WO2022022372A1 - 硫代苯并吡喃类化合物及其在制备治疗类风湿性关节炎药物中的应用 - Google Patents

硫代苯并吡喃类化合物及其在制备治疗类风湿性关节炎药物中的应用 Download PDF

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WO2022022372A1
WO2022022372A1 PCT/CN2021/107802 CN2021107802W WO2022022372A1 WO 2022022372 A1 WO2022022372 A1 WO 2022022372A1 CN 2021107802 W CN2021107802 W CN 2021107802W WO 2022022372 A1 WO2022022372 A1 WO 2022022372A1
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compound
thiobenzopyran
present
preparation
rheumatoid arthritis
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PCT/CN2021/107802
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French (fr)
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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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Priority to EP21850195.5A priority Critical patent/EP4190773A4/en
Priority to US18/013,069 priority patent/US20230242502A1/en
Priority to JP2022576231A priority patent/JP7426756B2/ja
Priority to AU2021317306A priority patent/AU2021317306B2/en
Publication of WO2022022372A1 publication Critical patent/WO2022022372A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • 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
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the invention relates to the field of medicinal chemistry, in particular to a thiobenzopyran compound 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
  • the 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 efficacy is equivalent to that of high-efficiency anti-rheumatic drugs and has 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, there are still serious side effects with long-term use, such as a marked increase in aminotransferase. Therefore, it is imperative to continue to develop new varieties.
  • the present invention provides a thiobenzopyran compound that can maintain the curative effect of iguratimod and have lower toxic and side effects.
  • the thiobenzopyran compounds of the present invention have the structure shown in the following formula I:
  • X is selected from O (oxygen), S (sulfur), -SO- (sulfinyl), -SO 2 - (sulfuryl); Y is S (sulfur); Z is H, Na or K.
  • the compounds of the present invention are a series of derivatives having the basic structure of thiobenzopyran methanesulfonamide.
  • thiobenzopyran compounds of the present invention can be compounds:
  • the present invention analyzes the advantages and disadvantages of its structure in combination with the structural characteristics of Ailamod.
  • the part with anti-inflammatory activity in its structure is retained, and through a series of chemical reactions, the compound of the present invention is formed.
  • the thiopyran compound of the present invention has strong anti-inflammatory effect through preliminary anti-inflammatory test, and iguratimod has lower toxic and side effects. 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 a mass spectrum of the sodium salt of Compound 1 of the present invention.
  • Fig. 3 is a 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.
  • Fig. 5 is a mass spectrum of the sodium salt of compound 2 of the present invention.
  • Figure 6 is a mass spectrum of the present compound 2 potassium salt.
  • Fig. 7 is a mass spectrum of compound 3 of the present invention.
  • Fig. 8 is a mass spectrum of the sodium salt of Compound 3 of the present invention.
  • Figure 9 is a mass spectrum of compound 3 potassium salt.
  • Figure 10 is a mass spectrum of Compound 4 of the present invention.
  • Figure 11 is a mass spectrum of the present compound 4 sodium salt.
