CN112358470B - Piperazine sulfonamide compound and preparation method and application thereof - Google Patents
Piperazine sulfonamide compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a piperazine sulfonamide compound and a preparation method and application thereof, wherein the structure of the piperazine sulfonamide compound is shown as a formula I; r in the formula I is selected from any one of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl. The preparation method comprises the following steps: (1) Mixing the compound A and the compound B, and adding a solvent and a condensing agent to react to obtain a compound C; (2) And (2) mixing the compound C obtained in the step (1) with an oxidant and a solvent for reaction to obtain the piperazine sulfonamide compound. The piperazine sulfonamide compound provided by the invention has the advantages of simple preparation process, easily obtained raw materials, high activity, high safety and wide application prospect.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a piperazine sulfonamide compound as well as a preparation method and application thereof, in particular to a piperazine sulfonamide compound with high activity as well as a preparation method and application thereof.
Background
Alzheimer's disease is a progressively developing fatal neurodegenerative disease, with clinical manifestations of continuously worsening cognitive and memory functions, progressive decline in daily living abilities, and various neuropsychiatric symptoms and behavioral disorders. Alzheimer's disease is one of the most common types of dementia in the elderly, and is one of the most common chronic diseases in the elderly.
The mechanism of action of the anti-senile dementia drugs discovered at present mainly comprises: the NMDA receptor antagonist is established by inhibiting the activity of acetylcholinesterase, reducing the degradation of acetylcholine and improving the cholinergic level in brain, and by inhibiting various action sites on the surface of the NMDA receptor or in an ion channel, reducing the excitatory effect of the NMDA receptor and inhibiting the activity of the NMDA receptor antagonist. In recent years, a more popular and well-recognized action mechanism is "amyloid-beta-amyloid (a β)", which considers that the formation of insoluble β amyloid aggregates after the APP protein precursor is hydrolyzed and cleaved constitutes senile plaques (amyloid plaques), thereby causing a series of pathological changes, including neuroinflammation, neuronal loss and death, and the like, and finally resulting in alzheimer's disease. According to the process of the mechanism, the aim of relieving or treating can be achieved by blocking each step in the circulation to change the progress of the disease. The development of new drugs based on this mechanism of action, such as beta-hydrolase inhibitors, gama-hydrolase inhibitors, vaccines, tau phosphorylation inhibitors, anti-neuritis, etc., is based mostly on the amyloid-beta theory.
CN106187891B discloses a series of compounds with anti-Alzheimer's disease effect, which uses anthranilic acid as raw material, and reacts with cyclohexanone to obtain 9-chloro-1, 2,3, 4-tetrahydroacridine, and then reacts with ethylenediamine to obtain 9- (beta-aminoethylenediamine) -1,2,3, 4-tetrahydroacridine; then reacting with cinnamic acid and derivatives thereof to prepare a series of compounds with the effect of resisting Alzheimer disease; the whole process has reasonable design, high yield, few byproducts and low cost, and the prepared compound has high purity, good Alzheimer disease resistance and can realize industrial mass production. But the reaction route is long and the synthesis is inconvenient. The structure is as follows:
CN105535131A discloses the use of cooked rhubarb micro powder in the preparation of Alzheimer's disease drugs. It also provides a pharmaceutical composition, which is a traditional Chinese medicine preparation prepared by taking cooked rhubarb micro powder as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients. It can be used for treating Alzheimer's disease with definite therapeutic effect, no addiction and dependence, and no obvious adverse side effect. However, the adoption of the traditional Chinese medicine preparation can cause potential influence on patients.
CN103788058B discloses a lignan compound extracted from schizandra chinensis bunge, which has protective effect on nerve cells and preventive and therapeutic effects on alzheimer disease, and can be used for preparing nerve cell protective agent and medicine for preventing and treating alzheimer disease. The structure is as follows:
at present, the alzheimer disease seriously threatens the life health of human beings, but no effective treatment medicine exists at present, so that the problem of how to provide the alzheimer disease treatment medicine which is simple to prepare and has good treatment effect is urgently needed to be solved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a piperazine sulfonamide compound and a preparation method and application thereof, and particularly provides a piperazine sulfonamide compound with high activity and a preparation method and application thereof. The product provided by the invention has the advantages of simple preparation process, easily obtained raw materials, suitability for industrial large-scale production, high activity and high safety.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a piperazine sulfonamide compound, wherein the structure of the piperazine sulfonamide compound is shown in formula I.
