WO2020192665A1 - 防治炎症反应的核苷类衍生物及其应用 - Google Patents

防治炎症反应的核苷类衍生物及其应用 Download PDF

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WO2020192665A1
WO2020192665A1 PCT/CN2020/080993 CN2020080993W WO2020192665A1 WO 2020192665 A1 WO2020192665 A1 WO 2020192665A1 CN 2020080993 W CN2020080993 W CN 2020080993W WO 2020192665 A1 WO2020192665 A1 WO 2020192665A1
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formula
group
acid
alkyl
preventing
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黄文�
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四川大学华西医院
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Priority to KR1020217034303A priority patent/KR20220046511A/ko
Priority to US17/605,676 priority patent/US20220288084A1/en
Publication of WO2020192665A1 publication Critical patent/WO2020192665A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine

Definitions

  • the invention belongs to the field of medicine, and relates to nucleoside derivatives for preventing and treating inflammatory reactions, and the application of the derivatives in preparing medicines for preventing and treating inflammatory diseases.
  • Inflammation is a basic biological response of the body against the invasion of pathogenic microorganisms, which can promote the repair of damaged cells and tissues and prevent further damage.
  • excessive inflammatory reactions can cause damage and necrosis of tissues, organs, and even organs throughout the body.
  • inflammation is a common and frequently-occurring disease that threatens human health.
  • people often use glucocorticoid steroidal anti-inflammatory drugs and traditional non-steroidal anti-inflammatory drugs.
  • the existing anti-inflammatory drugs can effectively control infectious and non-infectious inflammation, and can effectively eliminate the functional damage caused by inflammation, long-term use will cause the function of the adrenal cortex to decline and other complications.
  • traditional anti-inflammatory drugs have the shortcomings of poor selectivity and obvious side effects, their clinical application is greatly restricted. There is an urgent need for a new type of anti-inflammatory drugs with good curative effect and small side effects.
  • Pancreatitis is a common gastrointestinal disease.
  • the incidence of acute pancreatitis is 33.74 cases (per 100,000 people per year), and the mortality rate is 1.60 cases (per 100,000 people per year).
  • Acute pancreatitis in children has also become a more serious disease. The problem has become more and more common.
  • the current diagnosis and treatment levels are constantly improving, the incidence, recurrence and mortality of acute pancreatitis are still high.
  • the incidence of AP has also been increasing year by year.
  • the clinical epidemiological characteristics of 1,316 cases of acute pancreatitis in Guangdong show that from 1986 to 2005, the proportion of the total number of AP cases to the total number of hospitalizations in the same period increased from 0.19% rose to 0.71%.
  • the incidence of AP increased from 27.6 cases per 100,000 people in 1999 to 36.4 cases per 100,000 people in 2010, an average increase of 2.7% per year.
  • the main treatment plans include nutritional support and antibiotic treatment , Surgical treatment and integrated Chinese and Western medicine treatment. Therefore, it is necessary to develop drugs with significant anti-pancreatitis, especially acute pancreatitis effects.
  • the liver As an important organ of the body, the liver is responsible for the body's main metabolism, detoxification, secretion and other important physiological functions. At the same time, it is a lymphoid organ with unique immunological characteristics and participates in natural immunity and adaptive immune response. If liver function is impaired, It can produce various immune diseases. Autoimmune hepatitis is a chronic liver disease with unclear etiology and obvious autoimmune phenomena, with inflammatory necrosis as the main pathological change. The disease has a broad epidemiology, seriously harms human health, and brings more Economic losses.
  • Autoimmune hepatitis can lead to an increase in serum transaminases, the presence of autoantibodies in the circulation, hypergamma-globulinemia, characteristic changes in liver histology, and chronic inflammatory liver disease characterized by response to immunosuppressive therapy, which can lead to cirrhosis And liver failure. Therefore, it is necessary to develop drugs with significant anti-immune hepatitis effects.
  • Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic destructive joint disease. It mainly damages articular cartilage, bone, and joint capsule. In severe cases, it can lead to joint deformities and loss of function. Rheumatoid arthritis is characterized by synovitis, and the resulting destruction of articular cartilage and bone, which can eventually lead to joint deformities. Rheumatoid arthritis is likely to occur at all ages, with an incidence rate of about 1%, with a peak age of 30 to 50 years. Generally, the incidence rate in women is more than that in men; if not undergoing formal treatment, many patients will develop within 3 years Disabled.
  • Treatment methods mainly include general treatment, drug treatment, surgery and other treatments, but it is not clear which anti-rheumatic drugs should be the first choice for the treatment of rheumatoid arthritis to effectively improve the condition. If rheumatoid arthritis is not treated promptly and effectively, its disability rate is high.
  • the main purpose of treatment for rheumatoid arthritis is to control the condition, improve joint function and prognosis. There is an urgent need to develop drugs that are effective against rheumatoid arthritis.
  • the purpose of the present invention is to provide nucleoside derivatives for the prevention and treatment of inflammation in response to the defects and deficiencies of the existing drugs for preventing and treating inflammation, and the application of the derivatives in the preparation of drugs for preventing and treating inflammatory diseases, so as to improve the treatment of inflammatory diseases. Efficacy.
  • the nucleoside derivatives for preventing and treating inflammation provided by the present invention are obtained by modifying and optimizing the structure of coffee as the lead compound.
  • the structural formula of the nucleoside derivative for preventing and treating inflammation is as shown in formula (I) to formula (IV), or the derivative is a compound represented by formula (I) to formula (IV) that is pharmaceutically acceptable salt,
  • R 1 is H, an alkyl group, a heterocyclic group, an alkyl group substituted by an oxygen atom, a sulfur atom, a nitrogen atom or a halogen, an ester group, an amide group or an amino group
  • R 3 , R 4 is an alkyl group, a heterocyclic group, an alkyl group substituted by an oxygen atom, a sulfur atom, a nitrogen atom or a halogen
  • R 2 and R 5 are O or S
  • X and Y are N or C
  • Z is a halogen.
