WO2007147297A1 - The use of derviate of pyridone for preventing and treating radioactive injury of lungs - Google Patents

The use of derviate of pyridone for preventing and treating radioactive injury of lungs Download PDF

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Publication number
WO2007147297A1
WO2007147297A1 PCT/CN2006/002504 CN2006002504W WO2007147297A1 WO 2007147297 A1 WO2007147297 A1 WO 2007147297A1 CN 2006002504 W CN2006002504 W CN 2006002504W WO 2007147297 A1 WO2007147297 A1 WO 2007147297A1
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group
radiotherapy
radiation
formula
compound
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PCT/CN2006/002504
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English (en)
French (fr)
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Tieling Zhou
Ying Luo
Jun Wu
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Shanghai Genomics, Inc.
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Priority to JP2009514614A priority Critical patent/JP5213852B2/ja
Priority to AT06791093T priority patent/ATE533486T1/de
Priority to CA2656017A priority patent/CA2656017C/en
Priority to CN2006800549309A priority patent/CN101484167B/zh
Priority to EP06791093A priority patent/EP2036555B1/en
Priority to US11/958,353 priority patent/US8765726B2/en
Publication of WO2007147297A1 publication Critical patent/WO2007147297A1/zh
Priority to US14/275,562 priority patent/US20140249347A1/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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

Definitions

  • This invention relates to the field of pharmaceuticals, and more particularly to the novel use of pyridone derivatives for the prevention and treatment of radiation-induced lung injury. Background technique
  • Radiotherapy is a commonly used treatment for malignant tumors. After radiotherapy in lung cancer, breast cancer, esophageal cancer, malignant lymphoma or other malignant tumors of the chest, the normal lung tissue in the radiation field is damaged, causing an inflammatory reaction, that is, radiation-induced lung injury, an acute radiation pneumonitis.
  • Radioactive pneumonia is a more harmful side effect in radiation therapy, divided into early changes (radioactive pneumonia) and late changes (radioactive pulmonary fibrosis). Every patient exposed to the lungs has this change, but most do not develop symptoms. At this time, if there is an infection, the symptoms are called acute radiation pneumonitis. If symptoms do not occur, after the end of the irradiation, the inflammation gradually absorbs and dissipates, gradually forming different degrees of fibrosis of the lung parenchyma. Pulmonary fibrosis occurs about 6 months after irradiation and gradually increases, reaching the most severe point in one year.
  • the pathological changes in the acute phase of radiation pneumonitis occur mostly from 1 to 2 months after radiotherapy, and are also found as late after the end of treatment. It is characterized by congestion, edema and cell infiltration of pulmonary vessels, especially capillary lesions, low alveolar type II cell regeneration, lymphatic vessel expansion and transparent membrane formation. Acute changes may dissipate on their own, but often cause pulmonary connective tissue hyperplasia, fibrosis and glassy changes. The chronic phase often occurs after 9 months of radiation therapy.
  • the pathology is extensive alveolar fibrosis, lung contraction, capillary intimal thickening, sclerosis, stenosis or obstruction leading to increased pulmonary circulation resistance and pulmonary hypertension.
  • the pleura can also be thickened by inflammation and fibrosis.
  • the epithelial changes of the bronchioles and the secondary infection of the lungs can promote radioactive fibrosis.
  • radiation pneumonitis has the greatest relationship with the irradiation area, and it is also related to the dose and segmentation, the body factors, individual differences, the presence or absence of chronic lung disease and radiation pneumonitis.
  • anti-cancer drugs such as ADM, PYM, VCR and smoking in radiotherapy is also likely to promote the occurrence of radiation pneumonitis.
  • the severity of lung injury is closely related to radiation dose, lung irradiation area, and irradiation speed.
  • Pathological changes manifested as an exudative inflammatory response in the acute phase and extensive lung tissue fibrosis in the chronic phase.
  • the greater the dose received (more than 20 Gy) the more severe the degree of radiation pneumonitis, and further develop into extensive fibrosis of the lung.
  • the occurrence of radiation pneumonitis has caused great obstacles to the treatment of common and rapidly progressing chest malignancies, seriously affecting patients' life treatment, and even life-threatening. Its incidence rate is different at home and abroad, about 8.25%-58%.
  • Conventional treatment methods include:
  • Adrenal cortex hormones control inflammation.
  • Anticoagulant therapy is effective in preventing small blood vessel embolism.
  • the principles of medication are: 1. Patients with general radiation pneumonitis can choose oral prednisone or dexamethasone. 2. Severe cases of intravenous dexamethasone. 3. When combined with pulmonary infection, add antibiotics. However, there is still a question about the efficacy of hormone therapy, and studies have shown that hormones have no effect on radiation-induced lung injury.
  • Radiotherapy in the treatment of malignant tumors is very significant, but it is also necessary to see the existence of radiation reactions and injuries.
  • High-dose radiation kills cancer cells and also damages normal cells, and patients will have certain adverse reactions. If the dose is not limited, it will kill the tumor but kill normal cells.
  • Radiotherapy can only kill tumor cells to the maximum extent possible if normal tissues can tolerate them.
  • the dose of cancer cells will not damage normal tissues around the tumor, and radiation therapy can cure the tumor.
  • Some tumor cells have a radiation lethal dose similar to that of normal surrounding tissue cells, and killing cancer cells can also seriously damage normal tissues.
  • U.S. Patent 5,789,426 discloses a method of treating a fibrotic disease by administering a protein hydroxylation inhibitor wherein the inhibitor is an N-substituted hydroxypyridone derivative.
  • U.S. Patent 6,090,822 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(1 ⁇ )pyridone for the treatment of cancers such as lymphoma and leukemia.
  • ⁇ 1138329 discloses the use of 5-methyl-1-phenyl-2-(1 ⁇ )-pyridone for the treatment of fibrous damage.