R in the formula I is selected from any one of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.
The above compounds are effective in inhibiting microglial cell (BV) 2 ) The function of secreting interleukin-1 beta (IL-1 beta) has good treatment effect on Alzheimer disease.
Preferably, the substituents in the alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are independently selected from any one of aryl, arylalkyl, C1-C6 alkyl, C1-C6 alkoxy, haloalkyl, halogen, hydroxy, amino or cyano, wherein C1-C6 independently represent a group structure containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms and 6 carbon atoms.
In the substituents, the aryl group may be any of phenyl, naphthyl, anthryl or phenanthryl, the arylalkyl group may be any of benzyl, phenethyl, benzisopropyl, paraphenyldimethyl, orthophenyldimethyl or metaxylylene, the C1-C6 alkyl group may be any of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl, the C1-C6 alkoxy group may be any of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy or tert-butoxy, the haloalkyl group may be any of chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl or 2, 2-trifluoroethyl, and the halogen group may be any of fluorine, chlorine, bromine or iodine.
Preferably, the alkyl group is selected from C1-C6 alkyl, and may be any one of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl, for example.
Preferably, the cycloalkyl group is selected from C3-C6 cycloalkyl, and may be any one of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example.
Preferably, the heteroaryl group is selected from any one of pyridazinyl, indolyl, quinazolinyl, pyrrolyl, thienyl, indazolyl, pyrazolyl, quinolinyl, pyridyl, furyl, imidazolyl, pyrazinyl, pyrimidinyl, thiazolyl, isoquinolinyl, benzothiazolyl or naphthyridinyl.
Preferably, the heterocycloalkyl group is selected from any one of tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, tetrahydrothienyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, 1, 3-oxazinanyl or 1, 3-thiazinoalkyl.
Preferably, R is selected from any one of hydrogen, methyl, propyl, isopropyl, hexyl, cyclopropyl, cyclopentyl, adamantyl, phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-hydroxyphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 2, 4-difluorophenyl, 2, 3-dichlorophenyl, 2-chloro-6-fluorophenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-bromopyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 4, 6-dimethylpyrimidin-2-yl, pyridin-4-yl, pyridin-3-yl, pyrazin-2-yl, thiophen-2-yl, or thiazol-2-yl.
Preferably, the structure of the piperazine sulfonamide compound is selected from
In a second aspect, the present invention provides pharmaceutically acceptable salts and hydrates of the piperazine sulfonamide compounds described above.
Specifically, the pharmaceutically acceptable salt or hydrate of the piperazine sulfonamide compound may be any one of hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate, ethanesulfonate, toluenesulfonate, benzenesulfonate, acetate, maleate, tartrate, succinate, citrate, benzoate, ascorbate and salicylate, malonate, adipate, hexanoate, arginine, fumarate, nicotinate, phthalate, oxalate, lithium, sodium, potassium, barium, calcium, magnesium, aluminum, iron, ferrous, copper, zinc, morpholine, diethylamine, triethylamine, isopropylamine, trimethylamine, lysine, histidine, and hydrates thereof.
In a third aspect, the present invention provides a preparation method of the piperazine sulfonamide compound, including the steps of:
(1) Mixing the compound A and the compound B, and adding a solvent and a condensing agent to react to obtain a compound C;
(2) And (2) mixing the compound C obtained in the step (1) with an oxidant and a solvent for reaction to obtain the piperazine sulfonamide compound.
The reaction formula of the above steps is as follows:
the R has the same defined range as described above.
The preparation method has simple preparation process and easily obtained raw materials, and is suitable for industrial large-scale production.
Preferably, the molar ratio of compound a to compound B in step (1) is 1.
Preferably, the molar ratio of compound a to the condensing agent in step (1) is 1.
Preferably, the condensing agent comprises sodium hypochlorite and/or sulfuryl chloride.
Preferably, the temperature of the reaction in step (1) is 20-30 ℃.
Preferably, the reaction time in step (1) is 8-14h.
Preferably, the molar ratio of compound C to oxidant in step (2) is 1.
Preferably, the oxidant in step (2) includes any one of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid or potassium hydrogen peroxymonosulfate complex salt.
Preferably, the temperature of the reaction in step (2) is 20-30 ℃.
Preferably, the reaction time in step (2) is 8-14h.
Wherein, the molar ratio of compound a to compound B may be 1, 1.1, 1.2, 1.3, 1;1.5, 1.6, 1.7, 1.8, 1.9, 1;3.5, 1.
