrusive thoughts and compulsive behaviors. Depression is characterized by persistent low mood and loss of interest. Anxiety disorders are characterized by excessive worry, physical tension, and avoidance behaviors. These three disorders are psychiatric illnesses with different diagnostic criteria. Among them, depression and anxiety often have a high comorbidity rate.

[0005] Obsessive-compulsive disorder (OCD) is chronic, persistent, or recurrent, with unsatisfactory clinical treatment outcomes. Research indicates that most patients experience a subclinical phase for several years before onset, and over 80% develop a chronic course after onset. Drug therapy and psychotherapy are currently the first-line treatments for OCD, with psychotherapy primarily referring to cognitive behavioral therapy based on exposure / response prevention (ERP). OCD treatment guidelines in various countries recommend selective serotonin reuptake inhibitors (SSRIs) as first-line medications. However, SSRIs only alleviate obsessive-compulsive symptoms to a certain extent. Therefore, it is necessary to further understand the pathogenesis of this disease and seek new treatment methods.

[0006] Researchers have conducted extensive studies on the etiology of obsessive-compulsive disorder (OCD) from biological, psychological, and sociological perspectives. Research indicates that OCD is closely related to multiple factors, including genetics, environment, and psychology. No single factor can fully explain the occurrence of OCD; it is likely caused by the interaction of these factors. However, due to its complex pathogenesis, current treatments are not entirely effective, and a large proportion of patients do not experience adequate relief from their compulsive behaviors. Therefore, further in-depth research is needed on the pathogenesis of OCD and effective treatment methods.

[0007] The development of obsessive-compulsive disorder (OCD) is believed to be closely related to an excitatory / inhibitory imbalance involving gamma-aminobutyric acid (GABA) and glutamate in the brain. Proton magnetic resonance spectroscopy was used to measure glutamate and GABA levels in the anterior cingulate cortex and supplementary motor area of ​​healthy volunteers and OCD patients to assess the balance of excitatory and inhibitory neurotransmission. The results showed that OCD patients exhibited elevated glutamate and decreased GABA levels in this region of the anterior cingulate cortex. Plasma GABA expression levels were also significantly reduced in OCD patients, leading to an excitatory / inhibitory imbalance in the nervous system. The dopamine signaling pathway, co-regulated by GABA and serotonin, plays a crucial role in the development of obsessive-compulsive disorders. Summary of the Invention

[0008] In view of the shortcomings of existing drugs for treating obsessive-compulsive disorder, the present invention provides the use of a class of monoterpene derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention or treatment of obsessive-compulsive disorder.

[0009] The monoterpene derivative described in this invention has the following structural formula:

[0010] Where X is hydrogen or acyl.

[0011] Furthermore, in the structural formulas of the above monoterpene derivatives, X is -H, -COB, -COCH3, -COCH2CH3, -COCHC2H6, or -COCH2CH2CH3; where B in -COB is... R1 is -H, -OH, -OCH3 or -OCOCH3, R2 is -H, -Cl or -Br, and R3 is -H, -Cl, -Br or -CF3.

[0012] Preferably, the monoterpene derivative is selected from one of the following compounds:

[0013]

[0014]

[0015]

[0016] The drug for preventing or treating obsessive-compulsive disorder described in this invention contains the above-mentioned active ingredient, a monoterpene derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The carrier is adapted according to the drug dosage form, administration method, etc. The drug dosage form can be a conventional pharmaceutical formulation such as capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, and patches.

[0017] Furthermore, in a specific embodiment of the present invention, the drug carrier used is physiological saline, and the drug dosage form is an injection.

[0018] The medication for preventing or treating obsessive-compulsive disorder described in this invention can be used in any animal that may have or already has obsessive-compulsive disorder. These animals include both human and non-human animals, such as pets or livestock.

[0019] The drug for preventing or treating obsessive-compulsive disorder described in this invention also contains pharmaceutically acceptable excipients.

[0020] The concentration and dosage of the medication for preventing or treating obsessive-compulsive disorder described in this invention depend on the recipient's age, health and weight, treatment frequency, route of administration, etc.