  • Pirfenidone is a pharmacologically active compound invented in the 1970s. The original patent for Pirfenidone was granted in 1976 (US3974281), and the researchers subsequently discovered that it can be used to treat interstitial lung disease (AU5427080) and prevent tissue fibrosis (WO9426249). The clinical trial of idiopathic pulmonary fibrosis (IPF) is currently underway in the United States. The initial study found that it has a certain anti-inflammatory effect.
  • IPF idiopathic pulmonary fibrosis
  • a novel medicament for alleviating or treating the symptoms of radiation-induced lung injury, and in particular for the use of the medicament for preventing radiation-induced lung injury.
  • R 2 is a hydroxyl group at the 2, 3 or 4 position, a mercapto group, a C 6 alkoxy group (such as a methoxy group, an ethoxy group), or a C 6 thio group (such as a methylthio group or an ethylthio group); no,
  • the radiation damage is caused by radiation treatment of lung cancer, breast cancer, esophageal cancer, malignant lymphoma or other malignant tumors of the chest.
  • the compound is pirfenidone.
  • R 2 is a hydroxyl group, a mercapto group, a ( ⁇ . 6 alkoxy group, or a 6 alkylthio group) at the 2, 3 or 4 position; or a no, wherein it is used for the preparation of a drug for increasing the radioactive dose of radiotherapy.
  • the radiotherapy is radiotherapy for lung cancer, breast cancer, esophageal cancer, malignant lymphoma or other malignant tumors of the chest.
  • the compound is pirfenidone.
  • a method of preventing radiation lung injury in a mammal comprising the steps of:
  • R 2 is a hydroxyl group at the 2, 3 or 4 position, a mercapto group, a C 6 anthracene group, or a C 6 alkylthio group; or R: is none;
  • the mammal is then subjected to radiotherapy.
  • the radiotherapy is radiotherapy for lung cancer, breast cancer, esophageal cancer, malignant lymphoma or other malignant tumors of the chest.
  • a method of increasing radiation dose for radiotherapy in a mammal comprising the steps of:
  • R 2 is a hydroxyl group at the 2, 3 or 4 position, a fluorenyl group, a ( ⁇ -6 alkoxy group, or a 6 alkylthio group; or none;
  • the original radiation dose of the radiotherapy of the suckling animal is D Q ;
  • the radiation doses are 0! and 0. Satisfy the following formula:
  • the compound is pirfenidone.
  • the radiotherapy is for the treatment of lung cancer, breast cancer, esophageal cancer, malignant lymphoma or other malignant tumors of the chest.
  • the dose of the compound of formula I is administered from 1 to 50 mg/kg body weight per day.
  • Figure 1 shows the alveolar lavage cytometer of pirfenidone (PF) in a radiotherapy model mouse. The impact of the number.
  • Figure 2 shows the effect of pirfenidone (PF) on lung hydroxyproline content in radiotherapy model mice.
  • pyridone compounds such as pirfenidone have extremely significant preventive effects against radiation-induced lung injury. Therefore, by applying such a pyridone compound in advance, it is also possible to increase the radiation dose in the radiotherapy treatment, thereby achieving a more effective anti-therapeutic effect.
  • the present invention has been completed on this basis. Although the mechanism of action of the present invention is not clear, the zoological experiments of the present application clearly show that pirfenidone can effectively alleviate or cure radiation-induced lung injury. Therefore, pirfenidone is particularly suitable for the prevention or treatment of radiation-induced lung injury.
  • the active ingredient of the pharmaceutical composition of the present invention is pirfenidone and a pyridone compound of a similar structure.
  • the pirfenidone which can be used in the present invention is not particularly limited and includes a pharmaceutically acceptable salt, ester or the like. Pirfenidone can be administered alone or in combination with any pharmaceutically acceptable pharmaceutical excipient or carrier.
  • R 2 is a hydroxyl group at the 2, 3 or 4 position, a mercapto group, a 6 alkoxy group, or a ( ⁇ 6 alkylthio group; or R: none.
  • 1 is methyl and none.
  • 1 ⁇ is methyl and R: It is a hydroxyl group. More preferably, it is a methyl group at the 5-position, and R 2 is a hydroxyl group at the 4-position.
  • a particularly preferred compound is pirfenidone.
  • Another particularly preferred compound is 5-methyl-1-(4-hydroxyphenyl)-2-(1 ⁇ )-pyridone, and the compound is referred to as F351.
  • the compounds of the invention also include the form of a salt derived from a pharmaceutically or physiologically acceptable acid or base.
  • These salts include, but are not limited to, salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and salts with organic acids, while organic acids refer to acetic acid, oxalic acid, succinic acid, tartaric acid, and methanesulfonic acid. Acid and maleic acid.
  • Other salts include those formed 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 active part in the body).
  • the invention further encompasses pharmaceutical compositions and methods of treatment comprising administering to a mammal a pharmaceutically effective amount of a compound of formula I.
  • the compound of the present invention when used in the above-mentioned use, it may be mixed with one or more pharmaceutically acceptable carriers or excipients, such as a solvent, a diluent, etc., and may be orally administered in the form of tablets, pills, Capsules, dispersible powders, granules or suspensions (containing, for example, about 0.05-5% suspension), syrups (containing, for example, about 10-50% sugar), and elixirs (containing about 20-50% ethanol), or by external means. Administration: Ointment, gel, medicated tape, etc., or parenteral administration in the form of a sterile injectable solution or suspension (containing about 0.05-5% suspending agent in an isotonic medium).
  • these pharmaceutical preparations may contain from about 0.01% to about 99%, more preferably from about 0.1% to about 90% by weight of the active ingredient in admixture with the carrier.
