Application of sulfonamide compound in preparation of anti-encephaledema medicine

Abstract

The invention relates to an application of a sulfonamide compound or a pharmaceutical composition containing the sulfonamide compound in preparation of an anti-encephaledema drug. The sulfonamide compound can quickly reduce intracranial pressure, is used for treating encephaledema caused by various reasons and preventing cerebral hernia, is high in safety, has no serious adverse effects such as liver and kidney injury and the like, and is a novel anti-encephaledema medicine.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to use of a sulfonamide compound or a pharmaceutical composition containing the sulfonamide compound in the preparation of an anti-cerebral edema drug. Background Art

[0002] Brain edema is a very common complication of stroke and craniocerebral injury. It is a histopathological reaction caused by stimulation from a variety of exogenous or endogenous harmful factors such as physical, chemical, and biological factors. It manifests as abnormal increase in tissue water content and increase in brain volume. In severe cases, brain herniation or even death may occur. Brain edema is an inevitable pathophysiological process after cerebral hemorrhage, which can lead to secondary brain damage in the brain tissue after hemorrhage. At the same time, due to the increase in extracellular fluid when it occurs, intracranial pressure increases, which in turn impairs neurological function and causes serious adverse consequences. For patients with cerebral edema, active measures to reduce excessive intracranial pressure have become an urgent treatment. Dehydration and diuresis are the key to reducing intracranial pressure.

[0003] The existing drug for treating cerebral edema is mainly mannitol injection, but mannitol injection has obvious defects in clinical use. Generally speaking, patients with active intracranial hemorrhage, damaged blood-brain barrier, renal insufficiency and heart insufficiency cannot use mannitol injection to treat cerebral edema.

[0004] Therefore, there is an urgent need to develop new anti-cerebral edema drugs with better efficacy and safety in clinical practice. Summary of the invention

[0005] In view of the deficiency of the prior art in the lack of drugs for treating cerebral edema with good efficacy and few side effects, the present invention provides a use of a sulfonamide compound or a pharmaceutical composition containing the same in the preparation of an anti-cerebral edema drug. In previous studies, the inventors found that the sulfonamide compound shown in Formula I has a good diuretic effect (patent application number: 2023107035462). Based on this research and the above background, the inventors conducted in-depth research on this type of compound for the treatment of cerebral edema. Experimental studies have confirmed that the sulfonamide compound is Na + / K + / 2Cl - Symport inhibitors can quickly reduce intracranial pressure and are used to treat cerebral edema caused by various reasons and prevent brain herniation. They are highly safe and have no serious adverse effects such as liver and kidney damage. They are a new anti-cerebral edema drug.

[0006] The present invention is achieved through the following technical solutions: The first aspect of the present invention provides a use of a sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an anti-cerebral edema drug;

[0007] Wherein Y is O, CH2 or Y does not exist; Z is CH2 or Z does not exist; when both Y and Z do not exist, O is directly connected to P; when Y exists but Z does not exist, Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P; when Y and the phospholipid group do not exist, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R represents hydrogen or a pharmaceutically acceptable salt; R1 represents a C1-C6 alkane.

[0008] In a second aspect, the present invention provides a use of a sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof in combination with a dehydrating agent in the preparation of an anti-cerebral edema drug, wherein the dehydrating agent comprises mannitol, hypertonic saline, or glycerol fructose; Ⅰ Wherein Y is O, CH2 or Y does not exist; Z is CH2 or Z does not exist; when both Y and Z do not exist, O is directly connected to P; when Y exists but Z does not exist, Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P; when Y and the phospholipid group do not exist, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R represents hydrogen or a pharmaceutically acceptable salt; R1 represents a C1-C6 alkane.

[0009] Furthermore, the anti-cerebral edema may include clinical manifestations such as abnormal increase in brain tissue water content, increase in brain volume, or increase in intracranial pressure caused by causes such as cerebral stroke and craniocerebral injury; The pharmaceutically acceptable salts include salts formed between the compound of formula I and an organic base, or salts formed between the compound of formula I and a basic amino acid, or metal salts of the compound of formula I.

[0010] The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine or diisopropylethylamine; Optionally, the metal salt of the compound of formula I is selected from sodium salt or potassium salt; Optionally, the basic amino acid of the compound of formula I is selected from arginine, laryngine or histidine.