[0021] The monoterpene derivatives or their pharmaceutically acceptable salts described in this invention, based on Zz-001, can introduce halogen (-F, -Cl, -Br), trifluoromethyl (-CF3), and other groups to regulate the polarity, stability, and bioactivity of the compound. Halogen atoms are more electronegative than carbon atoms and contain lone pairs of electrons, which can generate p-π conjugation with aromatic rings, donating electrons to the ring and thus producing an electron-donating conjugation effect. This can enhance the lipophilicity of the molecule (the hydrophobicity and small atomic radius of halogens enhance the ability of drugs to penetrate cell membranes), metabolic stability (the C-halogen bond formed by halogens and C atoms has high stability, which can reduce liver metabolism and prolong half-life), and target binding ability.

[0022] This invention establishes a succinic acid-induced mouse model of obsessive-compulsive disorder (OCD). Experimental results show that the monoterpene derivative Zz-001 can act as a GABA receptor, exhibiting anti-obsessive-compulsive-like effects and effectively alleviating obsessive-compulsive symptoms in succinic acid-induced OCD mice. The monoterpene derivatives or pharmaceutically acceptable salts described in this invention can be used to prepare drugs for the prevention or treatment of OCD, thereby providing a new drug option for the treatment of OCD. Attached Figure Description

[0023] Figure 1This is a statistical graph showing the grooming behavior of normal C57BL / 6J mice and C57BL / 6J mice after a 3-week obsessive-compulsive disorder model was established by feeding them succinic acid. The graphs show the grooming behavior 1 hour, 3 days, and 5 days after the third tail vein injection of Zz-001 or saline containing 1% DMSO. (A) represents the total time of spontaneous grooming 1 hour after the third tail vein injection of Zz-001 or saline containing 1% DMSO, and the total time of facial grooming after corn oil application. (B) represents the total number of spontaneous grooming sessions 1 hour after the third tail vein injection of Zz-001 or saline containing 1% DMSO, and the total number of facial grooming sessions after corn oil application. (C) represents the total number of times the mice groomed spontaneously 1 hour after the third tail vein injection of Zz-001 or saline containing 1% DMSO, and the total number of times of facial grooming after corn oil application. The total time for spontaneous grooming and facial grooming after applying corn oil was measured 3 days after injection of Zz-001 or saline containing 1% DMSO. (D) represents the total number of spontaneous grooming and facial grooming events 3 days after the third tail vein injection of Zz-001 or saline containing 1% DMSO. (E) represents the total time for spontaneous grooming and facial grooming events 5 days after the third tail vein injection of Zz-001 or saline containing 1% DMSO. (F) represents the total number of spontaneous grooming and facial grooming events 5 days after the third tail vein injection of Zz-001 or saline containing 1% DMSO. Ctrl+Veh represents normal mice injected intravenously with saline containing 1% DMSO. Succinic acid+Zz-001 represents obsessive-compulsive disorder model mice injected intravenously with Zz-001. Succinic acid+Veh represents obsessive-compulsive disorder model mice injected intravenously with saline containing 1% DMSO. All data are expressed as mean ± SEM. *P<0.05, **P<0.01 compared with the control group. Detailed Implementation

[0024] Unless otherwise specified, the methods used in the following embodiments are conventionally used in the art. Unless otherwise specified, all raw materials used in the following embodiments are commercially available products. Unless otherwise defined, all technical and scientific terms used in this invention have the meanings commonly understood by one of ordinary skill in the art.

[0025] The monoterpene derivatives described in this invention can be prepared with reference to the literature [Cha JS, Moon SJ, Park J H. Solution of Borane in Tetrahydrofuran. A Stereoselective Reducing Agent for Reduction of Cyclic Ketones to Thermodynamically More Stable Alcohols[J]. The Journal of Organic Chemistry, 2001, 66(22):7514-5.].

[0026] The pharmaceutically acceptable salts of a class of monoterpene derivatives described in this invention can be prepared by reacting a free base or acid with an equistoichiometric or excess amount of an acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition, based on the monoterpene derivatives.

[0027] The present invention will now be described in further detail with reference to the embodiments and accompanying drawings.

[0028] Example 1

[0029] Experiments on Zz-001's improvement of obsessive-compulsive symptoms in a succinic acid-induced mouse model of obsessive-compulsive disorder.

[0030] (1) Construction of a succinic acid-induced obsessive-compulsive disorder mouse model

[0031] First, adult (6-8 weeks old) C57BL / 6J mice were used for behavioral testing; 5 mice per cage, with a 12-hour light-dark cycle (7 am-7 pm light). All mice had free access to a stable supply of water and food, and all animal experiments were approved by the Animal Protection and Use Committee of Southeast University and Shanghai Mental Health Center. The mice were randomly divided into 3 groups. Two groups drank a succinic acid solution (prepared by dissolving succinic acid in water to a concentration of 0.015 g / mL) daily for 3 weeks to establish a model group. The other group received normal drinking water daily as a control group.

