WO2022022373A1 - 苯并吡喃衍生物及其在制备治疗类风湿性关节炎的药物中的应用 - Google Patents

苯并吡喃衍生物及其在制备治疗类风湿性关节炎的药物中的应用 Download PDF

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WO2022022373A1
WO2022022373A1 PCT/CN2021/107803 CN2021107803W WO2022022373A1 WO 2022022373 A1 WO2022022373 A1 WO 2022022373A1 CN 2021107803 W CN2021107803 W CN 2021107803W WO 2022022373 A1 WO2022022373 A1 WO 2022022373A1
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compound
benzopyran derivative
preparation
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杨成
李东兴
戚苏民
张起愿
赵晓丹
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华创合成制药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

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  • the invention relates to the field of medicinal chemistry, in particular to a benzopyran derivative with anti-inflammatory activity and its use in preparing a medicament for treating rheumatoid arthritis.
  • RA Rheumatoid arthritis
  • the basic lesions are chronic synovial inflammation, abnormal synovial hyperplasia, thickening of the lining, and destruction of cartilage and bone tissue by vascularization. It leads to joint deformity and loss of function, which has a serious impact on human health and quality of life. In recent years, its incidence and disability rate have been increasing year by year.
  • the drugs currently in clinical use mainly include non-steroidal anti-inflammatory drugs, glucocorticoids, immunosuppressants and interferons.
  • Iguratimod T-614
  • Iguratimod T-614
  • Iguratimod T-614
  • Its chemical name is 3-carboxamido- 7-Methanesulfonamido-6-phenoxy-4H-1-benzopyran-4-one. It can selectively inhibit cyclooxygenase COX-2, can regulate T cells, and has autoimmune regulatory effects. Compared with previous therapeutic drugs, it has a rapid effect. Its curative effect is equivalent to that of high-efficiency anti-rheumatic drugs with low toxicity. It can also be taken orally. Dosing.
  • iguratimod As a relatively novel variety of non-steroidal anti-inflammatory drugs, iguratimod has the advantages of less dosage and less toxic and side effects. However, long-term use can still have serious side effects, such as elevated aminotransferases. Therefore, it is imperative to continue to develop new varieties.
  • the present invention provides a benzopyran derivative which can maintain the curative effect of iguratimod and has lower toxic and side effects.
  • the benzopyran derivative of the present invention has the structure shown in the following formula I:
  • X is -SO- or -SO 2 -
  • Y is H, Na or K.
  • the compounds of the present invention are benzopyran methanesulfonamides having a diphenyl sulfone or diphenyl sulfoxide structure.
  • the present invention combines the structural characteristics of Ailamod, analyzes the advantages and disadvantages of its structure, retains the part with anti-inflammatory activity in its structure, and forms the compound of the present invention through a series of chemical reactions.
  • the compound of the present invention has strong anti-inflammatory effect, and the effect is better than that of iguratimod. Compared with iguratimod, the aminotransferase was not significantly elevated at the same time of administration of the compound of the present invention.
  • Figure 1 is a mass spectrum of Compound 1 of the present invention.
  • Figure 2 is the mass spectrum of the sodium salt of Compound 1 of the present invention.
  • Figure 3 is the mass spectrum of the potassium salt of Compound 1 of the present invention.
  • Figure 4 is a mass spectrum of Compound 2 of the present invention.
  • Figure 5 is the mass spectrum of the sodium salt of Compound 2 of the present invention.
  • Fig. 6 is the mass spectrum of the potassium salt of compound 2 of the present invention.
  • the inventive compound N-(3-formamido-4-oxo-6-benzenesulfinyl-4H-7-benzopyranyl)methanesulfonamide is abbreviated as compound 1, and its corresponding salt Abbreviated as potassium salt or sodium salt of compound 1;
  • Abbreviated as compound N-(3-formamido-4-oxo-6-benzenesulfonyl-4H-7-benzopyranyl)methanesulfonamide 2 its corresponding salt is abbreviated as the potassium salt or sodium salt of compound 2.
