CN112358470A - 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 drug activation, and particularly relates to a piperazine sulfonamide compound and a preparation method and application thereof, and in particular relates to a piperazine sulfonamide compound with high activity and a preparation method and application thereof.
Background
Alzheimer's disease is a progressively developing lethal neurodegenerative disease, with clinical manifestations of progressive deterioration of cognitive and memory functions, progressive decline of daily living capacity, and various neuropsychiatric symptoms and behavioral disorders. Alzheimer's disease is one of the most common types of dementia and one of the most common chronic diseases in the elderly.
The action mechanism of the anti-senile dementia drug 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 alleviating or treating the disease can be achieved by blocking various steps in the cycle to change the progress of the disease. The majority of the new drugs developed based on this mechanism of action, such as beta-hydrolase inhibitors, gamma-hydrolase inhibitors, vaccines, tau phosphorylation inhibitors, anti-neuritis, etc., are based on the amyloid-beta theory.
CN106187891B discloses a series of compounds with anti-Alzheimer's disease effect, which take anthranilic acid as raw material, react with cyclohexanone to obtain 9-chloro-1, 2,3, 4-tetrahydroacridine, and then react 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 micropowder 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 prevention and treatment effect 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 a 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 compound can effectively inhibit 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, hydroxyl, amino or cyano, wherein C1-C6 respectively 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, aryl may be any of phenyl, naphthyl, anthryl or phenanthryl, arylalkyl may be any of benzyl, phenethyl, benzisopropyl, paraphenyldimethyl, orthophenyldimethyl or metaxylylene, for example, C1-C6 alkyl may be any of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl, C1-C6 alkoxy may be any of methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, haloalkyl may be any of chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl or 2,2, 2-trifluoroethyl, and halogen may be any of fluorine, chlorine, bromine or iodine, for example.
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 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, hexahydropyrimidyl, morpholinyl, 1, 3-oxazinanyl or 1, 3-thiazinoalkyl.
Preferably, R is selected from the group consisting 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, Any one of pyridine-2-yl, pyridine-4-yl, pyridine-3-yl, pyrazine-2-yl, thiophene-2-yl or thiazole-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 1:1 to 1:2.
Preferably, the molar ratio of compound a to condensing agent in step (1) is from 1:8 to 1: 12.
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 8-14 h.
Preferably, the molar ratio of compound C to oxidant in step (2) is from 1:2 to 1: 6.
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 8-14 h.
Wherein, the mol ratio of the compound A to the compound B can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1; 1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2, etc., the molar ratio of the compound a to the condensing agent may be 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, 1:11.5 or 1:12, etc., the reaction temperature in step (1) may be 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃,27 ℃, 28 ℃, 29 ℃ or 30 ℃, etc., the reaction time in step (1) may be 8h, 9h, 10h, 11h, 12h, 13h or 14h, etc., the molar ratio of the compound C to the oxidizing agent may be 1:2, 1:2.5, 1:3, 1; 3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6, the reaction temperature in step (2) may be 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃,27 ℃, 28 ℃, 29 ℃ or 30 ℃, and the reaction time in step (2) may be 8h, 9h, 10h, 11h, 12h, 13h or 14h, but is not limited to the recited values, and other values not recited within the above numerical ranges are also applicable.
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 1:1-1:2, adding a solvent and a condensing agent, and reacting at 20-30 ℃ for 8-14h to obtain a compound C;
(2) and (2) mixing the compound C obtained in the step (1) with an oxidant in a molar ratio of 1:2-1:6 and a solvent, and reacting at 20-30 ℃ for 8-14h to obtain the piperazine sulfonamide compound.
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 BV2Effect of 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.
3-mercapto-4-methyl-6-phenylpyridazine in the following examples according to Journal of Medicinal Chemistry,44(17), 2707-2718; 2001, other initial raw materials, reaction reagents and the like are all commercial products unless otherwise specified;
BV2cell lines were purchased from science ll, usa;
the C6 cell line was purchased from Tokyo (Shanghai) Biotech, Inc.;
KM mice were purchased from southern medical university.
