WO2005047256A1 - Derives de pyridone, et utilisation correspondante - Google Patents

Derives de pyridone, et utilisation correspondante Download PDF

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Publication number
WO2005047256A1
WO2005047256A1 PCT/CN2003/000968 CN0300968W WO2005047256A1 WO 2005047256 A1 WO2005047256 A1 WO 2005047256A1 CN 0300968 W CN0300968 W CN 0300968W WO 2005047256 A1 WO2005047256 A1 WO 2005047256A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
fibrosis
acceptable salt
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PCT/CN2003/000968
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English (en)
French (fr)
Inventor
Xianghui Yi
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Shanghai Genomics, Inc.
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Application filed by Shanghai Genomics, Inc. filed Critical Shanghai Genomics, Inc.
Priority to CA2545813A priority Critical patent/CA2545813C/en
Priority to US10/579,288 priority patent/US7825133B2/en
Priority to JP2005510535A priority patent/JP4614884B2/ja
Priority to EP03773437A priority patent/EP1683788B1/en
Priority to CNB2003801106910A priority patent/CN100358872C/zh
Priority to AU2003284808A priority patent/AU2003284808B2/en
Priority to PCT/CN2003/000968 priority patent/WO2005047256A1/zh
Publication of WO2005047256A1 publication Critical patent/WO2005047256A1/zh
Priority to US12/885,343 priority patent/US8084465B2/en
Priority to US12/885,353 priority patent/US8022087B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of medicine, and more particularly to a pyridone derivative for treating fibrosis, and a preparation method and application thereof. Background technique
  • Fibrosis is a very extensive disease that involves various organs of the human body. It is mainly due to the inflammatory response that leads to excessive collagen production and deposition, which impairs the function of the organs. Fibrosis can occur in many tissues and organs of the human body, such as the heart muscle, liver, lungs, kidneys, and skin. Once fibrosis occurs, it will often cause great harm to the function of the organ, and even the function of the entire human body.
  • scar tissue hyperplasia caused by skin trauma not only affects aesthetics, but also severely affects limb movement; myocardial fibrosis caused by coronary heart disease is the main cause of heart failure; kidneys caused by chronic glomerulonephritis and pyelonephritis Fibrosis, which accounts for more than 90% of uremia caused by renal failure; Pulmonary fibrosis caused by various lung diseases often leads to death due to respiratory failure.
  • lung tissue Fibrosis One of the main symptoms of atypical pneumonia that broke out in 2003 is lung tissue Fibrosis.
  • Hepatic fibrosis is a common pathological basis in the progress of chronic liver disease.
  • Various chronic injuries cause degeneration and necrosis of liver cells, abnormal proliferation and excessive deposition of fibrous connective tissue, enveloping regenerative liver cells, forming "false leaflets” and destroying the original liver tissue
  • the structure eventually made the liver nodular and hard, and the liver function was impaired, or even completely disappeared, and cirrhosis was formed.
  • Europe, America, Japan, and China liver cirrhosis is one of the main causes of death, second only to cerebrovascular disease, cardiovascular disease, and malignancy. After the tumor.
  • liver fibrosis such as chronic viral hepatitis, chronic alcoholism, cholestasis, metabolic disorders with congenital enzyme deficiency, and long-term exposure to poisons and drugs.
  • chronic viral hepatitis is the most common cause.
  • China is a high-incidence area of hepatitis B, and HBV antigen can be detected in about 76% of cirrhotic liver tissues.
  • hepatitis B virus carriers there are more than 500 million hepatitis B virus carriers worldwide, 600 million people in China have been infected with hepatitis B virus, about 120 million people have hepatitis B virus, and more than 30 million patients have chronic hepatitis B Among them, more than 20-30% of people will develop cirrhosis in 5-10 years, and about 20% of cirrhosis will turn into primary liver cancer.
  • hepatitis B virus, cirrhosis and liver cancer 400,000 people die from liver cirrhosis and liver cancer every year in China! How to effectively prevent liver fibrosis and liver cirrhosis in patients with liver disease is a major issue related to health.
  • antiviral and anti-inflammatory are the basic points of hepatitis B treatment, in fact, most patients will develop chronically and progressively after being infected with hepatitis B virus. Antiviral alone cannot prevent the progress of the disease.
  • liver failure A large proportion of these patients will gradually evolve into cirrhosis or liver failure. This is a late stage of chronic liver disease and is the result of liver fibrosis caused by prolonged hepatocyte necrosis. If the condition is not under control, further progress can lead to multiple organ damage, mainly due to severe complications such as impaired liver function and portal hypertension, gastrointestinal bleeding, hepatic encephalopathy, and concurrent infections. Due to the lack of effective treatments, the mortality rate is quite high. Hundreds of thousands of young adults are killed by these complications every year in areas with high incidence of liver diseases such as China and Southeast Asia.
  • Hepatic fibrosis is the primary stage of the development of various chronic liver diseases towards cirrhosis, and it is also the common pathological basis of cirrhosis. In terms of treatment, this stage is reversible, and treatment can be restored to its original state. Therefore, before the development of liver cirrhosis, early blocking and reversal of liver fibrosis is the key point and breakthrough for curing most refractory liver diseases.
  • anti-fibrotic drugs generally starts from the following perspectives: inhibition of collagen synthesis; inhibition of collagen mRNA expression; promotion of collagen degradation; inhibition of the body's immune response, etc.
  • some drugs such as interferon, colchicine, corticosteroid hormones, and marlotide have been used in anti-fibrosis research.
  • these drugs generally have the disadvantages of large toxic and side effects and high prices, and are not suitable for clinical promotion.
  • U.S. Patent No. 5,789,426 discloses a method for treating fibrotic diseases by administering a protein hydroxylation inhibitor, wherein the inhibitor is an N-substituted hydroxypyridone derivative.