  • the effective dose of the active ingredient employed will vary depending upon the compound employed, the mode of administration, and the severity of the condition being treated. However, generally, when the compound of the present invention is administered at a dose of about 0.25 to 1000 mg/kg of animal body weight per day, a satisfactory effect can be obtained, preferably administered in 2-4 divided doses per day, or in a sustained release form. Dosing. For most large mammals, the total daily dose is about 1-100 mg/kg, preferably about 2-80 mg/kg. Dosage forms suitable for internal administration comprising from about 0.25 to 500 mg of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier Things. This dosage regimen can be adjusted to provide an optimal therapeutic response. For example, several separate doses may be administered per day, or the dose may be proportionally reduced, as is critical to the condition of the treatment.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin
  • liquid carriers include: sterile water, polyethylene glycol, nonionic 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 desired.
  • Adjuvants which are usually used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, 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 (as free bases or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose or polyvinylpyrrolidone. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. These preparations contain preservatives to prevent microbial growth under normal conditions of storage and use.
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate fluid discharge from the syringe. It must be stable under the conditions of manufacture and storage and must be able to prevent the growth of microorganisms (such as bacteria and fungi).
  • the carrier may be a solvent or dispersion medium containing, for example, water, an alcohol (e.g., glycerol, propylene glycol, and a liquid, polyethylene glycol), a suitable mixture thereof, and a vegetable oil.
  • the compounds of the present invention can be used in combination with other drugs such as ⁇ -interferon, ⁇ -interferon, ⁇ -interferon, corticosteroid, and methotrexate.
  • the pharmaceutical compositions of the invention comprise a pharmaceutically acceptable carrier and a compound of formula I (e.g., pirfenidone).
  • a compound of formula I e.g., pirfenidone
  • the content of the compound of the formula I is from 0.01 to 99.99% by weight, preferably from 0.1 to 95% by weight, more preferably from 0.5 to 90% by weight.
  • it may contain a substance selected from the group consisting of protease inhibitors such as Sivelestat Sodium, anti-inflammatory drugs such as Ibuprofen, various types of interferons and other novel non-solids.
  • Alcohol anti-inflammatory drugs such as pentoxifylline, cytoprotective agent Amifostine, antioxidant N-acetylcysteine (Acetylcysteine against inflammatory cells and their mediators and Anti-endotoxin monoclonal antibodies, IL-1 receptor antagonists (IL-lm), TGF and its receptor antagonists, TNFGC and its receptor antagonists, and EGF/PDGF and its receptor antagonists
  • IL-1 receptor antagonists IL-1 receptor antagonists
  • TGF and its receptor antagonists TNFGC and its receptor antagonists
  • EGF/PDGF and its receptor antagonists the following Chinese medicines or their extracts may also be included: Salvia miltiorrhiza, Astragalus, armor, or a mixture thereof.
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited and may be in the form of a solid, a semi-solid or a liquid.
  • the pharmaceutical preparations of the invention may be administered by intravenous, subcutaneous, and other suitable routes.
  • a preferred mode is effective orally.
  • Another preferred mode is parenteral administration, such as intravenous injection, which reduces the time during which the drug works in the body.
  • the subject to be treated by the pharmaceutical compositions and methods of the invention is a mammal, especially a human.
  • the daily dose typically used in the prophylaxis is about 0.1-500 mg/kg, preferably 0.1-200 mg/kg, more preferably 0.5-100 mg/kg, more It is preferably 1-80 mg/kg.
  • the number of administrations can be once a day, or several times.
  • the present invention provides a method of preventing radiation lung injury.
  • the method comprises pre-administering a prophylactically effective amount of pirfenidone to a patient in need of radiation therapy, followed by radiotherapy.
  • the invention also provides a method of increasing the radiation dose of a radiotherapy.
  • the method includes pressing D as originally planned. Radiation therapy patient radiation dose previously administered prophylactically effective amount of pirfenidone, and then emitted radiation therapy at a dose D, where D ⁇ D ⁇ D Q ratio is preferably 20% larger, more preferably 50% larger.
  • prophylactically effective amount is an amount that can be administered to prevent the effects of radiation-induced lung injury. Generally, the prophylactically effective amount is from 1 to 50 mg/kg body weight per day.
  • pirfenidone may be used singly or in combination with a prodrug.
  • the main advantages of the invention are:
  • Pirfenidone has a significant preventive effect on radiation-induced lung injury, and the drug has less toxic side effects and is safe to use.
  • Source of illumination Varian 600C linac, 6 MV X-ray. 4
  • Irradiation method 6 babies in a conscious state were fixed in a special plexiglass container, covered with a 1.5 cm thick plexiglass plate to compensate for the dose-building effect, source skin distance 100 cm, field 2.5 X 18 cm, The straight lead door blocks the head and abdomen and only illuminates the chest of the mouse. A single shot of 1200 cGy. Experimental mice were placed in a clean animal room using a dedicated sealed transfer box with air filtration.
  • Model control group 60 rats: Only radiation was given and no treatment was given.
  • Prophylactic administration group 60 rats: A certain dose of the drug was administered for 2 weeks from the 2 days before the irradiation. The radiation treatment method and dose were the same as the model control group. Pirfenidone was administered once a day (dose of 200 mg/kg, dissolved in 0.5% CMC-Na and then administered in an amount of 0.1 ml/10 g) for a total of 3 months.
  • Therapeutic administration group 60 rats: A certain dose of the drug was administered from the day of irradiation to intervene. Radiotherapy treatment and dose were the same as the model control group, single irradiation. Pirfenidone was administered by gavage (diluent 200 mg/kg, dissolved in 0.5% CMC-Na and administered as 0.1 ml/10 g) once daily for 3 months.
  • Blank control group 60 rats: 0.5% CMC-Na was administered daily for 3 months without irradiation. Each group of mice was observed once a day after the irradiation to observe whether or not death occurred. After the experimental treatment, the cell count and count of the lavage fluid, the determination of collagen content (hydroxyproline), and pathological morphology were observed regularly.
