WO2013018685A1 - Dérivé de lactame et son utilisation à des fins médicales - Google Patents

Dérivé de lactame et son utilisation à des fins médicales Download PDF

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WO2013018685A1
WO2013018685A1 PCT/JP2012/069119 JP2012069119W WO2013018685A1 WO 2013018685 A1 WO2013018685 A1 WO 2013018685A1 JP 2012069119 W JP2012069119 W JP 2012069119W WO 2013018685 A1 WO2013018685 A1 WO 2013018685A1
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fibrosis
compound
lactam derivative
solvent
pirfenidone
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PCT/JP2012/069119
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English (en)
Japanese (ja)
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新之助 林
拓実 青木
庸平 宮本
克彦 伊関
陽介 井浦
千紗 久家
俊介 岩野
晃央 前田
目黒　裕之
戒能　美枝
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東レ株式会社
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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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6

Definitions

  • the present invention relates to a lactam derivative and its pharmaceutical use.
  • Fibrosis is a disease that adversely affects the function of various organs, mainly due to the overproliferation of fibroblasts and the overproduction and accumulation of extracellular matrix components, particularly the lungs, skin, digestive tract, It affects the kidneys and liver.
  • Renal fibrosis leads to renal failure at the end stage, requiring treatment by artificial dialysis or kidney transplantation.
  • Liver fibrosis leads to liver sclerosis and cirrhosis at the end stage, many of which progress to liver cancer.
  • pulmonary fibrosis respiratory failure occurs, and in the worst case, death occurs.
  • immunosuppressive agents and anti-inflammatory agents such as corticosteroids are mainly used for the treatment of fibrosis.
  • Non-Patent Documents 1 to 4 In recent years, as a drug effective for idiopathic pulmonary fibrosis, pirfenidone has obtained the world's first manufacturing and marketing approval. Pirfenidone has been found to have an anti-fibrotic effect in affected organs of various fibrotic animal models (Non-Patent Documents 1 to 4).
  • pirfenidone a therapeutic agent for idiopathic pulmonary fibrosis
  • pirfenidone a therapeutic agent for idiopathic pulmonary fibrosis
  • phototoxicity hepatotoxicity
  • digestive system disorders as serious side effects. If these side effects are observed, the drug must be discontinued. It was the present situation that we did not get.
  • an object of the present invention is to provide a highly safe treatment or prevention agent for fibrosis that does not have phototoxicity and has reduced hepatotoxicity and digestive system disorders.
  • the present invention provides a lactam derivative represented by the following chemical formula (I).
  • the present invention also provides a medicament, particularly a therapeutic or prophylactic agent for fibrosis, which contains the lactam derivative represented by the above formula (I) as an active ingredient.
  • the lactam derivative of the present invention has an anti-fibrotic effect on in vitro models and pathological animal models of fibrosis, has no phototoxicity, and has reduced hepatotoxicity and digestive system damage. It can be used as a highly safe treatment or prevention agent for fibrosis.
  • the lactam derivative of the present invention is characterized by being represented by the following chemical formula (I).
  • the above lactam derivatives are isomers due to the presence of asymmetric carbon (R-form, S-form, ⁇ -form, ⁇ -form, enantiomer), optical isomers having optical activity (D-form, L-form, d Body, l-form, (+)-form, (-)-form), a mixture of these in any proportion, and a racemic mixture.
  • the above lactam derivative can be synthesized, for example, according to the production method shown in Scheme 1.
  • the above lactam derivative obtained by the following production method can be isolated and purified by known means.
  • isolation and purification methods include, for example, solvent extraction, recrystallization, or chromatography.
  • X represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • N-arylpyridone compound represented by the formula (IV) is represented by the general formula (III) in the presence of a metal catalyst, a ligand and a base in a suitable solvent with respect to the hydroxypyridine represented by the formula (II). It can be synthesized by a coupling reaction in which the represented aryl halide is allowed to act.