  • U.S. Patent 6090822 discloses the use of N-substituted 2 (1H) pyridone or N-substituted 3 (1H) pyridone for the treatment of diseases caused by cell growth factors.
  • WO00 / 44381 discloses the use of N-substituted 2 (1H) pyridone or N-substituted 3 (1H) pyridone for the treatment of cancers such as lymphoma and leukemia.
  • EP 1138329 discloses the use of 5-methyl-1-phenyl-2- (1H) -pyridone for the treatment of fibrous damage.
  • Pirfenidone PF was a small-molecule compound first invented in the early 1980s. It has the effects of inhibiting collagen synthesis, reducing cytokine secretion, and preventing fibroblast proliferation. The specific drug target genes are unknown. Since the invention, fibrosis of the heart, kidney, lung, and inner wall of blood vessels has been successfully inhibited in various animal models. 'Clinical III trials for idiopathic pulmonary fibrosis (IPF) are currently underway in the United States. However, the inhibitory activity of PF is not satisfactory.
  • Antifibrotic drugs have great market demand. It is estimated that 45% of deaths in the United States can be attributed to physiological disorders such as liver fibrosis / sclerosis, renal fibrosis, cardiac fibrosis, and pulmonary fibrosis. Therefore, there is an urgent need in the art to develop new compounds and drugs that effectively inhibit various fibrosis. Summary of the invention
  • the purpose of the present invention is to provide a compound that effectively inhibits various fibrosis and its application.
  • a compound of formula I or a pharmaceutically acceptable salt thereof is provided:
  • Ri is a methyl, ethyl or trifluoromethyl group at the 3, 4, 5 or 6 position;
  • R is methyl and R is hydroxyl. More preferably, it is a methyl group at the 5-position, and R 2 is a hydroxyl group at the 4-position.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01-99% of the total weight, preferably 0.1-90%, more preferably 1-80% of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the dosage form of the pharmaceutical composition is a tablet, a capsule, an injection, or a pill.
  • a method for preparing a compound of formula I comprising the steps of-(a) in the presence of copper powder and anhydrous alkaline carbonate metal salt (such as potassium carbonate, sodium carbonate, etc.), The compound and the compound of formula III (molar ratio of about 0.8 to 1.2: 0.8 to 1.2) are reacted at 160-20 (TC, to form a compound of formula la;
  • anhydrous alkaline carbonate metal salt such as potassium carbonate, sodium carbonate, etc.
  • R 3 is-0C3 ⁇ 4,-SCH 3 ,-0C 2 H 5 or-SC 2 at the 2, 3 or 4 position H 5 ,
  • X is Cl, Br or I;
  • a method for preparing a pharmaceutical composition comprising the steps of: mixing a compound of formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier to form a compound of formula I which accounts for a total of Weight 0.
  • a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of fibrosis.
  • Also provided is a method of treating a fibrotic disease comprising administering to a subject in need of treatment a safe and effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows that F351 inhibits fibroblast proliferation and cell viability.
  • Figure 2 shows that F351 is more active in inhibiting fibroblast viability than the control Pirfenidone, which indicates that F351 significantly inhibits collagen synthesis.
  • Figure 3 is Masson triple staining of normal rat liver tissue, 2.5X10.
  • Figure 4 is the Masson triple staining of D3 ⁇ 41N model group at 4 weeks, 2.5 ⁇ 12.5. Collagen deposition and perisinus fibrosis after hemorrhage and necrosis;
  • Figure 5 is Masson's triple staining at 2.5 weeks in the DMN + F351 treatment group for 4 weeks. A small amount of collagen deposition and fibrous space formation were seen around the central and central veins after necrosis.
  • Figure 6 shows the 8-week HE staining of the D-painting model group, 2.5X20. Peripheral fibrosis of the central vein, hemosiderin deposition, and fresh bleeding.
  • Figure 7 shows the 8-week HE staining in the DMN + F351 treatment group, 2.5X16. There is less necrosis around the central vein, a smaller range of fibrosis, and more sinus fibrosis is more normal.
  • Figure 8 is Masson staining of CC1 4 model group for 4 weeks, 2.5X10.
  • Figure 9 is Masson's staining at 2.5 weeks for CC1 4 + F351 treatment group at 4 weeks.
  • FIG 10 shows serum alanine aminotransferase (ALT) levels after 4 weeks of F351 treatment.
  • the present inventors designed and synthesized a series of new compounds by analyzing the structure of various small molecule compounds known to inhibit inflammatory reactions, including Pirfenidone, and screened out a class of pyridone derivatives which significantly inhibited Cultured fibroblasts divide and proliferate, and have no observable toxicity to the cells.
  • compounds of the present invention and “compounds of formula I” are used interchangeably, and both refer to compounds of structural formula I or a pharmaceutically acceptable salt thereof, wherein each group is as defined above.
  • a particularly preferred compound is 5-methyl-1- (4-hydroxyphenyl) -2- (1 ⁇ ) -pyridone, and this compound is called F351.
  • the compound of the present invention such as F351 has the characteristics of small molecular weight ( ⁇ 200), high water solubility, oral administration, and easy synthesis.
  • the compound can inhibit the proliferation of fibroblasts in cell tissues, thereby greatly reducing collagen synthesis; animal experimental results show that F351 has a good anti-fibrotic effect, and it can significantly reduce liver while anti-fibrosis Cell necrosis can be used for the treatment of diseases such as acute viral hepatitis, and is used to reduce liver cell damage. Tests have shown that the compound is very safe in cellular tissues and animals, even at high concentrations.
  • the compounds of the present invention can be used for the treatment of various fibrotic diseases and inflammation leading to fibrosis, such as fibrosis of myocardium, liver, lungs, kidneys, blood vessels, skin and other tissues and fibrotic tumors.
  • fibrosis such as myocardium, liver, lungs, kidneys, blood vessels, skin and other tissues and fibrotic tumors.
