Heterocyclic compound, preparation method and application thereof, heterocyclic derivative, pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a heterocyclic compound, a preparation method and application thereof, a heterocyclic derivative, a pharmaceutical composition and application thereof. The invention provides a heterocyclic compound which has a structure as shown in a formula I. The heterocyclic compound provided by the invention can efficiently relieve acute methanol poisoning. In an acute methanol poisoning mouse model, the compound can significantly reduce the death rate of methanol poisoning mice. In addition, the heterocyclic compound provided by the invention has low toxic and side effects.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a heterocyclic compound and a preparation method and application thereof, a heterocyclic derivative and a pharmaceutical composition and application thereof. Background Art

[0002] Alcoholism is one of the most serious social problems facing mankind. Its causes are complex, with physiological and genetic factors as well as cultural and environmental influences. The most common disease caused by drinking is liver damage, and the mechanism of liver toxicity caused by ethanol is still not very clear. Studies have shown that ethanol also changes the transmission of many brain neurotransmitters: such as stimulating the transmission of dopamine, interfering with the transmission of serotonin, and interfering with the transmission of glutamine in the central nervous system. Long-term excessive drinking leads to neuropathic diseases.

[0003] Poisoning incidents caused by excessive amounts of methanol occur from time to time, causing consumers to be poisoned by methanol or even die. Methanol poisoning is a systemic toxic disease caused by ingestion or contact with preparations containing methanol. This disease is rare, and its main clinical features are central nervous system damage, eye damage and metabolic acidosis. The main symptoms are dizziness, blurred vision, headache, fatigue, etc. In severe cases, it can lead to blindness, coma, and even death. The disease is more common in people who drink bulk liquor mixed with methanol, as well as professional workers who are exposed to methanol. The main treatment method is to immediately leave the toxic environment, remove the poison as soon as possible, and give drug treatment (such as methylpyrazole), but the effect is poor. If necessary, hemodialysis is also required, and the cost of treatment is also high. Summary of the invention

[0004] The purpose of the present invention is to provide a heterocyclic compound and a preparation method and application thereof, a heterocyclic derivative and a pharmaceutical composition and application thereof. The heterocyclic compound provided by the present invention can significantly reduce the death caused by methanol poisoning.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides a heterocyclic compound having a structure shown in Formula I;

[0007]

[0008] The present invention also provides a method for preparing the heterocyclic compound described in the above technical solution, comprising the following steps:

[0009] The compound represented by formula II, the compound represented by formula III and an inert solvent are mixed and subjected to a salt-forming reaction to obtain the heterocyclic compound;

[0010]

[0011] Preferably, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1.

[0012] Preferably, the inert solvent is water.

[0013] Preferably, the temperature of the salt-forming reaction is 0 to 80° C., and the time is 0.1 to 60 h.

[0014] Preferably, the salt-forming reaction is carried out under nitrogen protection and stirring.

[0015] Preferably, the compound represented by formula II is prepared by: adding acetaldehyde solution to an aqueous solution containing the compound represented by formula 1, and performing an addition reaction to obtain the compound represented by formula II;

[0016]

[0017] The present invention also provides a heterocyclic derivative, which is a pharmaceutically acceptable salt, hydrate, solvate or prodrug of the heterocyclic compound described in the above technical solution.

[0018] The present invention also provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable carrier; the active ingredient comprises the heterocyclic compound described in the above technical solution or the heterocyclic derivative described in the above technical solution.

[0019] The present invention also provides the use of the heterocyclic compound described in the above technical solution, the heterocyclic derivative described in the above technical solution or the pharmaceutical composition described in the above technical solution in the preparation of a drug for preventing and / or treating related diseases, wherein the related diseases include methanol poisoning, acute alcohol poisoning, chronic alcohol poisoning, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases or fragile X syndrome.

[0020] The present invention provides a heterocyclic compound having a structure shown in Formula I;

[0021]

[0022] The heterocyclic compound provided by the present invention can effectively relieve acute methanol poisoning. In an acute methanol poisoning mouse model, the compound can significantly reduce the mortality rate of methanol poisoning mice. In addition, the heterocyclic compound provided by the present invention has low toxic and side effects.