  • R 1 is preferably H, (C 1 -C 18 )alkyl, (C 3 -C 12 ) hetero Cyclic group, (C 1 -C 18 )alkyl, ester group, amide group or amino group substituted by oxygen atom, sulfur atom, nitrogen atom or halogen;
  • R 3 , R 4 are preferably (C 1 -C 3 )alkane base.
  • R 1 is H, (C 1 -C 3 )alkyl, (C 3 -C 12 )heterocyclic group, substituted by oxygen atom, sulfur atom, nitrogen atom or halogen (C 1 -C 3 ) Alkyl group, or a group equivalent to the formula -A 1 OC(O)A 2 , -A 1 NHA 2 , -A 1 NHCOA 2 , wherein A 1 and A 2 are (C 1 -C 3 )alkyl groups, (C 1 -C 3 ) alkyl substituted by oxygen atom, sulfur atom, nitrogen atom or halogen.
  • R 1 is H, (C 1 -C 3 )alkyl, or a group corresponding to the formula -A 1 OC(O)A 2 , -A 1 NHA 2 , -A 1 NHCOA 2 , Wherein A 1 and A 2 are (C 1 -C 3 ) alkyl groups. More preferably, in formulas (I) to (II), R 1 is (C 1 -C 3 )alkyl, or is equivalent to formula -A 1 OC(O)A 2 , -A 1 NHA 2 ,- A 1 NHCOA 2 group, where A 1 and A 2 are (C 1 -C 3 ) alkyl groups; in formulas (III) to (IV), R 1 is H.
  • nucleoside derivative for preventing and treating inflammation is any one of the following compounds 1-19, or a pharmaceutically acceptable salt of any one of the following compounds 1-19:
  • the compounds represented by formula (I) to formula (IV) are pharmaceutically acceptable salts
  • any one of compounds 1 to 19 is pharmaceutically acceptable Accepted salts are the compounds represented by formula (I) to formula (IV) and any one of compounds 1-19 with hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, An addition salt formed by pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the nucleoside derivatives for preventing and treating inflammation provided by the present invention can be combined with a pharmaceutically acceptable carrier to jointly exert the activity of preventing and treating inflammation.
  • the nucleoside derivatives for preventing and treating inflammation provided by the present invention can be prepared into preparations such as oral and injection by conventional methods of medicine.
  • the invention also provides the application of the above-mentioned nucleoside derivatives in the preparation of drugs for preventing and treating inflammatory diseases.
  • the inflammatory diseases include pancreatitis, hepatitis, arthritis, and related complications of pancreatitis, hepatitis, and arthritis.
  • the pancreatitis includes acute pancreatitis
  • hepatitis includes immune hepatitis
  • arthritis includes rheumatoid arthritis.
  • the present invention proves through animal experiments that the above-mentioned nucleoside derivatives for preventing and treating inflammation can significantly improve pancreatitis, hepatitis, arthritis and other conditions, improve organ damage and inflammatory indicators, and have better effects than the positive control drug indomethacin .
  • the present invention proves through experiments that the nucleoside derivatives for preventing and treating inflammation provided by the present invention can significantly improve pancreatitis, hepatitis, arthritis and other conditions, improve organ damage and inflammatory indexes, and have better effects than the positive control drug indomethacin Xin. Moreover, the present invention has been confirmed through experiments that compared with the traditional anti-inflammatory drugs aspirin, ibuprofen, indomethacin, phenylbutazone, diclofenac, piroxicam and glucocorticoids, the prevention and treatment of inflammation provided by the present invention
  • the nucleoside derivatives have the advantage of significantly fewer side effects.
  • the nucleoside derivatives for preventing and treating inflammation provided by the present invention have simple structure and synthesis process, are suitable for industrial production, can reduce production costs, and have the advantage of high economy.
  • the Blab/c mice were randomly divided into a blank control group, a model control group, a caffeine treatment group, and a compound 1 to compound 19 treatment group, with 10 mice in each group.
  • the model was made with sodium taurocholate, fasted for 12 hours before the experiment, water was not allowed, and the operation was performed in a sterile environment. Inject 3.5% sodium pentobarbital into the intraperitoneal cavity. After anesthesia, sterilize the surgical site with an alcohol cotton ball. Place a sterile gauze on the surgical site. Make a laparotomy at the width of two fingers under the xiphoid process.
  • caffeine and compound 1 to compound 19 were given by tail vein injection at a dose of 17.5 mg/kg at 1 h, 3 h, and 6 h after the pancreatitis model was constructed.
  • the blank control group and the model control group were given equal volumes of isotonic saline.
  • pancreatic tissue and blood samples were taken to evaluate the pathological damage score of pancreatitis and the level of pancreatic amylase in serum.
  • pancreatic tissue pathological damage scores and pancreatic amylase levels of the mice in each group are shown in Table 1. From Table 1, it can be seen that the compounds 1-19 provided by the present invention can effectively reduce the pancreatic starch in the pancreatitis model induced by sodium taurocholate. Enzyme levels reduce pancreatic damage.
  • Animals Four SD rats in a cage, kept under constant temperature (25 ⁇ 2°C) and lighting control (12h day/night cycle). The animals are kept on standard feed and kept for at least 7 days before the start of the experiment To adapt to the environment.
  • SD rats were randomly divided into blank control group, model control group, caffeine treatment group, indomethacin treatment group, and compound 1 to compound 19 treatment groups, with 10 rats in each group.