  • Representative examples include (but are not limited to): liver fibrosis, cirrhosis, liver necrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, myocardial fibrosis, renal fibrosis, vascular fibrosis, skin scars, and the like.
  • the compounds of the invention also include salt forms derived from pharmaceutically or physiologically acceptable acids or bases.
  • These salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and salts with organic acids.
  • Organic acids refer to acetic acid, oxalic acid, succinic acid, tartaric acid, and methanesulfonic acid. Acid and maleic acid.
  • Other salts include salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates or other conventional "prodrugs" (when administered in this form) Can be converted into the active part in the body).
  • the invention also includes pharmaceutical compositions and methods of treatment which include administering to a mammal a pharmaceutically effective amount of a compound of formula I.
  • the compound of the present invention when used for the above purpose, it can be mixed with one or more pharmaceutically acceptable carriers or excipients, such as solvents, diluents, etc., and can be administered orally in the following forms: tablets, pills, Capsules, dispersible powders, granules or suspensions (containing, for example, about 0.05-5% suspending agent), syrups (containing, for example, about 10-50% sugar), and tinctures (containing about 20-50% ethanol), or other Mode of administration: ointment, gel, medicated tape, etc., or parenteral administration in the form of a sterile injectable solution or suspension (containing about 0.05-5% suspension in an isotonic medium).
  • pharmaceutically acceptable carriers or excipients such as solvents, diluents, etc.
  • these pharmaceutical preparations may contain from about 0.01 to 99%, more preferably from about 0.1% to 90% (weight) of active ingredient, mixed with a carrier.
  • the effective dose of the active ingredient used may vary with the compound used, the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention is administered at a daily dose of about 0.25-1000 mg / k g of animal body weight, a satisfactory effect can be obtained, preferably at a dose of 2-4 divided doses per day, or at Sustained release. For most large mammals, the total daily dose is about 1-100 mg / kg, preferably about 2-80 mg / kg.
  • Active Compounds are suitable for oral administration in a dosage form comprising intimately mixed with a solid or liquid pharmaceutically acceptable carrier.
  • This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of treating a condition, divided doses may be given several times a day, or the dose may be proportionally reduced.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and white clay
  • liquid carriers include: sterile water, polyethylene glycol, non-ionic surfactants, and edible oils (such as corn oil, Peanut oil and sesame oil) as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration required.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, pigments, preservatives and antioxidants such as vitamin E, vitamins (BHT, and BHA).
  • compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules. Oral administration of the compound is preferred.
  • active compounds can also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds can also be prepared in water suitably mixed with a surfactant (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone).
  • Dispersions can also be prepared in glycerol, liquids, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injection solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate discharge from the syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, alcohols (such as glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compound of the present invention can also be used in combination with other drugs for treating fibrosis, such as ⁇ -interferon, -interferon, ⁇ -interferon, corticosteroids, and carbamate.
  • fibrosis such as ⁇ -interferon, -interferon, ⁇ -interferon, corticosteroids, and carbamate.
  • drugs for treating fibrosis such as ⁇ -interferon, -interferon, ⁇ -interferon, corticosteroids, and carbamate.
  • the main advantages of the present invention are: (a) the effect of suppressing fibrosis is good; (b) the side effects are small; and (c) the inflammation and tissue necrosis that cause fibrosis can be suppressed.
  • the present invention is further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention.
  • the experimental methods in the following examples are not marked with specific conditions, usually according
  • the reaction mixture was below 65 ° C, evaporated under reduced pressure and concentrated.
  • the concentrated solution was extracted with dichloromethane and repeated several times until the organic phase had no product spots.
  • the extract was dried over anhydrous sodium sulfate and spin-dried to obtain a crude product.
  • 13 C should be R (ppm): 16. 9; 118. 3; 121. 0; 128.8; 129.8; 130. 5; 137.5; 142.5;
  • F351 The inhibitory effect of drug F351 on the proliferation of fibroblasts cultured in vitro was tested as follows. F351 was dissolved with 0.5% DMSO, and was treated for 5 days at different doses ( Figure 1 and Figure 2), and the drug was changed every 48 hours. Parallel experiments were performed with Pirfenidone to compare the effects of the two.
  • MTT method Take a 96-well plate with 4 wells in parallel, and add 100uL of cell suspension to each well. Dosage concentration and culture time remain unchanged. Then, 5 g / L of MTT (3- (4,5-dimethyl-2-thiazole) -2,5-diphenyltetrazolium bromide) lOuL was added to each well, and the culture was continued for 4 h. Add DMSO 100uL to each well, mix by gentle shaking, and use an enzyme-linked immunoassay BIO RAD 550 model for about 10 minutes :) Measure OD values at 570nm and 630nm, according to the following formula Calculate cell survival rate:
  • F351 inhibited fibroblasts more significantly than Pirfenidone ( Figure 1 and Figure 2).
  • Example 3 F351 shows obvious anti-fibrosis effect in liver fibrosis model, and can reduce necrosis of liver cells
  • liver fibrosis model of rats was induced with 0 14 and DMN (dimethylnitrosamine) respectively, and then the animals' livers were taken at 4 and 8 weeks after treatment with F351, and the pathological results were observed. Methods as below:
  • dimethylnitrosamine liver fibrosis model 4 weeks and dimethylnitrosamine liver fibrosis model (1% DMN intraperitoneal injection, 10mg / Kg, twice a week for 8 weeks).
  • Example 3 a rat liver fibrosis model induced by CCl n DMN was treated with F351. Observe rat weight and mortality.
  • F351 did not increase the mortality of rats for a model of liver fibrosis induced by 4 ; for a model of liver fibrosis induced by DMN F351 can significantly reduce the mortality of animals, compared with the control group (at 4 and 8 weeks, 25 rats in the control group survived 7 and 2 respectively, while the F351 treatment group survived 24 and 18 respectively Only).
