Use of sulfonamide compound in preparation of Anti-cerebral edema drug

Abstract

Provided is a use of a sulfonamide compound or a pharmaceutical composition comprising same in the preparation of an anti-cerebral edema drug. The sulfonamide compound can rapidly reduce intracranial pressure, and is used for treating cerebral edema of various causes.

Description

Use of a sulfonamide compound in the preparation of a cerebral edema resisting drug TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to use of a sulfonamide compound or a pharmaceutical composition containing the same in the preparation of a cerebral edema resisting drug. BACKGROUND

[0002] Cerebral edema is a very common complication of cerebral apoplexy and craniocerebral injury, which is caused by stimulation of various exogenous or endogenous harmful factors such as physics, chemistry and biology, and is a kind of histopathological reaction, which is characterized by abnormal increase of tissue water and increase of brain volume. In severe cases, cerebral hernia may occur, and even death. Cerebral edema is a pathological and physiological process that inevitably occurs after cerebral hemorrhage, which can cause secondary brain injury of the brain tissue after hemorrhage. At the same time, because of the increase of extracellular fluid at the time of occurrence, the intracranial pressure is increased, and then the nerve function is damaged, causing serious adverse consequences. For patients with cerebral edema, it is urgent to reduce the high intracranial pressure by active measures, and dehydration and diuresis are the key to reduce the intracranial pressure.

[0003] The existing drug for treating cerebral edema is mainly mannitol injection, but mannitol injection has obvious defects in clinical use. Generally, patients with intracranial activity period of hemorrhage, damaged blood-brain barrier, renal dysfunction and cardiac dysfunction generally cannot use mannitol injection to treat cerebral edema.

[0004] Therefore, it is urgent to develop a new anti-cerebral edema drug with better effectiveness and safety in clinic. SUMMARY

[0005] In view of the lack of drugs for treating cerebral edema with good efficacy and small side effects in the prior art, the present application provides use of a sulfonamide compound or a pharmaceutical composition containing the same in the preparation of an anti-cerebral edema drug. The present inventors found in the previous study that the sulfonamide compound shown in formula I has good diuretic effect (patent application number: 2023107035462). On the basis of this research and the above background, the present inventors carried out further research on the treatment of cerebral edema by the compound, and experimental research confirmed that the sulfonamide compound is a Na + / K + / 2Cl - symporter inhibitor, which can quickly reduce the intracranial pressure, is used for treating cerebral edema caused by various reasons, preventing cerebral hernia, and has high safety without serious adverse effects such as liver and kidney damage, and is a new anti-cerebral edema drug.

[0006] The present application is realized by the following technical scheme:

[0007] The first aspect of the present application provides a sulfonamide compound or a pharmaceutically acceptable salt thereof shown in formula I for use in the preparation of an anti-cerebral edema drug, wherein the sulfonamide compound or the pharmaceutically acceptable salt thereof shown in formula I has the following chemical structure:

[0008] Y is O, CH2 or Y is absent;

[0009] Z is CH2 or Z is absent;

[0010] PE is or PE is absent;

[0011] When Y and Z are both absent, O is directly connected to PE; when Y is present and Z is absent, Y is directly connected to O; when Z is present and Y is absent, Z is directly connected to PE; when Y and PE are absent, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R1 represents C1-C6 alkane; R2 and R3 independently represent hydrogen or a metal element.

[0012] The second aspect of the present application provides a sulfonamide compound or a pharmaceutically acceptable salt thereof shown in formula I in combination with a dehydrating agent for use in the preparation of an anti-cerebral edema drug, and optionally, the dehydrating agent includes mannitol, hypertonic saline, glycerol fructose;

[0013] Y is O, CH2 or Y is absent;

[0014] Z is CH2 or Z is absent;

[0015] PE is or PE is absent;

[0016] When Y and Z are both absent, O is directly connected to PE; when Y is present and Z is absent, Y is directly connected to O; when Z is present and Y is absent, Z is directly connected to PE; when Y and PE are absent, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R1 represents C1-C6 alkane; R2 and R3 independently represent hydrogen or a metal element.

[0017] When one of R2 and R3 is a hydrogen atom and the other is a metal element, the basicity of the entire compound is closer to human tolerance, and the drugability is better.

[0018] Further, the anti-cerebral edema can include the clinical manifestations of abnormal increase of water in brain tissue, increase of brain volume, or increase of intracranial pressure caused by reasons such as cerebral apoplexy and craniocerebral injury;

[0019] The pharmaceutically acceptable salt includes a salt of the compound of Formula I with an organic base, or a salt of the compound of Formula I with a basic amino acid, or a metal salt of the compound of Formula I.

[0020] The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine or diisopropylethylamine.

[0021] Optionally, the metal salt of the compound of Formula I is selected from a sodium salt or a potassium salt.