  • Model control group, caffeine treatment group, indomethacin treatment group, and compound 1 ⁇ compound 19 treatment group SD rats were intraperitoneally injected with 10% chloral hydrate solution at a dose of 3.5 mL/kg, and fixed in Supine position. Inject 0.1 mL of 1g/L sodium iodoacetate solution into the knee joint cavity. From the 5th day, the animals were driven to run for 30 minutes every day, and the animals were allowed to move freely in the cage during the rest of the time. After modeling, indomethacin and compound 1 to compound 19 were administered by intragastric administration at a dose of 100 mg/kg/d every day. The blank control group and the model control group were given equal volumes of isotonic saline.
  • the synovial fluid of each group of rats was taken to determine the content of MMP-13, and the rats were sacrificed to cut the subchondral bone plate of the medial tibial condyle of the right knee for processing into specimens and pathological scores.
  • the content of MMP-13 measured in the synovial fluid of each group of rats and the joint histopathological score are shown in Table 2. It can be seen from Table 2 that compared with the model control group, the compound 1 to compound 19 treatment group can effectively reduce the MMP of the arthritis model -13 level, reduce joint damage. At the same time, compared with the positive control drug indomethacin treatment group, the compound 1 to compound 19 treatment group has a significantly better improvement effect on arthritis.
  • Blab/c mice After adaptive feeding of Blab/c mice for one week, they were randomly divided into blank control group, model control group, caffeine treatment group, indomethacin treatment group, and compound 1 to compound 19 treatment groups, each with 10 mice.
  • indomethacin and compound 1 to compound 19 were administered by intragastric administration at a dose of 50 mg/kg every day.
  • the blank control group and the model control group were given equal volumes of isotonic saline.
  • ALT serum alanine aminotransferase
  • AST aspartate aminotransferase
  • mice in each group After administration for 6h, 12h, 24h and 48h, the serum alanine aminotransferase and aspartate aminotransferase levels of mice in each group are shown in Table 3. From Table 3, it can be seen that compared with the model control group, the compound The 1 ⁇ Compound 19 treatment group can significantly reduce serum alanine aminotransferase and aspartate aminotransferase levels, and reduce liver damage. At the same time, compared with the positive control drug indomethacin treatment group, the compound 1 to compound 19 treatment group has a significantly better improvement effect on hepatitis.
  • Compound 1-19 was administered to C57 mice at a dose of 100 mg/Kg/d for 180 consecutive days.
  • the administration method was intragastric administration.
