Application of pyranocarbazole oxime derivatives in pain treatment

Abstract

The application belongs to the technical field of medicine, and discloses application of pyrano-carbazole oxime derivatives in pain treatment. Specifically, the application discloses a pyrano-carbazole compound as shown in general formula I. The compound is prepared by an artificial synthesis method, contains a pharmaceutical composition thereof, and application thereof in analgesia.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the application of pyranocarbazole oxime derivatives in pain treatment. Background Technology

[0002] Chronic pain, such as inflammatory pain and neuropathic pain, is a major threat to human health, characterized by high incidence, long duration, and recurrent attacks, placing a heavy burden on families and society. Therefore, there is an urgent clinical need for highly effective and safe medications to treat this type of chronic pain.

[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 have potent analgesic effects and can be developed into novel analgesics with strong analgesic effects for chronic pain, including inflammatory pain, neuropathic pain, and cancer pain, with no tolerance or addiction and few side effects. 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 significantly improve pain symptoms in mice. Therefore, the compounds of this invention can be used to prepare drugs for the prevention / treatment of pain.

[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 prevention or treatment of pain.

[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 pain:

[0008]

[0009] 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.

[0010] R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3.

[0011] The first aspect of the present 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 medicaments for the prevention or treatment of pain:

[0012]

[0013] 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.

[0014] R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3;

[0015] R4 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, Ph, Bn.

[0016] The compounds are selected from the following group:

[0017]

[0018] 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.

[0019] The pyranocarbazooxime compounds mentioned above are artificially synthesized.

[0020] The second aspect of the present invention is to provide an application of a pharmaceutical composition in the preparation of a pain prevention or treatment drug, 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.

[0021] The pharmaceutically acceptable carrier is selected from microcapsules and microspheres, nanoparticles or liposomes.

[0022] The pharmaceutical composition is selected from injections, tablets, capsules, pills, granules, oral liquids, suspensions, sustained-release preparations, subcutaneous implants, and nano-suspensions.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] Beneficial technical effects

[0036] The pyranocarbazole oxime compound CXT-24 developed in this invention demonstrated significant therapeutic effects in two analgesic model experiments. In the hot plate test, CXT-24 showed significant analgesic effects at doses of 10 mg / kg and 30 mg / kg, specifically increasing the pain threshold in ICR mice on the hot plate. In the acetic acid writhing test, CXT-24 showed significant analgesic effects at doses of 10 mg / kg and 30 mg / kg, specifically increasing the pain latency after acetic acid injection in ICR mice and reducing the number of writhing movements within 10 minutes. Therefore, the compound of this invention can be used to treat pain. Attached Figure Description

[0037] Figure 1 Effect of compound CXT-24 on pain threshold in mouse hot plate test

[0038] Figure 2 Effect of compound CXT-24 on pain latency in mouse acetic acid writhing test

[0039] Figure 3 Effect of compound CXT-24 on the number of writhing movements in the acetic acid writhing test in mice Detailed Implementation

[0040] Pharmacological Experiment 1

[0041] Effects of compound CXT-24 on the hot plate test in ICR mice at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg

[0042] Experimental methods:

[0043] CXT-24 was provided by our synthesis laboratory and has a chemical purity >99.5%. During preparation, 0.5% CMC-Na was added, and the mixture was ground and then sonicated for 30 minutes.

[0044] (1) Mouse hot plate test

[0045] Male ICR mice were randomly assigned to groups based on body weight the day before the experiment and acclimatized to the instrument for 5 minutes. On the day of the experiment, the hot plate was set to 55.0℃. Animals were gently placed on the hot plate, and the time it took for an animal to lick its hind paws or jump within 60 seconds was recorded as the pain threshold. A second test was conducted 5 minutes later and recorded as the pre-drug pain threshold. The animal was then immediately given the drug, and after a 30-minute interval (60 minutes for positive controls), it was gently placed on the hot plate again to test the post-drug pain threshold. Animals with a pre-drug pain threshold <5 seconds or >30 seconds were excluded, and the post-drug pain threshold was statistically analyzed. Animals were euthanized with CO2 after the experiment.

[0046] (2) Grouping and administration

[0047] The animals were divided into 5 groups, with 20-22 animals in each group. The animals were divided into a solvent control group, a CXT-24 administration group (3mg / kg, 10mg / kg, 30mg / kg) and a positive control group (indomethacin). The drugs were administered orally via gavage at a volume of 0.1mL / 10g.

