Application of pyrrolopyrrolocarbazole oxime derivatives in preventing or treating post-stroke depression

Abstract

The application belongs to the technical field of medicine, and discloses application of a pyrano-carbazole oxime derivative in preventing or treating post-stroke depression. Specifically, the application discloses a pyrano-carbazole compound as shown in a general formula I. The compound is prepared by an artificial synthesis method, contains a pharmaceutical composition thereof, and is applied to treating post-stroke depression.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the use of pyranocarbazole oxime derivatives in the prevention or treatment of post-stroke depression. Background Technology

[0002] Stroke is a serious disease that severely endangers human health, ranking second globally and first in China as the leading cause of death, characterized by high recurrence and disability rates. Post-stroke depression is one of the most common complications of stroke, affecting approximately one-third of stroke patients. If not detected and treated promptly, it will impair the recovery of neurological function and the patient's ability to reintegrate into society. However, due to a general lack of awareness and diagnosis of post-stroke depression, the condition often becomes chronic, severely impacting the patient's quality of life.

[0003] Pyranocarbazole alkaloids possess a wide range of biological activities. This invention introduces oximes and nitrones into the pyranocarbazole alkaloid core to obtain pyranocarbazole oxime derivatives. Pharmacological experiments have confirmed that these derivatives can significantly reduce depressive-like behaviors and improve neurobehavioral function in animals, suggesting that this compound has significant therapeutic activity against post-stroke depression. Summary of the Invention

[0004] This invention discloses compounds of general formulas I and II. Pharmacological experiments have shown that the compounds and their formulations of this invention significantly improve depressive-like behavior in a male rat model of bilateral common carotid artery ligation. Therefore, the compounds of this invention can be used for the prevention and / or treatment of post-stroke depression.

[0005] The technical problem solved by this invention is to provide the use of pyranocarbazole oxime compounds represented by general formulas I and II and their pharmaceutically acceptable salts in the preparation of drugs for the prevention or treatment of post-stroke depression.

[0006] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0007] The first aspect of this invention is to provide the use of a class of pyranocarbazole oxime derivatives, as shown in general formula I, or pharmaceutically acceptable salts thereof, in the preparation of drugs for the prevention or treatment of post-stroke depression:

[0008]

[0009] R1 and R2 are independent and can be selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OCH3, OCH2CH3, respectively.

[0010] OCH2CH2CH3, CF3, OCF3;

[0011] R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3.

[0012] The first aspect of this invention also provides the use of a class of pyranocarbazole nitroketone derivatives of general formula II or pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention or treatment of post-stroke depression:

[0013]

[0014] R1 and R2 are independent of each other and can be selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, CF3, and OCF3, respectively.

[0015] R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3;

[0016] R4 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, Ph, Bn.

[0017] The compounds are selected from the following group:

[0018]

[0019] The pharmaceutically acceptable salt is selected from organic or inorganic acid salts, including hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, malate, fumarate, tartrate, methanesulfonate, carbonate, oxalate, lactate, succinate, or gluconate.

[0020] The pyranocarbazooxime compounds mentioned above are artificially synthesized.

[0021] The second aspect of the present invention is to provide the use of a pharmaceutical composition in the preparation of a drug for the prevention or treatment of post-stroke depression, characterized in that the pharmaceutical composition comprises the pyranocarbazole oxime derivatives described in the first aspect of the present invention, their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0022] The pharmaceutically acceptable carrier is selected from microcapsules and microspheres, nanoparticles or liposomes.

[0023] The pharmaceutical composition is selected from injections, tablets, capsules, pills, granules, oral liquids, suspensions, sustained-release preparations, subcutaneous implants, and nanosuspensions.

[0024] This pharmaceutical composition is prepared according to methods known in the art. It can be formulated into any dosage form suitable for human or animal use by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compounds of the present invention in its pharmaceutical composition is typically 0.1-95% by weight.

[0025] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0026] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0027] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0028] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannose, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0029] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0030] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. Various diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0031] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc. pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0032] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0033] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0034] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-30 mg / kg body weight. The above doses can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0035] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0036] Beneficial technical effects

[0037] The pyranocarbazooxime compound CXT-24 developed in this invention has demonstrated significant therapeutic effects in pharmacological experiments. CXT-24, at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg, showed a significant improvement in depressive-like behavior in SD rats with bilateral common carotid artery ligation. Specifically, it increased the struggle time in the forced swimming test and the center time, center count, and center distance in the open field test. These results indicate that CXT-24 has broad applicability and significant therapeutic potential, providing a new and effective drug option for the prevention and / or treatment of post-stroke depression. Attached Figure Description

[0038] Figure 1 Effects of compound CXT-24 on the time of forced swimming struggle in SD rats with bilateral common carotid artery ligation

[0039] Figure 2 Effect of compound CXT-24 on open field center time in SD rats with bilateral common carotid artery ligation