  • the mice were intraperitoneally injected with sodium pentobarbital (40 mg /kg) Anesthetize, put it on a constant temperature hot plate at 37 ⁇ 1°C, take blood from heart puncture or make pathological section to detect side effects (gastrointestinal reaction, nervous system toxicity, blood system toxicity, allergic reaction, nephrotoxicity, liver Toxicity, rash and asthma).

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Abstract

本发明提供了一类防治炎症反应的核苷类衍生物，以及该衍生物在制备防治炎症疾病的药物中的应用。本发明提供的防治炎症反应的核苷类衍生物能够明显改善胰腺炎、肝炎、关节炎等病情，改善器官受损和炎性指标，效果优于阳性对照药吲哚美辛。相比于传统抗炎药物阿司匹林、布洛芬、吲哚美辛、保泰松、双氯芬酸、吡罗昔康以及糖皮质激素，本发明提供的防治炎症反应的核苷类衍生物具有副作用明显更小的优势。

Description

防治炎症反应的核苷类衍生物及其应用 技术领域
本发明属于药物领域，涉及防治炎症反应的核苷类衍生物，以及该衍生物在制备防治炎症疾病的药物中的应用。
背景技术
炎症是机体对抗病原微生物入侵的一种基本生物学反应，可促进损伤细胞和组织修复，并阻止其进一步的损伤。然而，过度的炎性反应会导致组织器官乃至全身器官的损伤和坏死。
目前，炎症是一种威胁人类健康的常见病和多发病，对于炎症的治疗，人们常使用糖皮质激素类甾体抗炎药及传统非甾体抗炎药。即使现有的抗炎药物能够有效控制感染性炎症和非感染性炎症，并能有效消除炎症造成的功能性损伤障碍，但长期使用会引发肾上腺皮质的功能衰退以及其他并发症。由于传统抗炎药具有选择性较差和副作用明显的缺点，所以在临床应用受到很大限制，临床上急需一类疗效好且副作用小的新型抗炎药问世。
患者服用以地塞米松为主的糖皮质激素后，约35％的患者会出现显著的的不良反应，并且多发生在应用药理剂量时，与疗程、剂量、用药种类、用法及给药途径等有密切关系。常见不良反应有以下几类：医源性库欣综合征面容和体态、患者出现精神症状如谵妄等。核苷酸类衍生物进入体内后可以代谢成对人体有利的产物，并且对于炎症反应有较为显著的疗效，其不良反应的发生率低至3％。
胰腺炎是常见的胃肠道疾病，急性胰腺炎发生率为33.74例(每10万人每年)，死亡率为1.60例(每10万人每年)，而儿童患有急性胰腺炎也成为一个越来越普遍的问题。虽然现有诊断水平和治疗水平在不断地提高，但是急性胰腺炎的发病率、复发率和死亡率仍居高不下。在我国，AP发病率也呈逐年升高趋势，广东地区1316例急性胰腺炎的临床流行病学特征结果显示，从1986年至2005年，AP病例的总数占同期内外科住院总人数的比例由0.19％升至0.71％。在英国，AP的发病率从1999年的27.6例每10万人上升到2010年的36.4例每10万人，每年平均增加2.7％。对于急性胰腺炎的治疗，目前尚无特异性治疗方案，根据中国急性胰腺炎诊治指南(2014)和美国胃肠病学会急性胰腺炎治疗指南(2013)，主要的治疗方案有营养支持、抗生素治疗、外科手术治疗和中西医结合治疗。因此，研发具有显著抗胰腺炎、特别是急性胰腺炎效果的药物是很有必要的。
肝脏作为机体的重要器官，承担着机体的主要代谢、解毒、分泌等重要生理功能，同时它又是具有独特免疫学特性的淋巴器官，参与天然免疫和适应性免疫反应，若肝脏功能出现 障碍，则可产生各种免疫性疾病。自身免疫性肝炎是一种病因不明确且伴有明显自身免疫现象，以炎症性坏死为主要病理改变的慢性肝脏疾病，该病的流行病学较广，严重危害人类健康，且带来较大经济损失。自身免疫性肝炎可导致血清转氨酶的升高，循环中存在自身抗体，高γ-球蛋白血症、肝组织学特征性改变及对免疫抑制治疗应答为特点的慢性炎症性肝病，可导致肝硬化和肝衰竭。因此，研发抗免疫性肝炎效果显著的药物也是十分必要的。
类风湿关节炎是一种以慢性破坏性关节病变为主要特征的全身性自身免疫疾病，主要损害关节软骨、骨、关节囊，严重时可导致关节畸形和功能丧失等后果。类风湿关节炎病变特点为滑膜炎，及其由此导致的关节软骨和骨质的破坏，最终可导致关节畸形。类风湿关节炎在各年龄中皆有可能发病，其发病率在1％左右，高峰年龄在30～50岁，一般女性发病率多于男性；若不经过正规治疗，很多患者会在3年内出现残废。治疗方法主要包括一般治疗、药物治疗、外科手术以及其他治疗等，但目前尚不清楚治疗类风湿关节炎应首选何种抗风湿药物来有效改善病情。类风湿关节炎若未得到及时有效的治疗，则其致残率高，对于类风湿关节炎的治疗目的主要在于控制病情，改善关节功能和预后。目前迫切需要研发出可有效抗类风湿关节炎的药物。
发明内容
本发明的目的在于针对现有防治炎症的药物存在的缺陷和不足，提供防治炎症反应的核苷类衍生物，以及该衍生物在制备防治炎症疾病的药物中的应用，以改善对炎症疾病的疗效。
本发明提供的防治炎症反应的核苷类衍生物是以咖啡因为先导化合物，通过对其进行结构修饰和优化得到的。所述防治炎症反应的核苷类衍生物的结构式如式(Ⅰ)～式(Ⅳ)所示，或者该衍生物为式(Ⅰ)～式(Ⅳ)所示的化合物在药学上可接受的盐，
Figure PCTCN2020080993-appb-000001
式(Ⅰ)～式(Ⅳ)中，R 1为H，烷基，杂环基，被氧原子、硫原子、氮原子或卤素取代的烷基，酯基，酰胺基或胺基；R 3、R 4为烷基，杂环基，被氧原子、硫原子、氮原子或卤素取代的烷基；R 2、R 5为O或S，X、Y为N或C，Z为卤素。
上述防治炎症反应的核苷类衍生物的技术方案中，式(Ⅰ)～式(Ⅳ)中，R 1优选为H，(C 1-C 18)烷基，(C 3-C 12)杂环基，被氧原子、硫原子、氮原子或卤素取代的(C 1-C 18)烷基，酯基，酰胺基或胺基；R 3、R 4优选为(C 1-C 3)烷基。
进一步优选地，R 1为H，(C 1-C 3)烷基，(C 3-C 12)杂环基，被氧原子、硫原子、氮原子或卤素取代的(C 1-C 3)烷基，或者为相当于式-A 1OC(O)A 2、-A 1NHA 2、-A 1NHCOA 2的基团，其中A 1、A 2为(C 1-C 3)烷基、被氧原子、硫原子、氮原子或卤素取代的(C 1-C 3)的烷基。
更进一步优选地，R 1为H，(C 1-C 3)烷基，或者为相当于式-A 1OC(O)A 2、-A 1NHA 2、-A 1NHCOA 2的基团，其中A 1、A 2为(C 1-C 3)烷基。更进一步优选地，式(Ⅰ)～式(Ⅱ)，R 1为(C 1-C 3)烷基，或者为相当于式-A 1OC(O)A 2、-A 1NHA 2、-A 1NHCOA 2的基团，其中A 1、A 2为(C 1-C 3)烷基；式(Ⅲ)～式(Ⅳ)中，R 1为H。
再进一步优选地，上述防治炎症反应的核苷类衍生物为下述化合物1～19中的任意一种，或者为下述化合物1～19中的任意一种在药学上可接受的盐：
Figure PCTCN2020080993-appb-000002
上述防治炎症反应的核苷类衍生物的技术方案中，式(Ⅰ)～式(Ⅳ)所示的化合物在药学上可接受的盐，以及化合物1～19中的任意一种在药学上可接受的盐为式(Ⅰ)～式(Ⅳ)所示的化合物以及化合物1～19中的任意一种与盐酸、氢溴酸、硫酸、碳酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲基苯磺酸或阿魏酸形成的加成盐。