  • Example 5 F351 treatment can significantly improve liver function in rats with liver fibrosis model
  • F351 was used to treat rat model of rat liver fibrosis induced by (3 ⁇ 4 and DMN. Rat serum was collected to determine serum transaminase levels.
  • Talc powder 5-10mg According to the dosage of 1000 tablets (the formula is as above), F351, lactose and starch are weighed and sieved through an 80-mesh sieve, then mixed, and then mixed with polyvinylpyrrolidone and silicic acid. , Wet with water, use 16-18 It is made into granules by a mesh sieve, dried at 60 ° C, whole granulated, mixed with talc, and pressed into tablets.

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Description

吡啶酮衍生物及其应用
技术领域
本发明涉及药物领域， 更具体地涉及一种治疗纤维化的吡啶酮衍生物， 及其 制法和应用。 背景技术
纤维化是一种非常广泛的疾病， 涉及人体的各种器官， 主要有于炎症反应导 致胶原蛋白产生和沉积过多， 损害器官的功能。 人体的多种组织器官， 如心肌、 肝脏、 肺脏、 肾脏、 皮肤等， 都可发生纤维化。 一旦纤维化产生， 往往会对该器 官的功能、 乃至整个人体的机能产生极大的危害。 例如， 皮肤创伤导致的疤痕组 织增生， 不仅影响美观， 严重的还会影响肢体的运动； 冠心病导致的心肌纤维化， 是引起心力衰竭的主要因素； 慢性肾小球肾炎和肾盂肾炎引起的肾纤维化， 占肾 功能衰竭引发尿毒症的 90%以上； 多种肺部病变引起的肺纤维化， 常导致患者因 呼吸衰竭而死亡， 2003年爆发的非典型肺炎的主要症状之一就是肺组织纤维化，。
肝纤维化是慢性肝病进展中的共同病理基础， 各种慢性损伤引起肝细胞变 性、 坏死， 纤维结缔组织异常增生并过度沉积， 包裹再生的肝细胞， 形成 "假小 叶"破坏肝脏原有的组织结构， 最终使肝脏形成结节状、 变硬， 肝脏功能随之受 损， 乃至完全消失， 形成肝硬化。 全世界每年死于肝硬化者达近百万， 且仍呈上 升趋势， 在欧美、 日本、 中国， 肝硬化均为主要死亡原因之一， 仅次于脑血管意 夕卜、 心血管疾病、 恶性肿瘤之后。
多种慢性肝病均可引起肝纤维化， 如慢性病毒性肝炎、 慢性酒精中毒、 胆汁 淤积、 先天性酶缺陷的代谢障碍性疾病、 长期接触毒物和药物等。 其中， 慢性病 毒性肝炎是最常见的原因， 中国是乙型肝炎的高发区， 约有 76%的肝硬化肝组织 可检出 HBV抗原。根据科学调査发现： 全世界有 5亿多乙型肝炎病毒携带者， 中 国有 6亿人感染过乙型肝炎病毒， 约有 1.2亿人携带乙肝病毒， 患慢性乙型肝炎 的病人超过 3000万， 其中 20-30%以上的人经过 5-10年将发展成为肝硬化， 而肝 硬化中约 20%将转为原发性肝癌。鉴于乙肝病毒、肝硬化、肝癌之间的连锁关系， 每年中国死于乙肝后肝硬化、肝癌者达 40万人！如何有效地防止肝病患者发生肝 纤维化、 肝硬化是关系健康的大事。
虽然抗病毒、 抗炎是乙肝治疗的基本点， 但事实上， 感染乙肝病毒后， 大多 数患者的病情会呈慢性进行性发展， 单纯抗病毒并不能阻止病情前进的脚步， 其
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确 认 本 中有很大一部分患者必将逐渐演变为肝硬化或肝功能衰竭。 这是慢性肝病的后期 阶段， 是长期肝细胞坏死引发肝纤维化的结果。 如果病情得不到控制， 继续进展 可引发多脏器损害， 主要是肝功受损和门静脉高压， 消化道出血， 肝性脑病， 并 发感染等严重的并发症。 由于目前尚缺乏有效的治疗方法， 死亡率相当高。 在中 国和东南亚等肝病高发区， 每年有数十万青壮年被这些并发症夺去生命。
目前认为， 肝硬化的病变是不可逆的， 即使祛除原发病因， 病情仍会继续发 展、 恶化。 肝纤维化是各种慢性肝病是向肝硬化发展的初级阶段， 也是肝硬化的 共同病理基础。 在治疗上来说这一阶段是可逆的， 通过治疗是可以恢复原状。 因 此， 在尚未发展到肝硬化之前， 及早阻断和逆转肝纤维化， 是治愈大多数难治性 肝病的关键点和突破口。
抗纤维化药物的开发一般从以下几个角度出发： 抑制胶原合成； 抑制胶原质 mRNA的表达； 促进胶原的降解； 抑制机体免疫反应等。 目前已有一些药物如干 扰素、 秋水仙碱、 皮质固醇类激素、 马洛替脂等被应用于抗纤维化研究中。 然而， 这些药物普遍存在毒副作用大、 价格昂贵的缺点， 不宜临床推广。 纤维化目前尚 无有效治疗手段。
美国专利 5789426公开了一种通过施用蛋白羟基化抑制剂来治疗纤维化疾病 的方法， 其中该抑制剂是 N-取代的羟基吡啶酮衍生物。