[0023] The present invention also provides a method for preparing the hybrid compound described in the above technical solution. The preparation method provided by the present invention is simple and has a high yield of more than 69%. DETAILED DESCRIPTION

[0024] The present invention provides a heterocyclic compound having a structure shown in Formula I;

[0025]

[0026] The present invention also provides a method for preparing the heterocyclic compound described in the above technical solution, comprising the following steps:

[0027] The compound represented by formula II, the compound represented by formula III and an inert solvent are mixed and subjected to a salt-forming reaction to obtain the heterocyclic compound;

[0028]

[0029] In the present invention, the compound represented by formula II is preferably obtained by preparation, and the preparation method preferably comprises: adding acetaldehyde solution to an aqueous solution containing the compound represented by formula 1, and performing an addition reaction to obtain the compound represented by formula II;

[0030]

[0031] In the present invention, the molar ratio of the compound represented by Formula 1 to acetaldehyde in the acetaldehyde solution is preferably 1:1.05; the amount ratio of the compound represented by Formula 1 to water in the aqueous solution containing the compound represented by Formula 1 is preferably 25g:550mL; the mass concentration of the acetaldehyde solution is preferably 40%; the temperature of the addition reaction is preferably room temperature, the time is preferably 1.5h, and the addition reaction is preferably carried out under stirring; the addition reaction is preferably carried out at -5°C under nitrogen protection.

[0032] In the present invention, during the addition reaction, it is preferred to detect whether the compound shown in Formula 1 is completely reacted by HNMR. After the addition reaction is completed, the present invention also preferably includes reducing pressure, concentrating and drying the obtained reaction system, mixing the obtained product with ethanol and water, stirring at room temperature, and achieving concentration and purification; washing with ethanol after filtering, and then vacuum drying; the volume ratio of ethanol to water is preferably 10:1; the time of stirring at room temperature is preferably 16h. The present invention has no special limitation on the total amount of ethanol and water, as long as the product can be evenly dispersed.

[0033] In the present invention, the molar ratio of the compound represented by formula II to the compound represented by formula III is preferably 1:1. In the present invention, the inert solvent is preferably water. The present invention has no particular limitation on the amount of the inert solvent, as long as the reaction proceeds smoothly.

[0034] In the present invention, the temperature of the salt-forming reaction is preferably 0-80°C, specifically 0°C, 10°C, 20°C, 25°C (room temperature), 30°C, 40°C, 50°C, 60°C, 70°C, 80°C; the time of the salt-forming reaction is preferably 0.1-60h, specifically 0.1h, 1h, 5h, 10h, 20h, 30h, 40h, 50h, 60h; the salt-forming reaction is preferably carried out under nitrogen protection and stirring. In the present invention, the reactions involved in the salt-forming reaction are as follows:

[0035]

[0036] In the present invention, after the salt-forming reaction is completed, the obtained reaction solution is preferably concentrated under reduced pressure, and the obtained concentrate is washed with acetone and dried in sequence to obtain a compound of the structure shown in Formula I. In the present invention, the acetone washing preferably includes: mixing the product obtained by reduced pressure concentration with acetone and stirring at room temperature or concentrating under reduced pressure again, and repeating the above process three times. In the present invention, the drying method is preferably vacuum drying.

[0037] The present invention also provides a heterocyclic derivative, which is a pharmaceutically acceptable salt, hydrate, solvate or prodrug of the heterocyclic compound described in the above technical solution.

[0038] In the present invention, the "pharmaceutically acceptable salt" refers to a salt suitable for use as a drug formed by the heterocyclic compound provided by the present invention and an acid or a base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by the heterocyclic compound provided by the present invention and an acid. Acids suitable for forming salts include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt formed by the heterocyclic compound provided by the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (such as a lower alkanolammonium salt and other pharmaceutically acceptable amine salts, such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively).

[0039] In the present invention, the prodrug refers to a compound having the structure shown in Formula I which has undergone certain modifications and becomes a compound having the structure shown in Formula I after entering the body.

[0040] The present invention also provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable carrier; the active ingredient comprises the heterocyclic compound described in the above technical solution or the heterocyclic derivative described in the above technical solution.