[0022] Optionally, the basic amino acid of the compound of Formula I is selected from arginine, cysteine or histidine.

[0023] Further, in the use according to the first aspect or the second aspect of the present application, the sulfonamide compound of Formula I or the pharmaceutically acceptable salt thereof is selected from the following compounds or the pharmaceutically acceptable salt thereof:

[0024] In a third aspect of the present application, there is provided a use of a pharmaceutical composition in the preparation of an anti-cerebral edema drug, wherein the pharmaceutical composition comprises a sulfonamide compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0025] wherein Y is O, CH2 or Y is absent;

[0026] Z is CH2 or Z is absent;

[0027] PE is or PE is absent;

[0028] When Y and Z are both absent, O is directly connected to PE; when Y is present and Z is absent, Y is directly connected to O; when Z is present and Y is absent, Z is directly connected to PE; when Y and PE are absent, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R1 represents C1-C6 alkane; R2 and R3 independently represent hydrogen or a metal element.

[0029] Further, the sulfonamide compound or the pharmaceutically acceptable salt thereof in the pharmaceutical composition accounts for 0.05-95% of the mass of the pharmaceutical composition; preferably, the sulfonamide ester compound or the pharmaceutically acceptable salt thereof in the pharmaceutical composition accounts for 0.1-80% of the mass of the pharmaceutical composition; further preferably, the sulfonamide compound or the pharmaceutically acceptable salt thereof in the pharmaceutical composition accounts for 0.5-60% of the mass of the pharmaceutical composition.

[0030] Further, the pharmaceutically acceptable carrier is selected from one or more of diluents, glidants, lubricants, binders, disintegrants, osmotic pressure regulators, solvents. Further, the diluents are selected from one or more of starch, microcrystalline cellulose, sucrose, dextrin, mannitol, lactose, sugar powder, glucose; the glidants are selected from one or more of talc, colloidal silicon dioxide; the lubricants are selected from one or more of magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, poloxamer; the binders are selected from one or more of water, ethanol, starch paste, sugar syrup, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone; the disintegrants are selected from one or more of starch, sodium bicarbonate, citric acid, tartaric acid, low-substituted hydroxypropyl cellulose; the osmotic pressure regulators are selected from one or more of sodium chloride, glucose, phosphate or citrate; the solvents include water and / or balanced salt solution.

[0031] Further, the pharmaceutically acceptable carrier can further include a flavoring agent or a sweetening agent.

[0032] Further, the pharmaceutical composition containing the sulfonamide compound and the pharmaceutically acceptable salt thereof is an injection preparation or an oral preparation. Further, the injection preparation is an injection solution or a freeze-dried powder injection, and the oral preparation is a tablet, a capsule, a granule, an oral solution.

[0033] The present application has the following outstanding effects:

[0034] (1) The sulfonamide compound or the pharmaceutically acceptable salt thereof as the only active ingredient of the drug can rapidly reduce intracranial pressure and is used for treating brain edema caused by various reasons.

[0035] Specifically, the embodiment of the present application shows that the sulfonamide compound can significantly reduce intracranial hypertension and brain edema induced by different factors (nitroglycerin and collagenase IV) and reduce the water content in the brain. The mechanism of pharmacodynamic action is related to the inhibition of the activity of the co-transport system of the kidney, the reduction of the reabsorption of electrolytes, and the increase of water excretion. + -K + -2C1 - the co-transport system of the kidney, the reduction of the reabsorption of electrolytes, and the increase of water excretion.

[0036] (2) The sulfonamide compound has significant clinical advantages compared with the current first-line drug (mannitol injection), mainly showing lower onset dose and longer maintenance time of drug effect. In addition, the combination of the sulfonamide compound and mannitol can further increase the efficacy.

[0037] (3) In the 2-week repeated intravenous administration toxicity test of the compound, the NOAEL (no observed adverse effect level) of SD rats is 55 mg / kg, and no serious adverse reactions and liver and kidney damage are observed in animals, which has a significant safety advantage over mannitol injection. DETAILED DESCRIPTION

[0038] The application will be further described in detail below in combination with specific embodiments.