  • Cell count of alveolar lavage fluid Inject a certain amount of normal saline into the right lung, slowly aspirate, and collect 1.5 ⁇ 2.0ml of lavage fluid into the centrifuge tube. Immediately after collecting the alveolar lavage fluid, the inflammatory cell content was manually counted using a cell counting plate.
  • Determination of pulmonary hydroxyproline content Take lung tissue and measure according to the procedure of the hydroxyproline kit. Histopathological examination: The lung tissue was fixed with formalin, dehydrated and paraffin-embedded, HE stained and Masson trichrome stained. Evaluation criteria: Refer to Ashcroft interstitial pulmonary fibrosis semi-quantitative scoring criteria to assess radiation-induced lung injury
  • Pirfenidone can increase the tolerance to radiotherapy doses
  • Prevention group 60 rats: A certain dose of drug was administered from 2 days before the irradiation. The drug treatment was divided into two groups, and pirfenidone was administered by gavage (dose of 200 mg/kg, dissolved in 0.5% of CMC-Na and then administered in an amount of 0.1 ml/10 g) for a total of 3 months.
  • mice A total of 60 animals in each group. Each group of mice was observed once a day after irradiation to observe whether there was difficulty in breathing and death. After the experimental treatment, the lung weight, the lavage fluid cell count, the collagen content (hydroxyproline), the plasma cytokine assay (ACE, TGF- ⁇ , TNF- ⁇ , etc.), pathological morphology, etc. were observed regularly.
  • pirfenidone and sodium chloride were weighed, prepared into a solution, filled in a 10 ml injection bottle, and packaged after sterilization. For injection.
  • Stearyl magnesium 2-10m g According to the dosage of 1000 tablets (formulation as above), weigh pirfenidone, lactose, hydroxypropyl methylcellulose and sodium alginate separately after grinding through 80 mesh sieve, mix the hook, and then with microcrystalline cellulose. Mix well, wet with water, granulate with 16-18 mesh sieve, dry at 60 °C, whole grain, add stearyl magnesium and mix and compress to make tablets.
  • Example 5 According to the dosage of 1000 capsules, weigh the above excipients separately and sieve them, then mix them evenly, then add the pirfenidone and salvia miltiorrhiza extracts by equal addition method, fully grind them to make them evenly dispersed, and then pass through 80 mesh sieve. And then into a capsule.
  • Example 5 According to the dosage of 1000 capsules, weigh the above excipients separately and sieve them, then mix them evenly, then add the pirfenidone and salvia miltiorrhiza extracts by equal addition method, fully grind them to make them evenly dispersed, and then pass through 80 mesh sieve. And then into a capsule.
  • Example 5 Example 5
  • Example 1 was repeated except that 5-methyl-1-(4-hydroxyphenyl)-2-(m)-pyridone (F351) was used. The pirfenidone was replaced, and 20 animals per group.