[0011] Furthermore, in the use described in the first aspect or the second aspect of the present invention, the sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Compound 15 Compound 16 Compound 17 Compound 18 Compound 19 Compound 20 Compound 21 Compound 22 Compound 23 Compound 24 Compound 25 Compound 26 Compound 27 Compound 28 Compound 29 Compound 30 Torsemide M3 Control compound 1 Control compound 2 Control compound 3 Control compound 4 Control compound 5 The third aspect of the present invention provides a use of a pharmaceutical composition in the preparation of an anti-cerebral edema drug, wherein the pharmaceutical composition comprises a sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Ⅰ Wherein Y is O, CH2 or Y does not exist; Z is CH2 or Z does not exist; when both Y and Z do not exist, O is directly connected to P; when Y exists but Z does not exist, Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P; when Y and the phospholipid group do not exist, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R represents hydrogen or a pharmaceutically acceptable salt; R1 represents a C1-C6 alkane.

[0012] Further, the sulfonamide compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.05-95% of the mass of the pharmaceutical composition; preferably, the sulfonamide ester compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.1-80% of the mass of the pharmaceutical composition; further preferably, the sulfonamide compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.5-60% of the mass of the pharmaceutical composition; Further, the pharmaceutically acceptable carrier is selected from one or more of diluents, glidants, lubricants, binders, disintegrants, osmotic pressure regulators, and solvents. Further, the diluent is selected from one or more of starch, microcrystalline cellulose, sucrose, dextrin, mannitol, lactose, powdered sugar, and glucose; the glidant is selected from one or more of talc and colloidal silicon dioxide; the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, and poloxamer; the binder is selected from one or more of water, ethanol, starch slurry, syrup, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, and polyvinyl pyrrolidone; the disintegrant is selected from one or more of starch, sodium bicarbonate, citric acid, tartaric acid, and low-substituted hydroxypropyl cellulose; the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, phosphate, or citrate; the solvent includes water and / or a balanced salt solution.

[0013] Furthermore, the pharmaceutically acceptable carrier may also include a flavoring agent or a sweetener; Furthermore, the pharmaceutical composition comprising the sulfonamide compound and its pharmaceutically acceptable salt is an injection preparation or an oral preparation. Furthermore, the injection preparation is an injection solution or a lyophilized powder injection, and the oral preparation is a tablet, capsule, granule, oral solution.

[0014] The present invention has the following outstanding effects: (1) Sulfonamide compounds or their pharmaceutically acceptable salts are used as the sole active ingredient of the drug, which can quickly reduce intracranial pressure and is used to treat cerebral edema caused by various reasons.

[0015] Specifically, the present invention shows that sulfonamide compounds can significantly reduce intracranial hypertension and brain edema induced by different factors (nitroglycerin and collagenase IV) in animals, and reduce brain water content. + -K + -2C1 - The activity of the symporter system reduces electrolyte reabsorption and increases water excretion.

[0016] (2) Sulfonamide compounds have significant clinical advantages over the current first-line clinical drug (mannitol injection), mainly manifested in lower onset doses and longer duration of efficacy. In addition, combined use with mannitol can further increase the efficacy.

[0017] (3) In the toxicity test of repeated intravenous injection for 2 weeks, the no-observed-toxicity-effect-level (NOAEL) of SD rats was 55 mg / kg, and no serious adverse reactions and liver and kidney damage were observed in the animals. The compound of the present invention has a significant safety advantage over mannitol injection. DETAILED DESCRIPTION

[0018] The present invention is further described in detail below in conjunction with specific implementation modes.

[0019] Example 1: Study on the activity of compounds on nitroglycerin-induced intracranial hypertension in experimental rabbits Male experimental rabbits were divided into groups according to their body weight, namely: normal control group, model control group, mannitol group (1000 mg / kg), control group (10 mg / kg), and compound of the present invention group (10 mg / kg), with 4 rabbits in each group. After anesthesia, the animals in each group were fixed, and the normal control group was intravenously injected with 5 mL / kg of 0.9% sodium chloride injection. The other groups were firstly continuously intravenously dripped with nitroglycerin (0.04 mg / kg / min) for 10 min to establish the model. Except for the model control group, which was not given drug treatment, the other groups were then intravenously injected with corresponding drugs. Mannitol injection used a 20% (weight percent) aqueous solution, and the control group and the test drug were both made into a 10 mg / ml injection with physiological saline (i.e., 0.9% sodium chloride injection). The drugs were administered according to the weight of the animals, and the specific dosages were: the mannitol group was administered with a dosage of 1000 mg / kg, the control group was administered with a dosage of 10 mg / kg, and the test drug group was administered with a dosage of 10 mg / kg. The changes of intracranial pressure of experimental rabbits were detected before modeling (before intravenous drip of nitroglycerin), after modeling (10 minutes after intravenous drip of nitroglycerin), and 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, and 180 minutes after administration. The results are shown in Table 1.

