Medical use of tropine and its derivatives in preparing drugs for treating poisoning

Abstract

The present invention belongs to the field of medical technology, and specifically relates to the use of tropine and its derivatives in the preparation of drugs for treating poisoning and drugs for treating poisoning. The tropine and its derivatives are compounds of formula I-IV or pharmaceutically acceptable salts thereof, and compounds of formula I-IV or pharmaceutically acceptable salts thereof, esters, solvent compounds, enantiomers, diastereomers, tautomers, diploids, polyploid polymers or mixtures of any proportion thereof, including racemic mixtures. Animal experiments show that tropine and its derivatives have a broad-spectrum detoxification effect, and have a significant improvement effect on the pathological indicators of poisoning animal models caused by many poisons, can significantly improve the survival rate of poisoning experimental animals, and play a good organ or tissue protection effect, can adapt to the differences in the onset speed, progression and degree of damage to the body of different poisoning patients, and can be promoted and applied in the pharmaceutical industry.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to the use of tropine and its derivatives in preparing poisoning treatment drugs, and the poisoning treatment drugs. Background Art

[0002] Poisoning is a disease state caused by direct chemical action of pathogenic substances, which damages the body's functions and structures and even causes death. At present, more than 10,000 new chemical substances are synthesized every day in the world, including pesticides, coatings, solvents, heavy metals, household chemicals, and medicines. There are more than 2,000 known aquatic and terrestrial poisonous animals, plants, and fungi in my country's vast territory. These toxic substances can cause poisoning during production, transportation, storage, and use. According to statistics, since the early 1990s, there have been more than 10,000 cases of acute occupational poisoning each year, and at least 100,000 cases of organophosphorus pesticide poisoning each year. No less than 5% of emergency patients in large urban hospitals across the country are poisoned patients. According to WHO estimates, there are about 100,000 to 500,000 serious poisoning incidents worldwide each year. According to the speed of onset, progression, and degree of damage to the body, common clinical poisoning includes three categories: acute poisoning, subacute poisoning, and chronic poisoning. Acute poisoning is mainly a manifestation of serious damage to the body after a large amount of poison is exposed at one time. This situation often has an acute onset and a fast progression. In many cases, it will endanger the patient's life safety, and active treatment measures must be taken. Chronic poisoning is a manifestation of slow damage in the body after long-term, small doses, and multiple exposure to poisons. It slowly damages human tissues and organs and causes related conditions of decreased resistance. Subacute poisoning is a type of poisoning between acute poisoning and chronic poisoning. After a large amount of poison is exposed at one time, it slowly causes damage to the body. According to the cause of poisoning, it is divided into: 1. Metal poisoning; 2. Food poisoning; 3. Gas poisoning; 4. Organic chemical reagent poisoning; 5. Animal and insect bites and stings poisoning; 6. Various drug poisoning and addictive poisoning; 7. Pesticide poisoning; 8. Nuclear radiation poisoning; 9. Fungal toxin poisoning; 10. Household chemical poisoning.

[0003] Although there are many types of poisoning, most poisons do not have specific antidotes, which makes it very difficult to completely cure poisoned patients. For example, pesticide poisoning is an important social problem faced worldwide and is the most common cause of poisoning death among Chinese adults. Herbicides account for the largest proportion of pesticides, and herbicide poisoning incidents are gradually increasing. Due to the wide variety of herbicides, different poisoning mechanisms and clinical diagnosis and treatment, there is still a lack of systematic research on common herbicide poisoning, which makes clinical physicians face huge challenges in treatment; gas poisoning, especially irritating gases such as chlorine, nitrogen oxides and phosgene, has the characteristics of rapid onset, difficult treatment and high mortality. Clinical gas poisoning cases are becoming more and more common. Timely and effective pre-hospital emergency treatment and scientific and reasonable in-hospital treatment can improve the prognosis of patients; with the widespread application of nuclear technology in many fields such as industry, agriculture, medicine, and military, nuclear accidents have become public health emergencies that seriously damage public health, causing great panic and harm to mankind. Nuclear radiation can cause great damage to the human body. Its mechanism of action is mainly to destroy DNA molecular chains, proteins, denature, change the permeability of lipid bilayers, etc., thereby causing dysfunction of biological macromolecules and causing serious damage to the body. In order to prevent and reduce the damage of nuclear radiation events to organisms, the development of anti-radiation drugs has become a hot topic of research for scholars at home and abroad. There are some nuclear radiation drugs with better protective effects, but their adverse reactions cannot be ignored. Actively searching for new, highly effective and low-toxic nuclear radiation prevention and treatment drugs has become an urgent problem to be solved; common drug poisonings include benzodiazepines, analgesics and antidepressants. Drug poisoning involves poisoning caused by children taking drugs by mistake, poisoning caused by young and middle-aged people taking drugs to commit suicide, poisoning caused by iatrogenic medication in the elderly, and poisoning caused by self-overdose of drugs.