  • F351 5-methyl-1-(4-hydroxyphenyl)-2-(m)-pyridone
  • Lung injury is a common problem in chest tumors undergoing radiotherapy, divided into early and late stage radioactive lung injury.
  • Early lung injury (radioactive pneumonia) often occurs during radiotherapy, often causing serious consequences.
  • Lighter treatment leads to interruption of treatment and affects the efficacy of tumor treatment. In severe cases, it can directly lead to death.
  • Pulmonary infection also aggravates fibrosis of the lungs, and late radiation damage in the lungs is mainly prevented.
  • pirfenidone has the effect of inhibiting tissue fibrosis. It can improve lung function, anti-inflammatory and anti-fibrosis.
  • pirfenidone If pirfenidone is used before pulmonary fibrosis, it can inhibit collagen synthesis, prevent fibroblast proliferation, and down-regulate the production of many cytokines, thereby preventing the development of radiation pneumonitis and radiation-induced pulmonary fibrosis.

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Description

吡啶酮类衍生物预防和治疗放射性肺损伤的用途 技术领域
本发明涉及药物领域， 更具体地涉及吡啶酮类衍生物用于预防和治疗放 射性肺损伤的新用途。 背景技术
放疗是一种常用的治疗恶性肿瘤的手段。 肺癌、 乳腺癌、 食管癌、 恶性 淋巴瘤或胸部其他恶性肿瘤经放射治疗后， 在放射野内的正常肺组织受到损 伤， 引起炎症反应， 即放射性肺损伤一急性放射性肺炎。
放射性肺炎是放射治疗中出现的危害性较大的副作用，分为早期改变 (放 射性肺炎)和晚期改变 (放射性肺纤维化)。 每一位肺部照射的病人都有这种改 变， 但大多数不产生症状， 此时若有感染即产生症状， 叫急性放射性肺炎。 若不产生症状， 照射结束后， 炎症逐步吸收、 消散， 逐渐形成不同程度的肺 实质的纤维变。 肺纤维化发生于照射后 6个月左右， 逐渐加重， 到一年达到最 严重的地步。 放射性肺炎急性期的病理改变多发生于放射治疗后 1〜2月， 亦 有迟至治疗结束后半年始发现。表现为肺血管特别是毛细血管损伤产生充血、 水肿和细胞浸润， 肺泡 II型细胞再生低下， 淋巴管扩张和透明膜形成。 急性 变化有可能自行消散， 但常引起肺结缔组织增生， 纤维化和玻璃样变。 慢性 期往往发生于放射治疗 9个月以后， 病理为广泛肺泡纤维化， 肺脏收縮、 毛细 血管内膜增厚、硬化、管腔狭窄或阻塞而导致肺循环阻力增高和肺动脉高压。 胸膜也可因炎变和纤维化而增厚。细支气管粘膜上皮间变， 肺部继发性感染， 可促进放射性纤维化。
放射性肺炎的形成与照射面积关系最大， 与剂量及分割、 机体因素、 个 体差异、 有无慢性肺疾病与放射性肺炎的发生也有一定的关系。 放疗中并用 ADM、 PYM、 VCR等抗癌药及吸烟也易促使放射性肺炎的发生。
肺部损伤的严重程度与放射剂量、 肺部的照射面积以及照射速度密切相 关。病理变化表现为急性期的渗出性炎症反应和慢性期的广泛肺组织纤维化。 接受剂量愈大 (超过 20Gy)， 放射性肺炎程度愈严重， 进一步可发展为肺广泛 纤维化。 放射性肺炎的发生对临床常见及进展迅速的胸部恶性肿瘤的治疗造 成很大障碍、 严重影响了患者的生活治疗， 甚至危及生命。 其发病率国内外 报道不一， 约在 8.25%-58%左右。 目前临床上没有专门治疗放射性肺损伤的药物， 常规的治疗方法包括：
1.肾上腺皮质激素控制炎症。 2.抗凝疗法对防止小血管栓塞有效。 3.高浓度氧 疗以改善低氧血症。 4.适当应用抗生素以预防继发感染。 用药原则是： 1.一 般放射性肺炎患者可选用口服强的松或地塞米松。 2.重症者静滴地塞米松。 3.合并肺部感染时， 加用抗生素。 然而， 对于激素治疗的效果， 目前尚持怀 疑态度， 有研究显示激素对于放射性肺损伤没有疗效。
放疗在治疗恶性肿瘤中的作用十分显著已毫无疑问， 但也要看到放射反 应和损伤的存在。 高剂量射线在杀灭癌细胞同时也损伤了正常细胞， 病人就 会出现一定的不良反应。 照射剂量不加限制的话， 虽可消灭肿瘤但会杀灭正 常细胞。放疗只能在正常组织能够耐受的情况下， 最大限度地杀灭肿瘤细胞。 对放射线敏感的肿瘤，杀死癌细胞的剂量不会使肿瘤周围正常组织受到损伤， 放射治疗可以使肿瘤根治。 有的肿瘤细胞的放射线致死剂量与周围正常组织 细胞的致死或损伤剂量相似， 杀死癌细胞的同时也会严重损伤正常组织。 为 了既要治好肿瘤又不过度照射正常组织， 利用合理的治疗技术来提高肿瘤与 正常组织的受量比是必要的。 此外， 本领域迫切需要开发提高放疗剂量且减 少放射性损伤的方法。
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(1 H)吡啶酮或 N-取代的 3(1Η)吡啶酮用于 治疗淋巴瘤和白血病等癌症。
