WO2020151686A1 - N-杂芳基磺酰胺类衍生物及制备和在治疗自身免疫性疾病中的应用 - Google Patents

N-杂芳基磺酰胺类衍生物及制备和在治疗自身免疫性疾病中的应用 Download PDF

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WO2020151686A1
WO2020151686A1 PCT/CN2020/073362 CN2020073362W WO2020151686A1 WO 2020151686 A1 WO2020151686 A1 WO 2020151686A1 CN 2020073362 W CN2020073362 W CN 2020073362W WO 2020151686 A1 WO2020151686 A1 WO 2020151686A1
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fluorobenzyl
pyridin
propanesulfonamide
acid
piperidin
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PCT/CN2020/073362
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English (en)
French (fr)
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王晓路
胡永洲
叶青
胡秀爱
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杭州壹瑞医药科技有限公司
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Definitions

  • the invention belongs to the field of medicine, and relates to an N-heteroarylsulfonamide derivative as a Kv1.3 potassium channel inhibitor, a preparation method thereof, and a medicine for the treatment of autoimmune diseases mediated by Kv1.3 In the application.
  • Kv1.3 is an important subtype of the voltage-gated potassium channel Kv1 family, which is widely distributed in body tissues, including human T lymphocytes. Participate in a variety of physiological and pathological processes such as cell proliferation, migration, and apoptosis by regulating the potassium ion concentration [Toldi G.et al.Immunol Res.,2016,64(2):627-631].
  • the voltage-gated channel Kv1.3 is a 4-mer composed of 4 ⁇ subunits, that is, these subunits are assembled into a functional channel, in which the potassium ion-conducting hole is located in the center of the 4-mer.
  • Each subunit contains 6 transmembrane segments (S1-S6), a P loop and the N- and C-termini in the membrane.
  • S1-S6 transmembrane segments
  • P loop the N- and C-termini in the membrane.
  • the depolarization of the cell membrane is induced by the 4 arginines located in the S4 fragment, which then causes the channel to be opened and causes a conformational change.
  • Kv1.3 peptide blockers all act on the conduction holes at the outer end of the membrane, thereby inhibiting the conduction function of potassium ions [Chandy and Norton, Curr Opin Chen Biol, 2017, 38: 97-107] [Zhao et .al.Toxins(Basel),2015,7:1749-1764].
  • Kv1.3 is mainly expressed in T lymphocytes, and together with calcium-activated Kca3.1 potassium channels, it prevents depolarization of cell membranes.
  • T cells When T cells are activated, these channels produce potassium ions outflow, and through CRAC (Orai/Stim) channels, promote the inflow of calcium ions into the cytoplasm to counteract the outflow of cations.
  • CRAC Orai/Stim
  • NFAT transcription factor
  • the Kv1.3 and Kca3.1 channels in T cells are part of the cell membrane signal complex, that is, the extra-membrane stimulus signal is coupled to the signal cascade transmission within the T cell [Chandy and Norton, Curr Opin Chem Biol, 2017, 38:97-107].
  • naive T cells and central memory T cells up-regulate the expression level of Kca3.1 while the number of Kv1.3 has no significant change.
  • terminally differentiated effector memory T cells T EM
  • CD-45RA-expressing effector memory T cells T EMRA
  • selectively blocking Kca3.1 can inhibit the proliferation of naive T cells and central memory T cells (T CM ), thereby inhibiting the production of corresponding cytokines.
  • Kv1.3 can inhibit the proliferation of effector memory T cells (T EM and T EMRA ) and the production of corresponding cytokines, and also inhibit the migration of T cells in vivo, but does not affect the Kca3 .1
  • T EM and T EMRA effector memory T cells
  • T CM central memory T cells
  • autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type I diabetes and psoriasis
  • the naive T cells specific for their own antigens can evade immune regulation. Through repeated stimulation of homologous autoantigens, these cells are finally differentiated into T EM and T EMRA cells. Therefore, these autoreactive T cells related to diseases are mainly T EM and T EMR cells. According to the types of cytokines they produce, they can be specifically classified into Th1 and/or Th17 cells [Beeton et al. PNAS 2006,103:17414-17418].
  • PAP-1 Another Kv1.3 small molecule blocker, PAP-1, can effectively inhibit allergic contact dermatitis (ACD) when applied to the local skin model of rats [Azam et al,J Invest Dermatal 2007,127(6):1419 -1427].
  • ACD allergic contact dermatitis
  • injection or topical application of PAP-1 to the skin can reduce the thickness of the diseased epidermal hyperplasia by about 50%, and reduce the infiltration of CD3 + lymphocytes by 85%, which is significant sexually improved the symptoms of psoriasis [Kun clu-Raychaudhuri et al,J Antoimmun 2014,55:63-72].
  • Figure 1 is a graph showing the effect of compound 28 on a rat model of atopic dermatitis (ACD).
  • Figure 2 is a graph showing the effect of compound 29 on imiquimod-induced psoriasis in a rat model, where Figure A is the PASI score result, and Figure B is the Baker score result. Both PASI and Baker score results prove that Compound 29 has an effect on silver Scoria has a significant effect.
  • An object of the present invention is to provide an N-heteroarylsulfonamide derivative characterized in that it is an N-heteroarylsulfonamide compound represented by general formula (I) or general formula (II) or Its pharmaceutically acceptable salt or solvate,
  • Ring A is selected from containing 1-2 substituted five-membered or six-membered aromatic heterocycles containing O, N and S, and the substituted substituents are selected from And R 3 group; wherein ring A is preferably the following five-membered or six-membered aromatic heterocycle:
  • Ring B is selected from substituted or unsubstituted and contains 1-2 five-membered or six-membered alicyclic groups selected from O, N and S, and the substituted substituents are selected from Z and R 4 ; wherein ring B is preferably Said five-membered or six-membered aliphatic heterocyclic ring containing oxygen and/or nitrogen:
  • R 1 is selected from C1-6 linear, branched chain alkyl, cyclic alkyl or halogenated C1-6 linear, branched alkyl, unsubstituted or substituted phenyl or containing 1-2 nitrogen atoms
  • Five-membered or six-membered aromatic heterocyclic ring, benzene ring or aromatic heterocyclic ring is substituted with mono-, di- or tri-substituted, and the substituent is selected from the Ra group;
  • Ra is selected from H, halogen, nitro, cyano, C1-3 alkyl, C1-3 alkoxy, -C-O-C-;
  • R 2 is selected from unsubstituted or substituted phenyl, containing 1-2 five-membered or six-membered aromatic heterocycles selected from O, N and S, and the substitution is mono-substituted, di-substituted or tri-substituted, said substituent Selected from Rb groups;
  • Rb is selected from H, halogen, cyano, C1-3 alkyl, C1-3 alkoxy, -C-O-C-;
  • R 3 is selected from H, cyano, trifluoromethyl, alkamido
  • E, W, X, Y the same or different, each independently selected from N, O, S or C;
  • N-heteroarylsulfonamide derivatives of the present invention are preferably the following compounds:
  • Another object of the present invention is to provide a preparation method of the compound represented by general formula (I) or general formula (II), which can be achieved by the following steps:
  • 2-halo-5-nitropyridine is condensed with a nitrogen-containing five-membered or six-membered alicyclic heterocycle (ring B) under alkaline conditions, and the nitro group in the resulting condensate is condensed on palladium on carbon and/or stannous chloride Reduce to amino in the presence of;
  • the amino compound is then reductively aminated with aromatic aldehydes (selected substituted benzaldehyde, picolinaldehyde, pyrimidine formaldehyde or N-trifluoromethylpyrazole formaldehyde) to obtain N-benzyl derivatives, and then sulfonamidated to obtain the target Molecule: If there is a protective group on the B ring of the obtained sulfonamide molecule, it is then deprotected and derivatized with a terminal hydroxyl or amine group to obtain the target compound.
  • aromatic aldehydes selected substituted benzaldehyde, picolinaldehyde, pyrimidine formaldehyde or N-trifluoromethylpyrazole formaldehyde
  • 2-halo-5-nitropyridine reacts with N-substituted 4-hydroxyl or 4-mercapto or 4-aminopiperidine under alkaline conditions, then reduces the nitro group to an amino group, and then undergoes reductive amination to form a sulfonamide To get the target molecule.
  • the amino five-membered aromatic heterocyclic derivative is reductively aminated and sulfonamidated to obtain the target molecule; if there is a protective group on the B ring of the obtained sulfamidated product, the protective group is then deprotected and an acyl group is introduced into the ring to obtain the target Compound
  • Another object of the present invention is to provide the use of N-arylheterosulfonamide derivatives in the preparation of drugs for the treatment of autoimmune diseases.
  • the autoimmune disease is an autoimmune disease mediated by Kv1.3.
  • the N-arylheterosulfonamide derivatives provided by the present invention can specifically bind to and inhibit or reduce the activity of potassium channel Kv1.3, and can be used as selective Kv1.3 potassium channel inhibitors for the treatment of autoimmune diseases .
  • the medicament for treating autoimmune diseases comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, and the active ingredient is of general formula (I) or general formula (II) Any one or more of the shown N-arylheterosulfonamide compounds, their pharmaceutically acceptable salts, and their solvates.
  • the carrier or excipient includes conventional diluents, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and flavors can also be added if necessary.
  • the drug of the present invention can be made into various forms such as tablets, capsules, patches, emulsions, suspensions, gels, powders, granules, oral liquids and injections.
  • the above-mentioned drug in each dosage form can be in accordance with the pharmaceutical field Prepared by conventional methods.
  • the salt of the N-arylheterosulfonamide compound described in the present invention can be prepared by using methods well known to those skilled in the art.
  • the salt may be an inorganic acid salt, an organic acid salt, etc.
  • the inorganic acid salt may be formed with hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid, phosphoric acid, etc.
  • the corresponding salt; the organic acid salt includes malic acid, L-malic acid, D-malic acid, citric acid, fumaric acid, oxalic acid, lactic acid, camphorsulfonic acid, L-camphorsulfonic acid, D-camphorsulfonic acid Acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, etc. form corresponding salts.
  • the present invention also provides any compound represented by general formula (I) or general formula (II) and its pharmaceutically acceptable salt or solvate used alone and/or in combination with other drugs in the preparation of drugs for the treatment of autoimmune diseases Applications.
  • the present invention also provides a medicament for treating autoimmune diseases, the medicament comprising an N-arylheterosulfonamide compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof or Solvates are used as active components.
  • the present invention also provides a method for the treatment of immune diseases, which administers an effective amount of the N-arylheterosulfonamide compound represented by the general formula (I) or the general formula (II) to patients in need of treatment of autoimmune diseases Or a pharmaceutically acceptable salt or solvate thereof.
  • Kv1.3 potassium channel has been regarded as an important target for the treatment of autoimmune diseases. Therefore, selective Kv1.3 potassium channel inhibitors can be used to treat autoimmune diseases.
  • the autoimmune diseases include psoriasis, psoriatic arthritis, allergic and irritant contact dermatitis, atopic dermatitis, vitiligo, rheumatoid arthritis, type I diabetes, multiple sclerosis, Asthma, glomerulonephritis, periodontal disease, ciliary planitis, transplant rejection, neurodegeneration, obesity, high blood pressure.
  • the present invention has been confirmed through experiments that the N-heteroarylsulfonamide derivatives of the present invention can selectively inhibit the activity of Kv1.3 potassium channels and can be applied to treat human or animal autoimmunity caused by abnormal activation of Kv1.3 potassium channels Disease medicine.
  • the present invention also provides drugs and pharmaceutical compositions containing the N-heteroarylsulfonamide derivatives.
  • Dissolve 1a (2.0 g, 9.6 mmol) in 20 mL of acetic acid, add 0.2 g of 10% palladium on carbon, and hydrogenate at 30° C. for 1 h. After the reaction is over, filter, and the filtrate is directly thrown into the step reaction.
  • Benzaldehyde (1.02g, 9.6mmol) was added to the filtrate, stirred at room temperature for 1h, then cooled to about 10°C, sodium borohydride (0.55g, 14.4mmol) was added, and after the addition, the temperature was kept at this temperature for 30min.
  • the reaction solution was poured into water, the sodium carbonate solution was basified, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the synthesis steps refer to step 2 of Example 1, except that 2a-5a and p-fluorobenzaldehyde are used as raw materials to prepare compounds 2c-5c.