[0032] (2) Experimental Grouping

[0033] In the two model groups, after modeling, one group received a tail vein injection of Zz-001 solution (Succinic acid + Zz-001) once daily at a dose of 2 mg / kg, while the other group received a tail vein injection of an equal volume of physiological saline containing 1% DMSO (Succinic acid + Veh) for 3 consecutive days. The control group received a tail vein injection of an equal volume of physiological saline containing 1% DMSO (Ctrl + Veh) once daily at a dose of 2 mg / kg for 3 consecutive days. The concentration of Zz-001 solution was 0.2 mg / mL, prepared by dissolving Zz-001 in physiological saline to a concentration of 0.2 mg / mL.

[0034] (3) Hair grooming behavior test

[0035] The cylindrical apparatus used to detect grooming behavior in mice was 15 cm in diameter and 21 cm in height. After the third intravenous injection of Zz-001 or saline, the mice were allowed to acclimatize in a behavioral room for one hour, and their spontaneous grooming behavior was then recorded for 30 minutes using bilateral cameras. Immediately afterwards, 100 μL of corn oil was applied to the mice's faces to induce repeated grooming behavior, which was recorded for another 30 minutes. A double-blind method was used to analyze the frequency of grooming 5 minutes before and after the corn oil application, comparing baseline grooming behavior with induced grooming behavior. Longer duration and higher frequency of grooming indicated more severe obsessive-compulsive symptoms. The same method was used to test grooming behavior in mice 3 and 5 days after the third intravenous injection of Zz-001 or saline containing 1% DMSO.

[0036] (4) Data Analysis

[0037] All data are expressed as mean ± SEM. For all behavioral data, two-tailed Student's first-tests or two-way ANOVA followed by Tukey's post-hoc test were used.

[0038] (5) Results Analysis

[0039] Figure 1The figures show the grooming behavior of normal C57BL / 6J mice and C57BL / 6J mice that developed an obsessive-compulsive disorder model after being fed succinic acid for 3 weeks. The results were statistically significant at 1 hour, 3 days, and 5 days after the third intravenous injection of Zz-001 or saline containing 1% DMSO. The results showed that Zz-001 effectively alleviated the obsessive-compulsive symptoms induced by succinic acid in the mice. Specifically, figures (A) and (B) show that Zz-001 reversed the succinic acid-induced repetitive grooming compulsive phenotype in mice; figures (C) and (D) show that even 3 days after stopping administration, the reduced succinic acid-induced repetitive grooming compulsive phenotype induced by Zz-001 still existed; and figures (E) and (F) show that even 5 days after stopping administration, the reduced succinic acid-induced repetitive grooming compulsive phenotype induced by Zz-001 still existed.

Claims

1. The use of a class of monoterpene derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention or treatment of obsessive-compulsive disorder, characterized in that, The monoterpene derivative has the following structural formula: Where X is hydrogen or acyl.

2. The application according to claim 1, characterized in that, X is -H, -COB, -COCH3, -COCH2CH3, -COCHC2H6, -COCH2CH2CH3; where B in -COB is... R1 is -H, -OH, -OCH3 or -OCOCH3, R2 is -H, -Cl or -Br, and R3 is -H, -Cl, -Br or -CF3.

3. The application according to claim 1, characterized in that, Monoterpene derivatives are selected from one of the following compounds:

4. The application according to claim 1, characterized in that, The aforementioned drug for the prevention or treatment of obsessive-compulsive disorder contains the above-mentioned active ingredient monoterpene derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

5. The application according to claim 1, characterized in that, The drug dosage forms include capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches.

6. The application according to claim 5, characterized in that, The drug carrier used is physiological saline, and the drug dosage form is injection.

7. The application according to claim 1, characterized in that, The aforementioned medication for the prevention or treatment of obsessive-compulsive disorder is used in animals that may have or already have obsessive-compulsive disorder.

8. The application according to claim 1, characterized in that, Animals include both humans and non-human animals.

9. The application according to claim 1, characterized in that, The aforementioned medication for the prevention or treatment of obsessive-compulsive disorder also contains pharmaceutically acceptable excipients.

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