  • Step 1 Synthesis of 3-nitro-4-phenylthioanisole: add thiophenol (33.9g) and 4-chloro-3-nitroanisole (50g) to 100ml of DMF, stir evenly Further potassium tert-butoxide (48.5 g) was added, and the mixture was heated at 110°C for 4 hours. Poured into 200 ml of ice water, extracted three times with 300 ml of ethyl acetate, the organic phase was washed with 100 ml of 1M hydrochloric acid, and then washed with water. The organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness. Dichloromethane was added to the residue for crystallization to obtain 3-nitro4-phenylthioanisole.
  • Step 2 Synthesis of 3-amino-4-phenylthioanisole: Dissolve 3-nitro 4-phenylthioanisole (45 g) in 500 ml of absolute ethanol, in 10 wt% palladium carbon and 0.3 Under the hydrogen pressure of MPa, hydrogenation was carried out at room temperature for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the reduced product, which was recrystallized from toluene to obtain 3-amino-4-phenoxyanisole.
  • Step 3 Synthesis of 3-methylsulfonamido-4-phenylthioanisole: Dissolve 3-amino-4-phenylthioanisole (30 g) in 150 ml of pyridine, add at 0-5°C After adding 18 g of methanesulfonyl chloride, the mixture was stirred at room temperature for 1 hour. The reactant was poured into 200 ml of ice water, extracted three times with 300 ml of ethyl acetate, the organic phase was washed with 100 ml of 1M dilute hydrochloric acid, and then washed with water, the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 3-methylsulfonamido-4-phenylthioanisole.
  • Step 4 Synthesis of ⁇ -amino-2-methoxy-4-methanesulfonamido-5-phenylthioacetophenone hydrochloride: Aluminium trichloride (54 g) and aminoacetonitrile hydrochloride (18.5 g) Add in 200 ml of stirring nitrobenzene in batches at room temperature, cool to 10°C, add 3-methylsulfonamido-4-phenylthioanisole, pass in hydrogen chloride gas, and heat at 25-30°C was stirred at the same temperature for 10 hours. The reactant was poured into 500 ml of cooled 3M dilute hydrochloric acid, and a precipitate appeared. The precipitate was filtered, washed with ethyl acetate, and dried to obtain ⁇ -amino-2-methoxy-4-methanesulfonamido-5-phenylthio Acetophenone hydrochloride.
  • Step 5 Synthesis of 2-(2-aminoacetyl)-4-phenylsulfinyl-5-methanesulfonamidoanisole: ⁇ -amino-2-methoxy-4-methanesulfonamido-5 -Phenylthioacetophenone hydrochloride (25g) was dissolved in water (100ml), cooled to 0-5°C, 6.8g of 30wt% hydrogen peroxide was added dropwise, kept stirring for 5 hours, and then extracted with 100ml of isopropyl ether , the organic layer was evaporated to dryness, and column chromatography gave 2-(2-aminoacetyl)-4-phenylsulfinyl-5-methanesulfonamidoanisole as a pale yellow solid.
  • Step 6 Synthesis of 2-(2-aminoacetyl)-4-phenylsulfanyl-5-methanesulfonamidoanisole: ⁇ -amino-2-methoxy-4-methanesulfonamido-5- Phenylthioacetophenone hydrochloride (25g) was dissolved in water (100ml), cooled to 0-5°C, 13g of 30% hydrogen peroxide was added dropwise, kept stirring for 5 hours, then extracted with 100ml of isopropyl ether, organic The layer was evaporated to dryness, and the column chromatography gave 2-(2-aminoacetyl)-4-phenylsulfanyl-5-methanesulfonamidoanisole as a pale yellow solid.
  • Step 7 Combine 2-(2-aminoacetyl)-4-phenylsulfinyl-5-methanesulfonamidoanisole (33g) with pivaloyl chloride (15g), sodium formate (16.9g) and acetone (100ml) ) at room temperature, mixed and stirred for 10 hours, then added water (300ml), stirred for 30min, filtered, washed with isopropanol, and dried with hot air at 60°C.