[0004] In summary, due to the large number of exogenous substances that cause poisoning, different poisons have different toxicological mechanisms, and their clinical manifestations vary greatly. At present, there is no specific antidote for most poisoning diseases, and there are still certain difficulties and resistance in the development of clinical treatment. The first way to deal with poisoning in clinical practice is to completely stop contact with the poison, such as using methods such as skin cleaning, gastric lavage and catharsis; the second is to give patients antidotes as soon as possible, and give patients fluid replacement as soon as possible, promote metabolism, and use symptomatic and supportive drugs to protect organs; finally, blood purification can be considered for patients with more serious poisoning. In recent years, domestic toxicology research has made slow progress, there are great differences in the treatment concepts of poisoning at home and abroad, and the transformation of domestic research results on poisoning treatment is relatively slow. It is urgent to develop antidotes with small adverse reactions, fast onset, short course of treatment and easy use. Considering the differences in the onset speed, progression and degree of damage to the body of poisoned patients, the research and development of different drug dosage forms such as topical, oral and injection should also be taken into account. The present invention has been studied in a large number of experiments in the early stage, and the effectiveness of tropine (also known as 8-methyl-8-azabicyclo[3.2.1]-3-octanol) and its derivatives in treating poisoning has been clarified. Compared with other similar drugs, it has good safety. The raw material price of tropine is low, and the preparation cost of its derivatives is low. It can be prepared into various pharmaceutical dosage forms such as external use, oral administration and injection, and is an effective drug for preventing and treating poisoning by various poisons. Summary of the invention

[0005] In one aspect, the present invention provides the use of tropine and its derivatives, pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, tautomers, diploids, polyploid polymers or mixtures thereof in any proportions in the preparation of a drug for preventing and / or treating poisoning, wherein the tropine and its derivatives have a structure shown in the following formula A or B:

[0006]

[0007] Wherein, R1 is independently selected from -H or C1-C6 alkyl, and R2 and R3 are each independently selected from -H, -OH or C1-C6 alkoxy.

[0008] In the present invention, the C1-C6 alkyl group or the C1-C6 alkyl group in the C1-C6 alkoxy group is selected from methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl and sec-butyl), pentyl and hexyl.

[0009] In one embodiment, R1 is independently selected from -H or -CH3, and R2 and R3 are each independently selected from -H or -OH.

[0010] In one embodiment, R1 is selected from -H, and R2 and R3 are each independently selected from -H or -OH.

[0011] In one embodiment, R1 is selected from -CH3, and R2 and R3 are each independently selected from -H or -OH.

[0012] In one embodiment, at least one of R2 and R3 is selected from -OH.

[0013] In one embodiment, two of R2 and R3 are selected from -OH.

[0014] In one embodiment, the tropine alcohol and its derivatives are selected from the compounds represented by the following formulas A-1 to A-7 and B-1:

[0015]

[0016] Wherein, R1 is independently selected from -H or C1-C6 alkyl, and R2 and R3 are each independently selected from -OH or C1-C6 alkoxy.

[0017] In one embodiment, the tropine alcohol and its derivatives are selected from the compounds represented by the following formula I to formula IV:

[0018]

[0019] Wherein, formula I is tropine, formula II is 8-Azabicyclo[3.2.1]octan-3-ol, formula III is 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, formula IV is 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol. 2,4 ]nonan-7-ol).

[0020] Preferably, the poisoning includes acute poisoning, subacute poisoning and chronic poisoning.

[0021] The tropine alcohol and its derivatives of the present invention have detoxification and organ protection effects, have obvious improvement effects on pathological indicators of many acute poisoning, subacute poisoning and chronic poisoning animal models, can play a good detoxification effect, prolong the survival time of experimental animals, and reduce the mortality rate.

[0022] In one embodiment, the poisoning is selected from one or more of the following: 1. Metal poisoning, such as poisoning by lead, arsenic, mercury, chromium, barium, aluminum and other heavy metals. 2. Food poisoning, including food spoilage poisoning caused by microorganisms, such as spoilage poisoning of grains, vegetables, fruits, meat and other foods; poisoning caused by eating poisonous animals and plants, the toxins come from the food itself, including pufferfish poisoning, sprouted potato poisoning, poisonous mushrooms and poisoning by eating other animals and plants. 3. Gas poisoning, including poisoning by formaldehyde, fluorine, chlorine, nitrogen oxide gas, phosgene (phosgene), ammonia, sulfur dioxide, fire smoke, coal gas, mustard gas (2,2'-dichlorodiethyl sulfide), carbon monoxide, hydrogen sulfide, hydride and other gases. 4. Organic chemical reagent poisoning, including poisoning by carbon disulfide, chloroform, benzene, methanol, toluene, cyanide and other organic chemical reagents. 5. Animal and insect bites and poisoning, including poisoning by venomous snakes and other animals, bee stings and other insect stings. 6. Various drug poisoning and addiction poisoning, including benzodiazepines 7. Poisoning by drugs, barbiturates, opium, stimulants, salicylates, cancer chemotherapy, isoniazid, hormones, antibiotics, analgesics, toxic Chinese medicines and other drugs; preferably, including addictive poisoning of morphine. 7. Pesticide poisoning, including poisoning by organophosphorus and carbamate insecticides, herbicides, rat poison and other pesticides; preferably, including paraquat poisoning. 8. Nuclear radiation poisoning, such as various nuclear pollution and radiotherapy poisoning, including tissue damage caused by high-energy ionizing radiation (α, β particles, γ rays, X-rays and neutron rays, etc.), cobalt, radium, uranium, cesium and thorium and other radioactive isotopes. 9. Fungal toxin poisoning, including poisoning by aflatoxin, ochratoxin, fumonisin, zearalenone, vomitoxin, T-2 toxin and patulin. 10. Household chemical poisoning, including poisoning by alcohol, detergents, cosmetics and other daily necessities.