[0041] In the present invention, the "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds or derivatives provided by the present invention without significantly reducing the efficacy. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0042] The pharmaceutical composition provided by the present invention comprises a safe and effective amount of the heterocyclic compound or heterocyclic derivative provided by the present invention and a pharmaceutically acceptable carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In the present invention, one dose of the pharmaceutical composition contains 1 to 3000 mg (active dose range 3 to 30 mg / kg) of active ingredient, preferably, 10 to 2000 mg of active ingredient, and the "one dose" is a capsule or tablet or a single in vivo injection.

[0043] The present invention has no particular limitation on the administration of the hybrid compound, heterocyclic derivative and pharmaceutical composition. Representative administration methods include but are not limited to oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0044] In the present invention, solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert carrier (or excipient), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0045] In the present invention, solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.

[0046] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oil, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil or a mixture of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents and spices. In addition to the active ingredient, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum methylate, agar or a mixture of these substances.

[0047] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0048] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0049] The heterocyclic compound, heterocyclic derivative or pharmaceutical composition provided by the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0050] When using the pharmaceutical composition, a safe and effective amount of the heterocyclic compound or heterocyclic derivative provided by the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

[0051] The present invention also provides the use of the heterocyclic compound described in the above technical solution, the heterocyclic derivative described in the above technical solution or the pharmaceutical composition described in the above technical solution in the preparation of a drug for preventing and / or treating related diseases, wherein the related diseases include methanol poisoning, acute alcohol poisoning, chronic alcohol poisoning, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases or fragile X syndrome.

[0052] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0053] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. 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.

[0054] Example 1

[0055] Preparation of heterocyclic compound NBA05001:

[0056] Preparation of P1, the reaction formula is as follows:

[0057]

[0058] The specific operation is as follows: under nitrogen protection at -5°C, 40 wt% acetaldehyde solution (25 g, 0.22 mol, 1.1 eq) is added to an aqueous solution containing compound SM (25 g dissolved in 550 mL of water, 0.21 mol, 1.0 eq), and the resulting mixture is stirred and reacted at room temperature for 1.5 h;

[0059] After HNMR detection showed that most of the compound SM had reacted, the mixture was concentrated and dried under reduced pressure, and then 100 mL of ethanol and 10 mL of water were added. The resulting mixed system was stirred at room temperature for 16 hours, filtered, washed with 20 mL of ethanol, and then vacuum dried to obtain 26.8 g of product P1.

[0060] Preparation of NBA05001: The reaction formula is as follows:

[0061]

[0062] The specific operation is as follows: Compound P1 (26.3 g, 0.18 mol, 1.0 eq), Compound S1 (30.2 g, 0.18 mol, 1.0 eq) and water (360 mL) are mixed, and stirred at 25°C under nitrogen protection for 60 h; the mixture is concentrated under reduced pressure, and then 850 mL of acetone is added, and stirring is continued at room temperature for 16 h, and the mixture is concentrated under reduced pressure. The mixture is then washed three times with acetone, adding 30 mL of acetone each time, and concentrated under reduced pressure after each wash, and finally dried in vacuo to obtain 39.2 g of NBA05001 compound with a yield of 69.4%.

[0063] The NMR data of NBA05001 compound obtained: 1 H-NMR (300 MHz, DMSO-D 6 )δ 8.07(s,1H),5.70-5.40(brs,1H),4.77(s,2H),4.78-4.69(m,0.5H),4.65(s,2H),4.60-4.50(m,0.5H),4.40-4.30(m,0.5 H),4.00-3.90(m,0.5H),3.35-3.25(m,1H),3.15-3.05(m,0.5H),3.04-2.91(m,0.5H),2.53(s,3H),1.52-1.45(m,2.6H).

[0064] Performance Testing

[0065] Test Example 1

[0066] NBA05001 efficacy evaluation in mice

[0067] 1. Experimental Methods

[0068] Experimental method 1. Exploration of single oral administration of methanol and alcohol in mice (9*5=45 mice)

[0069] KM mice (male, 18-22g, SPF grade) were fasted for 12 hours but not allowed to drink water, and then given methanol alcohol (56% (V / V) Red Star Erguotou liquor containing 1% methanol). Each group of 5 mice was given methanol alcohol at 0.05, 0.1, 0.15, 0.18, 0.21, 0.24, 0.27, 0.30, and 0.33mL / 10g, respectively. The mice were still fasted but not allowed to drink water, and the mice were observed to see if they died within 24 hours.