[0039] Example 1: Activity study of the compound on a nitroglycerin-induced experimental rabbit intracranial hypertension model

[0040] Male experimental rabbits were grouped according to body weight, and were divided into the following groups: normal control group, model control group, mannitol group (1000 mg / kg), control group (10 mg / kg), and the compound 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 0.9% sodium chloride injection 5 mL / kg. The other groups were first continuously intravenously injected with nitroglycerin (0.04 mg / kg / min) for 10 min for modeling. Except for the model control group, the other groups were then intravenously injected with the corresponding drugs. The mannitol injection was prepared into a 20% (wt%) aqueous solution, and the control group and the test drug were prepared into 10 mg / ml injection solutions using normal saline (i.e., 0.9% sodium chloride injection). The animals were administered according to their body weight, and the specific dosages were as follows: the mannitol group was administered at a dose of 1000 mg / kg, the control group was administered at a dose of 10 mg / kg, and the test drug group was administered at a dose of 10 mg / kg. The intracranial pressure of the experimental rabbits was detected before modeling (before intravenous infusion of nitroglycerin), after modeling (10 min after intravenous infusion of nitroglycerin), 10 min, 20 min, 30 min, 60 min, 90 min, 120 min, 150 min, and 180 min after administration. The results are shown in Table 1.

[0041] Table 1 Effect of the compound of the application on the intracranial pressure reduction percentage of the nitroglycerin-induced experimental rabbit intracranial hypertension model

[0042] The results show that: after intravenous injection of nitroglycerin (0.04 mg / kg / min) for 10 min, the intracranial pressure of the experimental rabbits is obviously increased. After administration of each compound of the present application, the intracranial pressure of the experimental rabbits is obviously reduced, indicating that the compounds of the present application have the effects of rapidly reducing intracranial pressure and treating cerebral edema, and the activity level and action maintenance time are superior to mannitol injection and the control compound.

[0043] Example 2: Activity research of the compounds on collagenase IV induced experimental rabbit cerebral hemorrhage model

[0044] The experimental rabbits are randomly divided into normal control group, model control group, mannitol injection group, compound of the present application group and combined administration group according to gender and weight. The normal control group is intravenously injected with 0.9% sodium chloride injection 5 mL / kg, and the other groups are subdurally injected with 0.9% sodium chloride injection containing collagenase IV 0.5 μg / μl 1 μl for modeling. Except that the model control group is not given drug treatment, the other groups are respectively intravenously injected with corresponding drugs. The mannitol injection is an aqueous solution with a concentration of 20% (weight ratio), and the test drugs are all prepared into 10 mg / ml injection with normal saline (i.e. 0.9% sodium chloride injection) according to the animal weight. The specific dosages are as follows: the dosage of the mannitol group is 1000 mg / kg, the dosages of the compound of the present application group are all 3.0 mg / kg, and the dosages of the combined administration group are 1000 mg / kg of mannitol injection plus 3.0 mg / kg of the test drug. The administration speed is 6 mL / min, and the animals are treated at the time points of 24 h, 48 h and 72 h after modeling according to the set administration frequency. The animals are sacrificed by bloodletting from the femoral artery after anesthesia with propofol injection, and the brain around the lesion is immediately weighed. After drying in the thermostat, the brain is weighed again, and the brain water content is calculated. The results are shown in Table 2.

[0045] Table 2 Influence of the compound of the present application on brain water content of collagenase IV induced experimental rabbit cerebral hemorrhage model

[0046] The results show that: the compounds of the present application can all obviously reduce the increase of brain water content caused by cerebral hemorrhage in experimental rabbits, and the activity of reducing brain water content is superior to mannitol injection. The combination of mannitol and the compound of the present application can further enhance the efficacy; and the compound of the present application is superior to the control compound.

[0047] Example 3: Inhibition activity research of the compound of the present application on Na + , K + , Cl - pump

[0048] The control compound and the compound of the present application with a series of concentrations are used for the inhibition activity research on Na + -K+ -2Cl - Activity of the pump transport model. The concentration of rubidium ions in each group of buffer was detected by atomic absorption spectrometry, and the original concentration of RbCl was added to calculate the Na + -K + -2Cl - Activity of the pump, expressed as the half maximal effective concentration (EC 50 Activity. The results are shown in Table 3.

[0049] Table 3 Activity of the compounds on Na + -K + -2Cl - Activity of the pump

[0050] The results of the study show that the compounds of the present application have different degrees of inhibitory activity on the activity of Na + -K + -2Cl - Pump, and are superior to the control compounds, indicating that the compounds of the present application have good drug properties.

[0051] Example 4: Rat tissue distribution study of the compounds of the present application

[0052] SD rats weighing 300g ± 20g, half male and half female, were given a single intravenous injection of 10mg / kg of the compounds of the present application. Heart, liver, spleen, lung, kidney, brain, uterus, ovary, testis, epididymis, and skeletal muscle (quadriceps femoris) were collected at 5min, 30min, and 3h after administration, respectively. Drug concentration was determined by LC-MS / MS method.

[0053] The results of the study show that after SD rats were given a tail vein injection of 10mg / kg of the compounds of the present application, they were rapidly (about 5min) converted into the corresponding active metabolites, with a conversion rate of >98%, and then exerted pharmacodynamic activity. The corresponding active metabolites were widely distributed in tissues, with the highest content in the kidney and liver. High kidney distribution is conducive to its direct action on the pharmacodynamic target of the kidney, and rapid onset of action.