[0023] In one embodiment, the prevention and / or treatment of poisoning includes alleviating or eliminating damage to organs (eg, liver, lungs, kidneys, etc.) caused by poisoning, or alleviating or eliminating drug addiction (eg, addiction to morphine).

[0024] The second aspect of the present invention provides a preventive and / or therapeutic drug for acute poisoning, subacute poisoning and chronic poisoning, wherein the therapeutic drug contains tropine and its derivatives, pharmaceutically acceptable salts, solvent compounds, enantiomers, diastereomers, tautomers, diploids, polyploid polymers or mixtures thereof in any proportion.

[0025] The medicine for preventing and / or treating acute poisoning, subacute poisoning and chronic poisoning provided by the present invention has a broad-spectrum detoxification effect and a significant effect.

[0026] In one embodiment, the tropine alcohol and its derivatives, pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, tautomers, diploids, polyploid polymers or mixtures thereof in any proportion are used as active ingredients in the drug of the present invention. Preferably, they are used as the main active ingredient; more preferably, they are used as the only active ingredient.

[0027] In the above-mentioned uses and medicines, tropine and its derivatives, pharmaceutically acceptable salts, solvent compounds, enantiomers, diastereomers, tautomers, diploids, polyploid polymers or mixtures in any proportions thereof can be prepared with pharmaceutically acceptable carriers or excipients into pharmaceutical dosage forms for external use, oral administration or injection.

[0028] Therefore, in the present invention, the drug can be an external medicine, an oral medicine or an injectable medicine.

[0029] In the present invention, the drug may contain a pharmaceutically acceptable carrier or excipient. The drug may be prepared into various conventional solid dosage forms, liquid dosage forms or semisolid dosage forms, such as granules, tablets or capsules, etc., liquid dosage forms such as sprays and injections, and semisolid dosage forms such as creams, etc. In one aspect, the dosage form of the drug may be: powder, tablet, coated tablet, granule, capsule, solution, emulsion, suspension, injection, spray, nasal agent, aerosol, powder spray, lotion, liniment, ointment, plaster, paste, gel, patch, etc.

[0030] In the present invention, the term "pharmaceutically acceptable carrier or excipient" includes any and all solvents, co-solvents, dispersion media, coating materials, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, adhesives, excipients, diluents, glidants, granulating agents, disintegrants, thickeners, viscosity enhancers, lubricants, anti-caking agents, moisturizers, wetting agents, chelating agents, plasticizers, dyes, flavoring agents, etc. and combinations thereof, which are well known to those skilled in the art (for example, see Remington's Pharmaceutical Sciences, 19th Ed. Mack Printing Company, 1995; Shanghai Institute of Pharmaceutical Industry et al., Application Technology of Pharmaceutical Excipients (Second Edition), China Medical Science and Technology Press, 2002; Comparative Handbook of Pharmaceutical Excipients Standards of Various Countries 1 to 3, compiled by the National Pharmacopoeia Committee, China Medical Science and Technology Press, 2016; Handbook of Pharmaceutical Excipients, RC Raymond C Rowe, PJ Sheskey, PJ Weller (Paul J Weller, ed., translated by Zheng Junmin, Chemical Industry Press, 2005, etc.). Except for carriers and excipients that are incompatible with the active ingredient, any conventional carriers and excipients are considered for use in therapeutic or pharmaceutical compositions.

[0031] For example, in a solid dosage form, the pharmaceutically acceptable carrier or excipient may include at least one of the following: (a) a filler such as starch, corn starch, modified starch, compressible starch, lactose, lactose monohydrate, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, amino acid, etc.; (b) a binder such as starch slurry, gelatinized starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, polyvinyl pyrrolidone, gelatin, alginate, etc.; (c) a humectant such as glycerol; (d) a disintegrant such as glycerin; (e) disintegrants, such as dry starch, modified starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, effervescent disintegrants, cross-linked polyvinyl pyrrolidone, etc.; (e) solution retardants, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) absorbents, such as kaolin and bentonite; (i) lubricants, such as talc, stearic acid, magnesium or calcium stearate, micronized silica gel, hydrogenated castor oil and solid polyethylene glycol, polyethylene glycol 4000-20000, magnesium lauryl sulfate, etc.

[0032] In the present invention, the drug can be applied to humans or other warm-blooded animals. When the applicable object is a human, the single or mixed dosage of tropine and its derivatives is preferably 1 mg / kg.d to 700 mg / kg.d, and more preferably 20 mg / kg.d to 700 mg / kg.d. The therapeutically effective amount of the compound or pharmaceutical composition depends on the species, weight, age and individual condition of the individual, the disease to be treated or its severity. A physician, clinician or veterinarian with common skills can easily determine the effective amount of each active ingredient required to prevent, treat or inhibit the development of the disease.