[0048] (3) Statistical methods

[0049] All data were statistically analyzed using Graph Prism 8.0.1, 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.

[0050] Experimental results

[0051] Effects of compound CXT-24 on the hot plate test in ICR mice at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg

[0052] The pain threshold of male ICR mice on a hot plate was (8.66±1.07) s in the model group. After administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and indomethacin (10 mg / kg), the pain thresholds were (10.38±1.26) s, (12.59±1.59) s, (15.37±2.38) s, and (14.83±1.35) s, respectively. Compared with the control group, administration of compound CXT-24 at 10 mg / kg and 30 mg / kg significantly increased the pain threshold in mice (p<0.05), suggesting that compound CXT-24 has a certain analgesic effect.

[0053] Table 1. Effect of compound CXT-24 on pain threshold in hot plate test of ICR mice.

[0054]

[0055] *P<0.05 vs. model group, ***P<0.001 vs. model group n=20-22

[0056] Pharmacological Experiment 2

[0057] Effects of compound CXT-24 on acetic acid writhing test in ICR mice at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg

[0058] Experimental methods:

[0059] CXT-24 was provided by our synthesis laboratory and has a chemical purity >99.5%. During preparation, 0.5% CMC-Na was added, and the mixture was ground and then sonicated for 30 minutes.

[0060] (1) Mouse acetic acid writhing test

[0061] Seventy-five male ICR mice, weighing 18-22g, were randomly assigned to groups according to body weight the day before the experiment. Fifteen minutes after oral administration of 0.1mL / 10g CXT-24 (60 minutes for positive control), mice were intraperitoneally injected with 0.1mL / 10g BW (biological weight loss) of 0.6% acetic acid aqueous solution. The mice's writhing response was observed within 15 minutes, including abdominal concavity, trunk and hind limb extension, and hip elevation. The latency period and number of writhing movements at the first occurrence were recorded. The experiment was conducted by a single-blind scoring system. After the experiment, the mice were euthanized with CO2.

[0062] (2) Grouping and administration

[0063] The animals were divided into 5 groups of 15 each. The animals were divided into a solvent control group, a CXT-24 administration group (3 mg / kg, 10 mg / kg, 30 mg / kg) and a positive control group (indomethacin). The drugs were administered orally via gavage at a volume of 0.1 mL / 10 g.

[0064] (3) Statistical methods

[0065] All data were statistically analyzed using Graph Prism 8.0.1, 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.

[0066] Experimental results

[0067] Effects of compound CXT-24 on acetic acid writhing test in ICR mice at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg

[0068] The pain latency in male ICR mice after injection of 0.6% acetic acid solution was (346.7±44.23) s in the model group, while the latency after administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and indomethacin (10 mg / kg) was (450.3±73.45) s, (517.2±68.29) s, (506.7±69.66) s, and (747.5±51.92) s, respectively. In the 10 mg / kg group, compared with the control group, the pain latency of mice after acetic acid injection was significantly increased (p<0.05). In the 30 mg / kg group, compared with the control group, the pain latency of mice after acetic acid injection showed a trend of increasing (p=0.06), suggesting that CXT-24 has a certain analgesic effect.

[0069] Table 2. Effect of compound CXT-24 on the latency of acetic acid writhing test in ICR mice.

[0070]

[0071]

[0072] *P<0.05 vs. model group, ***P<0.001 vs. model group n=15

[0073] The number of writhing episodes in male ICR mice after injection of 0.6% acetic acid solution was (25.57±4.34) s in the model group, while the number of writhing episodes after administration of different doses of CXT-24 (3 mg / kg, 10 mg / kg, 30 mg / kg) and indomethacin (10 mg / kg) were (17.20±4.84) ​​s, (9.93±2.37) s, (8.67±2.90) s, and (2.67±1.09) s, respectively. In the oral administration groups of compound CXT-24 at 10 mg / kg and 30 mg / kg, the number of writhing episodes was significantly reduced after acetic acid injection compared to the control group (p<0.01), suggesting that compound CXT-24 has a certain analgesic effect.

[0074] Table 3. Effect of compound CXT-24 on the number of writhing events in the acetic acid writhing test of ICR mice.

[0075]

[0076] **P<0.01 vs model group, ***P<0.001 vs model group n=15.

Claims

1. 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 pain: 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. 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 pain: 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 pain prevention or treatment drug, 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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