美国专利 6090822公开了将 N-取代的 2(1H)吡啶酮或 N-取代的 3(1H)吡啶酮 用于治疗细胞生长因子造成的疾病。
WO00/44381公开了将 N-取代的 2(1H)吡啶酮或 N-取代的 3(1H)吡啶酮用于 治疗淋巴瘤和白血病等癌症。
EP 1138329公开了将 5-甲基 -1-苯基 -2-(1Η)-吡啶酮用于治疗纤维损伤。
Pirfenidone PF)最早是在 80年代初发明的小分子化合物， 它具有抑制胶原蛋 白合成， 减少细胞因子的分泌， 阻止成纤维细胞增生等作用，具体药物作用靶点 基因尚不清楚。 自发明以来， 在各种动物模型中成功地抑制了心、 肾、 肺、 以及 血管内壁的纤维化。 '目前正在美国进行治疗特发性肺纤维化 (IPF)临床 III试验。然 而， PF的抑制活性还不令人满意。
抗纤维化药具有很大的市场需求， 据估计， 在美国 45%的死因都可以归结到 纤维泛滥的生理失调， 例如肝纤维化 /硬化， 肾纤维化， 心纤维化以及肺纤维化。 因此， 本领域迫切需要开发有效抑制各种纤维化的新化合物和药物。 发明内容
本发明目的就提供一种有效抑制各种纤维化的化合物及其应用 发明的第一方面， 提供了一种式 I化合物或其药学上可接受的盐:
Figure imgf000004_0001
其中，
Ri为位于 3、 4、 5或 6位的甲基、 乙基或三氟甲基；
为位于 2、 3或 4位的羟基、 巯基、 甲硫基、 乙硫基。
在另一优选例中， ^为甲基， 而 为羟基。 更佳地， 为位于 5位的甲基， R2为位于 4位的羟基。
在本发明的第二方面， 提供了一种药物组合物， 它含有药学上可接受的载体 和安全有效量的式 I化合物或其药学上可接受的盐。
通常， 所述的药物组合物含有占总重量 0. 01-99%， 较佳地， 0. 1-90%， 更佳 地 1-80%的式 I化合物或其药学上可接受的盐。
在另一优选例中， 所述药物组合物的剂型是片剂、 胶囊、 针剂、 丸剂。
在本发明的第三方面， 提供了一种制备式 I化合物的方法， 包括步骤- (a) 在铜粉和无水碳酸碱土金属盐（如碳酸钾、 碳酸钠等）存在下， 将式 II 化合物和式 III化合物（两者摩尔比约为 0. 8-1. 2 : 0. 8-1. 2)在 160-20(TC下反应, 形成式 la化合物；
Figure imgf000005_0001
其中 为位于 3、 4、 5或 6位的甲基、 乙基或三氟甲基， R3是位于 2、 3或 4 位的- 0C¾、 - SCH3、 - 0C2H5或- SC2H5， X是 Cl、 Br或 I;
(b)将式 la化合物与 BBr3在惰性溶剂（如二氯甲烷、 四氯化碳、 苯、 甲苯、 环己烷或其混合溶剂等）中， 于- 10Ό至 15°C (较佳地- 5°C至 10Ό )反应形成式 I 化合物：
Figure imgf000005_0002
其中， 和 如上定义， 为- 0H或 - SH。
在本发明的第四方面， 提供了一种制备药物组合物的方法， 包括步骤： 将式 I化合物或其药学上可接受的盐与药学上可接受的载体的混合， 形成式 I化合物 占总重量 0.
Figure imgf000005_0003
在本发明的第五方面，提供了一种式 I化合物或其药学上可接受的盐的用途， 用于制备治疗防止纤维化的药物。
还提供了治疗纤维化疾病的方法， 包括给需要治疗的对象施用安全有效量的 式 I化合物或其药学上可接受的盐。 附图说明
图 1显示 F351抑制成纤维细胞的增殖和细胞活力。
图 2显示 F351抑制成纤维细胞活力的活性高于对照 Pirfenidone,这表明 F351 显著抑制胶原合成。 图 3是正常大鼠肝组织的 Masson三重染色， 2.5X10。
图 4是 D¾1N模型组 4周的 Masson三重染色， 2· 5X12.5。 出血坏死后胶原沉 积， 窦周纤维化； 图 5是 DMN + F351治疗组 4周的 Masson三重染色， 2.5X16。 中 央静脉周围见少量坏死后的胶原沉积及纤维间隔形成。
图 6是 D画模型组 8周的 HE染色， 2.5X20。 中央静脉周纤维化， 含铁血黄 素沉积， 伴新鲜出血。
图 7是 DMN+F351治疗组 8周的 HE染色， 2.5X16。 中央静脉周围坏死少，纤 维化范围小，窦周纤维化多见于正常。
图 8是 CC14模型组 4周的 Masson染色， 2.5X 10。
图 9是 CC14+F351治疗组 4周的 Masson染色， 2.5X10。
图 10显示了 F351治疗 4周后血清中丙氨酸氨基转移酶 (ALT)的水平。 具体实施方式
本发明人通过对包括 Pirfenidone在内的各类已知抑制炎症反应的小分子化合 物结构的分析， 设计和合成了一系列全新的化合物， 并且从中筛选出一类吡啶酮 衍生物， 它显著抑制体外培养的成纤维细胞的分裂和增殖， 并且对细胞没有可以 观察到的毒性。 如本文所用， 术语 "本发明化合物" 、 "式 I化合物"可互换使用， 都指具 有结构式 I的化合物或其药学上可接受的盐， 其中各基团定义如上所述。
Figure imgf000006_0001
一种特别优选的化合物是 5-甲基 -1- (4-羟基苯基）- 2-(1Η)-吡啶酮， 该化合 物称为 F351。
Figure imgf000007_0001
F351等本发明化合物具有分子量小(〜200)、 水溶性高、 可口服、 易合成的特 点。 该化合物能够抑制纤维原细胞在细胞组织中的增殖， 从而大大减少胶原质的 合成； 动物实验结果显示， F351具有良好的抗纤维化药效， 并且在抗肝纤维化的 同时， 能明显减轻肝细胞的坏死， 可用于急性病毒性肝炎等疾病的治疗， 用于减 轻肝细胞的损伤。 试验证明， 该化合物在细胞组织和动物中非常安全， 即使在高 浓度下也一样。