[0033] The pharmaceutically acceptable salts of the compounds of the present invention include base addition salts and acid addition salts thereof. Preferably, the base addition salt is selected from sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, zinc salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethylamine salt, trimethylammonium salt, ethylamine salt, diethanolamine salt, arginine salt or lysine salt; the acid addition salt is selected from organic acid salts such as acetate, aspartate, benzoate, benzenesulfonate, citrate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glucuronate, lactate, malate, trifluoroacetate, maleate, and inorganic acid salts such as hydrochloride, hydrobromide, bisulfate, nitrate, phosphate. The compounds of the present invention in free form can be converted into corresponding compounds in salt form; and vice versa. The compounds of the present invention in free form or salt form and solvate form can be converted into corresponding compounds in free form or salt form in non-solvate form; and vice versa.

[0034] The compounds of the present invention also include their solvate forms, which refer to the association formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

[0035] The compounds of the present invention may exist in the form of isomers and mixtures thereof; for example, tautomers, optical isomers, enantiomers, diastereomers. The compounds of the present invention may, for example, contain asymmetric carbon atoms and may therefore exist in the form of enantiomers or diastereomers and mixtures thereof, for example, in the form of racemates. The compounds of the present invention may exist in (α)-, (β)-, (α, β)-, (R)-, (S)- or (R, S)-configuration, preferably in the (α)-, (β)-, (R)- or (S)-configuration at a specific position of the compound.

[0036] Compared with the prior art, the present invention has the following advantages and effects:

[0037] (1) The present invention first discovered that tropine and its derivatives can significantly improve the pathological indicators of acute poisoning, subacute poisoning and chronic poisoning animal models;

[0038] (2) Tropine and its derivatives can exert good detoxification effects and reduce the mortality rate of experimental animals;

[0039] (3) Tropine and its derivatives are the main ingredients for treating acute, subacute and chronic poisoning. Compared with existing drugs, they have the advantages of less adverse reactions, quick onset, short course of treatment and convenient use. They also take into account the dosage forms of topical, oral and injection to adapt to the differences in the onset speed, progression and degree of damage to the body of poisoned patients.

[0040] (4) The tropinol and tropinol derivatives used in the present invention are easy to obtain and synthesize, low in price, stable in nature, easy to store and transport, and suitable for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Effects of Tropine and Its Derivatives on Lung Tissue Morphology in Paraquat-Poisoned Rats

[0042] Figure 2 .Effects of Tropine and its derivatives on liver pathology in lead poisoning mouse model (x400) DETAILED DESCRIPTION

[0043] The preferred embodiments of the present invention are described below in conjunction with the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention. The described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] Example 1: Study on the effect of tropine and its derivatives on paraquat poisoning rat model

[0045] 1. Animal grouping, modeling and drug administration

[0046] Preparation of paraquat acute poisoning model: 60 male SD rats (9-10 weeks, 250.0±10.0g) were gavaged once with 100% lethal dose (120 mg / rat) of methyl viologen aqueous solution. Two hours after gavage, the paraquat acute poisoning model was obtained for use in pharmacodynamic experimental studies.

[0047] Grouping and administration: 10 rats in the blank control group and 60 model rats were randomly divided into 6 groups, with 10 rats in each group, namely model group, positive drug group, tropine group (A), 8-azabicyclo[3.2.1]octan-3-ol (B), 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol (C), 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol (D). After the modeling was completed, each group was intraperitoneally injected with the corresponding drugs, 5 times a day, for 7 consecutive days. The grouping and administration scheme are shown in Table 1.

[0048] Table 1. Animal grouping, modeling and drug administration information (n=10)

[0049]

[0050]

[0051] 2. Index detection

[0052] During the treatment, the behavior of rats in each group was compared and observed. When rats appeared to be in a dying state, they were determined to have died of poisoning. The rats were anesthetized and dissected, and lung tissue was taken for histomorphological observation, and the mortality rate of rats in each group was calculated. The rats that did not die were anesthetized and dissected 7 days after treatment, and lung tissue was taken for histomorphological observation.

[0053] 3. Experimental results and discussion

[0054] Compared with the blank control group, the behavioral manifestations of the model group rats were fluffy and rough hair, curled up, shortness of breath, loose stools, reduced vitality, slow movements, decreased appetite and even refusal to eat, significant weight loss, bleeding from the mouth and nose when the rats were dying, and all died 3 days after modeling, with a mortality rate of 100%. During the treatment of the positive drug group, the overall behavior of the rats improved, the vitality increased, and the appetite improved, but all died after 3 days of treatment, with a mortality rate of 100%. During the treatment with tropine and its derivatives, most rats showed significant behavioral improvement, significantly increased vitality, significantly improved appetite, and significantly prolonged overall survival time. After 7 days of treatment, 5 rats died in the tropine group (A) and the 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol group (C), with a mortality rate of 50%; 4 rats died in the 8-azabicyclo[3.2.1]octan-3-ol (B) and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol (D), with a mortality rate of 40%. Figure 1As shown in the figure, the results of tissue morphological observation showed that compared with the blank control group, the lung tissue volume of the rats in the model group was enlarged, there was severe pulmonary congestion and edema, and most of them were dark red. After treatment with tropine and its derivatives, the morphological indicators of the rat lung tissue were significantly improved. Therefore, tropine and its derivatives have a significant detoxification effect on the paraquat poisoning rat model.