Preferably, the solvent in step (1) and step (2) is selected from any one of dichloromethane, tetrahydrofuran or acetonitrile.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) Mixing the compound A and the compound B in a molar ratio of 1-1;
(2) Mixing the compound C obtained in the step (1) with an oxidant in a molar ratio of 1-2-1.
In a fourth aspect, the invention also provides the application of the piperazine sulfonamide compound or the pharmaceutically acceptable salt or hydrate of the piperazine sulfonamide compound in preparing a medicament for preventing or treating neurodegenerative diseases, psychosis, epilepsy, convulsion or stroke.
Preferably, the medicament comprises the piperazine sulfonamide compound and/or the pharmaceutically acceptable salt and hydrate of the piperazine sulfonamide compound as described above and a pharmaceutical excipient.
Preferably, the dosage form of the drug comprises any one of a liquid dosage form, a semi-liquid dosage form or a solid dosage form.
Compared with the prior art, the invention has the following beneficial effects:
the piperazine sulfonamide compound provided by the invention is simple in preparation process, easy in raw material obtaining and suitable for industrial large-scale production; can effectively inhibit BV 2 Secretion of IL-1 beta, half the effective Inhibitory Concentration (IC) 50 ) 46.28 mu mol is achieved, and excellent treatment effect is shown; has no inhibition effect on IL-1 beta secretion of glioma cells (C6), and shows high safety.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.
The following examples 3-mercapto-4-methyl-6-phenylpyridazine was prepared according to the Journal of Medicinal Chemistry,44 (17), 2707-2718;2001, and other initial raw materials, reaction reagents and the like are all commercial products unless specified otherwise;
BV 2 cell lines were purchased from science ll, usa;
the C6 cell line was purchased from Tokuai Biotechnology, inc.;
KM mice were purchased from southern medical university.
Example 1 preparation of 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine, having the structure:
(1) 3-mercapto-4-methyl-6-phenylpyridazine (610mg, 3mmol) and 2-pyrimidinylpiperazine (740mg, 4.5mmol) were mixed, 30mL of dichloromethane was added, the mixture was cooled to 0 ℃, 10mL of a 15% sodium hypochlorite solution was slowly added dropwise, and the dropwise addition was completed. Slowly raising the temperature to 25 ℃, and stirring for 12h. After the reaction is completed, adding 50mL of water, extracting and separating an organic layer, drying, concentrating and performing silica gel column chromatography, and separating to obtain 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) thio) pyridazine (340 mg, yield 31%);
(2) 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) thio) pyridazine obtained in step (1) (300mg, 0.82mmol) was dissolved in 25mL of dichloromethane, and 85% m-chloroperoxybenzoic acid (666mg, 3.28mmol) was added. After the reaction was completed, the mixture was stirred at 25 ℃ for 12 hours, and then saturated sodium thiosulfate was added thereto and stirred for 20 minutes, and an organic layer was separated, washed with saturated sodium bicarbonate and saturated brine, dried, filtered, and subjected to silica gel column chromatography to obtain 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine (81 mg, yield 25%).
The product 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine was characterized as follows: 1 H-NMR(400MH,CDCl 3 )δ8.33(d,J＝4.8Hz,2H),8.03-8.05(m,2H),7.82(s,1H),7.53-7.55(m,3H),6.54(t,J＝4.8Hz,1H),4.07(bs,4H),3.76(m,4H),2.76(s,3H)；MS:m/e 397.1(M+H + ) The successful synthesis of 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine was demonstrated.
Example 2 preparation of 4-methyl-6-phenyl-3- ((4-methylpiperazin-1-yl) sulfonyl) pyridazine, the structure of which is as follows:
(1) 3-mercapto-4-methyl-6-phenylpyridazine (610mg, 3mmol) and N-methylpiperazine (450mg, 4.5mmol) were mixed, 30mL of dichloromethane was added, the mixture was cooled to 0 ℃, 10mL of 15% sodium hypochlorite solution was slowly added dropwise, and the dropwise addition was completed. Slowly raising the temperature to 30 ℃, and stirring for 8h. After the reaction is completed, adding 50mL of water, extracting and separating an organic layer, drying, concentrating, performing silica gel column chromatography, and separating to obtain 4-methyl-3- ((4-methylpiperazin-1-yl) thio) -6-phenylpyridazine (315 mg, yield 35%);
(2) The 4-methyl-3- ((4-methylpiperazin-1-yl) thio) -6-phenylpyridazine (300mg, 0.998mmol) obtained in the step (1) was dissolved in 25mL of dichloromethane, and 85% m-chloroperoxybenzoic acid (810mg, 3.992mmol) was added. After completion of the reaction, the mixture was stirred at 20 ℃ for 14 hours, saturated sodium thiosulfate was added and stirred for 20 minutes, and the organic layer was separated, washed with saturated sodium bicarbonate and saturated brine, dried, filtered, and subjected to silica gel column chromatography to give 4-methyl-6-phenyl-3- ((4-methylpiperazin-1-yl) sulfonyl) pyridazine (93mg, 28%).