ΕΡ 1138329公幵了将 5-甲基 -1-苯基 -2-(1Η)-吡啶酮用于治疗纤维损伤。 吡非尼酮 (Pirfenidone)是在 70 年代发明的一种具有药理作用的化合物。 吡 非尼酮 (Pirfenidone)的原始专利于 1976年授权 (US3974281), 随后研究人员在发 现其可用于治疗间质性肺病 (AU5427080)、 预防组织纤维化 (WO9426249)。 目前 正在美国迸行治疗特发性肺纤维化 (IPF)临床 III试验。最初的研究发现其具有一 定的抗炎作用， 近年来发现它对于组织的纤维化有抑制作用， 能够抑制胶原蛋 白合成， 减少炎性细胞因子的分泌， 阻止成纤维细胞增生， 具体药物作用靶点 基因尚不清楚。 在各种动物模型的研究中已证实， 吡非尼酮显示对心、 肾、 肺、 肝以及血管内壁等组织和器官的纤维化具有一定的抑制作用。
综上所述， 目前对于放射性肺损伤还缺乏有限的预防及治疗方法， 因此， 本领域迫切需要开发新的用于减轻或治疗放射性肺损伤的方法。 发明内容
本发明的目的就是提供一种新的减轻或治疗放射性肺损伤症状的药物， 尤其是该药物在预防放射性肺损伤方面的应用。 在本发明的第一方面，提供了一种式 I化合物或其药学上可接受的盐的用 途，
Figure imgf000004_0001
式中，
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、 C 6烷氧基 (如甲氧基、 乙氧基)、 或 C 6 垸硫基 (如甲硫基、 乙硫基)； 或 为无，
其中， 它被用于制备预防放射性肺损伤的药物。
在另一优选例中， 所述的放射性损伤是放射性治疗肺癌、 乳腺癌、 食管 癌、 恶性淋巴瘤或胸部其他恶性肿瘤时造成的损伤。
在另一优选例中， 所述的化合物为吡非尼酮。
在本发明的第二方面，提供了一种式 I化合物或其药学上可接受的盐的用
Figure imgf000005_0001
式中，
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、 （^.6烷氧基、 或 -6烷硫基； 或 为无， 其中， 它被用于制备提高放射性治疗的放射性剂量的药物。
在另一优选例中， 所述的放射性治疗是对肺癌、 乳腺癌、 食管癌、 恶性 淋巴瘤或胸部其他恶性肿瘤进行放射性治疗。
在另一优选例中， .所述的化合物为吡非尼酮。
在本发明的第三方面， 提供了一种预防哺乳动物放射性肺损伤的方法， 包 括步骤：
给所述哺乳动物施用预防有效量的式 I化合物或其药学上可接受的盐，
Figure imgf000005_0002
式中，
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、 C 6垸氧基、 或 C 6烷硫基； 或 R: 为无；
然后对该哺乳动物进行放射性治疗。 在另一优选例中， 所述的放射性治疗是对肺癌、 乳腺癌、 食管癌、 恶性 淋巴瘤或胸部其他恶性肿瘤进行放射性治疗。
在本发明的第四方面， 提供了一种提高哺乳动物放射性治疗的辐射剂量的 方法， 包括步骤：
(a)给需要进行放射性治疗的哺乳动物对象施用式 I化合物或其药学上可接 受的盐，
Figure imgf000006_0001
式中，
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、 （^_6烷氧基、 或 —6烷硫基； 或 为无；
其中， 所述晡乳动物的放射性治疗的原定辐射剂量为 DQ ; 和
(b)在辐射剂量 下， 对所述哺乳动物进行放射性治疗，
其中 D^D^
在另一优选例中， 所述的辐射剂量 0!和 0。满足下式：
(DrD0)/D0> 20%。
在另一优选例中， 所述的化合物是吡非尼酮。
在另一优选例中， 所述的放射性治疗是对肺癌、 乳腺癌、 食管癌、 恶性 淋巴瘤或胸部其他恶性肿瘤进行 ¾射性治疗。
在另一优选例中， 在进行放射性治疗之前约 1-10天 (如 2、 3、 4、 5、 6、 7、
8、 9天)给予式 I化合物。
在另一优选例中， 施用式 I化合物的剂量为每天 l-50mg/kg体重。 附图说明
图 1 显示了吡非尼酮 (PF)对于放射性治疗模型小鼠的肺泡灌洗液细胞计 数的影响。
图 2显示了吡非尼酮 (PF)对于放射性治疗模型小鼠的肺羟脯氨酸含量的 影响。 具体实施方式
本发明人首次发现， 吡非尼酮等吡啶酮类化合物对放射性肺损伤有极其 显著的预防效果。 因此， 通过预先施用这类吡啶酮化合物， 还可提高放射性 治疗中的辐射剂量， 从而取得更有效的防疗效果。在此基础上完成了本发明。 虽然本发明的作用机理还不清楚，但是，本申请的动物学实验明确表明， 吡非尼酮可以有效地减轻或治愈放射性肺损伤。 因此， 吡非尼酮特别适合预 防或治疗放射性肺损伤。
本发明药物组合物的活性成分是吡非尼酮和类似结构的吡啶酮类化合 物。可用于本发明的所述的吡非尼酮没有特别限制，包括药学上可接受的盐、 酯等形式。 吡非尼酮可以单独、 或者结合任何医学上可接受的药用赋形剂或 载体给药。
如本文所用， 术语 "本发明化合物" 、 "吡啶酮化合物" 或 "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，
Figure imgf000007_0001
式中，
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、 6烷氧基、 或（^6烷硫基； 或 R: 无。
在一优选例中， 1^为甲基， 而 为无。 在另一优选例中， 1^为甲基， 而 R: 为羟基。 更佳地， 为位于 5位的甲基， R2为位于 4位的羟基。
一种特别优选的化合物是吡非尼酮。
另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 imgf000008_0001
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 l-100mg/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 C、 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、 聚乙烯吡咯垸酮)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)的污染舉,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药物 (如 α -干扰素、 β -干扰素、 Υ -干扰素、 皮质激素以及氨甲喋吟等)联用。
在预防 (或治疗)急性肺损伤时，本发明的药物组合物含有药学上可接受的 载体和式 I化合物 (如吡非尼酮)。 其中， 式 I化合物的含量是 0.01-99.99wt%， 较佳 地 0.1-95wt%， 更佳地 0.5-90wt%。 此外， 还可含有选自下组的物质： 蛋白酶抑 制剂如西维来司纳（Sivelestat Sodium)， 抗炎药物如如布洛芬 (Ibuprofen),各型 干扰素 (interferons)及其它新型非固醇类抗炎药， 磷酸二酯酶抑制剂如己酮可 可碱 (Pentoxifylline) , 细胞保护剂氨磷汀 (Amifostine), 抗氧化剂 N-乙酰半胱 氨酸 (Acetylcysteine 针对炎症细胞及其介质和其些致病因子的抗内毒素单 抗、 IL-1受体拮抗剂 (IL-lm)、 TGF 及其受体拮抗剂， TNFGC及其受体拮抗剂, 以及 EGF/PDGF及其受体拮抗剂。 此外还可含有以下中药或其提取物： 丹参、 黄芪、 鳖甲、 或其混合物。