[0055] Example 2: Study on the effect of tropine and its derivatives on withdrawal in morphine-addicted mice

[0056] 1. Animal grouping, modeling and drug administration

[0057] 70 male BABL / c mice (5-6 weeks, 20.0±2.0g) were randomly divided into 7 groups, 10 mice in each group, including blank control group, model group, positive drug group, tropine group (A), 8-azabicyclo[3.2.1]octan-3-ol (B), 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol (C), 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol (D). Except for the blank control group, the mice in other groups were subcutaneously injected with 100 mg / kg of morphine hydrochloride every 12 hours for 14 consecutive times for 7 days to create a morphine addiction model. Each group was given corresponding drug treatment 4 days after the injection of morphine hydrochloride, twice a day, for 10 consecutive days. Except for the blank control group, each group received a subcutaneous injection of naloxone 5 mg / kg 6 hours after the last injection of morphine to induce addiction. The grouping and dosing schedule are detailed in Table 2.

[0058] Table 2. Animal grouping and dosing information (n=10)

[0059]

[0060] 2. Index detection

[0061] After naloxone injection, the mice were weighed immediately and placed in a barrel 35 cm high and 30 cm in diameter. The behavioral changes of mice in each group after addiction were observed, and the number of jumps of mice in each group within 30 minutes was recorded. The mice were weighed again after 1 hour, and the difference in weight between the two times was calculated.

[0062] 3. Experimental results and discussion

[0063] Compared with the blank group, the mice in the model group showed obvious withdrawal symptoms such as diarrhea, jumping, front paw tremor and "wet dog" shaking; compared with the model group, the withdrawal symptoms of the mice in the tropine alcohol and its derivatives group were significantly alleviated. As shown in Table 3, compared with the blank control group, the number of jumps of the mice in the model group increased significantly (P<0.01), and the body weight decreased significantly after withdrawal (P<0.01); compared with the model group, the number of jumps of the mice in the tropine alcohol and its derivatives group decreased significantly (P<0.01); compared with the blank control group, the weight change of the mice in the tropine alcohol and its derivatives group after withdrawal was not obvious (P>0.05). There was no significant difference in the effects of 8-azabicyclo[3.2.1]octan-3-ol and tropine (P>0.05), while oral administration of 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol had better therapeutic effects than tropine (P<0.05). Therefore, tropine and its derivatives can significantly counteract the addiction of mice induced by morphine.

[0064] Table 3. Effects of tropine and its derivatives on withdrawal in morphine-addicted mice (n=10, )

[0065]

[0066]

[0067] Note: Compared with the blank control group, ## P<0.01; compared with the model control group, **P<0.01; compared with tropine, △ P<0.05.

[0068] Example 3: Study on the effect of tropine and its derivatives on lead poisoning mouse model

[0069] 1. Animal grouping, drug administration and modeling

[0070] 70 male BABL / c mice (5-6 weeks, 20.0±2.0g) were randomly divided into 7 groups, 10 mice in each group, namely blank control group, model group, tropine group (A), 8-azabicyclo[3.2.1]octan-3-ol (B), 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol (C), 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol (D). Mice in the blank control group and model group were gavaged with 0.2mL / mouse saline on days 1-6, and mice in other groups were gavaged with corresponding drugs. Mice in the blank control group were gavaged with 0.4mL / mouse saline on day 7, and mice in other groups were gavaged with 7.5g / kg lead acetate solution on day 7 to induce acute lead poisoning model. Grouping, modeling and dosing schedule are detailed in Table 4.

[0071] Table 4. Animal grouping and dosing information (n=10)

[0072]

[0073] 2. Index detection

[0074] On the 8th day, mice in each group were fasted for 12 hours and then anesthetized. Blood was collected from the heart and then perfused with saline and fixed with paraformaldehyde. Liver tissue was collected and fixed in 4% paraformaldehyde for 24 hours. Blood was centrifuged for 10 minutes (3000rpm, 4℃), serum was collected, and the activities of serum liver function-related indicators alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected according to the instructions of the kit; liver tissue was paraffin-embedded, cut into 4μm thick sections, routinely stained with HE, and sealed, and histopathological changes were observed under a light microscope.

[0075] 3. Experimental results and discussion

[0076] Liver function test: As shown in Table 2, the ALT and AST activities in the serum of the mice in the model group increased (P<0.01), indicating that lead poisoning caused a certain degree of liver tissue damage or hepatocyte necrosis in mice. Compared with the model group, the ALT and AST activities in the serum decreased after administration of tropine and its derivatives (P<0.01). There was no significant difference in the therapeutic effect between 8-azabicyclo[3.2.1]octan-3-ol and tropine (P>0.05); while 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol both had better therapeutic effects than tropine (P<0.05). Therefore, tropine and its derivatives can improve the liver function of the lead poisoning mouse model.