  • aryl halide examples include those having a leaving group that allows the coupling reaction to proceed smoothly, such as iodobenzene, bromobenzene, or chlorobenzene, with iodobenzene or bromobenzene being preferred.
  • the amount of the aryl halide used is preferably 1 to 20 mol, more preferably 1 to 10 mol, per 1 mol of hydroxypyridine represented by the formula (II).
  • the metal catalyst examples include a palladium catalyst such as tris (dibenzylideneacetone) dipalladium, palladium acetate or tetrakis (triphenylphosphine) palladium, or a copper catalyst such as cuprous oxide, copper iodide or copper powder. Copper catalysts are preferred.
  • a palladium catalyst such as tris (dibenzylideneacetone) dipalladium, palladium acetate or tetrakis (triphenylphosphine) palladium
  • a copper catalyst such as cuprous oxide, copper iodide or copper powder. Copper catalysts are preferred.
  • the amount of the metal catalyst used is preferably 0.001 to 1 mol, more preferably 0.01 to 0.5 mol, per 1 mol of hydroxypyridine represented by the formula (II).
  • the ligand is appropriately selected according to the metal catalyst.
  • the palladium catalyst ligand include triphenylphosphine, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, and 4, Examples include phosphine derivatives such as 5-bis (diphenylphosphino) -9,9-dimethylxanthene, and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene is preferable.
  • the amount of the ligand used is preferably 0 to 1 mol, more preferably 0 to 0.5 mol, per 1 mol of hydroxypyridine represented by the formula (II).
  • Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal phosphates such as sodium phosphate and potassium phosphate, and phosphoric acid.
  • alkali metal hydrogen phosphates such as sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate or potassium dihydrogen phosphate are listed, and alkali metal carbonates are preferred.
  • the amount of the base used is preferably 0.5 to 10 mol, more preferably 1 to 5 mol, relative to 1 mol of hydroxypyridine represented by the formula (II).
  • reaction solvent a solvent that does not normally inhibit the reaction is appropriately selected.
  • ether solvents such as tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane or ethylene glycol dimethyl ether, and aromatic hydrocarbon solvents such as benzene or toluene.
  • An aprotic polar solvent such as N, N-dimethylformamide (hereinafter referred to as DMF) or dimethyl sulfoxide (hereinafter referred to as DMSO) or the absence of a solvent may be mentioned.
  • DMF N, N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • the reaction temperature is preferably 0 to 200 ° C, more preferably 30 to 150 ° C.
  • the reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 72 hours.
  • the above lactam derivative can be synthesized by a reduction reaction for reducing the diene of the N-arylpyridone compound represented by the formula (IV) in an appropriate solvent.
  • the reduction reaction include catalytic hydrogenation in which a metal catalyst is allowed to act in a hydrogen gas atmosphere.
  • metal catalyst used for catalytic hydrogenation examples include platinum dioxide, palladium / activated carbon or palladium hydroxide / activated carbon, with platinum dioxide being preferred.
  • the amount of the metal catalyst used is preferably 0.05 to 200% by weight, more preferably 1 to 100% by weight, based on 1 mole of the N-arylpyridone compound represented by the formula (IV).
  • the hydrogen gas pressure is preferably 1 to 10 atm, and more preferably 1 to 5 atm.
  • reaction solvent a solvent that does not normally inhibit the reaction is appropriately selected.
  • alcohol solvents such as methanol, ethanol or 2-propanol
  • ester solvents such as ethyl acetate or n-propyl acetate, THF, 1,4-dioxane, and the like.
  • an ether solvent such as ethylene glycol dimethyl ether, a halogen solvent such as dichloromethane, chloroform or 1,2-dichloroethane, water, or a mixed solvent thereof can be used, and an alcohol solvent is preferable.
  • the concentration of the N-arylpyridone compound represented by the formula (IV) in the reaction solution is preferably 0.001 to 5 mol / L, and more preferably 0.05 to 2 mol / L.
  • the reaction temperature is preferably 0 to 100 ° C, more preferably 10 to 60 ° C.