  • Step 8 Under the condition of controlling the temperature to be lower than 20°C in an ice-water bath, add aluminum trichloride (23g) to acetonitrile (100ml), then add sodium iodide (12g) and the product of step 1 (25g), at 20 After stirring for 5 hours, the reactant was poured into 300 ml of an aqueous solution containing 1wt% sodium sulfite, and a yellowish white precipitate was precipitated, filtered, washed with 250 ml of water and 200 ml of ethanol respectively, and the filter cake was dried with hot air at 60°C.
  • Step 9 Dissolve the product obtained in Step 2 (19g) in dichloromethane (100ml) at 0°C, then add dimethylformamide dimethylacetal (20g), add triethylamine (10ml), The reaction was stirred at 20 ° C for 6 hours, then 140 ml of water was added, filtered, and the filter cake was washed with dichloromethane, water and ethanol, respectively, and dried to obtain the target compound, namely N-(3-formamido-4-oxo-6- Benzenesulfonyl-4H-7-benzopyranyl)methanesulfonamide (abbreviated as compound 1).
  • the mass-to-charge ratio [M+H] + of the target compound ion was 407.18, which was consistent with the molecular weight of the target compound (406.03).
  • Step 1 Combine 2-(2-aminoacetyl)-4-phenylsulfanyl-5-methanesulfonamidoanisole (34g) and pivaloyl chloride (15g), sodium formate (16.9g) and acetone (100ml) Mix and stir at room temperature for 10 hours, then add water (300 ml), stir for 30 min, filter, wash with isopropanol, and dry with hot air at 60°C.
  • Step 2 Under the condition of controlling the temperature to be lower than 20°C in an ice-water bath, add aluminum trichloride (23g) to acetonitrile (100ml), then add sodium iodide (12g) and the product of step 1 (25.5g), Stir at 20°C for 5 hours, pour the reactant into 300ml of an aqueous solution containing 1wt% sodium sulfite, separate out a yellowish white precipitate, filter, wash with 250ml of water and 200ml of ethanol respectively, and dry the filter cake with hot air at 60°C.
  • Step 3 Dissolve the product obtained in Step 2 (19.5g) in dichloromethane (100ml) at 0°C, then add dimethylformamide dimethylacetal (20g), add triethylamine (10ml), 20 The reaction was stirred at °C for 6 hours, then 140 ml of water was added, filtered, and the filter cake was washed with dichloromethane, water and ethanol, respectively, and dried to obtain the target compound, namely N-(3-formamido-4-oxo-6-benzene Sulfonyl-4H-7-benzopyranyl)methanesulfonamide (compound 2 for short).
  • the mass-to-charge ratio [M+H] + of the target compound ion was 423.28, which was consistent with the molecular weight of the target compound (422.02).
  • the filtrate is evaporated to remove two-thirds of the solvent, cooled and crystallized, the crystals are filtered, the solid is rinsed with a small amount of absolute ethanol, and dried to obtain N-(3-formamido-4-oxo-6-benzenesulfinic acid) Acyl-4H-7-benzopyranyl)methanesulfonamide potassium salt (referred to as the potassium salt of compound 1).
  • the mass-to-charge ratio [M+H] + of the target compound ion is 445.12, which is consistent with the molecular weight of the target compound (444.00).
  • the filtrate was evaporated to remove two-thirds of the solvent, cooled and crystallized, the crystals were filtered, the solid was rinsed with a small amount of absolute ethanol, and dried to obtain N-(3-formamido-4-oxo-6-benzenesulfonyl -4H-7-benzopyranyl)methanesulfonamide sodium salt (referred to as the sodium salt of compound 2).
  • the mass-to-charge ratio [M+H] + of the target compound ion was 445.06, which was consistent with the molecular weight of the target compound (444.01).