[0077] Table 5. Effects of tropine and its derivatives on liver function in lead poisoning mouse model (n=10, )

[0078] Grouping ALT(KarU) AST(KarU) blank 31.27±5.45 36.34±5.48 Model <![CDATA[113.52±11.64 ## ]]> <![CDATA[146.18±13.54 ## ]]> Positive Drug 72.82±6.73** 94.63±8.62** A 68.79±9.75** 79.53±9.71** B 70.27±7.49** 80.64±10.16** C <![CDATA[61.04±6.91** △ ]]> <![CDATA[70.85±8.43** △ ]]> D <![CDATA[62.75±5.41** △ ]]> <![CDATA[70.75±7.45** △ ]]>

[0079] Note: Compared with the blank control group, ## P<0.01; compared with the model group, **P<0.01; compared with tropine, △ P<0.05.

[0080] Histopathological examination: Figure 2As shown in the figure, the liver cells of the mice in the model group were arranged in disorder, the boundaries of the liver cells were blurred or even disappeared, a large number of inflammatory cells were seen in the liver, the nuclei were condensed, some cells were lytically necrotic, and the liver sinusoids were dilated, so that a large number of gaps appeared between the cells. After the administration of tropine and its derivatives, some of the above pathological indicators were significantly improved, the morphology and arrangement of liver cells could be clearly identified, the liver sinusoids were only slightly dilated, especially the inflammatory cell aggregation and necrotic liver cells were significantly reduced, and the number of regenerating liver cells increased. This shows that tropine and its derivatives have a detoxifying effect on the lead poisoning mouse model.

[0081] Example 4: Preparation of Tropine and Its Derivatives Tablets

[0082] The prescription is shown in Table 6. According to prescription 1, the raw material (tropine) and excipients (lactose, microcrystalline cellulose, polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate and purified water) are taken, tropine, lactose, microcrystalline cellulose and polyvinyl pyrrolidone are added to a wet granulator, and wet granulation is performed using purified water as a wetting agent. Dry granules are obtained after wet granulation, drying and dry granulation, cross-linked sodium carboxymethyl cellulose, micropowder silica gel and magnesium stearate are added to the dry granules and mixed evenly, and the mixed material is compressed with a tablet press to obtain tropine tablets. The raw materials and excipients of prescriptions 2, 3 and 4 were taken respectively, and 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol tablets were prepared respectively according to the same process as above.

[0083] Table 6. Tablet prescription of tropine and its derivatives

[0084]

[0085]

[0086] Example 5: Preparation of coated tablets of tropine and its derivatives

[0087] The prescription is shown in Table 7. According to prescription 5, the raw material (tropine) and excipients (lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium lauryl sulfate, sodium carboxymethyl starch, micropowder silica gel, magnesium stearate, film coating premix and purified water) are taken, sodium lauryl sulfate is added to purified water and stirred to dissolve, tropine, lactose, microcrystalline cellulose and hydroxypropyl methylcellulose are added to a wet granulator, and an aqueous solution of sodium lauryl sulfate is used as a wetting agent for wet granulation. After wet granulation, drying and dry granulation, dry granules are obtained, sodium carboxymethyl starch, micropowder silica gel and magnesium stearate are added to the dry granules and mixed evenly, and the mixed materials are compressed into tablets using a tablet press to obtain tropine plain tablets. The film coating machine premix is ​​added to purified water, and stirring is continued for more than 1 hour to obtain a film coating solution, and then the obtained plain tablets are coated in a coating machine to obtain tropine coated tablets. The raw materials and excipients of prescriptions 6, 7 and 8 were taken respectively, and the coated tablets of 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol were prepared respectively according to the same process as above.

[0088] Table 7. Formulation of coated tablets of tropine and its derivatives

[0089]

[0090] Example 6: Preparation of Tropine and Its Derivatives Spray I

[0091] The prescription is shown in Table 8. According to prescription 9, the raw material (Tropinol) and excipients (polyvinyl pyrrolidone K30, propylene glycol monocaprylate, ethyl hydroxybenzoate, poloxamer, di-tert-butyl-p-cresol (BHT), 1N sodium hydroxide solution, ethanol and water) are taken, and the raw material, polyvinyl pyrrolidone K30, propylene glycol monocaprylate, ethyl hydroxybenzoate and BHT are added to ethanol and stirred to completely dissolve; poloxamer is added to an appropriate amount of water to dissolve; then the poloxamer aqueous solution is added to the alcohol solution of the above mixed materials, and the pH value is adjusted to a range of 3 to 8 with 1N sodium hydroxide solution; water is added to 200 ml to obtain a spray solution; the solution is filled into a spray bottle to obtain Tropine Spray I. The raw materials and excipients of prescriptions 10, 11 and 12 were taken respectively, and 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol were prepared respectively according to the same process as above.

[0092] Table 8. Prescription of Tropine and its derivatives spray I

[0093]

[0094] Example 7: Preparation of Tropine and Its Derivatives Spray II

[0095] The prescription is shown in Table 9. According to prescription 13, the raw material (tropine) and excipients (hydroxypropyl cellulose, propylene glycol monocaprylate, ethyl hydroxybenzoate, ethanol, water) are taken, the raw material, hydroxypropyl cellulose, propylene glycol monocaprylate, ethyl hydroxybenzoate are added to ethanol, stirred to completely dissolve, and water is added to 200 ml to obtain a spray solution; the solution is filled into a spray bottle to obtain tropine spray II. The raw materials and excipients of prescriptions 14, 15 and 16 are taken respectively, and 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol spray II are prepared respectively according to the same process as above.