本发明的药物组合物的剂型没有特别限制， 可以固体、 半固体或液体的 形式。 此外， 本发明的药物制剂可通过静脉、 皮下以及其他适合的途径给药。 一种优选方式是口服有效。另一种优选方式是非肠道给药方式， 如静脉注射， 这样可縮短药物在体内起效的时间。
可用本发明的药物组合物和方法治疗的对象是哺乳动物， 尤其是人。 尽管吡非尼酮的有效治疗剂量所治疗患者的年龄和病情， 但在预防时常 用的每日剂量为约 0.1-500mg/kg， 优选 0.1-200mg/kg， 更优选 0.5-100mg/kg， 更优选 l-80mg/kg。 给药次数可以是每天一次， 或数次。
本发明提供一种预防放射性肺损伤的方法。 该方法包括给需要进行放射 性治疗的病人预先施用预防有效量的吡非尼酮， 然后再进行放射性治疗。
本发明还提供了一种提高放射性治疗的辐射剂量的方法。 该方法包括给 原定按 D。辐射剂量进行放射性治疗的病人预先施用预防有效量的吡非尼酮， 然后在 D 射剂量下进行放射性治疗，其中 D^D^较佳地 比 DQ大 20%， 更佳地大 50%。
如本文所用， 术语 "预防有效量" 是可以达到预防放射性肺损伤效果的 施用量。 通常， 该预防有效量为 l-50mg/kg体重 /天。
在本发明中， 吡非尼酮可以单独使用， 也可以与前体药物联合使用。 本发明的主要优点在于：
(1) 吡非尼酮对放射性肺损伤的预防效果显著， 药物的毒副作用少， 使 用安全。
(2) 吡非尼酮可显著提高放射性治疗的辐射剂量。 ·
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， 或按照制造厂商所建议的条件。 实施例 1
吡非尼酮对放射性肺损伤的作用
(a) 照射方法：
照射源： Varian 600C 直线加速器， 6MV X射线。 4 照射方法：将清醒状态下小鼠 6个一排固定在特制的有机玻璃容器内，上盖 1.5cm厚的有机玻璃板以补偿剂量建成效应， 源皮距 100cm, 射野 2.5 X 18cm， 准直器铅门遮挡头部及腹部， 仅照射小鼠胸部。单次照射 1200cGy。 实验小鼠出 入清洁动物房应用带有空气滤过的专用密封转运箱。
动物： 10周龄的 BALB/C小鼠
(b) 动物分组：
模型对照组 (60只）： 仅给予照射， 不进行治疗。
预防给药组 (60只）： 自照射前 2天开始给予一定剂量的药物进行千预。 放 射线照射处理方法及剂量同模型对照组。每日灌胃给予吡非尼酮一次 (剂量为 200mg/kg, 以 0.5%的 CMC-Na溶解后按 0.1ml/10g的量给药）， 共给药 3个月。
治疗给药组 (60只）： 自照射当天开始给予一定剂量的药物进行干预。 放 射线照射处理方法及剂量同模型对照组， 单次照射。 灌胃给予吡非尼酮 (剂量 为 200mg/kg， 以 0.5%的 CMC-Na溶解后按 0.1ml/10g的量给药）， 每日一次， 共 3个月。
空白对照组 (60只）： 不进行照射， 每日给予 0.5%CMC-Na灌胃， 共 3个月。 照射后每天观察各组小鼠 1次， 观察是否出现死亡的情况。 实验处理后 定期观察灌洗液细胞分类计数、 胶原含量测定 (羟脯氨酸)、 病理形态学等。
肺泡灌洗液细胞计数： 注入一定量的生理盐水注入右肺， 缓慢抽吸， 共 收集灌洗液 1.5〜2.0ml到离心管中。 收集肺泡灌洗液后立即应用细胞计数板 手工计数炎性细胞含量。
肺羟脯氨酸含量测定： 取肺组织， 按羟脯氨酸试剂盒说明书程序测定。 组织病理学检查： 取肺组织以福尔马林固定， 脱水后石蜡包埋， HE染色 及 Masson三色染色。 评价标准： 参照 Ashcroft间质肺纤维化半定量评分标准 评定放射性肺损伤
结果：
实验表.明，吡非尼酮预防或治疗都能降低肺泡灌洗液中的炎性细胞数量， 表明吡非尼酮对放射照射所激发的肺部炎症反应有一定的抑制作用。 而预防 性给药疗效比治疗性给药效果更显著 (表 1和图 1)。 表 1 月 ΐ泡灌洗液细胞计数
第二月 第三月 第四月 第五月 第六月 空白对照 1.09 0.31 0.75 2.02 0.87 模型对照 5.16 4.72 18.51 60.61 46.21
治疗组 5.78 1.04 8.04 45.55 39.29 预防组 2.27 2.03 4.5 27.7 15 实验还表明， 吡非尼酮可明显降低肺组织中的羟脯氨酸含量， 即降低了 肺部胶原合成量， 表明吡非尼酮对于放射损伤后所形成的纤维化病变有一定 的抑制作用。 令人意外的是， 预防性给药疗效比治疗性给药效果更为显著， 尤其是在第 5、 6月时更为明显 (表 2和图 2)。 这提示， 预防性给药更为有利。 表 2 全肺羟脯氨酸测定
Figure imgf000012_0001
实施例 2
吡非尼酮可提髙对放射性治疗剂量的耐受
(a)方法： 同实施例 1。
预防组 (60只）： 自照射前 2天开始给予一定剂量的药物进行干预。 药物治 疗分两组， 灌胃给予吡非尼酮 (剂量为 200mg/kg， 以 0.5%的 CMC-Na溶解后按 0.1ml/10g的量给药）， 共给药 3个月。
每组动物共 60只。 照射后每天观察各组小鼠 1 次， 观察是否出现呼吸困 难以及死亡的情况。 实验处理后定期观察肺重、 灌洗液细胞分类计数、 胶原 含量测定 (羟脯氨酸)、 血浆细胞因子测定 (ACE、 TGF-β, TNF-α等)、 病理形 态学等。
结果表明，
在预防性施用了吡非尼酮的情况下， 肺泡灌洗液细胞计数低于对照组。 这提示， 预先给予吡非尼酮可提高放射性治疗中的辐射剂量。 实施例 3
12名健康受试者口服吡非尼酮胶囊 400mg， 1日 1次或 3次， 连续服药 5日， 并每天测得受试者的血药浓度。 结果表明， 连续给药 400mg的第 3天即已达到 稳态。 这提示， 预防性给予吡非尼酮 (如在照射之前 2天给药)， 使体内药物浓 度达到稳态水平， 有利于治疗作用的发挥。 实施例 4
制备含吡非尼酮的药物组合物
(a)注射液
吡非尼酮 20-100mg
氯化钠 l-5mg
注射用水 加至 10ml
按上述配方， 称取吡非尼酮和氯化钠， 配制成溶液后灌装于 10ml注射液瓶 中， 灭菌后包装。 供注射用。
(b)胶囊
吡非尼酮 50-500mg