本发明提供的防治炎症反应的核苷类衍生物可与药学上接受的载体相结合共同发挥防治炎症反应的活性。本发明提供的防治炎症反应的核苷类衍生物可采用药物常规方法制备成口服、注射等制剂。
本发明还提供了上述核苷类衍生物在制备防治炎症疾病的药物中的应用。进一步地，所述的炎症疾病包括胰腺炎、肝炎、关节炎，以及胰腺炎、肝炎、关节炎的相关并发症。更进一步地，所述胰腺炎包括急性胰腺炎，肝炎包括免疫性肝炎，关节炎包括类风湿关节炎。本发明通过动物实验证实了上述防治炎症反应的核苷类衍生物可明显改善胰腺炎、肝炎、关节炎等病情，改善器官受损和炎性指标，且效果优于阳性对照药吲哚美辛。
与现有技术相比，本发明的技术方案具有以下有益的技术效果：
本发明通过实验证实了本发明提供的防治炎症反应的核苷类衍生物能够明显改善胰腺炎、肝炎、关节炎等病情，改善器官受损和炎性指标，效果优于阳性对照药吲哚美辛。并且，本发明通过实验证实了，相比于传统抗炎药物阿司匹林、布洛芬、吲哚美辛、保泰松、双氯芬酸、吡罗昔康以及糖皮质激素等而言，本发明提供的防治炎症反应的核苷类衍生物具有副作用明显更小的优势。此外，本发明提供的防治炎症反应的核苷类衍生物的结构和合成工艺简单，适应于工业化生产，可降低生产成本，具有经济性高的优势。
具体实施方式
以下通过实施例对本发明提供的防治炎症反应的核苷类衍生物，以及该衍生物在制备防治炎症疾病的药物中的应用作进一步说明。有必要指出，以下实施例只用于对本发明作进一步说明，不能理解为对本发明保护范围的限制，所属领域技术人员根据上述发明内容，对本发明做出一些非本质的改进和调整进行具体实施，仍属于发明保护的范围。
实施例1
本实施例中，合成化合物1～19。
1.合成化合物1：1-乙基-3-7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加碘乙烷2mL(24.7mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得495mg(2.5mmol)化合物1，产率85％。
对化合物1进行核磁氢谱、核磁碳谱和质谱检测，结果为： 1H NMR(400MHz,DMSO)δ8.00(s,1H),3.92–3.85(m,5H),3.40(s,3H),1.11(t,J＝7.0Hz,3H)。
13C NMR(101MHz,DMSO)δ154.09(s),150.54(s),148.08(s),142.75(s),106.56(s),35.44(s),33.05(s),29.20(s),13.02(s)。
HRMS(TOF MS ES+)for C 9H 12N 4O 2Na +(M+Na +)calcd 231.0858,found 231.0856。
2.合成化合物2：7-异丙基-3-7-二甲基黄嘌呤
取茶碱1.08g(6mmoL)、NaH 1.8g(75mmol)溶于100mL DMF中，在搅拌下滴加碘代异丙烷10mL(100mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得1.83g(5.3mmol)化合物2，产率88％。
对化合物2进行核磁氢谱、核磁碳谱和质谱检测，结果为： 1H NMR(600MHz,DMSO)δ8.19(s,1H),4.91(hept,J＝6.5Hz,1H),3.42(s,3H),3.23(s,3H),1.50(d,J＝6.7Hz,6H)。
13C NMR(151MHz,DMSO)δ154.69(s),151.36(s),149.16(s),140.57(s),106.14(s),49.88(s),29.85(s),28.13(s),22.90(s)。
HRMS(TOF MS ES+)for C 10H 14N 4O 2Na +(M+Na +)calcd 245.1009,found 245.1013。
3.合成化合物3：1-乙基-3,9-二甲基黄嘌呤
取3,9-二甲基黄嘌呤3mmoL、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加碘乙烷2mL(24.7mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物3，产率89％。
对化合物3进行核磁氢谱检测，结果为： 1H NMR(400MHz,Methanol-d 4)δ7.88(s,1H),3.92(q,2H),3.72(s,3H),3.28(s,3H),1.14(t,3H)。
4.合成化合物4：1,3-二甲基-7-乙基黄嘌呤
取1,3-二甲基黄嘌呤3mmoL、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加碘乙烷2mL(24.7mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物4，产率86％。
对化合物4进行核磁氢谱、核磁碳谱和质谱检测，结果为： 1H NMR(400MHz,DMSO)δ8.08(s,1H),4.26(q,J＝7.2Hz,2H),3.41(s,3H),3.22(s,3H),1.39(t,J＝7.2Hz,3H)。
13C NMR(101MHz,DMSO)δ154.17,150.94,148.37,141.78,105.75,41.44,29.32,27.47,16.24.
HRMS(TOF MS ES+)for C 9H 12N 4O 2Na +(M+Na +)calcd 231.0858,found 231.0858。
5.合成化合物5：1,7-二乙基-3-甲基黄嘌呤
取3-甲基黄嘌呤3mmoL、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加碘乙烷4mL(49.4mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物5，产率92％。
对化合物5进行核磁氢谱、核磁碳谱和质谱检测，结果为： 1H NMR(400MHz,DMSO)δ8.09(s,1H),4.28(q,J＝7.2Hz,2H),3.91(q,J＝7.0Hz,2H),3.42(s,3H),1.41(t,J＝7.2Hz,3H),1.13(t,J＝7.0Hz,3H)ppm。
13C NMR(101MHz,DMSO)δ153.80(s),150.52(s),148.42(s),141.79(s),105.83(s),41.43(s),35.51(s),29.22(s),16.19(s),13.01(s)ppm。
HRMS(TOF MS ES+)for C 10H 14N 4O 2Na +(M+Na +)calcd 245.1014,found 245.1016。
6.合成化合物6：9-异丙基次黄嘌呤
取次黄嘌呤6mmoL、NaH 1.8g(75mmol)溶于100mL DMF中，在搅拌下滴加碘代异 丙烷10mL(100mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物6，产率75％。