The product 4-methyl-6-phenyl-3- ((4-methylpiperazin-1-yl) sulfonyl) pyridazine was characterized as follows: MS M/e 333.2 (M + H) + ) Successful synthesis of 4-methyl-6-phenyl-3- ((4-methylpiperazin-1-yl) sulfonyl) pyridazine was demonstrated.
Example 3 preparation of 4-methyl-6-phenyl-3- ((4-cyclopropylpiperazin-1-yl) sulfonyl) pyridazine, its structure is as follows:
(1) 3-mercapto-4-methyl-6-phenylpyridazine (610mg, 3mmol) and N-cyclopropylpiperazine (567mg, 4.5mmol) were mixed, 30mL of dichloromethane was added, the mixture was cooled to 0 ℃, 10mL of a 15% sodium hypochlorite solution was slowly added dropwise thereto, and the addition was completed. Slowly raising the temperature to 20 ℃, and stirring for 14h. After the reaction is completed, adding 50mL of water, extracting and separating an organic layer, drying, concentrating and performing silica gel column chromatography, and separating to obtain 3- ((4-cyclopropylpiperazin-1-yl) thio) -4-methyl-6-phenylpyridazine (323 mg, yield 33%);
(2) 3- ((4-Cyclopropylpiperazin-1-yl) thio) -4-methyl-6-phenylpyridazine (300mg, 0.919mmol) obtained in step (1) was dissolved in 25mL of dichloromethane, and 85% m-chloroperoxybenzoic acid (746 mg, 3.68mmol) was added. After the reaction was completed, the mixture was stirred at 30 ℃ for 8 hours, and saturated sodium thiosulfate was added thereto and stirred for 20 minutes, and the organic layer was separated, washed with saturated sodium bicarbonate and saturated brine, dried, filtered, and subjected to silica gel column chromatography to give 4-methyl-6-phenyl-3- ((4-cyclopropylpiperazin-1-yl) sulfonyl) pyridazine (102 mg, yield 31%).
The product 4-methyl-6-phenyl-3- ((4-cyclopropylpiperazin-1-yl) sulfonyl) pyridazine was characterized as follows: MS M/e 359.1 (M + H) + ) The successful synthesis of 4-methyl-6-phenyl-3- ((4-cyclopropylpiperazin-1-yl) sulfonyl) pyridazine was demonstrated.
Example 4 preparation of- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine, which has the following structure:
(1) 3-mercapto-4-methyl-6-phenylpyridazine (610mg, 3mmol) and N-p-fluorophenylpiperazine (811mg, 4.5mmol) were mixed, 30mL of dichloromethane was added, the mixture was cooled to 0 ℃, 10mL of 15% sodium hypochlorite solution was slowly added dropwise, and the dropwise addition was completed. Slowly raising the temperature to 25 ℃, and stirring for 12h. After the reaction is completed, adding 50mL of water, extracting and separating an organic layer, drying, concentrating and performing silica gel column chromatography, and separating to obtain 3- ((4- (4-fluorophenyl) piperazin-1-yl) thio) -4-methyl-6-phenylpyridazine (410 mg, yield 36%);
(2) 3- ((4- (4-fluorophenyl) piperazin-1-yl) thio) -4-methyl-6-phenylpyridazine (300mg, 0.788mmol) obtained in step (1) was dissolved in 25mL of dichloromethane, and 85% m-chloroperoxybenzoic acid (640mg, 3.152mmol) was added. After the reaction was completed, the mixture was stirred at 25 ℃ for 12 hours, and then saturated sodium thiosulfate was added thereto and stirred for 20 minutes, and the organic layer was separated, washed with saturated sodium bicarbonate and saturated brine, dried, filtered, and subjected to silica gel column chromatography to obtain 3- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine (94mg, 29%).