[0040] Figure 3 Effect of compound CXT-24 on the number of open field test centers in SD rats with bilateral common carotid artery ligation

[0041] Figure 4 Effect of compound CXT-24 on center distance in open field experiment of SD rats with bilateral common carotid artery ligation

[0042] Figure 5 Changes in body weight of male SD rats after three weeks of administration of compound CXT-24 Detailed Implementation

[0043] Pharmacological Experiment 1

[0044] Effects of CXT-24 at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg on depressive-like behavior in forced swimming tests in rats with bilateral common carotid artery ligation

[0045] Experimental methods:

[0046] (1) Preparation of a bilateral common carotid artery ligation model:

[0047] Methods (Xu Shuyun, ed., 3rd edition, pp. 1066-1067). Briefly, male SD rats were anesthetized with a gas anesthesia machine (1.5-2.5% isoflurane), and their body temperature was maintained at 37±0.5℃. They were fixed in a supine position on the operating table. The skin was incised along the midline of the neck, and the right common carotid artery (CCA) was carefully dissected and ligated. The skin was then incised along the midline of the neck, and the left common carotid artery (CCA) was carefully dissected and ligated. Blood flow to the middle cerebral artery was blocked. The opening of the ECA was ligated, and the surgical incision was sutured. The room temperature was maintained at 24-25℃ throughout the procedure. After one week of postoperative care, the rats were randomly assigned to groups according to their body weight.

[0048] (2) Grouping and administration

[0049] The animals were divided into 5 groups, with 8-11 animals in each group: solvent control group, CXT-24 3mg / kg group, CXT-24 10mg / kg group, CXT-24 30mg / kg group, and butylphthalide group 200mg / kg. All animals were administered orally by gavage for 3 weeks.

[0050] (3) Forced swimming test of rats

[0051] Pre-swimming phase (acclimatization phase): Rats were placed in a water tank and swam for 15 minutes. In the first 2-3 minutes, the rats continuously swam or climbed, attempting to escape the water. Their activity then decreased, intermittently exhibiting immobility or floating states, known as despair behavior. This behavior lasted longer and longer, peaking 5-6 minutes after introduction. For the remaining time, immobility accounted for approximately 80%. After the pre-test, the rats were removed, dried with a towel, and placed in a drying cage. The previous group was returned to their cages after the next group finished their pre-swimming; this process was repeated for all rats. Testing phase: 24 hours after the pre-test, the formal experiment was conducted. The rats were placed back in the tank, and the cumulative immobility time within 5 minutes was observed and recorded. Administered medication 30 minutes before the experiment.

[0052] (4) Statistical methods

[0053] All data were statistically analyzed using Graph Prism 9.2.0, and all results are expressed as mean ± SEM. Statistical analysis was performed using t-tests to compare differences between groups; a p-value < 0.05 was considered statistically significant.

[0054] Experimental results

[0055] Effects of compound CXT-24 on depressive-like behavior in forced swimming in rats with bilateral common carotid artery ligation. In SD rats, the struggle time during forced swimming after bilateral common carotid artery ligation was (27.7±5.986)%. After administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and butylphthalide (200 mg / kg), the struggle times were (50.57±5.957) s, (46.50±5.290) s, (39.44±1.914) s, and (46.55±5.096) s, respectively. The struggle time in forced swimming was significantly increased in all groups treated with oral CXT-24 compared to the control group, suggesting that CXT-24 has a certain therapeutic effect on post-stroke depression in SD rats.

[0056] Table 1. Effect of compound CXT-24 on the time of forced swimming struggle in SD rats with bilateral common carotid artery ligation.

[0057]

[0058] *P<0.05 vs. control group, n=8-10

[0059] Pharmacological Experiment 2

[0060] Effects of CXT-24 at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg on depressive-like behavior in open field experiments in rats with bilateral common carotid artery ligation

[0061] Experimental methods:

[0062] (1) Preparation of a bilateral common carotid artery ligation model:

[0063] Methods (Xu Shuyun, ed., 3rd edition, pp. 1066-1067). Briefly, male SD rats were anesthetized with a gas anesthesia machine (1.5-2.5% isoflurane), and their body temperature was maintained at 37±0.5℃. They were fixed in a supine position on the operating table. The skin was incised along the midline of the neck, and the right common carotid artery (CCA) was carefully dissected and ligated. The skin was then incised along the midline of the neck, and the left common carotid artery (CCA) was carefully dissected and ligated. Blood flow to the middle cerebral artery was blocked. The opening of the ECA was ligated, and the surgical incision was sutured. The room temperature was maintained at 24-25℃ throughout the procedure. After one week of postoperative care, the rats were randomly assigned to groups according to their body weight.

[0064] (2) Grouping and administration

[0065] The animals were divided into 5 groups, with 8-10 animals in each group: solvent control group, CXT-24 3mg / kg group, CXT-24 10mg / kg group, CXT-24 30mg / kg group, and butylphthalide group 200mg / kg; all were administered orally by gavage.