对化合物6进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ8.28(d,J＝7.6Hz,1H),7.64(s,1H),4.73(p,J＝6.3Hz,1H),1.52(d,J＝6.8Hz,6H)。
7.合成化合物7：1,7-二异丙基-3-甲基黄嘌呤
取3-甲基黄嘌呤6mmoL、NaH 1.8g(75mmol)溶于100mL DMF中，在搅拌下滴加碘代异丙烷10mL(100mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即化合物7，产率87％。
对化合物7进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ8.33(s,1H),4.92(hept,J＝6.2Hz,1H),4.32(hept,J＝6.2Hz,1H),3.21(s,2H),1.51(d,J＝6.1Hz,5H),1.31(d,J＝6.1Hz,5H)。
8.合成化合物8：1-(乙酸-2-乙酯)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加2-碘乙醇4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-乙羟基-3-7-二甲基黄嘌呤，产率94％。
取1-乙羟基-3-7-二甲基黄嘌呤3mmol，乙酸酐3mmol，氢氧化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物8，产率82％。
对化合物8进行核磁氢谱检测，结果为： 1H NMR(400MHz,DMSO)δ8.02(s,1H),4.20(t,J＝5.5Hz,2H),4.11(t,J＝5.6Hz,2H),3.88(s,3H),3.41(s,3H),1.95(s,3H). 13C NMR(101MHz,DMSO)δ170.74(s),154.86(s),151.39(s),148.82(s),143.52(s),107.01(s),61.34(s),33.63(s),29.83(s),21.09(s)。
9.合成化合物9：1-(丙酸-2-乙酯)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加2-碘乙醇4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-乙羟基-3-7-二甲基黄嘌呤，产率94％。
取1-乙羟基-3-7-二甲基黄嘌呤3mmol，丙酸酐3mmol，氢氧化钠0.3mmol，溶于80mLDMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物9，产率80％。
对化合物9进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.54(s,1H), 4.34(t,J＝6.3Hz,1H),3.76(s,1H),3.54(t,J＝6.32Hz,1H),3.54(s,1H),2.34(q,J＝7.4Hz,1H),1.43(t,J＝7.9Hz,1H)。
10.合成化合物10：1-(异丙酸-2-乙酯)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加2-碘乙醇4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-乙羟基-3-7-二甲基黄嘌呤，产率94％。
取1-乙羟基-3-7-二甲基黄嘌呤3mmol，异丙酸酐3mmol，氢氧化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物10，产率81％。
对化合物10进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.62(s,0H),4.43(t,J＝6.2Hz,1H),3.46(s,1H),3.48(t,J＝6.5Hz,1H),3.43(s,1H),2.53(hept,J＝7.2Hz,0H),1.25(d,J＝7.4Hz,3H)。
11.合成化合物11：1-(2-甲氨基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，甲胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物11，产率80％。
对化合物11进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.54(s,1H),4.33(t,J＝5.1Hz,2H),3.77(s,2H),3.32(s,2H),2.84(td,J＝5.4,3.5Hz,2H),2.56(d,J＝4.8Hz,3H),2.34(qt,J＝4.3,3.5Hz,1H)。
12.合成化合物12：1-(2-乙氨基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，乙胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物12，产率78％。
对化合物12进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.54(s,1H),4.01–3.72(m,4H),3.41(s,2H),2.83(td,J＝5.2,4.0Hz,2H),2.76(p,J＝4.3Hz,1H),2.62(qd,J＝7.2,4.2Hz,2H),1.32(t,J＝7.3Hz,3H)。
13.合成化合物13：1-(2-异丙氨基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，异丙胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物13，产率79％。
对化合物13进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),4.23(t,J＝5.3Hz,2H),3.84(s,2H),3.41(s,2H),3.03(td,J＝5.5,3.5Hz,2H),2.81(dp,J＝7.4,6.4Hz,1H),2.35(dt,J＝7.3,3.7Hz,1H),1.13(d,J＝6.1Hz,6H)。
14.合成化合物14：1-(2-丙氨基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，丙胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物14，产率78％。