本发明化合物可以用于各种纤维化疾病以及导致纤维化的炎症的治疗， 例如 心肌、 肝脏、 肺脏、 肾脏、 血管、 皮肤等组织的纤维化以及纤维化瘤。 代表性的 例子包括 (但并不限于)： 肝纤维化、 肝硬化、 肝坏死、 慢性阻塞性肺病、 肺纤维 化、 心肌纤维化、 肾纤维化、 血管纤维化、 皮肤疤痕等。
本发明化合物还包括由药学上或生理学可接受的酸或碱衍生的盐形式。 这些 盐包括 (但不限于）与如下无机酸形成的盐： 如盐酸、 硫酸、 硝酸、 磷酸、 以及与 有机酸形成的盐， 而有机酸则指乙酸、 草酸、 丁二酸、 酒石酸、 甲磺酸和马来酸。 其他盐包括与碱金属或碱土金属（如钠、 钾、 钙或镁）形成的盐， 以酯、 氨基甲酸 酯或其他常规的 "前体药物"的形式（当以这种形式给药时， 在体内可转化成活性 部分）。
本发明还包括药物组合物以及治疗方法， 它包括给哺乳动物施用药物有效量 的式 I化合物。
当本发明化合物用于上述用途时， 可与一种或多种药学上可接受的载体或赋 形剂混合， 如溶剂、 稀释剂等， 而且可以用如下形式口服给药： 片剂、 丸剂、 胶 囊、 可分散的粉末、 颗粒或悬浮液 (含有如约 0. 05- 5%悬浮剂）、 糖浆（含有如约 10- 50%糖）、 和酏剂（含有约 20- 50%乙醇）， 或以外用方式给药： 软膏剂、 凝胶、 含药胶布等， 或者以无菌可注射溶液或悬浮液形式（在等渗介质中含有约 0. 05-5% 悬浮剂）进行非肠胃给药。 例如， 这些药物制剂可含有与载体混合的约 0. 01-99%， 更佳地约为 0. 1%- 90% (重量）的活性成分。 所用的活性成分的有效剂量可随所用的化合物、 给药的模式和待治疗的疾病 的严重程度而变化。然而，通常当本发明的化合物每天以约 0. 25-1000mg/kg动物 体重的剂量给予时， 能得到令人满意的效果， 较佳地每天以 2-4次分开的剂量给 予， 或以缓释形式给药。 对大部分大型哺乳动物而言， 每天的总剂量约为 1- lOOmg/kg, 较佳地约为 2-80mg/kg。 适用于内服的剂量形式， 包含与固态或液态 药学上可接受的载体密切混合的约 0. 25- 500mg的活性化合物。可调节此剂量方案 以提供最佳治疗应答。 例如， 由治疗状况的迫切要求， 可每天给予若干次分开的 剂量， 或将剂量按比例地减少。
这些活性化合物可通过口服以及静脉内、 肌内或皮下等途径给药。 固态载体 包括： 淀粉、 乳糖、 磷酸二钙、 微晶纤维素、 蔗糖和白陶土， 而液态载体包括： 无菌水、聚乙二醇、 非离子型表面活性剂和食用油（如玉米油、花生油和芝麻油）， 只要适合活性成分的特性和所需的特定给药方式。 在制备药物组合物中通常使用 的佐剂也可有利地被包括， 例如调味剂、 色素、 防腐剂和抗氧化剂如维生素 E、 维生素 (、 BHT和 BHA。
从易于制备和给药的立场看， 优选的药物组合物是固态组合物， 尤其是片剂 和固体填充或液体填充的胶囊。 化合物的口服给药是优选的。
这些活性化合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂（如 羟丙基纤维素、 聚乙烯吡咯烷酮）的水中制备这些活性化合物（作为游离碱或药学 上可接受的盐）的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合 物中制备分散液。 在常规储存和使用条件下， 这些制剂中含有防腐剂以防止微生 物生长。
适应于注射的药物形式包括：无菌水溶液或分散液和无菌粉（用于临时制备无 菌注射溶液或分散液）。在所有情况中，这些形式必须是无菌的且必须是流体以易 于注射器排出流体。在制造和储存条件下必须是稳定的，且必须能防止微生物（如 细菌和真菌）的污染影响。 载体可以是溶剂或分散介质， 其中含有如水、 醇（如甘 油、 丙二醇和液态聚乙二醇）、 它们的适当混合物和植物油。
此外，本发明化合物还可与其他治疗纤维化的药物 (如 α -干扰素、 -干扰素、 Υ -干扰素、 皮质激素以及氨甲喋吟等)联用。 本发明的主要优点在于： （a)抑制纤维化的效果好； （b)副作用小； 和 (c)可抑 制导致纤维化的炎症及组织坏死。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说明 本发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方法， 通常按照常规条件，例如 Sambrook等人， 分子克隆：实验室手册 (New York: Cold Spring Harbor Laboratory Press, 1989)中所述的条件， 或按照制造厂商所建议的条
实施例 1、 F351的合成和鉴定
步骤 1: 合成 5-甲基吡啶酮
Figure imgf000009_0001
1. 2-氨基-甲基吡啶 （30g，0. 278mol)溶于 800ml的 6. 3%的硫酸中。
2.亚硝酸钠（36g，0. 522mol)溶于 100ml的水中，然后在室温下滴加到溶液中， 反应为放热反应， 并且放出大量气体。
3. 滴加完毕后室温搅拌 2个小时， 然后升温回流 4个小时， 溶液颜色由浅黄 加深变为黑色。 自然降至室温。
4. 在冰浴降温的情况下， 加入碳酸钠中和， 调 pH值为 8， 反应放热， 并且 放出大量气体。