[0020] Table 1 Effect of the compounds of the present invention on the percentage reduction of intracranial pressure in the experimental rabbit intracranial hypertension model induced by nitroglycerin

[0021]

[0022] The results of the study showed that after 10 minutes of intravenous injection of nitroglycerin (0.04 mg / kg / min) into the experimental rabbits, the intracranial pressure increased significantly. After the administration of the compounds of the present invention, the intracranial pressure of the experimental rabbits was significantly reduced, indicating that the compounds of the present invention have the effect of rapidly reducing intracranial pressure and treating cerebral edema, and the activity level and duration of action are better than those of mannitol injection and the control compound.

[0023] Example 2: Study on the activity of the compound on collagenase IV-induced experimental rabbit cerebral hemorrhage model The experimental rabbits were randomly divided into normal control group, model control group, mannitol injection group, compound of the present invention group, and combined administration group according to sex and weight. 。The normal control group was intravenously injected with 5 mL / kg of 0.9% sodium chloride injection, and the animals in the other groups were injected with 1 μl of 0.9% sodium chloride injection containing 0.5 μg / μl of collagenase IV under the dura mater for modeling. Except for the model control group, which was not given drug treatment, the other groups were intravenously injected with corresponding drugs. Mannitol injection used a 20% (weight ratio) aqueous solution, and the test drugs were all prepared with physiological saline (i.e., 0.9% sodium chloride injection) to form a 10 mg / ml injection. The drugs were administered according to the weight of the animals. The specific dosages were: the dosage of the mannitol group was 1000 mg / kg, the dosage of the compound of the present invention group was 3.0 mg / kg, and the dosage of the combined administration group was 1000 mg / kg of mannitol injection plus 3.0 mg / kg of the test drug. The administration speed was 6 mL / min, and the animals were treated according to the administration frequency set in the experiment. The animals were treated at 24h, 48h and 72h after modeling. The animals were anesthetized with propofol injection and then bled from the femoral artery to be killed. The area around the brain lesion was immediately weighed, dried in a constant temperature box, and weighed again to calculate the brain water content. The results are shown in Table 2.

[0024] Table 2 Effects of the compounds of the present invention on brain water content in the collagenase IV-induced experimental rabbit cerebral hemorrhage model

[0025]

[0026]

[0027]

[0028] The results of the study show that the compounds of the present invention can significantly reduce the increase in brain water content caused by cerebral hemorrhage in experimental rabbits, and their activity in reducing brain water content is better than that of mannitol injection. When used in combination with mannitol, the efficacy can be further enhanced; and the compounds of the present invention are superior to the control compounds.

[0029] Example 3: Effect of the compounds of the present invention on Na + , K + , Cl - Study on the inhibitory activity of the pump Effect of control compound and series of concentrations of the compound of the present invention on Na in pig kidney + -K + -2Cl - The activity of the pump transport model. The concentration of rubidium ions in each group of buffers was detected by atomic absorption spectroscopy, and the activity of each test / reference substance on Na + -K + -2Cl - The activity of the pump is measured as the median effective concentration (EC 50) indicates activity. The results are shown in Table 3.

[0030] Table 3 Compounds for Na + -K + -2Cl - Pump activity

[0031] The results show that the compounds of the present invention have an + -K + -2Cl - The pump activity of the compounds has different degrees of inhibitory activity, and is better than that of the control compound, indicating that the compounds of the present invention have good drugability.

[0032] Example 4: Tissue distribution study of the compounds of the present invention in rats SD rats weighing 300 g ± 20 g, half male and half female, were given a single intravenous injection of 10 mg / kg of the compound of the present invention. Heart, liver, spleen, lung, kidney, brain, uterus, ovary, testis, epididymis, skeletal muscle (quadriceps) were collected at 5 min, 30 min, and 3 h after administration, and samples were collected at each time point, and the drug concentration was determined by LC-MS / MS method.

[0033] The results of the study showed that after 10 mg / kg of the compound of the present invention was injected into the tail vein of SD rats, it could be rapidly (about 5 minutes) converted into the corresponding active metabolites, with a conversion rate of >98%, and then exert its pharmacological activity. The corresponding active metabolites were widely distributed in tissues, with the highest content in kidneys and liver. The high distribution in kidneys is conducive to its direct effect on the pharmacological target of kidneys and rapid onset of effect.