  • the synthesis procedure refers to step 3 of Example 1, except that 2c-5c and propanesulfonyl chloride are used as raw materials to prepare compound 2-5.
  • the synthesis procedure refers to step 1 in Example 1, except that 2a and the corresponding aromatic aldehyde/heteroaromatic aldehyde are used as raw materials to prepare compound 6c-12c
  • the synthesis procedure refers to step 3 of Example 1, except that 6c-12c and the corresponding sulfonyl chloride are used as raw materials to prepare compound 6-12.
  • the synthesis procedure refers to step 3 of Example 1, except that 4c and 4-fluorobenzenesulfonyl chloride are used as raw materials to prepare compound 13.
  • Dissolve 22a (3.0g 11.3mmol) in 100 mL of methanol, add 0.6g of 10% palladium on carbon, and hydrogenate and reduce at 30°C for 1 hour. After the reaction is completed, it is filtered under reduced pressure, and the filtrate is concentrated and directly thrown into the step reaction. Dissolve the above concentrate in 150mL of acetic acid, add p-fluorobenzaldehyde (1.8g, 14.5mmol) and 1.8g molecular sieve, stir at room temperature for 1h, cool to 10-15°C, add sodium borohydride (0.47g, 12.4mmol), After the addition, the reaction was incubated for 0.5h.
  • Dissolve 29a (15.0g54.0mmol) in 150mL of acetic acid, add 1.6g of 10% palladium on carbon, and hydrogenate and reduce at 30°C for 1h. After the reaction, the filtrate was filtered under reduced pressure, and the filtrate was directly thrown into the step reaction. 4-fluorobenzaldehyde (8.9g, 72.0mmol) was added to the filtrate, stirred at room temperature for 1h, then cooled to about 10°C, and sodium borohydride (4.13g, 108.0mmol), the reaction was incubated for 30min after the addition.
  • Dissolve 29c (12.0 g, 32.5 mmol) in 100 mL of dichloromethane, add pyridine (14.15 g, 179.0 mmol) and propanesulfonyl chloride (4.65 g, 32.5 mmol), and react at room temperature for 6 hours.
  • the synthesis procedure refers to steps 1-3 in Example 9, except that 1-(cyclopropylmethyl)piperazine was used instead of tert-butyl piperazine-1-carboxylate to prepare compound 35.
  • Step 5 The synthesis steps refer to Example 9. Step 5, except that 46 is used as a raw material to react with ethyl chloroformate, dimethylcarbamoyl chloride, dimethylaminosulfonyl chloride, acetyl chloride, and methanesulfonyl chloride to prepare compounds 47-51.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 52a was reacted with propanesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, and cyclopropylmethylsulfonyl chloride to prepare compounds 52-54.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 55a was reacted with 4-fluorobenzenesulfonyl chloride and propanesulfonyl chloride to prepare compounds 55 and 56.
  • Dissolve 57a (2.1g, 6.79mmol) in 25mL of methanol, add 0.22g of 10% palladium on carbon, and hydrogenate and reduce at room temperature for 3h. After the reaction is over, filter, and the filtrate is directly thrown into the step reaction. 4-fluorobenzaldehyde (0.58g, 6.8mmol) was added to the filtrate, stirred at room temperature for 1.5h, then cooled to about 10°C, sodium borohydride (0.55g, 14.4mmol) was added, and the reaction was kept at this temperature for 30 minutes.
  • Step 5 The synthesis steps refer to Example 9. Step 5, except that 57 is used as a raw material to react with ethyl chloroformate, dimethylcarbamoyl chloride, dimethylaminosulfonyl chloride, acetyl chloride, and methanesulfonyl chloride to prepare compounds 58-62.
  • Step 2 The synthesis steps refer to Preparation Example 18. Step 2, except that 63a, 64a and 4-fluorobenzaldehyde are used as raw materials to prepare 63c, 64c.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 63c, 64c and propanesulfonyl chloride are used as raw materials to prepare compounds 63 and 64.
  • Step 5 The synthesis steps refer to Example 9. Step 5, except that 65 and acetyl chloride are used as raw materials to prepare compound 66 with a yield of 80.6%.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 67a and propanesulfonyl chloride are used as raw materials to prepare compound 67 with a yield of 53.0%
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 68a and 69a were reacted with propanesulfonyl chloride to prepare compounds 68 and 69.
  • the compound's Kv1.3 inhibitory activity was evaluated using a CHO-K1 recombinant cell line (Charles River, California) stably expressing human Kv1.3.
  • the cells were cultured in an incubator containing 5% calf serum F-12K medium (Invitrogen, Carlsbad, CA) at 37° C. and an air humidity containing 6% CO 2 .
  • 5% calf serum F-12K medium Invitrogen, Carlsbad, CA
  • treat the adherent cells with Versene at 37°C for 6-7 minutes. After gently tapping the culture flask, resuspend the cells in PBS phosphate buffer, and then centrifuge at 50x g for 4 minutes . After a brief grinding, the cells were finally resuspended in the external recording solution at a density of approximately 1 ⁇ 10 6 /ml.
  • the final concentration gradient of 300 ⁇ was made on the master plate.
  • the final measured gradient concentrations were 0.00384, 0.00192, 0.096, 0.048, 0.24, 1.2, 6 and 30 ⁇ M.
  • the compound measurement plate was sealed and stored at -80°C until the day of measurement.
  • the compound assay plate was thawed at room temperature, and after centrifugation, 198 ⁇ l of external recording solution (its components: 130mM Na-Gluconate, 20mM NaCl, 4mM KCl, 1mM MgCl 2 , 1.8mM CaCl 2 , 5mM Glucose and 10mM HEPES, pH 7.3) and mix well.
  • This step provides a 1:100 dilution of compound. After adding cells to IonWorks, it is further diluted 1:3, so the total dilution is 1:300.
  • At least 8 wells on each assay plate are reserved for blank control, that is, only containing 0.3% DMSO, and at least 8 wells are reserved for positive control to detect the specificity of cell signals.
  • the compound used for the positive control was Fluoxetine, which was tested at its maximum blocking concentration (100 ⁇ M) and the second maximum blocking concentration (10 ⁇ M). Further, inside the recording test solution (having a composition: 100mM K-Gluconate, 40mM KCl , 1mM MgCl 2, 1mM EGTA and 10mM HEPES, pH7.3) containing a final concentration of 200 ⁇ g / ml amphotericin B ( Amphotericin B) to obtain the current channel in the cell. The osmotic pressure of the solution is adjusted with sucrose.
  • the experimental steps are carried out in accordance with the procedures set by the IonWorks Quattro system (Molecular Devices, San Jose, CA).
  • the current of human body Kv1.3 is induced to 0 millivolt (mV) by a pulse lasting 1 second, which is induced four times.
  • a potential of -80 mV is maintained between multiple pulses for 5 seconds.
  • the IonWorks Quattro system starts the pre-voltage application program, then adds the compound and incubates for 600 seconds. Then start the post-voltage application program until the entire test process is completed.
  • the maximum outward peak current was measured before and after the compound addition and the average terminal current induced when the fourth pulse rose to 0 mV was measured.
  • the current amplitude measured after the compound is added is divided by the current amplitude before the compound is added to calculate the compound's inhibitory activity against Kv1.3.
  • the filtering criteria are: sealing quality>30M ⁇ , sealing resistance drop ⁇ 50% and current amplitude>200pA.
  • the compound's Kv1.3 inhibitory activity was evaluated using a CHO-K1 recombinant cell line (Charles River, California) stably expressing human Kv1.3.
  • the cells were cultured in an incubator containing 5% calf serum F-12K medium (Invitrogen, Carlsbad, CA) at 37° C. and an air humidity containing 6% CO 2 .
  • the adherent cells were placed in the recording chamber under the inverted microscope. All experiments were performed at room temperature. Each cell uses itself as a control.
  • Extracellular fluid NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • the compounds were perfused with a perfusion system using its own gravity. At least two cells are tested per compound concentration. After the current is stable, compare the current changes before and after the compound is used to calculate the blocking effect of the compound.
  • the positive control used 1000 ⁇ M 4-AP.
  • the cells are transferred to the perfusion tank and perfused with extracellular fluid.
  • the intracellular fluid (mM) is: K-aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; pH 7.2 (KOH titration).
  • the intracellular fluid was stored in a small amount in a -80 degree refrigerator in batches and melted on the day of the experiment.
  • the electrode was drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered at one-fifth of the sampling frequency.
  • the compound's Kv1.5 inhibitory activity was evaluated using CHO-K1 recombinant cells stably expressing human Kv1.5. Strain (Charles River, California). The cells were cultured in an incubator containing 5% calf serum F-12K medium (Invitrogen, Carlsbad, CA) at 37° C. and an air humidity containing 6% CO 2 .
  • the adherent cells were placed in the recording chamber under the inverted microscope. All experiments were performed at room temperature. Each cell uses itself as a control.
  • Extracellular fluid NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • the compounds were perfused with a perfusion system using its own gravity. At least two cells are tested per compound concentration. After the current is stable, compare the current changes before and after the compound is used to calculate the blocking effect of the compound.
  • the positive control used 1000 ⁇ M 4-AP.
  • the cells are transferred to the perfusion tank and perfused with extracellular fluid.
  • the intracellular fluid (mM) is: K-aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; pH 7.2 (KOH titration).
  • the intracellular fluid was stored in a small amount in a -80 degree refrigerator in batches and melted on the day of the experiment.
  • the electrode was drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered at one-fifth of the sampling frequency.
  • Dexamethasone DXMS Sodium Phosphate Injection, 5mg/ml/bottle (Shiyao Yinhu Pharmaceutical Co., Ltd.); 1-Chloro-2,4-Dinitrobenzene (DNCB) (Tishai (Shanghai) Chemical Industry Co., Ltd.) Development Co., Ltd.); drug solvent and negative control: acetone/DMSO 9:1 (Vehicle, Model group).
  • mice were randomly divided into 3 groups according to their body weight, each with 10 animals, namely the negative control group (Vehicle), the positive control group (dexamethasone sodium phosphate injection 5mg/ml) and the 5% compound 28 group.
  • DNCB acetone DMSO solution (acetone-DMSO 9:1) was used to sensitize and stimulate the skin of rats to establish a rat model of allergic contact dermatitis (ACD).
  • the rats were normally fed in the SPF barrier system for 1 week.
  • the abdomen was depilated with depilatory cream, with a range of about 2cm ⁇ 2cm.
  • the depilated area was evenly coated with 50 ⁇ L of 7% DNCB acetone DMSO solution to sensitize the experiment.
  • 50 ⁇ L of 1% DNCB acetone DMSO solution was used to reinforce the sensitization once.
  • the rats’ right ear was dripped with 20 ⁇ L of 1% DNCB acetone DMSO solution for excitation, and the left ear was dripped with 20 ⁇ L of acetone DMSO (acetone-DMSO 9:1) solution as a control; Coated with 20 ⁇ L of acetone DMSO solution (9:1) as a control, the rat ears showed obvious erythema and swelling for 3 consecutive days, and a DNCB-induced ACD rat model was prepared.
  • Right ear rubbing administration the first administration 8h before the challenge, and three times a day after the challenge, 25 ⁇ l each time, continuous administration for 7 days; the right ear of the negative control group and the model control group were rubbed with blank matrix in equal volume .
  • Dexamethasone DXMS Sodium Phosphate Injection, 5mg/ml/bottle (Shiyao Yinhu Pharmaceutical Co., Ltd.); 5% Imiquimod cream, 0.25g/bag (Sichuan Mingxin Pharmaceutical Co., Ltd.); 300 Ten thousand U recombinant human interferon ⁇ -2a injection, 1.0ml/bottle (Shenyang Sansheng Pharmaceutical Co., Ltd.); drug solvent and negative control: acetone/DMSO 9:1 (Vehicle).
  • DXMS Dexamethasone
  • mice were randomly divided into 3 groups according to their body weight, each with 10 animals, namely the Normal group, the Model group and the 0.5% compound 29 group.
  • PESI score Skin lesion area and severity index (PASI) score: According to the PASI scoring standard, scores of 0-4 for erythema, scale and epidermal infiltration and thickening at the skin lesions of rats are given. The scoring criteria are as follows: 0, none; 1, mild; 2, moderate; 3, severe; 4, extremely severe. Take the average of the points of each group of rats, and observe the changes of the skin lesions of each group of rats.