5. 反应混合物在 65°C以下， 减压蒸熘浓缩， 浓缩液用二氯甲烷萃取， 重复 几次直到有机相点板无产物点。 萃取液用无水硫酸钠干燥， 旋干得到粗产物。
6. 用乙醚-二氯甲烷（10/1)重结晶， 得到浅黄色固体 27. 3g (0. 25mol)， 为标 题化合物， 产率为 89%。 步骤 2: 合成 5-甲基- 1- (4-甲氧基苯基) -2- (1Η)-吡啶酮
Figure imgf000009_0002
1. 对溴苯甲醚（115ml)、 5-甲基吡啶酮（26g)，无水碳酸钾（36. 4g)和铜粉 (520mg)在 180°C搅拌 18个小时， 然后降至室温。
2. 混合物用硅藻土过滤， 然后用二氯甲垸淋洗， 获得浓缩液。 3. 浓缩液减压蒸馏， 蒸除溶剂对溴苯甲醚， 残留物就是所要的粗产物。
4. 粗产物用乙酸乙酯作溶剂重结晶， 乙醚作淋洗剂， 得到标题化合物 28克， 产率 58%。
步骤 3: 合成 5-甲基- 1- (4-羟基苯基) -2- (1H) -吡啶酮
Figure imgf000010_0001
1. 5-甲基 -l- (4-甲氧基苯基) -2- (1H) -吡啶酮 100克溶于 2升二氯甲垸， 冰 浴下， 在 0°C下滴加三溴化硼（1000ml，lM溶于二氯甲烷）逐渐加入， 保持温度不超 过 5度。 三溴化硼溶液滴加到 2/3处时， 固体析出。 滴加完毕， 在 0°C下搅拌 1 小时。
2.滴加 400ml乙醚， 形成乙醚和三溴化硼的络合物， 反应放热， 控制滴加速 度， 保持体系温度不高于 10°C。 滴加完毕， 在 0Ό搅拌 40分钟。
3.加水淬灭反应， 反应放热， 控制加料速度， 不要超过 15°C。
4.抽滤， 搜集固体。
5.用乙醇作溶剂重结晶， 得到标题化合物 40克， 命名为 F351。 产率为 40%。
匪 R (CDC13， ppm)： 2. 16 (s， 3H)； 6. 58 (d, 1H)； 6. 92 (d, 2H)； 7. 19 (d, 2H)；
7. 39 (s， 1H)； 7. 51 (dd, 1H)
13C 應 R (ppm) : 16. 9 ; 118. 3 ; 121. 0 ; 127. 8 ; 129. 8 ; 130. 5 ; 137. 5 ; 142. 5 ;
145. 4 实施例 2、 F351对体外培养的人成纤维细胞增殖具有抑制作用
按以下方法检测药物 F351对体外培养的成纤维细胞增殖的抑制作用。 F351用 0.5%的 DMSO溶解，在不同剂量下 (图 1和图 2)下共作用 5天，每隔 48小时换药一次。 用 Pirfenidone进行平行实验， 比较二者的效果。
MTT法实验方法： 取 96孔板， 平行 4孔为一组， 每孔加入细胞悬液 100uL， 加 药浓度和培养时间保持不变。 然后各孔加入 5g/L的 MTT(3-(4， 5-二甲基 -2-噻唑) -2， 5-二苯基溴化四唑） lOuL,继续培养 4h。各孔加入 DMSO lOOuL,轻轻振荡混匀， lOmin 左右用酶联免疫检测仪BIO RAD 550型：)测 570nm和 630nm下 OD值，按下列公式 计算细胞存活率：
存活率 = [(实验孔 OD57Q—实验孔 OD63Q)/(对照孔 ODS7。一对照孔 OD63Q)] X 100% 抑制率 (或增殖率) =100%-存活率
结果显示 F351对成纤维细胞的抑制作用比 Pirfenidone更为明显 (图 1和图 2)。 实施例 3、 F351在肝纤维化模型中显示明显的抗纤维化作用， 并可减少肝细 胞的坏死
分别用 0 14和 DMN (二甲基亚硝胺)诱导建立大鼠的肝纤维化模型，然后应用 F351治疗 4周、 8周时取动物肝脏， 观察病理结果。 方法如下：
(a)制备四氯化碳模型 (40%CC14混合油剂腹腔注射， 0.4ml/100g， 一周两次， 连续
4周)和二甲基亚硝胺肝纤维化模型 (1%DMN腹腔注射， 10mg/Kg， 一周两次， 连续 8 周)。
(b)自建立模型第 0日起， 分别予以 F351灌胃， 剂量为 250mg/Kg， 每日一次， 连续 4或 8周。 结果：
(a)DMN模型：
与正常大鼠相比 (图 3)，实验 4周，模型组明显可见中央静脉周围肝细胞坏死， 出血和胶原沉积， 窦周纤维化； F351 治疗组的病变程度较模型组有明显减轻 (P <0.001), 中央静脉周围见少量坏死后的胶原沉积及纤维间隔形成 （图 4和 5) 。
8周时， 模型组中央静脉周细胞坏死后纤维化， 局部病灶炎细胞浸润， 向外 有新出血和坏死， 窦周纤维化及并有纤维间隔形成； 而 F351治疗组病理显示中央 静脉周围坏死范围小， 纤维化范围小， 且界限清晰， 窦周纤维化多见于正常， 但 明显优于对照组 (图 6和图 7)。
结果表明， F351对 DMN造成的肝细胞炎症及坏死有显著的治疗作用， 可发 挥阻止肝细胞坏死的疗效有效阻断 DMN致大鼠肝纤维化的进展 (P <0.001)。 F351 治疗后肝细胞坏死明显减少， 提示 F351 对肝细胞坏死有抑制作用。 因此， F351 可用于中毒性肝炎等疾病的治疗。 (b)CCl4模型：
实验 4周， 模型组病理评分为 S4-S6级， 而 F351的病变程度明显减轻， 中央 静脉周及窦周纤维化范围明显减小 (4周 P =0.001) (图 8和 9)。 这些结果表明， F351可以有效阻断大鼠 CC14模型组肝纤维化进展。 实施例 4、 F351治疗后肝纤维化模型大鼠死亡率下降
按实施例 3相同方式，用 F351对 CCl n DMN诱导建立的大鼠肝纤维化模型 进行治疗。 观察大鼠的体重和死亡率。