[0066] (3) Rat open field test

[0067] Rats were given the drug 30 minutes in advance and allowed 5 minutes for initial acclimatization. At the start of the experiment, the animals were placed in the center of the open field device with their heads facing the camera. The movement trajectory was recorded for 5 minutes, including the time spent in the center and corners of the open field, the number of times the animals entered, and the distance. After the experiment, the open field was wiped with gauze soaked in 75% alcohol.

[0068] (4) Statistical methods

[0069] All data were statistically analyzed using Graph Prism 9.2.0, and all results are expressed as mean ± SEM. Statistical analysis was performed using t-tests to compare differences between groups; a p-value < 0.05 was considered statistically significant.

[0070] Experimental results

[0071] Experimental results:

[0072] Effects of compound CXT-24 on depressive-like behavior in open field experiments in rats with bilateral common carotid artery ligation

[0073] After bilateral common carotid artery ligation in SD rats, the time to enter the central region in the open field experiment was (21.35±3.940) s. However, after administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and butylphthalide (200 mg / kg), the struggle times were (42.91±8.730) s, (30.78±4.042) s, (47.68±10.30) s, and (37.44±8.898) s, respectively. The time to reach the central region in the open field experiment was significantly longer in all groups treated with oral CXT-24 compared to the control group, suggesting that CXT-24 has a certain therapeutic effect on post-stroke depression in SD rats.

[0074] Table 2. Effect of compound CXT-24 on open field center time in SD rats with bilateral common carotid artery ligation.

[0075]

[0076]

[0077] *P<0.05 vs. control group, n=8-10

[0078] After bilateral common carotid artery ligation in SD rats, the number of times the rats entered the central region in the open field test was (9.50±1.258). However, after administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and butylphthalide (200 mg / kg), the number of times the rats entered the central region were (18.33±4.048), (14.75±1.449), (17.44±2.274), and (14.22±1.597), respectively. The number of times the rats entered the central region in the open field test was significantly higher in all groups treated with oral CXT-24 compared to the control group, suggesting that CXT-24 has a certain therapeutic effect on post-stroke depression in SD rats.

[0079] Table 3. Effect of compound CXT-24 on the number of open field test centers in SD rats with bilateral common carotid artery ligation.

[0080]

[0081] *P<0.05 vs. control group, n=8-10

[0082] After bilateral common carotid artery ligation in SD rats, the distance traveled in the central region during the open field test was (1748±259.1) mm. However, after administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and butylphthalide (200 mg / kg), the central region distances were (4101±1101) mm, (2968±361.2) mm, (3726±603.1) mm, and (3357±477.9) mm, respectively. The distance traveled in the central region during the open field test was significantly increased in all groups treated with oral CXT-24 compared to the control group, suggesting that CXT-24 has a certain therapeutic effect on post-stroke depression in SD rats.

[0083] Table 4. Effect of compound CXT-24 on the center distance in open field experiments of SD rats with bilateral common carotid artery ligation.

[0084]

[0085]

[0086] *P<0.05 vs control group, n=8-10.

Claims

1. The use of a class of pyranocarbazole oxime derivatives, as shown in Formula I, or pharmaceutically acceptable salts thereof, in the preparation of drugs for the prevention or treatment of post-stroke depression: R1 and R2 are independent of each other and can be selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, CF3, and OCF3, respectively. R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3.

2. The use of a class of pyranocarbazole nitroketone derivatives or pharmaceutically acceptable salts thereof, as shown in Formula II, in the preparation of drugs for the prevention or treatment of post-stroke depression: R1 and R2 are independent of each other and can be selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OCH3, OCH2CH3, OCH2CH2CH3, CF3, and OCF3, respectively. R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R4 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, Ph, Bn.

3. The application according to any one of claims 1 and 2, characterized in that, The compounds are selected from the following group:

4. The application according to any one of claims 1-3, characterized in that, The pharmaceutically acceptable salt is selected from organic or inorganic acid salts, including hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, malate, fumarate, tartrate, methanesulfonate, carbonate, oxalate, lactate, succinate, or gluconate.

5. The use of a pharmaceutical composition in the preparation of a drug for the prevention or treatment of post-stroke depression, characterized in that, The pharmaceutical composition comprises the pyranocarbazole oxime derivatives as described in any one of claims 1-3, their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

6. The application according to claim 5, characterized in that, The pharmaceutically acceptable carrier is selected from microcapsules and microspheres, nanoparticles or liposomes.

7. The application according to claim 5, characterized in that, The pharmaceutical composition is selected from injections, tablets, capsules, pills, granules, oral liquids, suspensions, sustained-release preparations, subcutaneous implants, and nano-suspensions.

8. The application according to any one of claims 1 and 2, characterized in that, The pyranocarbazooxime compounds mentioned above are artificially synthesized.

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