  • Figure 12 is a mass spectrum of the present compound 4 potassium salt.
  • Phenol (32.9 g) and 4-chloro-3-nitroanisole sulfide (50 g) were added to 100 ml of DMF, stirred evenly, then potassium tert-butoxide (47.5 g) was added, and heated at 110° C. for 4 hours.
  • Dichloromethane was added to the residue for crystallization to obtain 3-nitro4-phenoxyanisole sulfide.
  • 3-Nitro-4-phenoxyanisole sulfide (45g) was dissolved in 500ml of absolute ethanol, hydrogenated at room temperature for 3 hours under 10wt% palladium carbon and 0.3MPa hydrogen pressure, the reaction mixture was filtered, and the pressure was reduced. Concentration gave the reduced product. The reduced product was recrystallized from toluene to give 3-amino-4-phenoxyanisole sulfide.
  • 3-Amino-4-phenoxyanisole sulfide (30 g) was dissolved in 150 ml of pyridine, 18 g of methanesulfonyl chloride was added at a temperature of 0-5°C, and 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, and the organic phase was washed with 100 ml of 1M dilute hydrochloric acid and 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-phenoxyanisole sulfide.
  • Aluminium trichloride (54g) and aminoacetonitrile hydrochloride (18.5g) were added in batches to 200ml of nitrobenzene stirring constantly at room temperature, cooled to 10°C, and 3-methylsulfonamido-4- Phenoxyanisole sulfide was introduced into hydrogen chloride gas and stirred at 25-30°C 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-methylthio-4-methanesulfonamido-5-phenoxy Acetophenone hydrochloride.
  • 3-Nitro-4-phenylthioanisole (45 g) was dissolved in 500 ml of absolute ethanol, and hydrogenated at room temperature for 3 hours under 10 wt% palladium carbon and 0.3 MPa hydrogen pressure. 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 sulfide.
  • 3-Amino-4-phenylthioanisole sulfide (30 g) was dissolved in 150 ml of pyridine, 18 g of methanesulfonyl chloride was added at a temperature of 0-5°C, and 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, washed with water, the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol to obtain 3-methylsulfonamido-4-phenylthioanisole.
  • Aluminium trichloride (54g) and aminoacetonitrile hydrochloride (18.5g) were added in batches to 200ml of nitrobenzene stirring constantly at room temperature, cooled to 10°C, and 3-methylsulfonamido-4- Phenylthioanisole was introduced into hydrogen chloride gas and stirred at 25-30°C 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-methylthio-4-methanesulfonamido-5-phenylthio Acetophenone hydrochloride.
  • 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.
  • the above components are compressed into tablets according to conventional methods.
  • rat adjuvant joint AA
  • the research on the anti-arthritis activity of the compounds of the present invention took the rat adjuvant joint (AA) as the animal model.
  • rat AA rat adjuvant joint
  • the compound of the present invention, blank and positive control substance isolamod 50 ⁇ g/time/day were administered to the stomach for 5 consecutive days.
  • the degree of swelling of the feet of the rats in each group before and after administration was measured by the drainage method, and the rats before and after administration were calculated. foot swelling Determine if the drug is working.
  • test results prove that the anti-inflammatory effects of the compounds of the present invention are better than those of iguratimod, and the anti-inflammatory effects of compound 4 and its salts are even better.
  • 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 aminotransferase. The test results are shown in Table 4 below.