Example 14 preparation of methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine, its structure is as follows:
(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 15% sodium hypochlorite solution was slowly added dropwise, and the addition was completed. Slowly raising the temperature to 25 ℃, and stirring for 12 h. 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 (340mg, yield 31%);
(2) 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) thio) pyridazine (300mg, 0.82mmol) obtained in step (1) was dissolved in dichloromethane 25mL, and 85% m-chloroperoxybenzoic acid (666mg, 3.28mmol) was added. After completion of the reaction, the mixture was stirred at 25 ℃ for 12 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- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine (81mg, yield 25%).
The product 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine was characterized as follows:1H-NMR(400MH,CDCl3)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+) Successful synthesis of 4-methyl-6-phenyl-3- ((4- (pyrimidin-2-yl) piperazin-1-yl) sulfonyl) pyridazine was demonstrated.
Example 24-preparation of methyl-6-phenyl-3- ((4-methylpiperazin-1-yl) sulfonyl) pyridazine, its structure 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 addition was completed. Slowly raising the temperature to 30 ℃, and stirring for 8 hours. 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 (315mg, yield 35%);
(2) 4-methyl-3- ((4-methylpiperazin-1-yl) thio) -6-phenylpyridazine (300mg, 0.998mmol) obtained in step (1) was dissolved in 25mL of dichloromethane, and 85% m-chloroperoxybenzoic acid (810mg, 3.992mmol) was added. After the reaction was completed, the mixture was stirred at 20 ℃ for 14 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-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 34 preparation of 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 15% sodium hypochlorite solution was slowly added dropwise, and the addition was completed. Slowly raising the temperature to 20 ℃, and stirring for 14 h. 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 (323mg, 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 (746mg, 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 (102mg, 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)+) Successful synthesis of 4-methyl-6-phenyl-3- ((4-cyclopropylpiperazin-1-yl) sulfonyl) pyridazine was demonstrated.
Example 43 preparation of- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine, having the 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 addition was completed. Slowly raising the temperature to 25 ℃, and stirring for 12 h. 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 (410mg, 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 dichloromethane 25mL, 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 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- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine (94mg, 29%).
To give birth toThe material 3- ((4- (4-fluorophenyl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine was characterized with the following results: 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 preparation of 53- ((4- (pyridin-2-yl) piperazin-1-yl) sulfonyl) -4-methyl-6-phenylpyridazine, having the 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 ℃, and 10mL of 15% sodium hypochlorite solution was slowly added dropwise, completing the addition. Slowly raising the temperature to 25 ℃, and stirring for 12 h. 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 (349mg, yield 32%);
(2) 4-methyl-6-phenyl-3- ((4- (pyridin-2-yl) piperazin-1-yl) thio) pyridazine obtained in step (1) (300mg, 0.825mmol) was dissolved in dichloromethane 25mL, 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 (88mg, 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 microglia line BV2And glioma cell line C6 in DMEM medium containing 10% FBS, and culturing the cells from passage 6 to passage 15Screening for candidate compound activity. The cultured cells were seeded at 50000 cells/well in a 24-well cell culture plate, and after 1 day of culture, the culture was changed to a low serum medium (supplemented with 2% FBS) and continued for 16 h. 300ng/mL was added to the medium (for BV induction)2Cells) or 1mg/mL (for inducing C6 cells) lipopolysaccharide (Salmonella typhimurium) induces IL-1. beta. secretion in cultured cells. And simultaneously adding a compound to be tested (DMSO is less than or equal to 0.1%) according to the final concentrations of 200pM, 20nM, 2 muM and 200 muM; 0.1% 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 is calculated according to the formula (I), and the IC of each candidate compound is calculated50. By the compound pair BV2The positive inhibition rate of the secretion of IL-1 beta is a standard for judging 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.
The formula is: inhibition rate (%) ([ IL-1 β)]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 with the following results:
TABLE 1 the compounds provided in examples 1-5 inhibit BV2IL-1 beta secreting IC50
| Group of | IC50(μmol) | Group of | IC50(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 BV2The secretory IL-1 beta has good activity, and shows excellent treatment effect; meanwhile, the inhibitor has no obvious inhibition effect on the IL-1 beta secretion of C6 cells, and shows high safety.