[0070] Experimental Method 2: Efficacy study of NRB05001 in the mouse methanol alcohol model (3*10=30 mice, 2*10 mice in the test compound group, 10 mice in the placebo saline group)

[0071] KM mice (male, 18-22g, SPF grade) were fasted for 12 hours but not water deprivation, and then given normal saline and NRB05001 by gavage. Each group had 10 mice, and NRB05001 was given: 30mg / mL, 10mg / mL, 0mg / mL (normal saline) respectively. After 30 minutes, each mouse was given methanol liquor (56% (V / V) Red Star Erguotou liquor containing 1% methanol) 0.25mL / 10g mouse. Still fasting but not water deprivation, the mice that died within 24 hours were observed and recorded.

[0072] 2. Experimental results

[0073] The results of experimental method 1 are summarized in Table 1

[0074] Table 1 Exploration of oral dose of methanol alcohol in mice

[0075]

[0076]

[0077] The results of experimental method 2 are summarized in Table 2

[0078] Table 2 Evaluation of the efficacy of compounds on methanol alcohol

[0079]

[0080] The above results indicate that compound NBA05001 can significantly reduce the mortality of mice given a lethal dose of methanol alcohol by oral gavage under experimental conditions.

[0081] Test Example 2

[0082] Preliminary acute toxicity test of NBA05001 obtained in Example 1

[0083] 30 KM mice (male, 18-22g, SPF grade) were fasted for 12 hours but not water deprivation and then given NBA05001. Five mice in each group were given 1x (300mg / mL), 0.5x, 0.25x, 0.1x, 0.05x, 0.01x, 0.2mL by gavage. The mice were still fasted but not water deprivation, and observed for any abnormalities including death within 24 hours.

[0084] The results showed that all mice had no abnormal reactions, and no organ abnormalities were found in the autopsies of 5 mice that were given the maximum concentration of 1x (300 mg / mL). Therefore, NBA05001 is safe at a concentration of 300 mg / mL.

[0085] Based on the above experimental results, compound NBA05001 can significantly reduce the mortality caused by methanol poisoning in mice, and preliminary toxicity experiments show that the compound is safe at a dosage concentration of 300 mg / mL.

[0086] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A heterocyclic compound, characterized in that Having the structure shown in formula I; 2. The method for preparing the heterocyclic compound according to claim 1, characterized in that: The following steps are involved: The compound represented by formula II, the compound represented by formula III and an inert solvent are mixed and subjected to a salt-forming reaction to obtain the heterocyclic compound; 3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound represented by formula II to the compound represented by formula III is 1:

1.

4. The preparation method according to claim 2, characterized in that: The inert solvent is water.

5. The preparation method according to claim 2, characterized in that: The temperature of the salt-forming reaction is 0-80° C. and the time is 0.1-60 h.

6. The preparation method according to claim 2 or 5, characterized in that: The salt-forming reaction is carried out under the conditions of nitrogen protection and stirring.

7. The preparation method according to claim 2, characterized in that: The compound represented by formula II is obtained by preparation, and the preparation method comprises: adding acetaldehyde solution to an aqueous solution containing the compound represented by formula 1, and performing an addition reaction to obtain the compound represented by formula II; 8. A heterocyclic derivative, characterized in that: It is a pharmaceutically acceptable salt, hydrate, solvate or prodrug of the heterocyclic compound according to claim 1.

9. A pharmaceutical composition, characterized in that It comprises an active ingredient and a pharmaceutically acceptable carrier; the active ingredient comprises the heterocyclic compound according to claim 1 or the heterocyclic derivative according to claim 8.

10. Use of the heterocyclic compound according to claim 1, the heterocyclic derivative according to claim 8 or the pharmaceutical composition according to claim 9 in the preparation of a drug for preventing and / or treating related diseases, characterized in that: The related diseases include methanol poisoning, acute alcohol poisoning, chronic alcohol poisoning, alcoholic hepatitis, non-alcoholic hepatitis, central nervous system diseases or fragile X syndrome.

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