  • the filtrate was evaporated to remove two-thirds of the solvent, cooled and crystallized, the crystals were filtered, the solid was rinsed with a small amount of absolute ethanol, and dried to obtain N-(3-formamido-4-oxo-6-benzenesulfonyl -4H-7-benzopyranyl) methanesulfonamide potassium salt (referred to as the potassium salt of compound 2).
  • the mass-to-charge ratio [M+H] + of the target compound ion was 461.12, which was consistent with the molecular weight of the target compound (460.01).
  • Compound 1 50mg lactose 114mg corn starch 20mg Hypromellose 2mg silica 2mg Calcium Carboxymethyl Cellulose 10mg Magnesium stearate 2mg total 200mg
  • the above components are packed into hard capsules according to conventional methods.
  • Compound 1 and its potassium salt and sodium salt, and compound 2 potassium and sodium salt tablets were prepared by the same method.
  • the research on the anti-arthritis activity of the compounds of the present invention takes the rat adjuvant joint (AA) as the animal model.
  • rat adjuvant joint AA
  • the rats are divided into eight groups, 10 rats in each group, and the rats are respectively administered orally
  • the compound of the present invention, blank and positive control substance isolamod 50 ⁇ g/time/day were administered for 5 consecutive days.
  • the degree of swelling of the paws before and after administration of the rats in each group was measured by the drainage method, and the hind paws before and after administration of the rats were calculated. degree of swelling Determine if the drug is working.
  • Degree of swelling X (volume of toe after inflamed toe - volume of toe before inflamed)/volume of toe before inflamed x 100%.
  • test results prove that the compound of the present invention has better anti-inflammatory effect than iguratimod, among which compound 1 and its potassium and sodium salt have the best anti-inflammatory effect.
  • Elevated aminotransferase is a common side effect of Iguratimod.
  • the present invention takes the compound of the invention and Iguratimod for 15 days to healthy rats, and then measures the serum of the rat. content of aminotransferases. The test results are shown in Table 4 below.

Abstract

提供了一种苯并吡喃衍生物，其具有式I所示结构，其中，X为-SO-或-SO 2-，Y为H、Na或K。初步抗炎活性试验表明，所述苯并吡喃衍生物具有较强的抗炎效果。与现有的艾拉莫德相比，在服用时间相同的情况下，氨基转移酶没有明显升高。

Description

苯并吡喃衍生物及其在制备治疗类风湿性关节炎的药物中的应用