  • the reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 30 minutes to 48 hours.
  • the above lactam derivative has an excellent antifibrotic effect, does not have phototoxicity, has reduced liver toxicity and gastrointestinal disorders, and can be used as a highly safe pharmaceutical. It can be preferably used as a therapeutic or prophylactic agent for symptom.
  • Fibrosis is a disease in which fibrotic lesions are formed in tissues mainly due to overproliferation of fibroblasts and overproduction and accumulation of extracellular matrix components, and adversely affect the function of various organs, for example, Liver fibrosis, cirrhosis, liver necrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, myocardial fibrosis, renal fibrosis, vascular fibrosis or skin scars, but the above lactam derivatives are especially pulmonary fibrosis It is preferably used for treatment or prevention.
  • Pulmonary fibrosis is caused by various stimuli that damage the alveolar epithelium or basement membrane, resulting in fibrotic lesions in the lungs due to overproliferation of fibroblasts and overproduction and accumulation of extracellular matrix components during the repair process.
  • Diseases that are formed such as lung fibrosis seen late in pneumonia due to viral infection, pulmonary fibrosis caused by the progression of hypersensitivity pneumonia, idiopathic pulmonary fibrosis or radiation pulmonary fibrosis,
  • the lactam derivative is preferably used particularly for the treatment or prevention of idiopathic pulmonary fibrosis.
  • an in vitro model test it can be evaluated using an in vitro model test that the above lactam derivative is effective in treating or preventing fibrosis.
  • an in vitro model test to be used for example, a test using a collagen gel in which fibroblasts derived from various organs such as lung, liver, kidney, skin and the like are cultivated (Pulmonary Pharmacology & Therapeutics, 2009, Vol. 22, p.487-491, British Journal of Pharmacology, 2010, 159, pp.304-315, Kidney International, 2006, 70, p.298-305, Archives of Dermatological, Research, 20th year 304, p.217-222).
  • fibroblasts When activated in the process of tissue fibrosis, fibroblasts become hyperproliferative and produce excessive amounts of extracellular matrix components and acquire contractility.
  • fibroblasts When fibroblasts are embedded and cultured in a collagen gel, the collagen gel contracts as the fibroblasts contract due to fibroblast activation (for example, addition of TGF- ⁇ 1), and the collagen gel area decreases. Therefore, by measuring the collagen gel area, the contractility of fibroblasts, that is, the activation of fibroblasts can be evaluated.
  • a disease state model animal that the above lactam derivative is effective in treating or preventing fibrosis.
  • pathological model animals to be used include a bleomycin-induced pulmonary fibrosis model with bleomycin (European Journal of Pharmacology, 2008, 590, pp. 400-408), cirrhosis model with carbon tetrachloride (Journal of Hepatology, 2002). 37, p. 797-805), renal fibrosis model with ammonium metavanadate (Biochemical Pharmacology, 2002, 64, p.
  • the bleomycin-induced pulmonary fibrosis model is a common model of pulmonary fibrosis, but its pathological condition is considered to be close to idiopathic pulmonary fibrosis.
  • the effectiveness of the above lactam derivative for treating or preventing fibrosis is measured by measuring the area of collagen gel, which is an index of fibroblast contractility, using the in vitro model test described above, and indicating the reduction in area. Can be evaluated. Further, by using the above-mentioned disease state model animal, for example, a decrease in the amount of tissue hydroxyproline, which is a characteristic index of fibrosis, can be evaluated as an index.
  • Phototoxicity generally refers to the property that a drug absorbed in the skin, when activated by photochemical reaction by light energy, acquires toxicity and damages tissue.
  • Hepatotoxicity means local pain, joint pain, gastrointestinal dysfunction, general malaise, jaundice, hepatomegaly, ascites, spleen enlargement, edema, hepatic encephalopathy, liver It causes symptoms such as coma or tenderness, and hepatotoxicity observed with pirfenidone has been reported to be due to induction of cytochrome P450 (hereinafter CYP) (EUROPEAN MEDICINES AGENCY, CHMP assessment report, 2010, Procedure No. EMEA). / H / C / 002154).