The product, 3- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine, was characterized as follows: MS M/e 413.2 (M + H) + ) Successful synthesis of 3- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine was demonstrated.
Example 5 preparation of 3- ((4- (pyridin-2-yl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine, which has the following structure:
(1) 3-mercapto-4-methyl-6-phenylpyridazine (610mg, 3mmol) and N- (pyridin-2-yl) piperazine (735mg, 4.5mmol) were mixed, 30mL of dichloromethane was added, the mixture was cooled to 0 ℃, 10mL of 15% sodium hypochlorite solution was slowly added dropwise, and the addition was completed. Slowly raising the temperature to 25 ℃, and stirring for 12h. After the reaction is completed, adding 50mL of water, extracting and separating an organic layer, drying, concentrating and performing silica gel column chromatography, and separating to obtain 4-methyl-6-phenyl-3- ((4- (pyridine-2-yl) piperazine-1-yl) thio) pyridazine (349 mg, yield 32%);
(2) 4-methyl-6-phenyl-3- ((4- (pyridin-2-yl) piperazin-1-yl) thio) pyridazine (300mg, 0.825mmol) obtained in step (1) was dissolved in 25mL of dichloromethane, and 85% m-chloroperoxybenzoic acid (670mg, 3.3mmol) was added. After completion of the reaction, the mixture was stirred at 25 ℃ for 12 hours, saturated sodium thiosulfate was added and stirred for 20 minutes, and the organic layer was separated, washed with saturated sodium bicarbonate and saturated brine, dried, filtered, and subjected to silica gel column chromatography to give 3- ((4- (pyridin-2-yl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine (88 mg, yield 27%).
The product, 3- ((4- (pyridin-2-yl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine, was characterized as follows: MS M/e 396.1 (M + H) + ) Successful synthesis of 3- ((4- (pyridin-2-yl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine was demonstrated.
In vitro activity assay:
the detection method comprises the following steps: taking mouse microglial cell line BV 2 And glioma cell line C6 were cultured in DMEM medium containing 10% fbs, respectively, and the 6 th to 15 th passage cells were cultured for candidate compound activity screening. The cultured cells were seeded into a 24-well cell culture plate at 50000 cells/well, and after 1 day of culture, the culture was changed to a low serum medium (2% FBS addition) and continued for 16h. 300ng/mL was added to the medium (for BV induction) 2 Cells) or 1mg/mL (for inducing C6 cells) lipopolysaccharide (Salmonella typhimurium) induces IL-1 beta secretion from cultured cells. And simultaneously adding a compound to be tested (DMSO is less than or equal to 0.1%) according to final concentrations of 200pM,20nM,2 mu M and 200 mu M; DMSO was added to the blank as a solvent control. After lipopolysaccharide induction/drug treatment for 24h, collecting culture fluid and quantitatively detecting the IL-1 beta level in the culture fluid. The culture solution samples were centrifuged (8000G) at 4 ℃ for 10min to remove suspended particulate impurities from the culture solution. The supernatant was diluted 1-fold, and 150. Mu.L of the sample was used for ELISA (Bioso. Mu.rce) detection. Culture cell treatment and ELISA detection were performed by a double-blind method. The inhibitory efficiency of the test compound was calculated according to formula (1), and the IC of each candidate compound was calculated 50 . By the compound pair BV 2 Inhibition of secretion of IL-1 beta is positiveAs a criterion for determining the effectiveness of the compound; and the inhibition rate of the C6 secretion of IL-1 beta is negative as an index for judging the safety of the compound.
Formula (1): inhibition ratio (%) = ([ IL-1. Beta.)] LPS Induction -[IL-1β] Drug treatment )/[IL-1β] LPS Induction ×100％
The compounds provided in examples 1-5 and the positive control GIBH-130 were tested as described above and the results were as follows:
TABLE 1 the compounds provided in examples 1-5 inhibit BV 2 IL-1 beta secreting IC 50
| Group of | IC 50 (μmol) | Group of | IC 50 (μmol) |
| GIBH-130 | 67.63 | Example 3 | 42.32 |
| Example 1 | 41.99 | Example 4 | 38.76 |
| Example 2 | 43.25 | Example 5 | 46.28 |
TABLE 2 inhibition of IL-1 β secretion from C6 cells by the compounds provided in examples 1-5
From the above data, the present invention provides compounds for inhibiting BV 2 The secretory IL-1 beta has good activity, and shows excellent treatment effect; meanwhile, the inhibitor has no obvious inhibition effect on the secretion of IL-1 beta by C6 cells, and shows high safety.