本申请要求于2020年07月25日提交中国专利局、申请号为2020107265634、发明名称为“一种苯并吡喃衍生物及其在类风湿性关节炎治疗中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学领域，具体涉及具有抗炎活性的苯并吡喃类衍生物及在制备治疗类风湿性关节炎的药物中的用途。
背景技术
类风湿关节炎(rheumatoid arthritis，RA)是一种常见的全身性自身免疫疾病，基本病变为慢性滑膜炎症、滑膜异常增生、衬里层增厚、血管形成软骨与骨组织的破坏，最终会导致关节畸形和功能丧失，对人类的健康和生活质量造成严重影响，近年来其发病率及致残率呈逐年升高趋势。
目前，对于类风湿性关节炎，还没有药物能够治愈，药物所产生的作用都是延缓病情发展。临床目前使用的药物主要有非甾体抗炎药、糖皮质激素类、免疫抑制剂类及干扰素类。艾拉莫德(Iguratimod，T-614)作为一种治疗风湿关节炎的新型非甾体抗炎药物，是由日本富山与卫材制药公司联合研制开发的，化学名为3-甲酰胺基-7-甲磺酰胺基-6-苯氧基-4H-1-苯并吡喃-4-酮。它可选择性抑制环氧化酶COX-2，能调节T细胞，具有自身免疫调节作用，与以往的治疗药物相比显效迅速，其疗效与高效的抗风湿药物等同且毒性低，还可以口服给药。
作为非甾体抗炎药物中比较新颖的一个品种，艾拉莫德具有用药量较少，毒副作用较小的优点。但是，长期服用仍会有严重的副作用，如氨基转移酶升高。因此，持续研制新的品种势在必行。
发明内容
为了解决现有技术中存在的问题，本发明提供一种既能保持艾拉莫德疗效又有较低毒副作用的苯并吡喃衍生物。
本发明所述的苯并吡喃衍生物具有以下式I所示的结构：
Figure PCTCN2021107803-appb-000001
其中，X为-SO-或-SO 2-，Y为H、Na或K。
简而言之，本发明化合物是具有二苯砜或二苯亚砜结构的苯并吡喃甲磺酰胺。
本发明的有益效果
本发明结合艾拉莫德的结构特点，分析了其结构的优势和劣势，对其结构中具有抗炎活性的部分予以保留，经过一系列化学反应，形成了本发明的化合物。
经初步抗炎试验，本发明的化合物具有较强的抗炎效果，且效果优于艾拉莫德。与艾拉莫德相比，在服用本发明的化合物的时间相同的情况下，氨基转移酶没有明显升高。
附图说明
图1为本发明化合物1的质谱图。
图2为本发明化合物1钠盐的质谱图。
图3为本发明化合物1钾盐的质谱图。
图4为本发明化合物2的质谱图。
图5为本发明化合物2钠盐的质谱图。
图6为本发明化合物2钾盐的质谱图。
具体实施方式
为了更好地说明本发明的实质和实施本发明，提供如下实施实例。应用本发明的领域内技术人员应当知晓，实施例只是为了示范本发明的过程，并不影响本发明的范围。
为了方便描述，将发明化合物N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺简称为化合物1，其对应的盐简称为化合物1的钾盐或钠盐；将发明化合物N-(3- 甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺简称为化合物2，其对应的盐简称为化合物2的钾盐或钠盐。
本发明化合物的制备选用了市面上常见的化工原料，发明人构思并实践了如下三种方案。
方案1：以4-氯-3-硝基苯甲醚为原料，经苯硫醚化、硝基还原、甲磺酰化、乙酰化、甲酰化、环合、氧化等步骤，再进一步分离提纯，得到目标化合物。该方案的合成路线如下：
Figure PCTCN2021107803-appb-000002
方案2：以4-氯-3-硝基苯甲醚为原料，经过苯硫醚化、还原、甲磺酰化、乙酰化、氧化、甲酰化、环合等步骤，再进一步分离提纯，得到目标化合物。该方案的合成路线如下：
Figure PCTCN2021107803-appb-000003
Figure PCTCN2021107803-appb-000004
方案3：以4-氯-3-硝基苯甲醚为原料，经过苯硫醚化、还原、氧化、甲磺酰化、乙酰化、甲酰化、环合等步骤，再进一步分离提纯，得到目标化合物。该方案的合成路线如下：
Figure PCTCN2021107803-appb-000005
Figure PCTCN2021107803-appb-000006
以上三种方案均可得到目标化合物，通过控制氧化的深度，进一步分离提纯，可以获得单一的苯磺酰基或苯亚磺酰基产物。但方案1的收率稍低，方案3较难得到纯度较高的发明化合物。本发明仅以方案2来详细说明发明化合物的制备过程。
实施例1
化合物1的合成
步骤1：3-硝基-4-苯硫基苯甲醚的合成：将苯硫酚(33.9g)和4-氯-3-硝基苯甲醚(50g)加入DMF 100ml中，搅拌均匀后再加入叔丁醇钾(48.5g)，110℃下加热4小时。倒入冰水200ml中，用乙酸乙酯300ml分三次萃取，有机相用1M盐酸100ml洗涤，然后用水洗。有机相用无水硫酸镁干燥，浓缩至干。残留物中加入二氯甲烷析晶，得3-硝基4-苯硫基苯甲醚。
步骤2：3-氨基-4-苯硫基苯甲醚的合成：将3-硝基4-苯硫基苯甲醚(45g)溶于无水乙醇500ml中，在10wt％的钯碳及0.3MPa氢气气压下，室温氢化3小时。过滤反应混合物，减压浓缩得到还原产物，甲苯重结晶，得3-氨基-4-苯氧基苯甲醚。
步骤3：3-甲基磺酰胺基-4-苯硫基苯甲醚的合成：将3-氨基-4-苯硫基苯甲醚(30g)溶于吡啶150ml中，0-5℃下加入甲磺酰氯18g，加完后再在室温下搅拌1小时。将反应物倒入冰水200ml中，用乙酸乙酯300ml分三次萃取，有机相用1M稀盐酸100ml洗涤，然后用水洗，有机相采用无水硫酸镁干燥，浓缩。残留物用乙醇重结晶，得到3-甲基磺酰胺基-4- 苯硫基苯甲醚.