[0096] Table 9. Prescription of Tropine and its derivatives spray II

[0097]

[0098] Example 8: Preparation of Tropine and Its Derivatives Injection I

[0099] The prescription is shown in Table 10. According to prescription 17, the raw material drug (Tropinol) and excipients (sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, poloxamer, sodium bisulfite and water for injection) are taken, the raw material drug and poloxamer are added to the water for injection to dissolve, then sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium bisulfite are added to the above solution to dissolve, and finally water is added to 100 mL to obtain an injection solution; the above injection solution is filled into an ampoule or vial of corresponding volume to obtain Tropine Injection I. The raw materials and excipients of prescriptions 18, 19 and 20 were taken respectively, and according to the same process as above, 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol injection I were prepared respectively.

[0100] Table 10. Prescription of Tropine and its derivatives injection I

[0101]

[0102] Example 9: Preparation of Tropine and Its Derivatives Injection II

[0103] The prescription is shown in Table 11. According to prescription 21, take the raw material (tropine) and excipients (sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tween 80, water for injection), add the raw material and Tween 80 into water for injection to dissolve, then add sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate into the above solution to dissolve, and finally add water to 100mL to obtain the injection solution; fill the above injection solution into an ampoule or vial of corresponding volume to obtain Tropine Injection II. Take the raw materials and excipients of prescriptions 22, 23 and 24 respectively, and prepare 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol injection II according to the same process as above.

[0104] Table 11. Prescription of Tropine and its derivatives injection II

[0105]

[0106] Example 10: Preparation of Tropine and Its Derivatives Cream I

[0107] The prescription is shown in Table 12. According to prescription 25, the raw material drug (tropine) and excipients (white vaseline, hexadecanol, Tween 80, diethylene glycol monoethyl ether, ethyl hydroxybenzoate, BHT, propylene glycol, citric acid / sodium citrate and water) were taken, and the preparation process was as follows: (1) Dissolution of the raw material drug: Weigh propylene glycol, add the raw material drug, and stir to dissolve at 40-50°C: (2) Preparation of oil phase: Weigh white vaseline, hexadecanol, ethyl hydroxybenzoate and BHT, heat to 60-80°C, stir to dissolve, and mix the dissolved raw material Add the raw materials slowly, continue to stir, mix evenly, and set aside; (3) Preparation of aqueous phase: weigh purified water, add Tween 80 and diethylene glycol monoethyl ether, heat to 60-80°C, adjust the pH value with citric acid / sodium citrate, stir and dissolve for later use; (4) Emulsification: slowly add the aqueous phase to the oil phase, maintain 70°C, homogenize, and continue to stir for more than 30 minutes; (5) Paste formation: cool down, stop heating, continue to stir, gradually cool to room temperature and cool into paste, and fill. Tropine alcohol cream I is obtained. Take the raw materials and excipients of prescriptions 26, 27 and 28 respectively, and prepare 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol cream I according to the same process as above.

[0108] Table 12. Tropine and its derivatives cream I prescription

[0109] Material Name Prescription 25 Prescription 26 Prescription 27 Prescription 28 Tropine 4g — — — 8-Azabicyclo[3.2.1]octan-3-ol — 4g — — 8-Methyl-8-azabicyclo[3.2.1]octane-3,6-diol — — 4g — 9-Methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonan-7-ol — — — 4g White Vaseline 20g 20g 20g 20g Cetyl Alcohol 40g 40g 40g 40g Twain 80 10g 10g 10g 10g Diethylene glycol monoethyl ether 20g 20g 20g 20g Ethylparaben 0.4g 0.4g 0.4g 0.4g BHT 0.4g 0.4g 0.4g 0.4g Propylene glycol 20g 20g 20g 20g Citric Acid / Sodium Citrate Moderate Moderate Moderate Moderate water Add to 200g

[0110] Example 11: Preparation of Tropine and Its Derivatives Cream II

[0111] The prescription is shown in Table 13. According to prescription 29, the raw material drug (tropine) and excipients (white vaseline, hexadecanol, poloxamer 407, propylene glycol monocaprylate, sodium benzoate, BHA, propylene glycol, glacial acetic acid / sodium acetate and water) were taken, and the preparation process was as follows: (1) Dissolution of the raw material drug: weigh propylene glycol, add the raw material drug, and stir to dissolve at 40-50°C; (2) Preparation of oil phase: weigh white vaseline, hexadecanol, propylene glycol monocaprylate and BHA, heat to 60-80°C, stir to dissolve, and then add the solution to the mixture. Slowly add the dissolved raw materials, continue to stir, mix evenly, and set aside; (3) Preparation of aqueous phase: weigh purified water, add poloxamer 407 and sodium benzoate, heat to 60-80°C, adjust the pH value with glacial acetic acid / sodium acetate, stir and dissolve for later use; (4) Emulsification: slowly add the aqueous phase to the oil phase, maintain 70°C, homogenize, and continue to stir for more than 30 minutes; (5) Paste formation: cool down, stop heating, continue to stir, gradually cool to room temperature and cool into paste, and fill. Tropine cream II is obtained. Take the raw materials and excipients of prescriptions 30, 31 and 32 respectively, and prepare 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol cream II according to the same process as above.