[0034] Example 5: Toxicity study of repeated administration of the compounds of the present invention to SD rats via tail vein injection for 2 consecutive weeks SD rats, half male and half female, were divided into a vehicle control group, a low-dose group (50 mg / kg), a medium-dose group (100 mg / kg), and a high-dose group (200 mg / kg). The rats were injected with 20 mL / kg via the tail vein, once a day, 7 days a week, for 2 consecutive weeks to observe drug toxicity.

[0035] Administration compounds: Compounds 1-8, Compounds 10-23, Compounds 25-30.

[0036] The results of the study showed that the compound of the present invention was administered to SD rats via tail vein injection for 2 consecutive weeks. The drug had no obvious accumulation in the body of SD rats and was completely cleared from the body after 2 weeks of drug withdrawal. It could cause increased urination and electrolyte disturbance in animals, which could be restored after 2 weeks of drug withdrawal. The no-observed-toxicity-effect-level (NOAEL) was 55 mg / kg.

[0037] The above-mentioned embodiments only express some specific implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Use of a sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of an anti-cerebral edema drug: Ⅰ Wherein Y is O, CH2 or Y does not exist; Z is CH2 or Z does not exist; when both Y and Z do not exist, O is directly connected to P; when Y exists but Z does not exist, Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P; when Y and the phospholipid group do not exist, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R represents hydrogen or a pharmaceutically acceptable salt; R1 represents a C1-C6 alkane.

2. A use of a sulfonamide compound of formula I or a pharmaceutically acceptable salt thereof and a dehydrating agent in the preparation of an anti-cerebral edema drug, wherein the dehydrating agent comprises mannitol, hypertonic saline, or glycerol fructose; Ⅰ Wherein Y is O, CH2 or Y does not exist; Z is CH2 or Z does not exist; when both Y and Z do not exist, O is directly connected to P; when Y exists but Z does not exist, Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P; when Y and the phospholipid group do not exist, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R represents hydrogen or a pharmaceutically acceptable salt; R1 represents a C1-C6 alkane.

3. The use according to claim 1, characterized in that The pharmaceutically acceptable salts include salts formed between the compound of formula I and an organic base, or salts formed between the compound of formula I and a basic amino acid, or metal salts of the compound of formula I.

4. The salt according to claim 3, characterized in that The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine or diisopropylethylamine.

5. The salt according to claim 3, characterized in that The metal salt is selected from sodium or potassium.

6. The salt according to claim 3, characterized in that The basic amino acid is selected from arginine, laeline or histidine.

7. The use according to claim 1 or 2, characterized in that: The sulfonamide compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Compound 15 Compound 16 Compound 17 Compound 18 Compound 19 Compound 20 Compound 21 Compound 22 Compound 23 Compound 24 Compound 25 Compound 26 Compound 27 Compound 28 Compound 29 Compound 30.

8. Use of a pharmaceutical composition in the preparation of an anti-cerebral edema drug, characterized in that: The pharmaceutical composition comprises a sulfonamide compound represented by the following formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Ⅰ Wherein Y is O, CH2 or Y does not exist; Z is CH2 or Z does not exist; when both Y and Z do not exist, O is directly connected to P; when Y exists but Z does not exist, Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P; when Y and the phospholipid group do not exist, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R represents hydrogen or a pharmaceutically acceptable salt; R1 represents a C1-C6 alkane.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutically acceptable carrier is selected from one or more of a filler, a glidant, a lubricant, a binder, a disintegrant, an osmotic pressure regulator, and a solvent; Optionally, the filler is selected from one or more of starch, microcrystalline cellulose, sucrose, dextrin, mannitol, lactose, powdered sugar, and glucose; Optionally, the glidant is selected from one or more of talc and colloidal silicon dioxide; Optionally, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, and poloxamer; Optionally, the binder is selected from one or more of water, ethanol, starch slurry, syrup, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, and polyvinyl pyrrolidone; Optionally, the disintegrant is selected from one or more of starch, sodium bicarbonate, citric acid, tartaric acid, and low-substituted hydroxypropyl cellulose; Optionally, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, phosphate, and citrate; Optionally, the solvent comprises water and / or a balanced salt solution; Optionally, the pharmaceutically acceptable carrier further comprises a flavoring agent or a sweetener.

10. The pharmaceutical composition according to claim 8 or 9, characterized in that The dosage form of the pharmaceutical composition is an injection preparation or an oral preparation.

11. The dosage form according to claim 10, characterized in that The injection preparation is an injection solution or a freeze-dried powder injection.

12. The dosage form according to claim 10, characterized in that The oral preparation is a tablet, capsule, granule, or oral solution.

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