  • HE staining After modeling (day 11), the rat back skin lesions are taken, fixed with 4% neutral formaldehyde, embedded in paraffin, and sectioned. After HE staining, observe the morphological changes of the skin tissue under a microscope. Baker score. The Baker scoring criteria are as follows: Munro small abscess found in the epidermis is 2.0 points; hyperkeratosis is 0.5 points; incomplete keratosis is 1.0 points; the granular layer thins or disappears 1.0 points; the spinous layer thickens 1.0 points; Mild, moderate and severe scores are respectively 0.5 points, 1.0 points, and 1.5 points.
  • the infiltration of mononuclear or multinucleated cells in the dermis was scored 0.5 points, 1.0 points, and 1.5 points according to the degree of mild, moderate and severe; 0.5 points for the upper mastoid and 0.5 points for telangiectasia.

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Abstract

本发明提供一种N-杂芳基磺酰胺类衍生物及制备和应用，所述N-杂芳基磺酰胺类衍生物为通式(I)或通式(II)所示的N-杂芳基磺酰胺类化合物或其药学上可接受的盐或溶剂合物。经实验证实，本发明提供的N-杂芳基磺酰胺类衍生物能够特异性结合并抑制或降低钾通道Kv1.3的活性，可应用于治疗人或动物由Kv1.3钾通道异常激活引起的自身免疫性疾病。本发明还提供制备该N-杂芳基磺酰胺类衍生物的方法、以及包含该N-杂芳基磺酰胺类衍生物的药物和药物组合物。

Description

N-杂芳基磺酰胺类衍生物及制备和在治疗自身免疫性疾病中的应用 技术领域
本发明属于医药领域，涉及一种作为Kv1.3钾通道抑制剂的N-杂芳基磺酰胺类衍生物及其制备方法、以及在制备治疗由Kv1.3介导的自身免疫性疾病的药物中的应用。
背景技术
1984年DeCoursey和Matteson等人同时发现了一个电压门控钾通道，其在人体T淋巴细胞中表达(DeCoursey et al.Nature 1984,307:465-468；Matteson et al.Nature 1984,307:468-471)。该钾通道1990年被Grissmer等人正式鉴定为Kv1.3，也称KCNA3(Grissmer et al.PANS 1990,87:9411-9415)。现已知Kv1.3是电压门控型钾离子通道Kv1家族的一个重要亚型，其广泛分布在机体组织中，包括人类T淋巴细胞中。通过调控钾离子浓度参与细胞的增殖、迁移、凋亡等多种生理病理过程[Toldi G.et al.Immunol Res.,2016,64(2):627-631]。
电压门控通道Kv1.3是由4个α亚基组成的4聚体，即由这些亚基组装成功能性通道，其中传导钾离子的孔穴位于4聚体的中心。每个亚基含有6个跨膜片段(S1-S6)、一个P环及膜内N-和C-末端。细胞膜的去极化由位于S4片段的4个精氨酸感应，然后导致通道被开放且引起构象改变。已知的Kv1.3肽类阻断剂均作用于膜外端的传导孔穴口，从而抑制其钾离子的传导功能[Chandy and Norton,Curr Opin Chen Biol,2017,38:97-107][Zhao et.al.Toxins(Basel),2015,7:1749-1764]。
Kv1.3主要在T淋巴细胞表达，与钙激活的Kca3.1钾通道一起，防止细胞膜的去极化。当T细胞激活时，这些通道产生钾离子外流，并通过CRAC(Orai/Stim)通道，促进钙离子内流进入细胞质，以平衡抵消阳离子的流出。最终胞浆内钙离子的升高激活钙调磷酸酶(Calcineurin)，导致活化T细胞的转录因子(NFAT)去磷酸化后转位到核内，促成RNA转录而产生一系列免疫激活的生物效应。所以，T细胞中的Kv1.3和Kca3.1通道是细胞膜信号复合体的一部分，即将膜外刺激信号偶联到T细胞内的信号联级传导[Chandy and Norton,Curr Opin Chem Biol,2017,38:97-107]。
据文献报道，当处激活状态时，幼稚T细胞和中央记忆T细胞(T CM)上调Kca3.1表达水平而Kv1.3的数量无显著性变化。相反,处激活状态的已终端分化的效应器记忆T细胞(T EM)和表达CD-45RA的效应器记忆T细胞(T EMRA)上 调Kv1.3表达水平而不影响Kca3.1的表达量。因此，选择性地阻断Kca3.1能抑制幼稚T细胞和中央记忆T细胞(T CM)的增殖从而抑制相应的细胞因子产生。另一方面，选择性地阻断Kv1.3能抑制效应器记忆T细胞(T EM和T EMRA)的增殖和所对应的细胞因子的产生，也抑制T细胞的体内迁移，但不影响被Kca3.1通道所保护的幼稚T细胞和中央记忆T细胞(T CM)的功能[Cahalan and Chandy,Immunol Rev,2009,231:59-87][Wulff et al.J Clin Invest,2003,111:1703-1713]。
在自身免疫性疾病中，如多发性硬化症、类风湿性关节炎、I型糖尿病和银屑病等，其自身抗原特异性的幼稚T细胞能逃避免疫调节。通过同源自身抗原的反复刺激，这些细胞最终被分化成T EM和T EMRA细胞。故这些与疾病相关的自身反应性T细胞主要为T EM和T EMR细胞。根据其产生的细胞因子的种类，具体可以分为Th1和/或Th17等细胞[Beeton et al.PNAS 2006,103:17414-17418]。在动物模型中，选择性地阻断Kv1.3通道或敲除Kv1.3基因能预防和治疗多种自身免疫性疾病，同时不损害具保护作用的幼稚T细胞和中央记忆T细胞(T CM)的免疫应答功能。实验证明，当Kv1.3完整时，T EM细胞激活后被转化成效应细胞，而缺乏Kv1.3时，这些T EM细胞激活后可转变为起抗原特异性抑制效应的细胞。这种可塑性极大地支持了基于Kv1.3通道的靶向治疗，即抑制有害的自身反应性T EM细胞和T EMRA细胞，同时，通过诱导具有自身抗原特异性抑制效应的细胞的产生，促进长期的免疫耐受性[Chandy and Norton,Curr Opin Chem Biol,2017,38:97-107]。
近些年来，已报道发现了数个Kv1.3的特异性肽类阻断剂(如SHK-186等)或小分子阻断剂(如PAP-1等)，并用于治疗T EM细胞介导的自身免疫性疾病的动物模型的研究，如大鼠慢性多发性自身免疫性脑脊髓炎(EAE)、普利司坦诱导的关节炎、自发性自身免疫性糖尿病和肾小球肾炎。结果十分令人鼓舞。例如用SHK-186阻断Kv1.3能抵抗EAE的诱导发生并抑制IFN-γ和IL-17的产生，结果提示阻断Kv1.3可用于治疗多化性硬化症[Gocke et al,J Immunol 2012,188:5877-5886]。同样，在用卵清蛋白诱发的哮喘大鼠模型中，SHK-186能有效抑制Kv1.3高表达的Th2T EM细胞增殖和细胞因子的产生[Valverde et al,J Bone Miner Res 2004,19:155-164]。在自身免疫性肾小球基底膜肾炎的大鼠模型中，给大鼠腹腔内注射一个小分子Kv1.3阻断剂Psora-4，能显著减少蛋白尿和新月体肾小球，提示了Psora-4在治疗快速发展性肾小球肾炎具有重要作用[Hyodo et al,Am J Physial Renal Physiol 2010,299:F1258-69]。另一个Kv1.3小分子阻断剂PAP-1应用于大鼠局部皮肤模型时，能有效地抑制过敏性接触性皮炎(ACD)[Azam et al,J Invest Dermatal 2007,127(6):1419-1427]。进一步在SCID小鼠银屑病异种移植模型的实验中，注射或皮肤局部应用PAP-1能够将病变表皮增生的厚度减少约50％，并将所浸润的CD3 +淋巴细胞减少了85％，显著性地改善了银屑病症状[Kun clu-Raychaudhuri et al,J Antoimmun 2014,55:63-72]。值得一提的是，据最新报 道，Kv1.3肽类阻断剂SHK-186(Dalazatide)和小分子阻断剂PAP-1均已被用于治疗银屑病的I/II期临床试验，证明了其在人体内应用的安全性及有效性，统计学结果显示对银屑病症状的改善率高达90％以上[Tarch et al,PLoS ONE 2017,12(7):1-19][Press Relase by Circassia,13 August 2018]。
附图说明
图1是表示化合物28对大鼠特应性皮炎(ACD)模型的作用的图，化合物28连续给药4天或7天，均显著性减弱特应性皮炎(ACD)大鼠耳朵炎肿。
图2是表示化合物29对咪喹莫特诱导银屑病大鼠模型的作用的图，其中，图A是PASI评分结果，图B是Baker评分结果，PASI和Baker评分结果均证明化合物29对银屑病有显著疗效。
发明内容
本发明的一个目的是提供一种N-杂芳基磺酰胺类衍生物，其特征在于，其为通式(I)或通式(II)所示的N-杂芳基磺酰胺类化合物或其药学上可接受的盐或溶剂合物，
Figure PCTCN2020073362-appb-000001
其中：
环A选自包含1-2个含O、N和S的取代五元或六元芳杂环，所述取代的取代基选自
Figure PCTCN2020073362-appb-000002
和R 3基团；其中环A优选下述五元或六元芳杂环：
Figure PCTCN2020073362-appb-000003
环B选自取代或无取代的包含1-2个选自O、N和S的五元或六元脂杂环基，所述取代的取代基选自Z和R 4；其中环B优选下述含氧和/或氮的五元或六元脂杂环：
Figure PCTCN2020073362-appb-000004
R 1选自C1-6直链、支链烷基、环状烷基或卤代的C1-6直链、支链烷基，无取代或取代的苯基或包含1-2个氮原子的五元或六元芳杂环，苯环或芳杂环上取代为单取代、双取代或三取代，所述的取代基选自Ra基团；
Ra选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-；
R 2选自无取代或取代的苯基、包含1-2个选自O、N和S的五元或六元芳杂环,取代为单取代、双取代或三取代，所述的取代基选自Rb基团；
Rb选自H、卤素、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-；
R 3选自H、氰基、三氟甲基、烷酰胺基；
R 4选自H、卤素、＝O、OH、NH 2、甲酸酯基、氨基甲酸酯基、烷酰基、乙酸酯基、磺酰胺基、吡咯烷酮基、环丙基、氨基甲酰胺基、二甲基氨基乙氧基,烷酰氧基、烷酰胺基；
E、W、X、Y、相同或不同，分别独立选自N、O、S或C；
Z选自O、S、NH、C＝O或缺失；
除非另有说明，本文所述被任选取代的成分可以在任何化学上可能的位置被取代。
更具体地，本发的N-杂芳基磺酰胺类衍生物优选以下的化合物：
N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-(6-(4,4-二氟哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)丙磺酰胺、
N-(4-氟苄基)-N-(6-(吡咯烷-1-基)吡啶-3-基)丙磺酰胺、
N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-4-基甲基)丙磺酰胺、
N-(6-(哌啶-1-基)吡啶-3-基)-N-(嘧啶-4-基甲基)丙磺酰胺、
N-(6-(哌啶-1-基)吡啶-3-基)-N-((1-(三氟甲基)-1H-吡唑-3-基)甲基)丙磺酰胺、
N-(4-氟苄基)-2-甲基-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺、
3,3,3-三氟甲基-N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺、
N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺、
4-氟-N-(6-哌啶-1-基)吡啶-3-基-N-(嘧啶-4-基甲基)苯磺酰胺、
4-氟-N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)苯磺酰胺、
N-(1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)吡咯烷-3-基)乙酰胺、
N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-(4-氟苄基)-N-(6-(4-乙酰氨基哌啶-1-基)吡啶-3-基)丙磺酰胺、
1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯、
N-(4-氟苄基)-N-(6-(4-吡咯烷-1-酮)哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-(4-氟苄基)-N-(6-(4-(2-氧代吡咯烷-1-基)哌啶-1-基)吡啶-3-基)丙磺酰胺、
1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌啶-4-磺酰胺、
1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯、
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)苯磺酰胺、
N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺、