[0112] Table 13. Tropine and its derivatives cream II prescription

[0113]

[0114]

[0115] Example 12: Preparation of nasal preparation I of tropine and its derivatives

[0116] The prescription is shown in Table 14. According to prescription 33, the raw material (tropine) and excipients (sorbitol, citric acid / sodium citrate, sodium benzoate and purified water) are taken, and the preparation process is as follows: sorbitol is added to purified water to dissolve, and then the raw material and sodium benzoate are added to the above solution to dissolve, and the pH value is adjusted to the range of 4.0 to 6.5 with citric acid / sodium citrate, and purified water is added to 100mL to obtain a nasal preparation solution, and finally the solution is filled into a dropper bottle or a spray bottle to obtain tropine nasal preparation I. The raw materials and excipients of prescriptions 34, 35 and 36 are taken respectively, and the same process as above is used to prepare 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol nasal preparation I.

[0117] Table 14. Prescription of nasal preparations of tropine and its derivatives I

[0118]

[0119] Example 13: Preparation of nasal preparation II of tropine and its derivatives

[0120] The prescription is shown in Table 15. According to prescription 37, the raw material drug (tropine) and excipients (sodium chloride, hydroxypropyl methylcellulose, Tween 80, sodium metabisulfite, sodium edetate, 1N sodium hydroxide solution, benzalkonium chloride and purified water) are taken, and the preparation process is as follows: add hydroxypropyl methylcellulose to purified water, continue stirring to dissolve it completely, add sodium chloride and Tween 80 to the hydroxypropyl methylcellulose solution to dissolve, then add the raw material drug, sodium metabisulfite, sodium edetate and benzalkonium chloride to the above solution to dissolve, adjust the pH value to within the range of 4.5 to 6.5 with 1N sodium hydroxide solution, add purified water to 100 ml to obtain a nasal preparation solution, and finally fill the solution into a dropper bottle or a spray bottle to obtain tropine nasal preparation II. The raw materials and excipients of prescriptions 38, 39 and 40 were taken respectively, and the nasal preparations II of 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol were prepared respectively according to the same process as above.

[0121] Table 15. Prescription of nasal preparation II of tropine and its derivatives

[0122]

[0123] Example 14: Preparation of tropine and its derivative granules

[0124] The prescription is shown in Table 16. According to prescription 41, the raw material (tropine) and excipients (lactose, polyvinyl pyrrolidone, cross-linked polyvinylpyrrolidone, purified water) are taken, and the preparation process is as follows: the raw material, lactose and cross-linked polyvinylpyrrolidone are added to the fluidized bed, and the aqueous solution of polyvinylpyrrolidone is used as a binder to perform top spray granulation, wet granulation or dry granulation to obtain tropine granules. The raw materials and excipients of prescriptions 42, 43 and 44 are taken respectively, and the same process as above is used to prepare 8-azabicyclo[3.2.1]octan-3-ol, 8-methyl-8-azabicyclo[3.2.1]octane-3,6-diol, and 9-methyl-3-oxo-9-azatricyclo[3.3.1.02,4]nonane-7-ol granules.

[0125] Table 16. Prescription of tropine and its derivative granules

[0126]

[0127] The above describes the preferred embodiments of the present invention, but it is not intended to limit the present invention. Those skilled in the art may make improvements and changes to the embodiments disclosed herein without departing from the scope and spirit of the present invention.

Claims

1. Use of tropine and its derivatives, and pharmaceutically acceptable salts thereof in the preparation of a drug for treating poisoning, wherein the tropine and its derivatives have a structure shown in the following formula A or B: ； in, R1 is independently selected from -H or -CH3, R2 and R3 are each independently selected from -H or -OH; The poisoning is selected from metal poisoning, morphine addiction poisoning, and paraquat poisoning, and the metal is selected from lead.

2. The use according to claim 1, characterized in that The tropine alcohol and its derivatives are selected from the compounds shown in the following formula I to formula IV: 。 3. The use according to claim 1 or 2, characterized in that The medicine is an external medicine, an oral medicine or an injectable medicine.

4. The use according to claim 1 or 2, characterized in that: The medicine further comprises a pharmaceutically acceptable carrier or excipient.

5. The use according to claim 1 or 2, characterized in that: The medicine is in solid dosage form, liquid dosage form or semisolid dosage form.

6. The use according to claim 1 or 2, characterized in that: The dosage forms of the medicine are: powder, tablet, granule, capsule, solution, emulsion, suspension and ointment.

7. The use according to claim 1 or 2, characterized in that: The treatment of poisoning includes alleviating or eliminating organ damage caused by poisoning.

8. The use according to claim 1 or 2, characterized in that: The treatment of poisoning includes alleviating or eliminating the damage to the liver, lungs, and kidneys caused by poisoning, or alleviating or eliminating the addiction to morphine.

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