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  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

本发明公开了一种式I所示的硫代苯并吡喃类化合物及其药学上可接受的盐在制备治疗类风湿性关节炎的药物中的应用，其中，X选自氧原子、硫原子、-SO-和-SO2-；Y为硫原子，Z为H、Na或K。通过初步抗炎活性试验，式I的化合物具有抗类风湿性关节炎作用。

Description

硫代苯并吡喃类化合物及其在制备治疗类风湿性关节炎药物中的应用
本申请要求于2020年07月25日提交中国专利局、申请号为2020107265649、发明名称为“一种硫代苯并吡喃类化合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硫代苯并吡喃类化合物及在制备治疗类风湿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，艾拉莫德是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，例如，氨基转移酶明显升高。因此，持续研制新的品种，是势在必行的。
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硫代苯并吡喃类化合物。
本发明所述的硫代苯并吡喃类化合物具有以下式I所示的结构：
Figure PCTCN2021107802-appb-000001
其中，X选自O(氧)、S(硫)、-SO-(亚硫酰基)、-SO 2-(硫酰基)；Y为S(硫)；Z为H、Na或K。
简而言之，本发明化合物是具有硫代苯并吡喃甲磺酰胺基本结构的一系列衍生物。
具体而言，本发明的硫代苯并吡喃类化合物可以是化合物：
Figure PCTCN2021107802-appb-000002
Figure PCTCN2021107802-appb-000003
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。本发明的硫代吡喃类化合物经初步抗炎试验，具有较强的抗炎效果且艾拉莫德具有更低的毒副作用。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是本发明化合物1的质谱图。
图2是本发明化合物1钠盐的质谱图。
图3是本发明化合物1钾盐的质谱图。
图4是本发明化合物2的质谱图。
图5是本发明化合物2钠盐的质谱图。
图6是本发明化合物2钾盐的质谱图。
图7是本发明化合物3的质谱图。
图8是本发明化合物3钠盐的质谱图。
图9是化合物3钾盐的质谱图。
图10是本发明化合物4的质谱图。
图11是本发明化合物4钠盐的质谱图。
图12是本发明化合物4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。
本发明化合物制备选用了市面上常见的化工原料，经过一系列步骤，得到目标化合物， 部分反应步骤参考了US4411910关于艾拉莫德的制备方法，用反应方程式表示如下：
Figure PCTCN2021107802-appb-000004
其中，X为O或S。
实施例1
3-硝基4-苯氧基苯甲硫醚的合成
将苯酚(32.9g)和4-氯-3-硝基苯甲硫醚(50g)加入DMF 100ml中，搅拌均匀后再加入叔丁醇钾(47.5g)，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，水洗，有机相采用无水硫酸镁干燥，浓缩至干。向残留物加入二氯甲烷进行析晶，得到3-硝基4-苯氧基苯甲硫醚。
实施例2
3-氨基-4-苯氧基苯甲硫醚的合成
将3-硝基4-苯氧基苯甲硫醚(45g)溶于无水乙醇500ml中，在10wt％的钯碳及0.3MPa氢气气压下，室温氢化反应3小时，过滤反应混合物，减压浓缩得到还原产物。还原产物用甲苯重结晶，得到3-氨基-4-苯氧基苯甲硫醚。
实施例3
3-甲基磺酰胺基-4-苯氧基苯甲硫醚的合成
将3-氨基-4-苯氧基苯甲硫醚(30g)溶于吡啶150ml中，在0-5℃的温度下加入甲磺酰 氯18g，加完后再在室温下搅拌1小时。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，水洗。有机相用无水硫酸镁干燥，浓缩。残留物用乙醇重结晶，得到3-甲基磺酰胺基-4-苯氧基苯甲硫醚。
实施例4
α-氨基-2-甲硫基-4-甲磺酰胺基-5-苯氧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)在室温下分批加入不断搅着的硝基苯200ml中，冷却到10℃，加入3-甲基磺酰胺基-4-苯氧基苯甲硫醚，通入氯化氢气体，在25-30℃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-甲硫基-4-甲磺酰胺基-5-苯氧基苯乙酮盐酸盐。
实施例5
α-甲酰胺基-2-甲硫基-4-甲磺酰胺基-5-苯氧基苯乙酮的制备