对化合物14进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.63(s,1H),4.03(t,J＝5.4Hz,2H),3.92(s,2H),3.48(s,2H),2.82(td,J＝5.4,4.2Hz,2H),2.76(p,J＝4.3Hz,1H),2.86(td,J＝6.2,4.2Hz,2H),1.54(qt,J＝7.4,6.1Hz,2H),0.92(t,J＝7.4Hz,3H)。
15.合成化合物15：1-(2-乙酰基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，乙酰胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物15，产率79％。
对化合物15进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.54–7.65(m,1H),4.12(t,J＝5.4Hz,1H),3.65(s,1H),3.65(td,J＝5.4,4.4Hz,1H),3.48(s,1H),1.87(s,1H)。
16.合成化合物16：1-(2-丙酰基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，丙酰胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物16，产率76％。
对化合物16进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.54(t,J＝4.1Hz,1H),7.65(s,1H),4.21(t,J＝5.3Hz,2H),3.76(s,2H),3.65(td,J＝5.4,4.4Hz,2H),3.54(s,2H),2.24(q,J＝7.9Hz,2H),1.25(t,J＝7.9Hz,3H)。
17.合成化合物17：1-(2-异丙酰基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，异丙酰胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物17，产率79％。
对化合物17进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.65(t,J＝4.4Hz,1H),4.43(t,J＝5.3Hz,2H),3.65(s,2H),3.65(td,J＝5.5,4.1Hz,2H),3.43(s,2H),2.35(hept,J＝7.2Hz,1H),1.32(d,J＝7.3Hz,5H)。
18.合成化合物18：1-(2-丁酰基乙基)-3,7-二甲基黄嘌呤
取可可碱540mg(3mmoL)、NaH 720mg(30mmol)溶于80mL DMF中，在搅拌下滴加1,2-二碘乙烷4mmol，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物1-(2-碘代乙基)3-7-二甲基黄嘌呤，产率89％。
取1-(2-碘代乙基)3-7-二甲基黄嘌呤3mmol，丁酰胺3mmol，氢化钠0.3mmol，溶于80mL DMF中，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH3CH2OCOCH3＝3:1(v/v)作为流动相过硅胶柱，即得化合物18，产率79％。
对化合物18进行核磁氢谱检测，结果为： 1H NMR(500MHz,Chloroform-d)δ7.73–7.62(m,1H),4.13(t,J＝5.5Hz,1H),3.76(s,1H),3.46(td,J＝5.4,4.2Hz,1H),3.43(s,1H),2.43–2.13(m,1H),1.54(h,J＝7.4Hz,1H),0.98(t,J＝7.4Hz,1H)。
19.合成化合物19：3-异丙基-5-氟尿嘧啶
取5-氟尿嘧啶6mmoL、NaH 1.8g(75mmol)溶于100mL DMF中，在搅拌下滴加碘代异丙烷1mL(10mmol)，反应4小时后加水淬灭反应，减压旋干，以石油醚:CH 3CH 2OCOCH 3＝3:1(v/v)作为流动相过硅胶柱，即得化合物19，产率87％。
对化合物19进行核磁氢谱检测，结果为： 1H NMR(400MHz,DMSO)δ11.72(s,1H),8.13(d,J＝7.3Hz,1H),4.64(dt,J＝13.6,6.8Hz,1H),1.24(d,J＝6.8Hz,6H)。
实施例2
实施例中，测试实施例1制备的化合物1～19对胰腺炎的改善作用。
1.试验方法
(1)动物：成年健康雄性Blab/c小鼠，25～30g。
(2)分组
将Blab/c小鼠随机分为空白对照组、模型对照组、咖啡因治疗组、以及化合物1～化合物19治疗组，每组10只。
(3)构建胰腺炎模型
牛黄胆酸钠造模，实验前禁食12h，不禁水，在无菌环境下进行手术。用3.5％的戊巴比妥钠腹腔注射，麻醉后，用酒精棉球将手术部位消毒，无菌纱布置于手术部位，于剑突下两手指宽度处剖腹，看到肝脏后开始往下切口，将生理盐水浸湿的棉签伸入腹腔，于肝脏背部寻找十二指肠，将其翻出置于无菌纱布上，寻找胰胆管和十二指肠乳头，以对准乳头方向用1mL注射器针头在十二指肠上穿一个孔，将24G留置针软管沿着乳头插入胰胆管中，用动脉血管夹将肝脏下方总胆管闭合，以0.1mL/100g的剂量和0.1mL/min的流速注射浓度为3.8％的牛黄胆酸钠，此过程中注意将生理盐水滴加到暴露在外的胰腺和十二指肠上，保持湿润，注射完毕后慢慢将软管取出，继续闭合胆总管，3min后将血管动脉夹取下，还纳十二指肠，双层缝合腹腔。空白对照组注射等体积等渗盐水。
(4)给药
对于咖啡因治疗组、以及化合物1～化合物19治疗组，分别于构建胰腺炎模型后1h、3h、6h按照17.5mg/kg的剂量尾静脉注射给予咖啡因、化合物1～化合物19。
空白对照组及模型对照组给予等体积的等渗盐水。
(5)指标测定
24h后，取胰腺组织和血样，评价胰腺炎组织病理损伤评分和血清中胰淀粉酶水平。
2.结果
各组小鼠的胰腺组织病理损伤评分以及胰淀粉酶水平如表1所示，由表1可知，本发明提供的化合物1～19可以有效降低牛磺胆酸钠诱导的胰腺炎模型的胰淀粉酶水平，减轻胰腺受损。
表1各组小鼠的胰腺组织病理损伤评分以及胰淀粉酶水平(n＝10)
Figure PCTCN2020080993-appb-000003
实施例3
实施例中，测试实施例1制备的化合物1～19对关节炎的改善作用。
1.试验方法
(1)动物：SD大鼠四只一笼，饲养在恒温(25±2℃)、照明控制(12h白天/黑夜循环)的条件下，动物均以标准饲料饲养，实验开始前至少饲养7天以适应环境。
(2)分组
将SD大鼠随机分为空白对照组、模型对照组、咖啡因治疗组、吲哚美辛治疗组、以及化合物1～化合物19治疗组，每组10只。
(3)SD大鼠术前12h禁食，并在手术开始前称重记录。空白对照组不做任何处理。
模型对照组、咖啡因治疗组、吲哚美辛治疗组、以及化合物1～化合物19治疗组SD大鼠按照3.5mL/kg的剂量腹腔注射10％水合氯醛溶液，待麻醉完全后，固定于仰卧位。于膝关节腔内注射1g/L碘乙酸钠溶液0.1mL。从第5天起每天驱赶动物奔跑30min，其余时间任其笼内自由活动。造模后按100mg/kg/d的剂量，每天灌胃给予吲哚美辛、化合物1～化合物19。空白对照组及模型对照组给予等体积的等渗盐水。