结果表明， DMN或 ( 14处理可明显影响大鼠体重及死亡率。 施用 F351后， 对于 04诱导的肝纤维化模型， F351未增加大鼠的死亡率； 对于 DMN诱导的肝 纤维化模型， F351则能明显降低动物的死亡率， 与对照组相比有显著差异 (4周和 8周时， 对照组 25只大鼠分别存活 7只和 2只， 而 F351治疗组分别存活 24和 18 只）。 实施例 5、 F351治疗能显著改善肝纤维化模型中大鼠肝脏的功能
按实施例 3相同方式， 用 F351对 ( (¾和 DMN诱导建立的大鼠肝纤维化模型进 行治疗。 抽取大鼠血清测定血清转氨酶水平。
结果表明， 实验 4周， F351即可降低 D丽或 CC14诱导的肝纤维化大鼠血清
ALT水平（对照组 27 ± 5. 09、CC14模型组 52 ± 17. 15、 CL4模型组 + F351 45 ± 17. 68; D讓模型组 74± 18. 25、 D丽模型组土 F351组 54± 17. 25; P<0. 05) (图 10)。 这提 示， F351可有效降低血清转氨酶水平， 改善肝脏功能。 实施例 6
制备含 F351的药物组合物
(a)片剂
F351 100-500rag
聚乙烯吡咯烷酮 2-4mg
lmg
Figure imgf000012_0001
l—5mg
乳糖 5 - lOmg
滑石粉 5-10mg 按 1000个片剂（配方如上）的用量， 称取 F351、 乳糖、 淀粉分别研细过 80目 筛后，混匀，再与聚乙烯吡咯烷酮、硅酸混匀，加入淀粉混合， 以水润湿，用 16-18 目筛制成颗粒， 于 60°C干操， 整粒， 加滑石粉混匀， 压制成片即得。
(b)注射液
F351 20-100mg
氯化钠 1一 5mg
注射用水 加至 10ml
按上述配方， 称取 F351和氯化钠: 配制成溶液后灌装于 10ml注射液瓶中 灭菌后包装。 供注射用。
(3)胶囊
F351 50 200mg
聚乙烯吡咯垸酮 2 lOmg
淀粉 50 lOOmg
乳糖 2 lOmg
按 1000个胶囊的用量，称取以上各辅料分别研细过筛后混合均匀，然后用等 量递加法加入 F351， 充分研磨， 使其分散均匀， 再过 80 目筛， 然后灌制成胶囊。 在本发明提及的所有文献都在本申请中引用作为参考， 就如同每一篇文献被 单独引用作为参考那样。 此外应理解， 在阅读了本发明的上述讲授内容之后， 本 领域技术人员可以对本发明作各种改动或修改， 这些等价形式同样落于本申请所 附权利要求书所限定的范围。 '

Claims

权 利 要 求
1. 一种式 I化合物或其药学上可接受的盐-
Figure imgf000014_0001
其中，
为位于 3、 4、 5或 6位的甲基、 乙基或三氟甲基；
R2为位于 2、 3或 4位的羟基、 巯基、 甲硫基、 乙硫基。
2.如权利要求 1所述的化合物， 其特征在于， 其中 ^为甲基， 而 为羟基。
3.如权利要求 1所述的化合物， 其特征在于， 为位于 5位的甲基， R2为位于 4位的羟基。
4. 一种药物组合物， 其特征在于， 它含有药学上可接受的载体和安全有效量 的权利要求 1所述的式 I化合物或其药学上可接受的盐。
5.如权利要求 3所述的药物组合物， 其特征在于， 它含有占总重量 0. 01-99% 的式 I化合物或其药学上可接受的盐。
6. 如权利要求 3所述的药物组合物， 其特征在于， 所述药物组合物的剂型是 片剂、 胶囊、 针剂、 丸剂。
7. 一种制备式 I化合物的方法， 其特征在于， 包括步骤：
(a) 在铜粉和无水碳酸碱土金属盐存在下， 将式 II化合物和式 III化合物在 160- 200°C下反应， 形成式 la化合物；
Figure imgf000015_0001
其中 为位于 3、 4、 5或 6位的甲基、 乙基或三氟甲基， R3是位于 2、 3或 4 位的- 0CH3、 - SC¾、 - OC2H5或- SC2H5， X是 Cl、 Br或 I ;
(b)将式 la化合物与 BBr3在惰性溶剂中，于- 10°C至 15 °C反应形成式 I化合物：
Figure imgf000015_0002
其中， 和 如上定义， 为- 0H或- SH。
8.—种制备药物组合物的方法， 其特征在于， 包括步骤： 将权利要求 1所述的 式 I化合物或其药学上可接受的盐与药学上可接受的载体的混合， 形成式 I化合 物占总重量 0. 01- 99\^%的药物组合物。
9.一种权利要求 1所述的式 I化合物或其药学上可接受的盐的用途，其特征在 于， 用于制备治疗防止纤维化的药物。
10.—种治疗纤维化疾病的方法，其特征在于，包括给需要治疗的对象施用安 全有效量的权利要求 1所述的式 I化合物或其药学上可接受的盐。
PCT/CN2003/000968 2003-11-14 2003-11-14 Derives de pyridone, et utilisation correspondante WO2005047256A1 (fr)

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US20070049624A1 (en) 2007-03-01
US7825133B2 (en) 2010-11-02
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CA2545813A1 (en) 2005-05-26
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