Pharmacokinetic experiments:
8 KM mice were selected, and the male mice were selected to have a body weight of 30-40 g. The compound provided in example 1 was 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 for 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 concentration was then analyzed using LC-Ms and the results are 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 piperazine sulfonamide compounds of the present invention and the preparation method and application thereof are illustrated by the above examples, but the present invention is not limited to the above examples, i.e., it is not meant that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, 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 the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. A piperazine sulfonamide compound is characterized in that 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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.
2. The piperazine sulfonamide compound according to claim 1, wherein the substituents in the alkyl group, the cycloalkyl group, the aryl group, the heteroaryl group and the heterocycloalkyl group are independently selected from any one of an aryl group, an arylalkyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a haloalkyl group, a halogen group, a hydroxyl group, an amino group and a cyano group.
3. Piperazine sulfonamide compound according to claim 1 or 2, wherein the alkyl group is selected from C1-C6 alkyl;
preferably, said cycloalkyl is selected from C3-C6 cycloalkyl;
preferably, the heteroaryl 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 is selected from any one of tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, tetrahydrothienyl, piperazinyl, hexahydropyrimidyl, morpholinyl, 1, 3-oxazinanyl or 1, 3-thiazinoalkyl;
preferably, R is selected from the group consisting 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, cyclohexyl, cyclopropyl, cyclopentyl, adamantyl, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-dichlorophenyl, 2-chloro-6-fluorophenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, pyrimidin-, Any one of pyridine-2-yl, pyridine-4-yl, pyridine-3-yl, pyrazine-2-yl, thiophene-2-yl or thiazole-2-yl.
4. The piperazine sulfonamide compound according to any one of claims 1 to 3, wherein the structure of the piperazine sulfonamide compound is selected from:
any one of them.
5. The piperazine sulfonamide compound according to any one of claims 1 to 4, as a pharmaceutically acceptable salt or hydrate.
6. The process for the preparation of piperazine sulfonamide compounds according to any one of claims 1 to 4, 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:
said R having the same limits as in claim 1.
7. The process for producing piperazine sulfonamide compound according to claim 6, wherein the molar ratio of the compound A to the compound B in the step (1) is 1:1 to 1: 2;
preferably, the molar ratio of the compound A to the condensing agent in the step (1) is 1:8 to 1: 12;
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 the step (1) is 8-14 h;
preferably, the molar ratio of the compound C to the oxidant in step (2) is 1:2 to 1: 6;
preferably, the oxidant in the step (2) comprises any one of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid or potassium hydrogen peroxymonosulfate composite salt;
preferably, the temperature of the reaction in step (2) is 20-30 ℃;
preferably, the reaction time in step (2) is 8-14 h.
8. The process for the preparation of piperazine sulfonamide compounds according to claim 6 or 7, comprising the steps of:
(1) mixing the compound A and the compound B in a molar ratio of 1:1-1:2, adding a solvent and a condensing agent, and reacting at 20-30 ℃ for 8-14h to obtain a compound C;
(2) and (2) mixing the compound C obtained in the step (1) with an oxidant in a molar ratio of 1:2-1:6 and a solvent, and reacting at 20-30 ℃ for 8-14h to obtain the piperazine sulfonamide compound.
9. Use of the piperazine sulfonamide compound according to any one of claims 1 to 4 or the piperazine sulfonamide compound according to claim 5 in the preparation of a medicament for preventing or treating a neurodegenerative disease, psychosis, epilepsy, convulsion, or stroke.
10. The use according to claim 9, characterized in that the medicament comprises a pharmaceutically acceptable salt, hydrate and pharmaceutical excipient of a piperazine sulfonamide compound according to any one of claims 1-4 and/or a piperazine sulfonamide compound according to claim 5;
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.
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| WO2012031383A1 (en) * | 2010-09-06 | 2012-03-15 | 中国科学院广州生物医药与健康研究院 | Amide compounds |
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| WO2012031383A1 (en) * | 2010-09-06 | 2012-03-15 | 中国科学院广州生物医药与健康研究院 | Amide compounds |
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