步骤4：α-氨基-2-甲氧基-4-甲磺酰胺基-5-苯硫基苯乙酮盐酸盐的合成：将三氯化铝(54g)和氨基乙腈盐酸盐(18.5g)在室温下分批加入搅拌中的硝基苯200ml中，冷却到10℃，加入3-甲基磺酰胺基-4-苯硫基苯甲醚，通入氯化氢气体，在25-30℃的温度下搅拌10小时。反应物倒入冷却的3M稀盐酸500ml中，出现沉淀，将沉淀过滤，用乙酸乙酯洗涤，干燥，得α-氨基-2-甲氧基-4-甲磺酰胺基-5-苯硫基苯乙酮盐酸盐。
步骤5：2-(2-氨基乙酰基)-4-苯亚硫酰基-5-甲磺酰胺基苯甲醚合成：将α-氨基-2-甲氧基-4-甲磺酰胺基-5-苯硫基苯乙酮盐酸盐(25g)溶于水(100ml)中，降温到0-5℃，滴加30wt％过氧化氢6.8g，保温搅拌5小时，然后用异丙醚100ml萃取，有机层蒸干溶剂，柱层析，得2-(2-氨基乙酰基)-4-苯亚硫酰基-5-甲磺酰胺基苯甲醚，为浅黄色固体。
步骤6：2-(2-氨基乙酰基)-4-苯硫酰基-5-甲磺酰胺基苯甲醚合成：将α-氨基-2-甲氧基-4-甲磺酰胺基-5-苯硫基苯乙酮盐酸盐(25g)溶于水(100ml)中，降温到0-5℃，滴加30％过氧化氢13g，保温搅拌5小时，然后用异丙醚100ml萃取，有机层蒸干溶剂，柱层析，得2-(2-氨基乙酰基)-4-苯硫酰基-5-甲磺酰胺基苯甲醚浅黄色固体。
步骤7：将2-(2-氨基乙酰基)-4-苯亚硫酰基-5-甲磺酰胺基苯甲醚(33g)和特戊酰氯(15g)、甲酸钠(16.9g)及丙酮(100ml)室温下混合搅拌10小时，然后加水(300ml)，搅拌30min，过滤，异丙醇洗涤，60℃热风烘干。
步骤8：在冰水浴下，控制温度低于20℃条件下，将三氯化铝(23g)加入乙腈(100ml)中，然后加入碘化钠(12g)、步骤1产物(25g)，在20℃搅拌5小时，反应物倒入含亚硫酸钠1wt％水溶液300ml中，析出黄白色沉淀，过滤，分别用水250ml和乙醇200ml洗涤，滤饼采用60℃热风烘干。
步骤9：将步骤2所得产物(19g)在0℃的温度下溶于二氯甲烷(100ml)中，然后加入二甲基甲酰胺二甲缩醛(20g)，加入三乙胺(10ml)，20℃下搅拌反应6小时，然后加入水140ml，过滤，滤饼分别用二氯甲烷、水和乙醇洗涤，干燥得到目标化合物，即N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺(简称化合物1)。目标化合物离子的质荷比[M+H] +为407.18，与目标化合物分子量(406.03)一致。
实施例2
步骤1：将2-(2-氨基乙酰基)-4-苯硫酰基-5-甲磺酰胺基苯甲醚(34g)和特戊酰氯(15g)、甲酸钠(16.9g)及丙酮(100ml)室温下混合搅拌10小时，然后加水(300ml)，搅拌30min， 过滤，异丙醇洗涤，60℃热风烘干。
步骤2：在冰水浴下，控制温度低于20℃条件下，将三氯化铝(23g)加入乙腈(100ml)中，然后加入碘化钠(12g)、步骤1产物(25.5g)，在20℃搅拌5小时，反应物倒入含亚硫酸钠1wt％水溶液300ml中，析出黄白色沉淀，过滤，分别用水250ml和乙醇200ml洗涤，滤饼60℃热风烘干。
步骤3：将步骤2所得产物(19.5g)在0℃下溶于二氯甲烷(100ml)中，然后加入二甲基甲酰胺二甲缩醛(20g)，加入三乙胺(10ml)，20℃下搅拌反应6小时，然后加入水140ml，过滤，滤饼分别用二氯甲烷、水和乙醇洗涤，干燥得目标化合物，即N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺(简称化合物2)。目标化合物离子的质荷比[M+H] +为423.28，与目标化合物分子量(422.02)一致。
实施例3
N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺钠盐的制备