N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-(4-((1-乙酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)苯磺酰胺、
N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺、
N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺、
N-苄基-N-(6-(哌嗪-1-基)吡啶-3-基)丙烷磺酰胺、
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-4-甲酸乙酯、
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺、
4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪磺酰胺、
N-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
N-(4-氟苄基)-N-(6-(4-甲磺酰基)哌嗪-1-基)吡啶-3-基)丙磺酰胺、
N-(6-(4-环丙基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙烷-1-磺酰胺、
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺、
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺、
N-(5-腈基-6-(哌啶-1-基)哌啶-3-基)-N-(吡啶-2-基甲基)丙磺酰胺、
N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-甲氧基苄基)-4-氟苯磺酰胺、
N-(4-氯苄基)-N-(5-腈基-6-吗啉基吡啶-3-基)丙磺酰胺、
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺、
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2,4-二氟苄基)-1-环丙基甲磺酰胺、
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2-氟苄基)-2-甲基丙烷-1-磺酰胺、
N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺、
N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-1-甲酸乙酯、
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺、
4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺、
N-(6-(4-乙酰基哌嗪-1-基)-5-腈基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
N-(5-腈基-6-(4-(甲磺酰基)哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)丙磺酰胺、
4-氟-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)苯磺酰胺、
1-环丙基-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)甲磺酰胺、
4-氟-N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)苯磺酰胺、
N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)丙磺酰胺、
N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺、
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)哌嗪-1-甲酸乙酯、
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺、
4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺、
N-(2-(4-乙酰基哌嗪-1-基)嘧啶-5-基)-N-(4-氟苄基)丙磺酰胺、
N-(4-氟苄基)-N-(2-(4-甲磺酰基)哌嗪-1-基)嘧啶-5-基)丙磺酰胺、
N-(6-((1-乙酰基哌啶-4-基)氧)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺、
N-(6-((1-乙酰基哌啶-4-基)硫)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺、
N-(4-氟苄基)-N-(1-(哌啶-4-基)-1-H-吡唑-4-基)丙磺酰胺、
N-(1-(1-乙酰哌啶-4-基)-1-H-吡唑-4-基)-N-(4-氟苄基)丙磺酰胺、
N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺、
N-(4-氟苄基)-N-(1-甲基-2-(哌啶-1-基)-1-H-咪唑-4-基)丙磺酰胺、
N-(4-氟苄基)-N-(2-(哌啶-1-基)噻唑-4-基)丙磺酰胺、
以及上述化合物的药学上可接受的盐或溶剂合物。
本发明的另一个目的是提供通式(I)或通式(II)所示的化合物的制备方法，该制备方法可以通过以下步骤实现：
1.通式(I)的化合物的制备方法：
(1)当通式(I)的化合物中，环A为吡啶环、嘧啶环或R 3-吡啶环，同时Z缺失时，其制备方法采用方案一，以环A为吡啶环作为实例说明：
2-卤代-5-硝基吡啶在碱性条件下与含氮五元或六元脂杂环(环B)缩合，将所得缩合物中的硝基在钯碳和/或氯化亚锡存在下还原成氨基；
氨基物进而分别与芳醛(选用取代苯甲醛、吡啶甲醛、嘧啶甲醛或N-三氟甲基吡唑甲醛)经还原胺化制得N-苄基衍生物，再经磺酰胺化制得目标分子；若所得磺酰胺分子B环上存在保护基时，再经脱保护基、末端羟基或胺基衍生化，得到目标化合物。
也可以采用2-卤代-5-硝基吡啶先经硝基还原，进而经还原胺化，磺酰胺化，所得到中间体再在碱性条件下与含O、N五元或六元脂杂环(环B)缩合制得目标分子；若所得缩合物分子B环上存在保护基时，再经脱保护基、末端羟基或胺基衍生化，得到目标化合物。
正如对本领域技术人员而言是熟悉的，当环A为嘧啶环或R 3-吡啶环时，可采 用与方案一类似的方法制备通式(I)的化合物，仅是反应条件有所不同，具体参见实施例。
化合物1-62按照下列合成路线制备：
Figure PCTCN2020073362-appb-000005
(2)当通式(I)的化合物中，环A为吡啶环，环B为哌啶，Z选自O、S、NH时，其制备方法采用方案二：
2-卤代-5-硝基吡啶在碱性条件下与N-取代4-羟基或4-巯基或4-氨基哌啶反应，再将硝基还原成氨基，进而经还原胺化，磺酰胺化，得到目标分子。
化合物63,64按照下列合成路线制备：
Figure PCTCN2020073362-appb-000006
2.通式(II)的化合物的制备方法：
(1)当通式(II)的化合物中，环A为吡唑、N-甲基吡唑、噻唑、咪唑时，其制备方法采用方案三：
氨基五元芳杂环衍生物经还原胺化，磺酰胺化制得目标分子；若所得磺酰胺化产物B环上有保护基时，再经脱保护基，进而在环上引入酰基，得到目标化合物；
化合物65-69按照下列合成路线制备：
Figure PCTCN2020073362-appb-000007
本发明的再一个目的是提供N-芳杂基磺酰胺类衍生物在制备治疗自身免疫性疾病的药物中的用途。所述自身免疫性疾病是由Kv1.3介导的自身免疫性疾病。本发明提供的N-芳杂基磺酰胺类衍生物能够特异性结合并抑制或降低钾通道Kv1.3的活性，其能够作为选择性Kv1.3钾通道抑制剂，用于治疗自身免疫性疾病。
所述治疗自身免疫性疾病的药物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂，所述活性组分是通式(I)或通式(II)所示的N-芳杂基磺酰胺类化合物、其在药学上可接受的盐、其溶剂合物中的任意一种或任意多种。
所述载体或赋形剂包括药学领域的常规稀释剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。本发明的药物可以制成片剂、胶囊、贴剂、乳剂、混悬剂、凝胶剂,粉剂、颗粒剂、口服液及注射剂等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述的N-芳杂基磺酰胺类化合物的盐。所述盐可以是无机酸盐、有机酸盐等，所述无机酸盐包括与氢卤酸(如氢氟酸、氢溴酸、氢碘酸、盐酸)，硝酸，碳酸，硫酸，磷酸等形成相应的盐；所述有机酸盐包括与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸等形成相应的盐。
本发明还提供通式(I)或通式(II)所示的任意化合物及其在药学上可接受的盐或溶剂合物单独和/或与其他药物联合使用在制备治疗自身免疫疾病药物中的应用。
本发明还提供一种治疗自身免疫性疾病的药物，所述药物包含通式(I)或通式(II)所示的N-芳杂基磺酰胺类化合物或其药学上可接受的盐或溶剂合物作为活性组分。
本发明还提供一种治疗免疫性疾病的方法，其对需要治疗自身免疫性疾病的患者投与有效量的通式(I)或通式(II)所示的N-芳杂基磺酰胺类化合物或其药学上可接受的盐或溶剂合物。
Kv1.3钾通道已被视为是自身免疫性疾病治疗的重要靶点，因此，选择性 Kv1.3钾通道抑制剂可用于治疗自身免疫性疾病。所述的自身免疫性疾病包括银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、I型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症、高血压。
本发明通过实验证实，本发明的N-杂芳基磺酰胺类衍生物可选择性抑制Kv1.3钾通道活性，可应用于治疗人或动物由Kv1.3钾通道异常激活引起的自身免疫性疾病的药物中。本发明还提供包含该N-杂芳基磺酰胺类衍生物的药物以及药物组合物。
具体实施方式
本发明结合实施例作进一步的说明，以下实施例仅是说明本发明，而不是以任何方式限制本发明。
制备实施例1.N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺(化合物1)的合成
Figure PCTCN2020073362-appb-000008
步骤1. 5-硝基-2-(哌啶-1-基)吡啶(中间体1a)的合成
将2-溴-5-硝基吡啶(2.0g,9.8mmol)溶于四氢呋喃30mL中，加入碳酸钾(2.7g,19.7mmol)和哌啶(1.3g,14.8mmol)，加热回流4h。反应结束后将反应液过滤，滤液浓缩,残留物用硅胶柱层析分离(PE:EA＝4:1,v/v)，得类白色固体1a，收率58.3％；ESI-MS:m/z＝208[M+1] +。
步骤2.N-苄基-6-(哌啶-1-基)吡啶-3-胺(中间体1c)的合成
将1a(2.0g,9.6mmol)溶于醋酸20mL，加入10％钯碳0.2g，于30℃加氢还原1h。反应结束后，过滤，滤液直接投下步反应。
在滤液中加入苯甲醛(1.02g,9.6mmol)，室温搅拌1h，然后降温至10℃左右，加入硼氢化钠(0.55g,14.4mmol)，加完后保持此温度反应30min。将反应液倒入水中，碳酸钠溶液碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝4:1,v/v)，得到固体1c，两步收率68.0％；ESI-MS:m/z＝268[M+1] +。
步骤3.N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺(化合物1)的合成
将1c(1.74g,6.5mmol)，溶于二氯甲烷20mL，再加入吡啶(2.83g,35.8mmol) 和丙磺酰氯(0.93g,6.5mmol)，室温反应6h。反应结束后将反应液倒入水中，用稀盐酸酸化，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝3:1,v/v)，得到白色固体1，收率34.2％。 1H NMR(500MHz,DMSO-d 6)δ7.94(d,J＝2.6Hz,1H),7.44(dd,J＝9.1,2.6Hz,1H),7.33-7.20(m,5H),6.71(d,J＝9.1Hz,1H),4.79(s,2H),3.47-3.45(m,4H),3.21-3.16(m,2H),1.82-1.73(m,2H),1.60-1.53(m,2H),1.51-1.47(m,4H),1.01(t,J＝7.4Hz,3H)；ESI-MS:m/z＝374[M+1] +。
制备实施例2.化合物2-5的合成
Figure PCTCN2020073362-appb-000009
步骤1.中间体2a-5a的合成
在一组平行反应瓶中，分别加入2-氯-5-硝基吡啶(2.5mmol)，并均用四氢呋喃20mL溶解，再分别加入碳酸钾1.74g(12.62mmol)和相应的脂环胺(哌啶、4-二氟哌啶，吗啉、四氢吡咯,各9.47mmol)，回流反应2h。反应结束后将反应液冷却至室温，减压过滤，滤液减压浓缩，残留物后用乙酸乙酯重结晶，得到固体物2a-5a。
步骤2.中间体2c-5c的合成
合成步骤参考实施例1步骤2，只是2a-5a和对氟苯甲醛为原料制备化合物2c-5c。
表1.1中间体2a-5a,2c-5c的质谱数据
Figure PCTCN2020073362-appb-000010
Figure PCTCN2020073362-appb-000011
步骤3.化合物2-5的合成
合成步骤参考实施例1步骤3，只是用2c-5c和丙磺酰氯为原料制备化合物2-5。
制备实施例3.化合物6-12的合成
Figure PCTCN2020073362-appb-000012
步骤1.中间体6c-12c的合成
合成步骤参考实施例1步骤1，只是2a和相应的芳醛/杂芳醛为原料制备化合物6c-12c
步骤2.化合物6-12的合成
合成步骤参考实施例1步骤3，只是用6c-12c和相应的磺酰氯为原料制备化合物6-12。
制备实施例4. 4-氟-N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)苯磺酰胺(化合物13)的合成