  • CYP cytochrome P450
  • the low drug metabolizing enzyme CYP-inducing action of the lactam derivative can be evaluated, for example, in a CYP induction test using human frozen hepatocytes (Nippon Pharmacology, 2009, Vol. 134, p. 330-333).
  • Gastrointestinal disorders are those that cause symptoms such as upper abdominal discomfort, abdominal pain, abdominal bloating, loss of appetite, nausea, vomiting or diarrhea depending on the drugs taken.
  • the low digestive system damage action of the above lactam derivative can be evaluated by, for example, a test on gastric excretion ability using a pigment in rats, a test on small intestine transport ability using carbon powder, or a test on ferret emesis.
  • the above lactam derivative improves or treats the pathology of fibrosis when administered to mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys or humans), particularly humans. Or a preventive effect can be exhibited.
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys or humans
  • a preventive effect can be exhibited.
  • the above lactam derivative can be administered orally or parenterally in a non-added state or as a preparation containing a pharmaceutically acceptable carrier.
  • Examples of dosage forms for oral administration of the above-mentioned preparations containing lactam derivatives include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules and microcapsules). ), Syrups, emulsions or suspensions.
  • Examples of dosage forms for parenteral administration include injections, infusions, drops, and suppositories.
  • the above lactam derivative may be a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, butyric acid polymer and glycolic acid polymer mixture or poly In combination with glycerol fatty acid ester), it is possible to obtain a sustained-release preparation, which is effective in treating fibrosis.
  • a drug delivery system including a preparation technique such as microcapsule, micronization or packaging can be used.
  • a pharmaceutical dosage form containing the above lactam derivative as an active ingredient can be prepared according to a method generally used in the pharmaceutical field.
  • it can be prepared by containing excipients, binders, lubricants, disintegrating agents, sweeteners, surfactants, suspending agents, emulsifiers and the like that are generally used in the pharmaceutical field as necessary. .
  • Tablets can be prepared, for example, containing excipients, binders, disintegrants or lubricants, and pills and granules can be prepared, for example, with excipients, binders or disintegrants. It can be made to contain.
  • the preparation of powders and capsules can be carried out, for example, by containing excipients, and the preparation of syrups can be carried out, for example, by containing sweeteners, and preparation of emulsions and suspensions.
  • excipient examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate or calcium sulfate.
  • binder examples include starch paste, gum arabic, gelatin, tragacanth, carboxymethylcellulose, sodium alginate, and glycerin.
  • disintegrant examples include starch and calcium carbonate.
  • lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweetening agent include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester or polyoxyl 40 stearate.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.
  • emulsifier examples include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • the dose of the above lactam derivative varies depending on the target therapeutic effect, administration method, age or body weight, and thus cannot be defined unconditionally.
  • the daily oral dose is usually 100 to 10,000 mg as an active ingredient. Is preferable, and 200 to 8000 mg is more preferable. This may be divided into 1 to 5 doses per day.
  • Cuprous oxide (0.197 g, 1.38 mmol), potassium carbonate (4.18 g, 30.2 mmol) and bromobenzene (8.64 mL, 82.5 mmol) were added to the reaction mixture, and the reaction vessel was filled with argon. After the replacement, the mixture was stirred at 120 ° C. for 24 hours. The reaction mixture was filtered through celite, the obtained filtrate was concentrated under reduced pressure, and water was added to the residue. After extraction with dichloromethane, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Dichloromethane, hexane and diethyl ether were added to the obtained residue for recrystallization, and the precipitated solid was collected by filtration.
  • Example 2 Effect on contraction of collagen gel in which lung fibroblasts are embedded and cultured: The effect of the compound of Example 1 on the contraction of collagen gel in which HFL-1 cells, which are human lung fibroblasts, were cultured. Collagen gel contraction is described in Pulmonary Pharmacology & Therapeutics, 2009, Vol. 22, p. The method described in 487-491 was partially modified and evaluated.