取N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺1g，加入无水乙醇200ml，加热回流溶解，然后滴加乙醇钠180mg，搅拌2小时，加入活性炭0.3g，再搅拌30分钟，过滤，滤液蒸掉三分之二的溶剂，冷却析晶。将晶体过滤，固体用少量无水乙醇淋洗，干燥，即得N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺钠盐(简称化合物1的钠盐)。目标化合物离子的质荷比[M+H] +为429.15，与目标化合物分子量(428.01)一致。
实施例4
N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺钾盐的制备
取N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺1g，加到无水乙醇200ml中，加热回流溶解，然后加入乙醇钾189mg，搅拌2小时，加入活性炭0.3g，再搅拌30分钟，过滤。滤液蒸除三分之二的溶剂，冷却析晶，将晶体过滤，固体用少量无水乙醇淋洗，干燥，即得N-(3-甲酰氨基-4-氧代-6-苯亚磺酰基-4H-7-苯并吡喃基)甲磺酰胺钾盐(简称化合物1的钾盐)。目标化合物离子的质荷比[M+H] +为445.12，与目标化合物分子量(444.00)一致。
实施例5
N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺钠盐的制备
取N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺1g，加到无水乙醇200ml中，加热回流溶解，然后加入乙醇钠176mg，搅拌2小时，加入活性炭0.3g，再搅拌30分钟，过滤。滤液蒸除三分之二的溶剂，冷却析晶，将晶体过滤，固体用少量无水乙醇淋洗，干燥，即得N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺钠盐(简称化合物2的钠盐)。目标化合物离子的质荷比[M+H] +为445.06，与目标化合物分子量(444.01)一致。
实施例6
N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺钾盐的制备
取N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺1g，加到无水乙醇200ml中，加热回流溶解，然后加入乙醇钾183mg，搅拌2小时，加入活性炭0.3g，再搅拌30分钟，过滤。滤液蒸除三分之二的溶剂，冷却析晶，将晶体过滤，固体用少量无水乙醇淋洗，干燥，即得N-(3-甲酰氨基-4-氧代-6-苯磺酰基-4H-7-苯并吡喃基)甲磺酰胺钾盐(简称化合物2的钾盐)。目标化合物离子的质荷比[M+H] +为461.12，与目标化合物分子量(460.01)一致。
实施例7
包含化合物1的硬胶囊的制备
表1 包含化合物1的硬胶囊的处方
化合物1 50mg
乳糖 114mg
玉米淀粉 20mg
羟丙纤维素 2mg
二氧化硅 2mg
羧甲基纤维素钙 10mg
硬脂酸镁 2mg
总计 200mg
将以上组分按照常规方法装入硬胶囊。
采用同样的方法制备化合物1钠盐及钾盐、化合物2及其钠盐钾盐的硬胶囊。
实施例8
包含化合物2的片剂的制备
表2 包含化合物2的片剂的处方
化合物2 25mg
乳糖 50mg
微晶纤维素 26mg
羟丙纤维素 2mg
羧甲基纤维素 6.6mg
硬脂酸镁 1.2mg
滑石粉 1.2mg
总计 100mg
将上述处方按照常规方法压制成片剂。
采用同样的方法制备化合物1及其钾盐钠盐、化合物2的钾盐及钠盐片剂。
试验例1