将特戊酰氯(15g)溶于100ml丙酮中，加入一水合甲酸钠(17g)，在室温下剧烈搅拌4小时，然后加入α-氨基-2-甲硫基-4-甲磺酰胺基-5-苯氧基苯乙酮盐酸盐(33g)，再搅拌5小时，加入水300ml，有沉淀析出。将沉淀过滤，水洗，异丙醇洗涤，干燥得粗品。采用乙腈重结晶，得到纯品α-甲酰胺基-2-甲硫基-4-甲磺酰胺基-5-苯氧基苯乙酮。
实施例6
α-甲酰胺基-2-巯基-4-甲磺酰胺基-5-苯氧基苯乙酮的制备
在冰水浴下，控制温度低于20℃条件下，将三氯化铝(23g)加入100ml乙腈中，然后加入碘化钠12.8g、α-甲酰胺基-2-甲硫基-4-甲磺酰胺基-5-苯氧基苯乙酮(26g)，在20℃的温度下搅拌6小时，反应物倒入1wt％的亚硫酸钠水溶液350ml中，析出黄白色沉淀。将沉淀过滤，分别用水250ml和乙醇200ml洗涤，干燥得粗品。采用乙睛重结晶，得到纯品α-甲酰胺基-2-巯基-4-甲磺酰胺基-5-苯氧基苯乙酮。
实施例7
目标产品3-甲酰胺基-7-甲磺酰胺基-6-苯氧基-4H-I-硫代苯并吡喃-4-酮(即化合物1)的合成
将α-甲酰胺基-2-巯基-4-甲磺酰胺基-5-苯氧基苯乙酮(20g)在10℃下溶于二氯甲烷100ml中，然后加入N,N-二甲基甲酰胺二甲缩醛(20g)，加入三乙胺10ml，20℃下搅拌6小时，然后加入水150ml，过滤，滤饼分别用二氯甲烷、水和乙醇洗涤，干燥得粗品。将粗品采用乙腈重结晶，得到目标化合物，命名为化合物1。目标化合物离子的质荷比[M+H] + 为391.18，与目标化合物分子量(390.03)一致。
实施例8
3-硝基4-苯硫基苯甲硫醚的合成
将苯硫酚(32.9g)和4-氯-3-硝基苯甲硫醚(50g)加到DMF100ml中，搅拌均匀后再加入叔丁醇钾(47.5g)，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，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，得到3-硝基4-苯硫基苯甲硫醚。
实施例9
3-氨基-4-苯硫基苯甲硫醚的合成
将3-硝基4-苯硫基苯甲硫醚(45g)溶于无水乙醇500ml中，在10wt％的钯碳及0.3MPa氢气压力下，室温氢化反应3小时。过滤反应物混合物，减压浓缩得到还原产物，采用甲苯重结晶，得到3-氨基-4-苯氧基苯甲硫醚。
实施例10
3-甲基磺酰胺基-4-苯硫基苯甲硫醚的合成
将3-氨基-4-苯硫基苯甲硫醚(30g)溶于吡啶150ml中，在0-5℃的温度下加入甲磺酰氯18g，加完后再在室温下搅拌1小时。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，水洗，有机相用无水硫酸镁干燥，浓缩。残留物用乙醇重结晶得3-甲基磺酰胺基-4-苯硫基苯甲硫醚。
实施例11
α-氨基-2-甲硫基-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)在室温下分批加入不断搅着的硝基苯200ml中，冷却到10℃，加入3-甲基磺酰胺基-4-苯硫基苯甲硫醚，通入氯化氢气体，在25-30℃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-甲硫基-4-甲磺酰胺基-5-苯硫基苯乙酮盐酸盐。
实施例12
α-甲酰胺基-2-甲硫基-4-甲磺酰胺基-5-苯硫基苯乙酮的制备
将特戊酰氯(15g)溶于100ml丙酮中，加入一水合甲酸钠(17g)，在室温下剧烈搅拌4小时，然后加入α-氨基-2-甲硫基-4-甲磺酰胺基-5-苯硫基苯乙酮盐酸盐(33g)，再搅拌5 小时，加入水300ml，有沉淀析出。将沉淀过滤，水洗，异丙醇洗涤，干燥得粗品。采用乙腈重结晶，得到纯品α-甲酰胺基-2-甲硫基-4-甲磺酰胺基-5-苯硫基苯乙酮。
实施例13
α-甲酰胺基-2-巯基-4-甲磺酰胺基-5-苯硫基苯乙酮的制备
在冰水浴下，控制温度低于20℃条件下，将三氯化铝(23g)加入100ml乙腈中，然后加入碘化钠12.8g、α-甲酰胺基-2-甲硫基-4-甲磺酰胺基-5-苯硫基苯乙酮(26g)，在20℃搅拌6小时，反应物倒入1％的亚硫酸钠水溶液350ml中，析出黄白色沉淀，过滤，分别用水250ml和乙醇200ml洗涤，干燥得粗品。采用乙睛重结晶，得到纯品α-甲酰胺基-2-巯基-4-甲磺酰胺基-5-苯硫基苯乙酮。
实施例14
目标产品3-甲酰胺基-7-甲磺酰胺基-6-苯硫基-4H-1-硫代苯并吡喃-4-酮(即化合物2)的合成
将α-甲酰胺基-2-巯基-4-甲磺酰胺基-5-苯硫基苯乙酮(20g)在10℃下溶于二氯甲烷100ml中，然后加入N,N-二甲基甲酰胺二甲缩醛(20g)，加入三乙胺10ml，20℃下搅拌6小时，然后加入水150ml，过滤，滤饼分别用二氯甲烷、水和乙醇洗涤，干燥得粗品，乙腈重结晶，得到目标化合物，命名为化合物2。目标化合物离子的质荷比[M+H] +为407.15，与目标化合物分子量(406.01)一致。
实施例15
目标产品N-(7-(甲磺酰胺基)-4-氧-6-(苯亚磺酰基)-4H-硫代苯并吡喃-3-基)甲酰胺(即化合物3)的合成
将化合物2(15g)与水混合均匀，室温下滴加30wt％双氧水(4.1g)，加完后室温搅拌反应10小时至原料反应完全，过滤，水洗。将反应产物进行柱分离，得到目标化合物，命名为化合物3。目标化合物离子的质荷比[M+H] +为423.08，与目标化合物分子量(422.01)一致。