羟丙基甲基纤维素 2-10mg
淀粉 50-100mg
乳糖 2-10mg
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 等量递加法加入吡非尼酮， 充分研磨， 使其分散均匀， 再过 80目筛， 然后灌制 成胶囊。
(c)缓释片
吡非尼酮 50-500mg
羟丙基甲基纤维素 20-100mg
海藻酸钠 50-100mg
乳糖 100-200mg
微晶纤维素 50-200mg
硬脂酯镁 2-10mg 按 1000个片剂 (配方如上)的用量， 称取吡非尼酮、 乳糖、 羟丙基甲基纤 维素、 海藻酸钠分别研细过 80目筛后， 混勾， 再与微晶纤维素混匀， 以水润 湿， 用 16-18 目筛制成颗粒， 于 60°C干操， 整粒， 加硬脂酯镁混匀压制成片。
(d)胶囊
吡非尼酮 50-500mg
丹参提取物 50mg
羟丙基甲基纤维素 2-10mg
淀粉 50-100mg
乳糖 2-10mg
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吡非尼酮和丹参提取物， 充分研磨， 使其分散均匀， 再 过 80目筛， 然后灌制成胶囊。 . 实施例 5
吡非尼酮类似物的合成
式 (1)中 为位于 4位的甲基， R2为位于 4位的羟甲基， 通过以下反应得到类
Figure imgf000014_0001
将 4-methylpyridin-2(lH)-one溶于二氯甲烷中， 加入催化量的吡啶， 温度 控制在 0-5°C , 慢慢滴加入 l-bromo-4-methoxybenzene， 在室温条件下反应 2 小时。 将反应液倒入冰水中， 用二氯甲烷萃取二次， 合并有机层。 有机层用 饱和食盐水洗涤， 硫酸钠干燥， 浓缩， 得到粗品。 柱层析得到化合物。 实施例 6
5_甲基小 (4_羟基苯基) _2-(1Η)-吡啶酮对放射性肺损伤的作用
重复实施例 1，不同点在于，用 5-甲基 -1-(4-羟基苯基) -2-(m)-吡啶酮 (F351) 替换吡非尼酮， 而且每组动物为 20只。
实验表明， 化合物 F351预防或治疗都能降低肺泡灌洗液中的炎性细胞数 量， 而预防性给药疗效比治疗性给药效果更显著。 讨论
肺损伤是胸部肿瘤接受放疗时的常见问题， 分早期和后期放射性肺损伤 两种。 早期肺损伤 (放射性肺炎)常发生在放疗过程中， 常常会引起严重后果， 轻者导致疗程中断而影响肿瘤治疗疗效， 重者会直接导致患者死亡。 肺部感 染也加重肺的纤维化， 肺的后期放射损伤主要是靠预防。 目前临床上没有专 门治疗放射性肺损伤的药物， 对于放射性肺损伤的预防性药物目前也仍无报 道。
一旦肺纤维化产生， 其治疗将是一个复杂、 漫长的过程。 即便吡非尼酮 有着很好的治疗放射性肺损伤的临床治疗效果， 也不能保证病人能够彻底恢 复， 不留下后遗症。 所以病发前的预防要比病发后的治疗更具有实际意义。 吡非尼酮作为一个小分子化合物， 具有抑制组织纤维化的作用。 可以改善肺 功能、 抗炎、 抗纤维化。 如在肺纤维化产生之前用吡非尼酮， 则能抑制胶原 蛋白的合成， 阻止成纤维细胞增生， 并下调许多细胞因子的产生， 从而预防 放射性肺炎和放射性肺纤维化的产生。
由于放疗过程中放射性肺损伤是不可避免的， 如将吡非尼酮类化合物在 放疗之前进行治疗干预， 一方面可以杀死肿瘤组织， 另一方面又可以最大限 度的预防放射性肺损伤的产生， 提高病人的生活质量， 使治疗取得事半功倍 的效果， 在理论与临床上都具有重要的意义和价值。 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的用途，
Figure imgf000016_0001
式中，
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、 6烷氧基、 或 0^6垸硫基； 或 为无， 其特征在于， 用于制备预防放射性肺损伤的药物。
2. 如权利要求 1所述的用途， 其特征在于， 所述的放射性损伤是放射性 治疗肺癌、 乳腺癌、 食管癌、 恶性淋巴瘤或胸部其他恶性肿瘤时造成的损伤。
3.如权利要求 1所述的用途， 其特征在于， 所述的化合物为吡非尼酮。
4. 一种式 I化合物或其药学上可接受的盐的用途，
Figure imgf000016_0002
式中，
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、 CL6垸氧基、 或 <^_6垸硫基； 或 为无, 其特征在于， 用于制备提高放射性治疗的放射性剂量的药物。
5.如权利要求 4所述的用途， 其特征在于， 所述的放射性治疗是对肺癌、 乳腺癌、 食管癌、 恶性淋巴瘤或胸部其他恶性肿瘤进行放射性治疗。
6.如权利要求 4所述的用途， 其特征在于， 所述的化合物为吡非尼酮。
7. 一种预防哺乳动物放射性肺损伤的方法， 其特征在于， 包括步骤： 给所述晡乳动物施用预防有效量的式 I化合物或其药学上可接受的盐，
Figure imgf000017_0001
式中，
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、 C 6垸氧基、 或 .6烷硫基； 或1 2 为无；
然后对该哺乳动物进行放射性治疗。
8.如权利要求 7所述的方法， 其特征在于， 所述的放射性治疗是对肺癌、 乳腺癌、 食管癌、 恶性淋巴瘤或胸部其他恶性肿瘤进行放射性治疗。
9.一种提高晡乳动物放射性治疗的辐射剂量的方法， 其特征在于， 包括步 骤：
(a)给需要进行放射性治疗的哺乳动物对象施用式 I化合物或其药学上可接 受的盐，
Figure imgf000018_0001
式中，
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、 CL6烷氧基、 或 C^6烷硫基； 或 R 为无;
其中， 所述哺乳动物的放射性治疗的原定辐射剂量为 DQ； 和
(b)在辐射剂量 下， 对所述哺乳动物进行放射性治疗，
其中 D E
10. 如权利要求 9所述的方法， 其特征在于， 所述的辐射剂量 0!和 0 满足下式：
(D Po)/D0> 20%。
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CA2656017A1 (en) 2007-12-27
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JP5213852B2 (ja) 2013-06-19
ATE533486T1 (de) 2011-12-15

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