本发明化合物的抗关节炎活性研究是以大鼠佐剂性关节性(AA)为动物模型，在建立大鼠AA的基础上，将大鼠分为八组，每组10只，分别灌胃给予本发明化合物、空白及阳性对照物艾拉莫德50μg/次/天，连续给药5天，采用排水法测定各组大鼠给药前后足肿胀程度，计算出大鼠给药前后后足肿胀度
Figure PCTCN2021107803-appb-000007
确定药物是否有效。
肿胀度X＝(致炎后足趾体积-致炎前足趾体积)/致炎前足趾体积×100％。
试验结果如下表3。
表3
Figure PCTCN2021107803-appb-000008
试验结果证明，本发明的化合物具有比艾拉莫德更好的抗炎效果，其中化合物1及其钾钠盐抗炎效果最好。
试验例2
氨基转移酶升高是艾拉莫德的常见副作用，为了考察发明化合物对氨基转移酶是否有影响，本发明通过给健康大鼠服用本发明化合物及艾拉莫德15天，然后测定大鼠血清中氨基转移酶的含量。试验结果见下表4。
表4
组别 例数 ALT(U/L) AST(U/L)
空白组 10 31.52±4.58 35.80±5.44
艾拉莫德组 10 173±9.86 145±10.98
化合物1组 10 138±10.24 105±8.22
化合物1钠盐组 10 132±9.24 103±8.09
化合物1钾盐组 10 137±10.21 104±8.19
化合物2组 10 143±9.43 102±9.58
化合物2钠盐组 10 140±10.05 104±8.15
化合物2钾盐组 10 141±9.88 102±8.75
从以上结果可以看出，本发明化合物的副作用明显小于艾拉莫德，其中化合物1及其钾钠盐副作用最小。

Claims (3)

  1. 苯并吡喃衍生物或其药学上可接受的盐，其特征在于，所述苯并吡喃衍生物具有式I所示结构：
    Figure PCTCN2021107803-appb-100001
    其中，X为-SO-或-SO 2-；Y为H、Na或K。
  2. 一种药物组合物，其特征在于，包括权利要求1所述的苯并吡喃衍生物或其药学上可接受的盐。
  3. 根据权利要求1所述的苯并吡喃衍生物或其药学上可接受的盐，或权利要求2所述的药物组合物在制备治疗类风湿性关节炎的药物中的应用。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4954518A (en) * 1987-10-08 1990-09-04 Toyama Chemical Company, Ltd. 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient
CN101486702A (zh) * 2009-03-04 2009-07-22 江苏先声药物研究有限公司 一种艾拉莫德类似物及其分离方法
CN101597271A (zh) * 2008-06-05 2009-12-09 杨喜鸿 艾拉莫德的衍生物,其制备方法和药物应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4954518A (en) * 1987-10-08 1990-09-04 Toyama Chemical Company, Ltd. 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient
CN101597271A (zh) * 2008-06-05 2009-12-09 杨喜鸿 艾拉莫德的衍生物,其制备方法和药物应用
CN101597272A (zh) * 2008-06-05 2009-12-09 杨喜鸿 艾拉莫德的钾盐化合物,其制备方法和药物应用
CN101486702A (zh) * 2009-03-04 2009-07-22 江苏先声药物研究有限公司 一种艾拉莫德类似物及其分离方法

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