Figure PCTCN2020073362-appb-000013
合成步骤参考实施例1步骤3，只是用4c和4-氟苯磺酰氯为原料制备化合物13。
制备实施例5.化合物14-20的合成
Figure PCTCN2020073362-appb-000014
步骤1.N-(4-氟苄基)-2-氟-5-氨基吡啶(14a)的合成
将2-氟-5-氨基吡啶(0.09mol)溶于醋酸60mL，向其中加入4-氟苯甲醛(0.1mol)，室温搅拌1h，将反应液冷却至10-15℃，加入氰基硼氢化钠(0.2mol)，保温搅拌30min，然后用碳酸钠溶液碱化，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤并减压浓缩，残留物用乙酸乙酯重结晶得到固体14a，收率75.6％；ESI-MS:m/z＝221[M+1] +。
步骤2.N-(4-氟苄基)-N-(6-氟吡啶-3-基)丙磺酰胺(14b)的合成
合成步骤参考实施例1步骤3，只是用14a和丙磺酰氯为原料制备化合物14b，收率73.5％；ESI-MS:m/z＝327[M+1] +。
步骤3.化合物14-20的合成通法
将14b(0.5mmol)，相应的4-取代哌啶或取代四氢吡咯(0.55mmol)，碳酸钾(1.3mmol)加入到DMF4mL中，升温至80℃反应2h，反应完后将反应液冷却至室温，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝15-20:1)，得到固体物14-20。
表1.2化合物2-20的核磁及质谱数据
Figure PCTCN2020073362-appb-000015
Figure PCTCN2020073362-appb-000016
Figure PCTCN2020073362-appb-000017
Figure PCTCN2020073362-appb-000018
Figure PCTCN2020073362-appb-000019
制备实施例6. 1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯(化合物21)的合成
Figure PCTCN2020073362-appb-000020
步骤1.N-(3-氟-4-甲氧基苄基)-2-氟-5-氨基吡啶(21a)的合成
合成步骤参考实施例5.步骤1，只是用2-氟-5-氨基吡啶和3-氟-4-甲氧基苯 甲醛为原料制备化合物21a,收率80.0％；ESI-MS:m/z＝251[M+1] +。
步骤2.N-(3-氟-4-甲氧基苄基)-N-(6-氟吡啶-3-基)丙磺酰胺(21b)的合成
合成步骤参考实施例5.步骤2，只是用21a和丙磺酰氯为原料制备化合物21b，收率70.5％；ESI-MS:m/z＝357[M+1] +。
步骤3. 1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯(化合物21)的合成
合成步骤参考实施例5.步骤3，只是用21b和哌啶-4-甲酸乙酯为原料制备化合物21,收率60.8％； 1HNMR(500MHz,CDCl 3)δ8.02(s,1H),6.97(m,2H),6.89(m,1H),6.80(d,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,1H),4.73(s,1H),4.16(q,J＝7.1Hz,2H),3.83(s,3H),3.14-3.02(m,6H),2.33(m,1H),1.98-1.69(m,6H),1.22(t,J＝7.2Hz,3H),0.97(t,J＝7.2Hz,3H)；ESI-MS：m/z＝494[M+1] +。
制备实施例7.化合物22-27的合成
Figure PCTCN2020073362-appb-000021
步骤1. 8-(5-硝基吡啶-2-基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(22a)的合成
将2-氯-5-硝基吡啶(14.0g,88.0mmol)溶于四氢呋喃200mL中，加入碳酸钾(32.4g,234.4mmol)和1,4-二氧杂-8-氮杂螺[4.5]癸烷盐酸盐(150.8g,88.0mmol)，回流反应12h。反应结束后将反应液冷却至室温，减压过滤，滤液浓缩，残留物用硅胶柱层析纯化(PE:EA＝4:1,v/v)，得到固体22a，收率62.1％；ESI-MS:m/z＝266[M+1] +。
步骤2.N-(4-氟苄基)-6-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-3-氨基吡啶(22c)的合成
将22a(3.0g 11.3mmol)溶于甲醇100mL，加入10％钯碳0.6g，于30℃加氢还原1h。反应结束后减压过滤，滤液浓缩后直接投下步反应。将上述浓缩物溶于醋酸150mL，再加入对氟苯甲醛(1.8g,14.5mmol)和分子筛1.8g，室温搅拌1h，冷却至10～15℃，加入硼氢化钠(0.47g,12.4mmol)，加完后保温反应0.5h，反应毕,将反应液慢慢加入冰的碳酸氢钠溶液中，乙酸乙酯萃取，合并有机相，用饱 和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝4:1,v/v)，得到固体物22c，两步收率33.2％；ESI-MS:m/z＝344[M+1] +。
步骤3.中间体22d-24d的合成
在三个平行反应瓶中，分别加入将22c(0.26g 0.76mmol)，二氯甲烷15mL，吡啶(0.32g 4.14mmol)和相应的磺酰氯(1.12mmol)，40℃反应10h。反应结束后将反应液倒入水中，用稀盐酸酸化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(DCM:EA＝10:1,v/v)，分别得到中间体22d-24d。
步骤4.化合物22-24的合成
将22d-24d(各0.44mmol)分别溶于四氢呋喃6mL中，再分别加入10％稀硫酸6mL，室温反应12h。反应结束后将反应液倒入水中，碳酸钠溶液碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1.0-1.5:1,v/v)，得到化合物22-24。
步骤5.化合物25-27的合成
将化合物22-24(各0.25mmol)分别溶于乙醇5mL中，再分别加入硼氢化钠(0.15mmol)，室温反应6h。将反应液慢慢加入预先冷却的碳酸氢钠溶液中，乙酸乙酯萃取，合并有机相，先后用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝3:1,v/v)，得到化合物25-27。
表1.3化合物22-27的核磁及质谱数据
Figure PCTCN2020073362-appb-000022
Figure PCTCN2020073362-appb-000023
制备实施例8.N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺(化合物28)的合成
Figure PCTCN2020073362-appb-000024
合成步骤：将化合物25(0.23g 0.56mmol)溶于二氯甲烷20mL，再加入三乙胺0.084g(0.83mmol)和乙酰氯(0.052g,0.67mmol)，室温搅拌1h。反应结束后，有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)，得到化合物28，收率为61.2％。 1HNMR(500MHz,CDCl 3)：δ8.01(d,J＝2.0Hz,1H),7.37(dd,J＝7.5,5.0Hz,2H),7.12(m,2H),6.80(d,J＝7.5Hz,1H),6.67(d,J＝7.5Hz,1H),5.22(m,1H),4.73(s,2H),3.24-3.00(m,6H),2.03(s,1H),1.87-1.62(m,6H),1.01(t,J＝7.2Hz,3H)；ESI-MS：m/z＝450[M+1] +。
制备实施例9.化合物29-34的合成
Figure PCTCN2020073362-appb-000025
步骤1. 4-(5-硝基吡啶-2-基)哌嗪-1-甲酸叔丁酯(29a)的合成
将2-溴-5-硝基吡啶(20.0g,98.0mmol)溶于四氢呋喃300mL，加入碳酸钾(27.0g,197.0mmol)和哌嗪-1-甲酸叔丁酯(27.5g,148.0mmol)，加热回流4h。反应结束后将反应液过滤，滤液浓缩后用硅胶柱层析提纯(PE:EA＝3:1,v/v)，得到固体29a，收率60.3％；ESI-MS:m/z＝309[M+1] +。
步骤2. 4-(5-((4-氟苄基)氨基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(29c)的合成
将29a(15.0g54.0mmol)溶于醋酸150mL，加入10％钯碳1.6g，于30℃加氢还原1h。反应结束后，减压过滤,滤液直接投下步反应，在滤液中加入4-氟苯甲醛(8.9g,72.0mmol)，室温搅拌1h，然后降温至10℃左右，加入硼氢化钠(4.13g,108.0mmol)，加完后保温反应30min。反应结束后将反应液倒入水中，碳酸钠溶液碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝4:1,v/v)，得到固体29c，两步收率65.0％；ESI-MS:m/z＝387[M+1] +。
步骤3. 4-(5-(N-(4-氟代苄基)丙基磺酰胺基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(29d) 的合成
将29c(12.0g,32.5mmol)，溶于二氯甲烷100mL，再加入吡啶(14.15g,179.0mmol)和丙磺酰氯(4.65g,32.5mmol)，室温反应6h。反应结束后将反应液倒入水中，用稀盐酸酸化，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝3:1,v/v)，得29d，收率58.2％；ESI-MS:m/z＝493[M+1] +。
步骤4.N-(4-氟苄基)-N-(6-(哌嗪-1-基)吡啶-3-基)丙烷-1-磺酰胺(29)的合成
将化合物29d(4.0g,7.5mmol)溶于DCM120mL中，向其中加入三氟乙酸(25.0g,215.5mmol),室温搅拌1h，用碳酸钠溶液碱化，二氯甲烷萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(DCM:MeOH＝20:1,v/v)，得到固体29，收率78.0％。
步骤5.化合物30-34的合成
将29(0.45mmol)溶于DCM5mL中，加入三乙胺(0.49mmol)，冰浴冷却下,再加入氯甲酸乙酯(0.67mmol)，保持此温度搅拌30分钟，室温搅拌1h，将反应液倒入5％碳酸钠水溶液中，分出有机层，水层用DCM提取，有机液用饱和NaCl溶液洗，无水Na 2SO 4于燥，减压浓缩，残留物用硅胶柱层析纯化(DCM:EtOH＝15:1,v/v)，得到化合物30。
化合物31-34按同法制备，只是分别用二甲氨基甲酰氯、二甲氨基磺酰氯、乙酰氯、甲磺酰氯替代氯甲酸乙酯。
制备实施例10.N-(6-(4-环丙基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙烷-1-磺酰胺(化合物35)的合成
Figure PCTCN2020073362-appb-000026
合成步骤参考实施例9步骤1-3，只是用1-(环丙甲基)哌嗪替代哌嗪-1-甲酸叔丁酯制备化合物35。
表1.4化合物29-35的核磁及质谱数据
Figure PCTCN2020073362-appb-000027
Figure PCTCN2020073362-appb-000028
制备实施例11.N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺(化合物36)的合成
Figure PCTCN2020073362-appb-000029
步骤1. 5-硝基-2-(哌啶-1-基)-3-腈基吡啶(36a)的合成
将2-溴-5-硝基-3-腈基吡啶(2.28g,10.0mmol)溶于四氢呋喃30mL，加入碳酸钾2.76g(20.0mmol)和哌啶1.3g(14.8mmol)，加热回流4h。反应结束后将反应液过滤，滤液浓缩后用硅胶柱层析提纯(PE:EA＝4:1,v/v)，得到中间体36a，收率60.3％；ESI-MS:m/z＝233[M+1] +。
步骤2. 5-氨基-2-(哌啶-1-基)-3-腈基吡啶(36b)的合成
在反应瓶中加入36a(2.32g,10.0mmol)，二水合氯化亚锡11.12g(49.3mmol)和无水乙醇110mL，回流反应1.5h，反应毕,将反应液冷却至室温，加入碳酸钠溶液碱化，抽滤，滤液用乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯重结晶得固体36b，收率68.3％；ESI-MS:m/z＝203[M+1] +。
步骤3. 5-((4-4-氟苄基)氨基)-2-(哌啶-1-基)-3-腈基吡啶(36c)的合成
将36b(2.03g 10.0mmol)溶于醋酸10mL中，加入4-氟苯甲醛(1.6g,13.0mmol)，室温搅拌1h，将反应液冷却至10-15℃，向其中加入硼氢化钠(0.4g,11.0mmol)，保温反应10min，然后将反应液用碳酸钠溶液碱化，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，残留物用乙酸乙酯重结晶,得到中间体36c，收率85.0％；ESI-MS:m/z＝311[M+1] +。
步骤4.N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺(化合物36)的合成
合成步骤参考实施例5.步骤2，只是用36c和丙磺酰氯为原料制备化合物36,收率45.5％； 1HNMR(500MHz,CDCl 3)：δ8.05(s,1H),7.67(s,1H),7.40(dd,J＝7.5,5.0Hz,2H),7.08(dd,J＝8.7,2.5Hz,2H),4.64(s,2H),3.74-3.65(m,4H),3.10(t,J＝7.2Hz,2H),1.63-1.55(m,8H),1.00(t,J＝7.2Hz,3H)；ESI-MS:m/z＝417[M+1] +。
制备实施例12.化合物37-39的合成
Figure PCTCN2020073362-appb-000030
步骤1.中间体37a-39a的合成