(4)指标测定
术后第4周抽取各组大鼠的关节液测定MMP-13的含量，处死大鼠切取右膝胫骨内髁软骨下骨板，以处理成标本，并做病理学评分。
2.结果
各组大鼠的关节液测定MMP-13的含量和关节病理组织评分如表2所示，由表2可知，相对于模型对照组，化合物1～化合物19治疗组可以有效降低关节炎模型的MMP-13水平，减轻关节受损。同时，相对于阳性对照药吲哚美辛治疗组，化合物1～化合物19治疗组对关节炎的改善作用明显更好。
表2各组大鼠的关节液测定MMP-13的含量和关节病理组织评分(n＝10)
Figure PCTCN2020080993-appb-000004
Figure PCTCN2020080993-appb-000005
实施例4
实施例中，测试实施例1制备的化合物1～19对肝炎的改善作用。
1.试验方法
(1)动物：成年健康雄性Blab/c小鼠，25～30g。
(2)分组
将Blab/c小鼠适应性喂养一周后，随机分为空白对照组、模型对照组、咖啡因治疗组、吲哚美辛治疗组、以及化合物1～化合物19治疗组，每组10只。
(3)模型对照组、咖啡因治疗组、吲哚美辛治疗组、以及化合物1～化合物19治疗组Blab/c小鼠按照的15mg/kg剂量，尾静脉注射刀豆蛋白A(ConA)溶液形成小鼠肝炎模型。空白对照组注射等体积的等渗盐水。
造模后按50mg/kg的剂量，每天灌胃给予吲哚美辛、化合物1～化合物19。空白对照组及模型对照组给予等体积的等渗盐水。
(4)指标测定
分别于给药后6h、12h、24h及48h摘眼球取血及肝脏组织。检测血清丙氨酸氨基转移酶(alanine transaminase,ALT)和天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)水平。
2.结果
(1)血清血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶水平
在给药6h、12h、24h及48h后，各组小鼠血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶水平如表3所示，由表3可知，相对于模型对照组，化合物1～化合物19治疗组可以显著降低血清血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶水平，减轻肝脏受损。同时，相对于阳性对照药吲哚美辛治疗组，化合物1～化合物19治疗组对肝炎的改善作用明显更好。
表3各组小鼠的血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶水平(n＝10)
Figure PCTCN2020080993-appb-000006
Figure PCTCN2020080993-appb-000007
实施例5
本实施例中，对实施例1制备的化合物1-19进行毒性分析。
以100mg/Kg/d剂量给予C57小鼠化合物1-19，连续给药180天，给药方式为灌胃给药，在最后一次给予药物1h后，小鼠腹腔注射戊巴比妥钠(40mg/kg)麻醉，将其放在37±1℃的恒温热板上，心脏穿刺取血或做病理切片检测副作用(胃肠道反应、神经系统毒性、血液系统毒性、过敏反应、肾毒性、肝毒性、皮疹及哮喘)。按照与化合物1-19相同的给药方式设置阿司匹林、布洛芬、吲哚美辛、保泰松、双氯芬酸、吡罗昔康以及糖皮质激素组进行副作用考察。结果如表4所示，相比于传统的抗炎药物阿司匹林、布洛芬、吲哚美辛、保泰松、双氯芬酸、吡罗昔康以及糖皮质激素，本发明提供的化合物1-19具有副作用明显更小的优势。
表4毒性测试结果
Figure PCTCN2020080993-appb-000008
Figure PCTCN2020080993-appb-000009

Claims (9)

  1. 防治炎症反应的核苷类衍生物，其特征在于，该衍生物的结构式如式(Ⅰ)～式(Ⅳ)所示，或者该衍生物为式(Ⅰ)～式(Ⅳ)所示的化合物在药学上可接受的盐，
    Figure PCTCN2020080993-appb-100001
    式(Ⅰ)～式(Ⅳ)中，R 1为H，烷基，杂环基，被氧原子、硫原子、氮原子或卤素取代的烷基，酯基，酰胺基或胺基；R 3、R 4为烷基，杂环基，被氧原子、硫原子、氮原子或卤素取代的烷基；R 2、R 5为O或S，X、Y为N或C，Z为卤素。
  2. 根据权利要求1所述防治炎症反应的核苷类衍生物，其特征在于，式(Ⅰ)～式(Ⅳ)中，R 1为H，(C 1-C 18)烷基，(C 3-C 12)杂环基，被氧原子、硫原子、氮原子或卤素取代的(C 1-C 18)烷基，酯基，酰胺基或胺基；R 3、R 4为(C 1-C 3)烷基。
  3. 根据权利要求2所述防治炎症反应的核苷类衍生物，其特征在于，式(Ⅰ)～式(Ⅳ)中，R 1为H，(C 1-C 3)烷基，(C 3-C 12)杂环基，被氧原子、硫原子、氮原子或卤素取代的(C 1-C 3)烷基，或者为相当于式-A 1OC(O)A 2、-A 1NHA 2、-A 1NHCOA 2的基团，其中A 1、A 2为(C 1-C 3)烷基、被氧原子、硫原子、氮原子或卤素取代的(C 1-C 3)的烷基。
  4. 根据权利要求3所述防治炎症反应的核苷类衍生物，其特征在于，式(Ⅰ)～式(Ⅳ)中，R 1为H，(C 1-C 3)烷基，或者为相当于式-A 1OC(O)A 2、-A 1NHA 2、-A 1NHCOA 2的基团，其中A 1、A 2为(C 1-C 3)烷基。
  5. 根据权利要求4所述防治炎症反应的核苷类衍生物，其特征在于，式(Ⅰ)～式(Ⅱ)，R 1为(C 1-C 3)烷基，或者为相当于式-A 1OC(O)A 2、-A 1NHA 2、-A 1NHCOA 2的基团，其中A 1、A 2为(C 1-C 3)烷基；式(Ⅲ)～式(Ⅳ)中，R 1为H。
  6. 根据权利要求5所述防治炎症反应的核苷类衍生物，其特征在于，该核苷类衍生物为下述化合物1～19中的任意一种，或者为下述化合物1～19中的任意一种在药学上可接受的盐：
    Figure PCTCN2020080993-appb-100002
  7. 根据权利要求1至6中任一权利要求所述防治炎症反应的核苷类衍生物，其特征在于，式(Ⅰ)～式(Ⅳ)所示的化合物在药学上可接受的盐，以及化合物1～19中的任意一种在药学上可接受的盐为式(Ⅰ)～式(Ⅳ)所示的化合物以及化合物1～19中的任意一种与盐酸、氢溴酸、硫酸、碳酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲基苯磺酸或阿魏酸形成的加成盐。
  8. 权利要求1至7中任一权利要求所述核苷类衍生物在制备防治炎症疾病的药物中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述的炎症疾病包括胰腺炎、肝炎、关节炎，以及胰腺炎、肝炎、关节炎的相关并发症。
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