[0054] Example 5: Two-week repeated dose toxicity study of SD rats given the compounds of the present application by tail vein injection

[0055] SD rats, half male and half female, were divided into a vehicle control group, a low-dose group (50mg / kg), a medium-dose group (100mg / kg), and a high-dose group (200mg / kg). The drugs were administered by tail vein injection at 20mL / kg once a day, 7 days a week, for 2 consecutive weeks, and drug toxicity was observed.

[0056] Compounds administered: Compounds 1-8, Compounds 10-23, Compounds 25-30.

[0057] The results of the study show that SD rats were given the compound by tail vein injection for 2 weeks, and no significant accumulation of the drug was found in the SD rats. After 2 weeks of drug withdrawal, the drug was completely cleared from the body. It can cause increased urination and electrolyte imbalance in animals, which can recover after 2 weeks of drug withdrawal. The non-observed adverse effect level (NOAEL) is 55 mg / kg.

[0058] The above examples only express some specific embodiments of the present application, which are described in more detail and in more detail, but cannot be understood as limiting the scope of the patent of the present application. It should be noted that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. Use of a sulfonamide compound represented by Formula I: ###00001### or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cerebral edema: ​ Y is O, CH2, or Y is absent; Z is CH2, or Z is absent; PE is or PE is absent; When Y and Z are both absent, O is directly connected to PE; when Y is present and is not O and Z is absent, Y is directly connected to O; when Z is present and Y is absent, Z is directly connected to PE; when Y and PE are absent, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R1 represents C1-C6 alkane; R2 and R3 independently represent hydrogen or a metal element.

2. Use according to claim 1, characterized in that, A sulfonamide compound represented by Formula I or a pharmaceutically acceptable salt thereof is used in combination with a dehydrating agent; optionally, the dehydrating agent includes mannitol, hypertonic saline, glycerol fructose; Y is O, CH2, or Y is absent; PE is Z is CH2, or Z is absent; or PE is absent; 3. Use according to claim 1, characterized in that, When Y and Z are both absent, O is directly connected to PE; when Y is present and is not O and Z is absent, Y is directly connected to O; when Z is present and Y is absent, Z is directly connected to PE; when Y and PE are absent, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R1 represents C1-C6 alkane; R2 and R3 independently represent hydrogen or a metal element.

4. Use according to claim 3, characterized in that, The pharmaceutically acceptable salt includes a salt of the compound of Formula I with an organic base, or a salt of the compound of Formula I with a basic amino acid, or a metal salt of the compound of Formula I.

5. Use according to claim 3, characterized in that, The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine or diisopropyl ethylamine.

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

7. The method of claim 1 or 2, wherein, The sulfonamide compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

8. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises a sulfonamide compound represented by the following formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The basic amino acid is selected from arginine, leucine or histidine. Y is O, CH2, or Y is absent; PE is Z is CH2, or Z is absent; or PE is absent; 9. The pharmaceutical composition of claim 8, wherein, When Y and Z are both absent, O is directly connected to PE; when Y is present and is not O and Z is absent, Y is directly connected to O; when Z is present and Y is absent, Z is directly connected to PE; when Y and PE are absent, Z is H; X represents halogen, trifluoromethyl, difluoromethyl, monofluoromethyl; R1 represents C1-C6 alkane; R2 and R3 independently represent hydrogen or a metal element. 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, a solvent; Optionally, the filler is selected from one or more of starch, microcrystalline cellulose, sucrose, dextrin, mannitol, lactose, sugar powder, glucose; Optionally, the glidant is selected from one or more of talc, colloidal silicon dioxide; Optionally, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, poloxamer; Optionally, the binder is selected from one or more of water, ethanol, starch paste, sugar syrup, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinyl pyrrolidone. Optionally, the disintegrant is selected from one or more of starch, sodium bicarbonate, citric acid, tartaric acid, low-substituted hydroxypropyl cellulose; Optionally, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, phosphate, citrate; Optionally, the solvent includes water and / or a balanced salt solution; 10. The pharmaceutical composition according to claim 8 or 9, characterized in that, Optionally, the pharmaceutically acceptable carrier further includes a flavoring agent or a sweetening agent.

11. The pharmaceutical composition of claim 10, wherein, The dosage form of the pharmaceutical composition is an injection preparation or an oral preparation. The injection preparation is an injection solution or a lyophilized powder injection.

12. The pharmaceutical composition of claim 10, wherein, The oral formulation is a tablet, a capsule, a granule, or an oral solution. The oral formulation is a tablet, a capsule, a granule, or an oral solution. The oral formulation is a tablet, a capsule, a granule, or an

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