合成步骤参考实施例11.步骤3，只是用36b和2-吡啶甲醛或4-甲氧基苯甲醛为原料制备化合物37a-39a。
步骤2.化合物37-39的合成
合成步骤参考实施例5.步骤2，只是用37a-39a分别和相应的磺酰氯反应制备化合物37-39。
制备实施例13.化合物40-43的合成
Figure PCTCN2020073362-appb-000031
步骤1.中间体40a的合成
合成步骤参考实施例11.步骤1，只是用2-溴-5-硝基-3-腈基吡啶和吗啉为原料制备化合物40a，收率65.5％；ESI-MS:m/z＝235[M+1] +。
步骤2.中间体40b的合成
合成步骤参考实施例11.步骤2，只是用40a为原料制备化合物40b,收率63.5％；ESI-MS:m/z＝204[M+1] +。
步骤3.中间体40c-44c的合成通法
合成步骤参考实施例11.步骤3，只是用40c-44c和相应的磺酰氯为原料制备化合物40-44。
制备实施例14.化合物45，46的合成
Figure PCTCN2020073362-appb-000032
步骤1. 4-(3-腈基.-5-硝基吡啶-2-基)哌嗪-1-甲酸叔丁酯(45a)的合成
合成步骤参考实施例11.步骤1，只是用2-溴-5-硝基-3-腈基吡啶和哌嗪-1-甲酸叔丁酯为原料制备化合物45a,收率67.8％；ESI-MS:m/z＝334[M+1] +。
步骤2. 4-(3-腈基-5-((4-氟苄基)氨基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(45c)的合成
合成步骤参考实施例9.步骤2，只是用45a和4-氟苯甲醛为原料制备化合物45c,收率62.0％；ESI-MS:m/z＝412[M+1] +。
步骤3.中间体45d,46d的合成
合成步骤参考实施例9.步骤3，只是用45c分别与4-氟苯磺酰氯或丁磺酰氯反应制备化合物45d,46d。
步骤4.化合物45,46的合成
合成步骤参考实施例9.步骤4，只是用45d,46d为原料分别制备化合物45,46。
制备实施例15.化合物47-51的合成
Figure PCTCN2020073362-appb-000033
合成步骤参考实施例9.步骤5，只是用46为原料分别与氯甲酸乙酯、二甲氨基甲酰氯、二甲氨基磺酰氯、乙酰氯、甲磺酰氯反应制备化合物47-51。
表1.4化合物37-51的核磁及质谱数据
Figure PCTCN2020073362-appb-000034
Figure PCTCN2020073362-appb-000035
Figure PCTCN2020073362-appb-000036
制备实施例16.化合物52-54的合成
Figure PCTCN2020073362-appb-000037
步骤1.N-(4-氟苄基)-2-(哌啶-1-基)-5-氨基嘧啶(52a)的合成
合成步骤参考实施例1.步骤2，只是用5-氨基-2-(哌啶-1-基)嘧啶和4-氟苯甲醛为原料制备化合物52a；ESI-MS:m/z＝287[M+1] +。
步骤2.化合物52-54的合成
合成步骤参考实施例1.步骤3，只是用52a分别与丙磺酰氯、4-氟苯磺酰氯、环丙甲基磺酰氯反应制备化合物52-54。
制备实施例17.化合物55,56的合成
Figure PCTCN2020073362-appb-000038
步骤1.N-(4-氟苄基)-2-吗啉基-5-氨基嘧啶(55a)的合成
合成步骤参考实施例1.步骤2，只是用2-吗啉基-5-氨基嘧啶和4-氟苯甲醛为原料制备化合物55a；ESI-MS:m/z＝289[M+1] +。
步骤2.化合物55,56的合成
合成步骤参考实施例1.步骤3，只是用55a分别与4-氟苯磺酰氯、丙磺酰氯反应制备化合物55,56。
表1.5化合物52-56的核磁及质谱数据
Figure PCTCN2020073362-appb-000039
制备实施例18.N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺(化合物57)的合成
Figure PCTCN2020073362-appb-000040
步骤1. 4-(5-硝基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(57a)的合成
将2-氯-5-硝基嘧啶(2.5g,15.7mmol)溶于干燥DMF25mL中，加入哌嗪甲酸-1-叔丁酯(3.2g,17.2mmol),搅拌下再加入三乙胺(6.5mL,46.9mmol),加热到90℃反应10小时，减压蒸除溶剂，残留物加二氯甲烷(50mL)稀释，水洗，有机层用无水Na 2SO 4干燥，过滤，蒸除溶剂，残留物乙酸乙酯/石油醚重结晶，得57a,收率75.0％；ESI-MS:m/z＝310[M+1] +。
步骤2. 4-(5-氨基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(57c)的合成
将57a(2.1g,6.79mmol)溶于甲醇25mL，加入10％钯碳0.22g，于室温加氢还原3h。反应结束后，过滤,滤液直接投下步反应。在滤液中加入4-氟苯甲醛(0.58g,6.8mmol)，室温搅拌1.5h，然后降温至10℃左右，加入硼氢化钠(0.55g,14.4mmol)，保持此温度反应30min。将反应液倒入水中，10％碳酸钠溶液碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝3:1,v/v)，得到固体57c，两步收率63.0％；ESI-MS:m/z＝388[M+H] +。
步骤3. 4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(57d)的合成
合成步骤参考实施例1.步骤3，只是用57c和丙磺酰氯为原料制备化合物57d；ESI-MS:m/z＝494[M+1] +。
步骤4.N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺(化合物57)的合成
将57d(2.76g,5.6mmol)加入到二氧六环6mL中，冷至0℃,加入饱和氯化氢二氧六环溶液15mL,室温反应3小时，减压蒸除溶剂，残畄物用5％Na 2CO 3液调pH到8，二氯甲烷萃取，饱和食盐水洗，过滤，滤液无水Na 2SO 4干燥,过滤，蒸除溶剂，残留物用硅胶柱层析纯化(PE:EA＝2.5:1,v/v)，得到化合物57，收率82.0％； 1HNMR(500MHz,CDCl 3)：δ9.85(br,1H),8.14(s,2H),7.38(dd,J＝7.5,5.0Hz,2H), 7.07(m,2H),4.70(s,2H),3.30-3.21(m,4H),3.10(t,J＝7.1Hz,2H)，2.79-2.67(m,4H),1.68(m,2H),1.01(t,J＝7.4Hz,3H)；ESI-MS:m/z＝394[M+1] +。
制备实施例19.化合物58-62的合成
Figure PCTCN2020073362-appb-000041
合成步骤参考实施例9.步骤5，只是用57为原料分别与氯甲酸乙酯、二甲氨基甲酰氯、二甲氨基磺酰氯、乙酰氯、甲磺酰氯反应制备化合物58-62。
制备实施例20.化合物63,64的合成
Figure PCTCN2020073362-appb-000042
步骤1.化合物63a,64a的合成
将N-乙酰基4-羟基哌啶(0.72g,5.0mmol)，溶于无水DMF10mL中，降温至0℃，加入60％氢化钠(0.24g,6.0mmol)，保温搅拌0.5h，再加入2-溴-5-硝基吡啶(0.97g,4.8mmol)，室温反应2h，将反应液倒入水中，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1:1,v/v)，得到固体63a，收率59.8％；ESI-MS:m/z＝266[M+1] +。
中间体64a用同法制备，只是用N-乙酰基4-巯基哌啶为原料，收率67.2％；ESI-MS:m/z＝282[M+1] +。
步骤2.化合物63a,64a的合成
合成步骤参考制备实施例18.步骤2，只是用63a,64a和4-氟苯甲醛为原料制备63c,64c。
步骤3.化合物63,64的合成
合成步骤参考实施例1.步骤3，只是用63c,64c和丙磺酰氯为原料制备化合物63,64。
表1.6化合物58-64的核磁及质谱数据
Figure PCTCN2020073362-appb-000043
Figure PCTCN2020073362-appb-000044
制备实施例21.化合物65,66的合成
Figure PCTCN2020073362-appb-000045
步骤1. 4-(4-硝基-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(65a)的合成
将4-硝基吡唑(0.56g,5.0mmol)，4-羟基哌啶-1-甲酸叔丁酯(1.1g,5.5mmol)，三苯基膦(1.97g,7.5mmol)溶于无水四氢呋喃20mL中，氮气保护下于0～5℃缓慢滴加DEAD(2.61g,7.5mmol)的THF溶液5mL，加毕，保温反应4h，反应完后加水20mL稀释，乙酸乙酯萃取，饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝1:1,v/v)，得到固体物65a,收率85.0％；ESI-MS:m/z＝297[M+H] +。
步骤2. 4-(4-((4-氟苄基)氨基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(65c)的合成
合成步骤参考制备实施例18.步骤2，只是用65a和4-氟苯甲醛为原料制备65c，收率40.9％；ESI-MS:m/z＝375[M+1] +。
步骤3. 4-(4-(N-(4-氟苄基)丙磺酰胺基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(65d)的合成
合成步骤参考实施例1.步骤3，只是用65c和丙磺酰氯为原料制备化合物65d,收率73.3％；ESI-MS:m/z＝481[M+1] +。
步骤4.N-(4-氟苄基)-N-(1-(哌啶-4-基)-1H-吡唑-4-基)丙磺酰胺(化合物65)的合成
合成步骤参考实施例18.步骤4，只是用65d为原料制备化合物65,收率83.2％。
步骤5.N-(1-(1-乙酰哌啶-4-基)-1H-吡唑-4-基)-N-(4-氟苄基)丙磺酰胺(化合物66)的合成
合成步骤参考实施例9.步骤5，只是用65和乙酰氯为原料制备化合物66,收率80.6％。
制备实施例22.N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺(化合物67)的合成
Figure PCTCN2020073362-appb-000046
步骤1.N-(4-氟苄基)-1-甲基-3-(哌啶-1-基)-1H-吡唑-5-胺(67a)的合成
将1-甲基-3-(哌啶-1-基)-1H-吡唑-5-胺(1.26g,7.0mmol)溶于甲醇20mL，再加入4-氟苯甲醛(0.58g,6.8mmol)，室温搅拌1.5h，然后降温至10℃左右，加入硼氢化钠(0.55g,14.4mmol)，保持此温度反应30min。将反应液倒入水中，10％碳酸钠溶液碱化，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，残留物用硅胶柱层析纯化(PE:EA＝2:1,v/v)，得到固体67a，收率63.0％；ESI-MS:m/z＝289[M+1] +。
步骤2.N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺(化合物67)的合成
合成步骤参考实施例1.步骤3，只是用67a和丙磺酰氯为原料制备化合物67，收率53.0％
制备实施例23.化合物68,69的合成
Figure PCTCN2020073362-appb-000047
步骤1.中间体68a,69a的合成
合成步骤参考实施例22.步骤1，只是用1-甲基-2-(哌啶-1-基)-1H-咪唑-4-胺或2-(哌啶-1-基)噻唑-4-胺分别与4-氟苯甲醛反应制备68a,69a。
步骤2.化合物68,69的合成
合成步骤参考实施例1.步骤3，只是用68a,69a分别与丙磺酰氯反应制备化合物68,69。
表1.7化合物65-69的核磁及质谱数据
Figure PCTCN2020073362-appb-000048
Figure PCTCN2020073362-appb-000049
实施例24生物学评估
一、对Kv1.3的抑制活性的IonWorks全自动膜片钳测定
对于Kv1.3 IonWorks测定的原理和方法参见施罗德等人的文献报道[Schroeder et al.J Biomol Screen 2003,8(1):50-64]
1、细胞培养
化合物对Kv1.3抑制活性的评估使用稳定表达人体Kv1.3的CHO-K1重组细胞株(Charles River,California)。细胞在含有5％小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6％CO 2的空气湿度条件的培养箱中培养。在IonWorks系统中使用之前，用凡尔赛(Versene)在37℃下处理粘附细胞6-7分钟，轻轻敲打培养瓶后，重新将细胞悬浮在PBS磷酸盐缓冲液，然后经50x g离心4分钟。在短暂的研磨后，最终将细胞以大约1×10 6/ml的密度重新悬浮在外部记录溶液中。
2、化合物测定板的准备
化合物经DMSO溶解后，在母板上制成300×倍的最终测定梯度浓度。最终测定的梯度浓度为0.00384、0.00192、0.096、0.048、0.24、1.2、6和30μM。将所有300x倍浓度的化合物DMSO原液转移到384-孔的化合物测定板，每孔放置2μl。将化合物测定板密封后在-80℃保存至测定当天。
测定当天，将化合物测定板在室温下解冻，经离心后，加入198μl的外部记录溶液(其成分为：130mM Na-Gluconate,20mM NaCl,4mM KCl,1mM MgCl 2,1.8mM CaCl 2,5mM Glucose和10mM HEPES,pH7.3)并充分混合。这步骤提供了化合物1:100的稀释。在IonWorks中加入细胞后进一步稀释1:3，故总稀释度为1:300。每个测定板上至少保留8个孔用于空白对照，即仅含0.3％DMSO，另外至少保留8个孔用于阳性对照，以检测细胞信号的特异性。用于阳性对照的化合物为氟西汀(Fluoxetine)，在其最大阻断浓度(100μM)和次级最大阻断浓度 (10μM)下进行测试。另外，在测试用的内部记录溶液(其成分为：100mM K-Gluconate,40mM KCl,1mM MgCl 2,1mM EGTA和10mM HEPES,pH7.3)中含有最终浓度为200μg/ml的两性霉素B(Amphotericin B)，以获得细胞内的电流通道。溶液的渗透压用蔗糖调节。