实施例16
目标产品N-(7-(甲磺酰胺基)-4-氧-6-(苯磺酰基)-4H-硫代苯并吡喃-3-基)甲酰胺(即化合物4)的合成
将化合物2(15g)与水混合均匀，室温下滴加30wt％双氧水(6.5g)，加完后室温搅拌反应10小时至原料反应完全，过滤，水洗。将反应产物进行柱分离，得到目标化合物4。 目标化合物离子的质荷比[M+H] +为439.18，与目标化合物分子量(438.00)一致。
实施例17
化合物1钠盐的制备
取1g化合物1置于烧瓶中，加入无水乙醇200ml，加热回流溶解，然后滴加乙醇钠182mg，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，过滤，固体用少量无水乙醇淋洗，干燥，即得化合物1钠盐。
采用同样的方法合成化合物2、化合物3和化合物4的钠盐。
实施例18
化合物1钾盐的制备
取1g化合物1，加入无水乙醇200ml，加热回流溶解，然后滴加乙醇钾187mg，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，过滤。固体用少量无水乙醇淋洗，干燥，即得化合物1钾盐。
采用同样的方法合成了化合物2、化合物3和化合物4的钾盐。
实施例19
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的方法装入硬胶囊中。
采用同样的方法制备化合物1的钠盐及钾盐的硬胶囊、化合物2及其钠盐的硬胶囊、钾盐、化合物3及其钠盐和钾盐、化合物4及其钠盐和钾盐的硬胶囊。
实施例20
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
将上述组分按照常规方法压制成片剂。
采用同样的方法制备化合物1及其钾盐钠盐的片剂、化合物2的钾盐及钠盐的片剂、化合物3及其钾盐和钠盐的片剂、化合物4及其钾盐和钠盐的片剂。
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，将大鼠分为十四组，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 PCTCN2021107802-appb-000005
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所示。
表3
Figure PCTCN2021107802-appb-000006
Figure PCTCN2021107802-appb-000007
试验结果证明，本发明化合物的抗炎效果均优于艾拉莫德，其中化合物4及其盐的抗炎效果更佳。
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所示。
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 10 125±10.24 75±8.22
化合物1钠盐组 10 129±10.18 76±9.22
化合物1钾盐组 10 126±10.05 78±8.74
化合物2组 10 108±9.43 80±9.28
化合物2钠盐组 10 104±9.05 76±9.56
化合物2钾盐组 10 109±9.11 77±9.02
化合物3组 10 143±7.83 90±8.76
化合物3钠盐组 10 140±8.83 87±9.06
化合物3钾盐组 10 141±7.89 89±8.91
化合物4组 10 133±9.04 79±9.82
化合物4钠盐组 10 130±9.15 83±8.09
化合物4钾盐组 10 132±8.79 85±6.87
从以上结果可以看出，服用本发明化合物所产生的副作用明显小于艾拉莫德，其中化合物2及其盐类副作用更小。

Claims (4)

  1. 一种式I所示的硫代苯并吡喃类化合物及其药学上可接受的盐，
    Figure PCTCN2021107802-appb-100001
    其中，X选自氧原子、硫原子、-SO-、-SO 2-；
    Y为硫原子；
    Z为H、Na或K。
  2. 根据权利要求1所述的硫代苯并吡喃类化合物及其药学上可接受的盐，其中，式I所示的硫代苯并吡喃类化合物选自以下化合物：
    Figure PCTCN2021107802-appb-100002
    Figure PCTCN2021107802-appb-100003
  3. 一种药物组合物，其特征在于，所述药物组合物包括权利要求1或2所述的硫代苯并吡喃类化合物或其药学上可接受的盐。
  4. 根据权利要求1或2所述的硫代苯并吡喃类化合物或其药学上可接受的盐在制备治疗类风湿性关节炎的药物中的应用。
PCT/CN2021/107802 2020-07-25 2021-07-22 硫代苯并吡喃类化合物及其在制备治疗类风湿性关节炎药物中的应用 WO2022022372A1 (zh)

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