Pharmacokinetic experiments:
8 KM mice were selected, and the male KM mice were selected to have a body weight of 30-40 g. The compounds provided in example 1 were formulated in 2% dmso/4% ethanol/4% castor oil/90% deionized water. The test compounds were administered by gavage at 5mg/kg and tail vein injection at 1mg/kg, respectively. KM mice were divided into 2 groups of 4 mice each. Fasted for 12h before the test, water was freely available. After the intragastric administration, 0.1mL of blood is collected from retroorbital venous plexus at 5min, 15min, 30min, 1h, 3h, 5h and 8h respectively; after tail vein injection administration, 0.1mL of blood is collected from retroorbital venous plexus for 5min, 15min, 30min, 1h, 3h, 5h and 8h respectively, placed in a heparin tube, centrifuged at 8000rpm at 4 ℃ for 6min to separate plasma, and stored at-20 ℃ for detection. The drug concentrations were then analyzed using LC-Ms, with the results shown in the following table:
TABLE 3 pharmacokinetic analysis
From the table, the compound provided by the invention has excellent pharmacokinetic properties, and can be used for preparing a safe and effective new drug for treating Alzheimer disease.
The applicant states that the present invention is illustrated by the above examples of the piperazine sulfonamide compound of the present invention and the preparation method and application thereof, but the present invention is not limited to the above examples, that is, it is not intended that the present invention is implemented by relying on the above examples. It should be understood by those skilled in the art that any modifications of the present invention, equivalent substitutions of the raw materials of the product of the present invention, and the addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that, in the above embodiments, the various features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, the present invention does not separately describe various possible combinations.
Claims (15)
1. A piperazine sulfonamide compound and a pharmaceutically acceptable salt thereof are characterized in that the structure of the piperazine sulfonamide compound is shown as a formula I:
2. The method for producing piperazine sulfonamide compounds according to claim 1, comprising the steps of:
(1) Mixing the compound A and the compound B, and adding a solvent and a condensing agent to react to obtain a compound C;
(2) Mixing the compound C obtained in the step (1) with an oxidant and a solvent for reaction to obtain the piperazine sulfonamide compound;
the reaction formula of the above steps is as follows:
and R is a pyrimidin-2-yl group.
3. The process for producing piperazine sulfonamide compounds according to claim 2, wherein the molar ratio of compound a to compound B in step (1) is 1.
4. The process for producing piperazine sulfonamide compounds according to claim 2, wherein the molar ratio of compound a to the condensing agent in step (1) is 1.
5. The method for producing piperazine sulfonamide compounds according to claim 2, wherein the condensing agent is selected from sodium hypochlorite and/or sulfuryl chloride.
6. The process for producing piperazine sulfonamide compound according to claim 2, wherein the temperature of the reaction in step (1) is 20 to 30 ℃.
7. The process for preparing piperazine sulfonamide compounds according to claim 2, wherein the reaction time in step (1) is 8 to 14 hours.
8. The process for preparing piperazine sulfonamide compounds according to claim 2, wherein the molar ratio of the compound C to the oxidizing agent in step (2) is 1.
9. The method for preparing piperazine sulfonamide compounds according to claim 2, wherein the oxidizing agent in step (2) is selected from any one of m-chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic acid, and potassium monopersulfate complex salts.
10. The process for producing piperazine sulfonamide compound according to claim 2, wherein the temperature of the reaction in step (2) is 20 to 30 ℃.
11. The process for preparing piperazine sulfonamide compound according to claim 2, wherein the reaction time in the step (2) is 8 to 14 hours.
12. The process for the preparation of piperazine sulfonamide compounds according to claim 2, comprising the steps of:
(1) Mixing the compound A and the compound B in a molar ratio of 1-1;
(2) Mixing the compound C obtained in the step (1) with an oxidant in a molar ratio of 1-2.
13. The use of piperazine sulfonamide compounds according to claim 1 and pharmaceutically acceptable salts thereof for the preparation of a medicament for the prevention or treatment of neurodegenerative diseases, psychosis, epilepsy, convulsions or stroke.
14. The use according to claim 13, wherein the medicament comprises the piperazine sulfonamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
15. The use of claim 13, wherein the dosage form of the medicament comprises any one of a liquid dosage form, a semi-liquid dosage form, or a solid dosage form.
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