3、实验步骤和数据分析
实验步骤按照IonWorks Quattro系统(Molecular Devices,San Jose,CA)设定的程序进行。人体Kv1.3的电流经持续1秒钟的脉冲诱导至0毫伏(mV)，共诱导四次。多脉冲之间维持-80毫伏的电位势，持续5秒钟。首先IonWorks Quattro系统起动前期电压施加程序，然后加入化合物并进行600秒钟的孵育。接下来起动后期电压施加程序，直至完成全部测试过程。
在化合物加入前后均测量最大外向峰值电流以及测量在第四脉冲升至0毫伏时诱发的平均末端电流。将化合物加入后所测得的电流幅度除以化合物加入前的电流幅度，即可计算化合物对Kv1.3的抑制活性。
所有数据经IonWorks Quattro系统设置的数据过滤程序校正。其过滤标准为：封接质量>30MΩ，封接电阻下降<50％及电流幅度>200pA。
表2.1化合物对Kv1.3的抑制活性(全自动膜片钳法)
Figure PCTCN2020073362-appb-000050
Figure PCTCN2020073362-appb-000051
二、对Kv1.3的抑制活性的传统膜片钳测定
为了比较不同测定方法对化合物抑制活性的影响，同时采用传统膜片钳法测定了化合物3、4、9、19、33、36、44对于Kv1.3的抑制活性。传统膜片钳测定的原理和方法参见格里斯默尔等人的文献报道[Grissmer et al.Molecular Pharmacology 1994,45:1227-1234]
1、细胞培养
化合物对Kv1.3抑制活性的评估使用稳定表达人体Kv1.3的CHO-K1重组细胞株(Charles River,California)。细胞在含有5％小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6％CO 2的空气湿度条件的培养箱中培养。
实验时，贴壁细胞放置在倒置显微镜下的记录室中。所有实验都在室温下进行。每个细胞都以自身为对照。
2、化合物的测试
测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为：NaCl,137；KCl,4；CaCl 2,1.8；MgCl 2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。
化合物均采用利用自身重力的灌流系统进行灌流。化合物每个浓度至少测试两个细胞。在电流稳定后，再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。阳性对照物使用1000μM 4-AP。
3、电生理
将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液(mM)为：K-aspartate,130；MgCl 2,5；EGTA 5；HEPES,10；pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱，实验当天融化。电极用PC-10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。
4、测试过程和结果分析
将细胞钳制在–80mV，然后用持续2秒方波去极化到0mV，以得到Kv1.3电流。这一程序每20秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。
资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说明用来计算化合物在此溶度的作用。
表2.2部分化合物对Kv1.3的抑制活性(传统膜片钳法)
化合物编号 Kv1.3(IC 50,μM) 化合物编号 Kv1.3(IC 50,μM)
3 0.022 33 0.058
4 0.038 36 0.042
19 0.025 44 0.022
三、对Kv1.5的抑制活性的传统膜片钳测定
对于Kv1.5传统膜片钳测定的原理和方法参见格里斯默尔等人的文献报道[Grissmer et al.Molecular Pharmacology 1994,45:1227-1234]。
1、细胞培养
化合物对Kv1.5抑制活性的评估使用稳定表达人体Kv1.5的CHO-K1重组细胞。株(Charles River,California)。细胞在含有5％小牛血清F-12K培养液(Invitrogen,Carlsbad.CA)在37℃和含6％CO 2的空气湿度条件的培养箱中培养。
实验时，贴壁细胞放置在倒置显微镜下的记录室中。所有实验都在室温下进行。每个细胞都以自身为对照。
2、化合物的测试
测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为:NaCl,137；KCl,4；CaCl 2,1.8；MgCl 2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。
化合物均采用利用自身重力的灌流系统进行灌流。化合物每个浓度至少测试两个细胞。在电流稳定后，再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。阳性对照物使用1000μM 4-AP。
3、电生理
将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液(mM)为：K-aspartate,130；MgCl 2,5；EGTA 5；HEPES,10；pH 7.2(KOH滴定)。细胞内液分批少量储存于-80度冰箱，实验当天融化。电极用PC-10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。
4、测试过程和结果分析
将细胞钳制在–80mV，然后用持续2秒方波去极化到20mV，以得到Kv1.5电流。这一程序每20秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。
资料采集和分析使用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说明用来计算化合物在此溶度的作用。
表2.3部分化合物对Kv1.5的抑制活性(传统膜片钳法)
化合物编号 Kv1.5(IC 50,μM) 化合物编号 Kv1.5(IC 50,μM)
3 0.205 33 2.010
4 0.588 36 0.088
19 1.015 44 0.056
四、化合物28对大鼠变态反应性接触性皮炎模型(ACD模型)的影响
1、实验动物
采用SPF级SD雌性大鼠，体重150～180g。
2、药物及试剂
地塞米松(DXMS)磷酸钠注射液，5mg/ml/支(石药银湖制药有限公司)；1-氯-2,4-二硝基苯(DNCB)(梯希爱(上海)化成工业发展有限公司)；药物溶剂和阴性对照:丙酮/DMSO 9:1(Vehicle、Model group)。
3、实验方法
3.1动物按体重随机分为3组，每组10只，分别为阴性对照组(Vehicle)、阳性对照组(地塞米松磷酸钠注射液5mg/ml)和5％化合物28组。
3.2造模及给药：用DNCB丙酮DMSO溶液(丙酮－DMSO 9∶1)致敏和激发大鼠皮肤建立大鼠变应性接触性皮炎(ACD)模型。大鼠正常饲养于SPF屏障系统内1周，于实验前1天在腹部用脱毛膏脱毛，范围约2cm×2cm，实验第1天脱毛部位均匀涂以7％DNCB丙酮DMSO溶液50μL致敏，实验第2天用1％DNCB丙酮DMSO溶液50μL重复强化致敏1次。实验第5天开始，每日大鼠右耳滴涂1％DNCB丙酮DMSO溶液20μL进行激发，左耳滴涂丙酮DMSO(丙酮－DMSO 9∶1)溶液20μL作为对照；阴性对照组在相同部位仅涂以丙酮DMSO溶液(9∶1)20μL作对照，连续3天，大鼠耳出现明显红斑、肿胀，制得DNCB诱发的ACD大鼠模型。右耳擦涂给药，第一次给药在激发前8h，激发后每天擦涂三次，每次25μl，连续给药7d；阴性对照组及模型对照组大鼠右耳等体积擦涂空白基质。
3.3测量耳厚度差：激发前、末次给药后，用电子数显卡尺分别测量每组大鼠左、右耳中部的厚度，平行测量2次，取平均值，计算耳厚度差(右耳厚度－左耳厚度)。
4、结论：化合物28连续给药4天或7天，均显著性减弱特应性皮炎(ACD)大鼠耳朵炎肿。实验结果参照图1。
五、化合物29对咪喹莫特诱导大鼠银屑病模型的影响
1、实验动物
采用SPF级Wista雌性大鼠，体重200g左右。
2、药物及试剂
地塞米松(DXMS)磷酸钠注射液，5mg/ml/支(石药银湖制药有限公司)；5％咪喹莫特乳膏，0.25g/袋(四川明欣药业有限责任公司)；300万U重组人干扰素α-2a注射液，1.0ml/瓶(沈阳三生制药有限责任公司)；药物溶剂和阴性对照：丙酮/DMSO 9:1(Vehicle)。
3、实验方法
3.1动物按体重随机分为3组，每组10只，分别为正常对照组(Normal group)、模型对照组(Model group)和0.5％化合物29组。
3.2造模及给药大鼠适应性喂养数日后，将各大鼠背部中央区域(2cm×2cm)的毛剃去后，用温和型脱毛膏脱去表面短毛，洗净擦干，备用。若实验过程中背毛再次长出，则用剃毛刀剔除毛发。每日上午，模型对照组及各给药组大鼠背部按照20mg/cm 2均匀涂抹5％咪喹莫特乳膏(每袋0.25g，涂抹3只)，10min后将重组人干扰素α-2a注射液按照1万U/500g腹腔注射；正常对照组大鼠不做处理，1次/d，连续10天。下午各给药组按相应剂量涂抹药物(大鼠背部按100μl/只滴涂相应浓度药物，分两次涂，每次50μl，1次/d，连续10天。
3.3皮损面积和严重程度指数(PASI)评分：依据PASI评分标准，给予大 鼠皮损处红斑、鳞屑及表皮浸润增厚程度0～4的积分。评分标准如下：0，无；1，轻度；2，中度；3，重度；4，极重度。对各组大鼠积分取平均值，观察各组大鼠皮损的变化情况。
3.4HE染色：造模结束后(第11天)，将大鼠背部皮损组织取材，4％中性甲醛固定、石蜡包埋、切片，经HE染色，显微镜下观察皮肤组织形态学变化，进行Baker评分。Baker评分具体标准如下：表皮层中发现Munro小脓肿2.0分；角化过度0.5分；角化不全1.0分；颗粒层变薄或消失1.0分；棘层增厚1.0分；皮突延长、起伏根据轻中重度分别计0.5分、1.0分、1.5分。真皮层中单一核或多核细胞浸润根据轻中重度分别计0.5分、1.0分、1.5分；乳突上顶0.5分；毛细血管扩张0.5分。
3.5统计学方法：所有数据以均数±标准差(x±s)表示，数据运用SPSS 20.0统计软件处理，多样本均数比较采用单因素方差分析(one-way ANOVA)，P<0.05为有统计学意义。对非正态或方差不齐的数据，采用秩和检验进行统计。
4、结论：PASI、Baker评分结果和病理分析结果均证明化合物29对银屑病有显著疗效。实验结果参见图2。

Claims (22)

  1. 一种N-杂芳基磺酰胺类衍生物，其特征在于，其为通式(I)或通式(II)所示的N-杂芳基磺酰胺类化合物或其药学上可接受的盐或溶剂合物，
    Figure PCTCN2020073362-appb-100001
    其中：
    环A选自包含1-2个O、N和S的取代五元或六元芳杂环，所述取代的取代基选自
    Figure PCTCN2020073362-appb-100002
    和R 3基团；
    环B选自取代或无取代的包含1-2个选自O、N和S的五元或六元脂杂环基，所述取代的取代基选自Z和R 4；
    R 1选自C1-6直链、支链烷基、环状烷基或卤代的C1-6直链、支链烷基，无取代或取代的苯基或包含1-2个氮原子的五元或六元芳杂环，苯环或芳杂环上取代为单取代、双取代或三取代，所述的取代基选自Ra基团；
    Ra选自H、卤素、硝基、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-；
    R 2选自无取代或取代的苯基、包含1-2个选自O、N和S的五元或六元芳杂环,取代为单取代、双取代或三取代，所述的取代基选自Rb基团；
    Rb选自H、卤素、氰基、C1-3烷基、C1-3烷氧基、-C-O-C-；
    R 3选自H、氰基、三氟甲基、烷酰胺基；
    R 4选自H、卤素、＝O、OH、NH 2、甲酸酯基、氨基甲酸酯基、烷酰基、乙酸酯基、磺酰胺基、吡咯烷酮基、环丙基、氨基甲酰胺基,二甲基氨基乙氧基,烷酰氧基、烷酰胺基；
    E、W、X、Y、相同或不同，分别独立选自N、O、S或C；
    Z选自O、S、NH、C＝O或缺失。
  2. 如权利要求1所述的N-杂芳基磺酰胺类衍生物，其特征在于，环A选自 下列五元或六元芳杂环：
    Figure PCTCN2020073362-appb-100003
  3. 如权利要求1所述的N-杂芳基磺酰胺类衍生物，其特征在于，环B选自下列含氧和/或氮的五元或六元脂杂环：
    Figure PCTCN2020073362-appb-100004
  4. 如权利要求1所述的N-杂芳基磺酰胺类衍生物，其特征在于，所述N-杂芳基磺酰胺类衍生物选自以下化合物：
    N-苄基-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-(6-(4,4-二氟哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-(吡咯烷-1-基)吡啶-3-基)丙磺酰胺、
    N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-4-基甲基)丙磺酰胺、
    N-(6-(哌啶-1-基)吡啶-3-基)-N-(嘧啶-4-基甲基)丙磺酰胺、
    N-(6-(哌啶-1-基)吡啶-3-基)-N-((1-(三氟甲基)-1H-吡唑-3-基)甲基)丙磺酰胺、
    N-(4-氟苄基)-2-甲基-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺、
    3,3,3-三氟甲基-N-(4-氟苄基)-N-(6-(哌啶-1-基)吡啶-3-基)丙基-1-磺酰胺、
    N-(6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺、
    4-氟-N-(6-哌啶-1-基)吡啶-3-基-N-(嘧啶-4-基甲基)苯磺酰胺、
    4-氟-N-(4-氟苄基)-N-(6-吗啉基吡啶-3-基)苯磺酰胺、
    N-(1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)吡咯烷-3-基)乙酰胺、
    N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-(4-乙酰氨基哌啶-1-基)吡啶-3-基)丙磺酰胺、
    1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌啶-4-基)氨基甲酸乙酯、
    N-(4-氟苄基)-N-(6-(4-吡咯烷-1-酮)哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-(4-(2-氧代吡咯烷-1-基)哌啶-1-基)吡啶-3-基)丙磺酰胺、
    1-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌啶-4-磺酰胺、
    1-(5-(N-3-氟-4-甲氧基芐基)丙磺酰胺基)吡啶-2-基)哌啶-4-甲酸乙酯、
    N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)苯磺酰胺、
    N-(4-氟苄基)-N-(6-(4-氧代哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺、
    N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-(4-((1-乙酰基哌啶-4-基)硫)-3-腈基苯基)-N-(4-氟苄基)苯磺酰胺、
    N-(4-氟苄基)-N-(6-(4-羟基哌啶-1-基)吡啶-3-基)2,2-二甲基丙烷-1-磺酰胺、
    N-(4-氟苄基)-N-(6-(4-乙酰氧基哌啶-1-基)吡啶-3-基)丙磺酰胺、
    N-苄基-N-(6-(哌嗪-1-基)吡啶-3-基)丙烷磺酰胺、
    4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-4-甲酸乙酯、
    4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺、
    4-(5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪磺酰胺、
    N-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
    N-(4-氟苄基)-N-(6-(4-甲磺酰基)哌嗪-1-基)吡啶-3-基)丙磺酰胺、
    N-(6-(4-环丙基哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙烷-1-磺酰胺、
    N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-氟苄基)丙基磺酰胺、
    N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(吡啶-2-基甲基)苯磺酰胺、
    N-(5-腈基-6-(哌啶-1-基)哌啶-3-基)-N-(吡啶-2-基甲基)丙磺酰胺、
    N-(5-腈基-6-(哌啶-1-基)吡啶-3-基)-N-(4-甲氧基苄基)-4-氟苯磺酰胺、
    N-(4-氯苄基)-N-(5-腈基-6-吗啉基吡啶-3-基)丙磺酰胺、
    N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺、
    N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2,4-二氟苄基)-1-环丙基甲磺酰胺、
    N-(5-腈基-6-吗啉基吡啶-3-基)-N-(2-氟苄基)-2-甲基丙烷-1-磺酰胺、
    N-(5-腈基-6-吗啉基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
    N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)-4-氟苯磺酰胺、
    N-(5-腈基-6-(哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
    4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)哌嗪-1-甲酸乙酯、
    4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺、
    4-(3-腈基-5-(N-(4-氟苄基)丙磺酰胺基)吡啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺、
    N-(6-(4-乙酰基哌嗪-1-基)-5-腈基吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
    N-(5-腈基-6-(4-(甲磺酰基)哌嗪-1-基)吡啶-3-基)-N-(4-氟苄基)丙磺酰胺、
    N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)丙磺酰胺、
    4-氟-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)苯磺酰胺、
    1-环丙基-N-(4-氟苄基)-N-(2-(哌啶-1-基)嘧啶-5-基)甲磺酰胺、
    4-氟-N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)苯磺酰胺、
    N-(4-氟苄基)-N-(2-吗啉基嘧啶-5-基)丙磺酰胺、
    N-(4-氟苄基)-N-(2-(哌嗪-1-基)嘧啶-5-基)丙磺酰胺、
    4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)哌嗪-1-甲酸乙酯、
    4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-甲酰胺、
    4-(5-(N-(4-氟苄基)丙磺酰胺基)嘧啶-2-基)-N,N-二甲基哌嗪-1-磺酰胺、
    N-(2-(4-乙酰基哌嗪-1-基)嘧啶-5-基)-N-(4-氟苄基)丙磺酰胺、
    N-(4-氟苄基)-N-(2-(4-甲磺酰基)哌嗪-1-基)嘧啶-5-基)丙磺酰胺、
    N-(6-((1-乙酰基哌啶-4-基)氧)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺、
    N-(6-((1-乙酰基哌啶-4-基)硫)吡啶-3-基)-N-(4-氟苄基)丙烷磺酰胺、
    N-(4-氟苄基)-N-(1-(哌啶-4-基)-1-H-吡唑-4-基)丙磺酰胺、
    N-(1-(1-乙酰哌啶-4-基)-1-H-吡唑-4-基)-N-(4-氟苄基)丙磺酰胺、
    N-(4-氟苄基)-N-(1-甲基-3-(哌啶-1-基)-1H-吡唑-5-基)丙磺酰胺、
    N-(4-氟苄基)-N-(1-甲基-2-(哌啶-1-基)-1-H-咪唑-4-基)丙磺酰胺、
    N-(4-氟苄基)-N-(2-(哌啶-1-基)噻唑-4-基)丙磺酰胺、
    以及上述化合物的药学上可接受的盐或溶剂合物。
  5. 一种制备方法，用于制备权利要求1所述的通式(I)所示的N-杂芳基磺酰胺类化合物，所述通式(I)中，环A为吡啶环、嘧啶环或R 3-吡啶环，且Z缺失，
    所述制备方法的特征在于，包括以下步骤：
    环A化合物在碱性条件下与含氮五元或六元脂杂环(环B)缩合，将所得缩合物中的硝基在钯碳和/或氯化亚锡存在下还原成氨基；氨基物进而与芳醛经还原胺化制得N-苄基衍生物，再经磺酰胺化，制得目标分子；若所得分子上存在保护基时，再经脱保护基、末端羟基或胺基衍生化得到目标化合物；
    或者，采用环A化合物先经硝基还原，进而经还原胺化，磺酰胺化，所得到中间体再在碱性条件下与含O、N五元或六元脂杂环(环B)缩合，制得目标化合物；若所得分子上存在保护基时，再经脱保护基、末端羟基或胺基衍生化得到目标化合物，
    所述制备方法按照下述合成路线制备：
    Figure PCTCN2020073362-appb-100005
  6. 如权利要求5所述的制备方法，其特征在于，
    环A为吡啶环，环A化合物为2-卤代-5-硝基吡啶。
  7. 一种制备方法，用于制备权利要求1所述的通式(I)所示的N-杂芳基磺酰胺类化合物，所述通式(I)中，环A为吡啶环，环B为哌啶，Z选自O、S、NH，
    所述制备方法的特征在于，包括以下步骤：
    2-卤代-5-硝基吡啶在碱性条件下与N-取代的4-羟基或4-巯基或4-氨基哌啶反应，再将硝基还原成氨基，进而经还原胺化，磺酰胺化，得到目标化合物，
    所述制备方法按照下述合成路线制备：
    Figure PCTCN2020073362-appb-100006
  8. 一种制备方法，用于制备权利要求1所述的通式(II)所示的N-杂芳基磺酰胺类化合物，所述通式(II)中，环A为吡唑、N-甲基吡唑、噻唑或咪唑，
    所述制备方法的特征在于，包括以下步骤：
    氨基取代的五元芳杂环衍生物经还原胺化、磺酰胺化，制得目标分子，若所得磺酰胺化产物B环上有保护基时，再经脱保护基，进而在环上引入酰基，得到目标化合物；
    所述制备方法按照下述合成路线制备：
    Figure PCTCN2020073362-appb-100007
  9. 权利要求1～4中任一项所述的N-杂芳基磺酰胺类衍生物作为选择性Kv1.3钾通道抑制剂在制备治疗自身免疫性疾病的药物中的用途。
  10. 如权利要求9所述的用途，其特征在于，所述治疗自身免疫性疾病的药物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂，所述活性组分是通式(I)或通式(II)所示的N-杂芳基磺酰胺类化合物、其在药学上可接受的盐、其溶剂合物中的任意一种或任意多种。
  11. 如权利要求10所述的用途，其特征在于，所述载体或赋形剂选自药学领域的常规稀释剂、填充剂、粘合剂、湿润剂、崩解剂，吸收促进剂、表面活性 剂、吸附载体、润滑剂、香味剂和甜味剂中的任意一种以上。
  12. 如权利要求10所述的用途，其特征在于，所述治疗自身免疫性疾病的药物的剂型为片剂、胶囊、贴剂、乳剂、混悬剂、凝胶剂,粉剂、颗粒剂、口服液或注射剂。
  13. 如权利要求10所述的用途，其特征在于，所述N-杂芳基磺酰胺类化合物的盐为无机酸盐或有机酸盐，所述无机酸盐选自与氢卤酸、硝酸、碳酸、硫酸、磷酸形成的盐中的任意一种以上的盐；所述有机酸盐选自与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸形成的盐中的任意一种以上的盐。
  14. 如权利要求9所述的用途，其特征在于，所述自身免疫性疾病为银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、I型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症或高血压。
  15. 一种治疗自身免疫性疾病的药物，其特征在于，所述药物包含权利要求1～4中任一项所述的N-杂芳基磺酰胺类衍生物作为活性组分。
  16. 如权利要求15所述的药物，其特征在于，所述药物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂，所述活性组分是通式(I)或通式(II)所示的N-杂芳基磺酰胺类化合物、其在药学上可接受的盐、其溶剂合物中的任意一种或任意多种。
  17. 如权利要求16所述的药物，其特征在于，所述载体或赋形剂选自药学领域的常规稀释剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、香味剂和甜味剂中的任意一种以上。
  18. 如权利要求16所述的药物，其特征在于，所述药物的剂型为片剂、胶 囊、贴剂、乳剂、混悬剂、凝胶剂、粉剂、颗粒剂、口服液或注射剂。
  19. 如权利要求16所述的药物，其特征在于，所述N-杂芳基磺酰胺类化合物的盐为无机酸盐或有机酸盐，所述无机酸盐选自与氢卤酸，硝酸，碳酸，硫酸，磷酸形成的盐中的任意一种以上的盐；所述有机酸盐选自与苹果酸、L-苹果酸、D-苹果酸、枸橼酸、富马酸、草酸、乳酸、樟脑磺酸、L-樟脑磺酸、D-樟脑磺酸、对甲苯磺酸、甲磺酸、苯甲酸形成的盐中的任意一种以上的盐。
  20. 如权利要求15所述的药物，其特征在于，所述自身免疫性疾病为银屑病、银屑病性关节炎、变应性以及刺激性接触性皮炎、特应性皮炎、白癜风、类风湿性关节炎、I型糖尿病、多发性硬化、哮喘、肾小球肾炎、牙周疾病、睫状体扁平部炎、移植排斥、神经退行性变、肥胖症或高血压。
  21. 如权利要求1～4中任一项所述的N-杂芳基磺酰胺类衍生物，其特征在于，其作为选择性Kv1.3钾通道抑制剂，用于治疗自身免疫性疾病。
  22. 一种自身免疫性疾病的治疗方法，其特征在于，对需要治疗自身免疫性疾病的患者投与有效量的权利要求1～4中任一项所述的N-杂芳基磺酰胺类衍生物。
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WO2010130638A1 (en) * 2009-05-14 2010-11-18 Evotec Ag Sulfonamide compounds, pharmaceutical compositions and uses thereof
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WO2010023445A1 (en) * 2008-08-29 2010-03-04 Xention Limited Novel potassium channel blocker
WO2010130638A1 (en) * 2009-05-14 2010-11-18 Evotec Ag Sulfonamide compounds, pharmaceutical compositions and uses thereof
CN109705033A (zh) * 2019-01-22 2019-05-03 杭州壹瑞医药科技有限公司 N-杂芳基磺酰胺类衍生物及制备和应用

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