  • Rat type I collagen (Becton Dickinson) dissolved in 0.02N acetic acid was diluted with penicillin / streptomycin-containing low glucose Dulbecco's Modified Eagle Medium (hereinafter DMEM) and suspended in the same medium. Mixed with cells (Human Science Research Resource Bank). The mixture was neutralized with 1N NaOH and 0.5 mL (collagen concentration: 2.5 mg / mL, cell density: 3 ⁇ 10 5 cells / mL) was dispensed into each well of a 24-well flat bottom plate. Incubated for minutes to allow the mixture to gel. DMEM was added to the top of the collagen gel and further incubated at 37 ° C. for 24 hours.
  • DMEM penicillin / streptomycin-containing low glucose Dulbecco's Modified Eagle Medium
  • Example 1 inhibits the contraction of lung fibroblasts, and thus exhibits a fibrosis inhibiting action.
  • Example 3 Evaluation in a mouse bleomycin-induced pulmonary fibrosis model The effect of the compound of Example 1 on the amount of hydroxyproline in lung tissue of a mouse bleomycin-induced pulmonary fibrosis model was examined.
  • a mouse bleomycin-induced pulmonary fibrosis model European Journal of Pharmacology, 2008, Vol. 590, p. The method described in 400-408 was used with some modifications.
  • Fibrosis was induced by administering bleomycin (Nippon Kayaku) at a dose of 10 mg / kg to ICR mice (male, 13 weeks old, Nippon Charles River) once daily for 5 days. Mice that did not induce fibrosis (normal group) were similarly administered with physiological saline.
  • Example 1 To the mice in which fibrosis was induced, the compound of Example 1 was orally administered at a dose of 33 mg / kg three times a day for 10 days from the start of bleomycin administration (100 mg / kg / day). The compound of Example 1 was used after being suspended in a 0.5% methylcellulose solution. A 0.5% methylcellulose solution was similarly administered to the normal group and the solvent group.
  • Example 2 The day after the compound administration end of Example 1, the left lung was collected after exsanguination under isoflurane anesthesia. The amount of hydroxyproline in lung tissue, which is an index of fibrosis, was quantified as follows by partially modifying the Woessner method (Archives of Biochemistry and Biophysics, 1961, Vol. 93, pp. 440-447). 1 mL of distilled water was added to the collected left lung (total) and homogenized, and 1 mL of concentrated hydrochloric acid was added thereto and heated at 120 ° C. for 24 hours. Thereafter, 2.4 mL of 5N NaOH was added for neutralization, and this was used as a measurement sample.
  • the sample for measurement was appropriately diluted with distilled water, 1 mL of 1.4% chloramine T solution was added and reacted at room temperature for 20 minutes, and then 3.15 M perchloric acid and 20% paradimethylaminobenzaldehyde / 2-methoxyethanol. 1 mL of each solution was added and reacted at 60 ° C. for 20 minutes. Then, it immediately cooled in the water bath and measured the light absorbency. The absorbance was measured at a measurement wavelength of 570 nm with a microplate reader (Bio-Rad, Model 680). The amount of hydroxyproline in the lung tissue (left lung) was calculated from a calibration curve (1 to 15 ⁇ g) obtained by linear regression analysis.
  • the amount of hydroxyproline in the lung tissue of the solvent group was statistically significantly increased compared to the normal group, indicating that pulmonary fibrosis was induced by bleomycin administration.
  • the amount of hydroxyproline in lung tissue was suppressed to a level equivalent to that in the normal group, and the value was statistically higher than that in the solvent group. Significantly decreased.
  • Example 4 Phototoxicity assessment of compounds in mice The phototoxic effect of the compound of Example 1 in mice was compared with pirfenidone.
  • BALB / c mice female, 7 weeks old, Charles River, Japan
  • the compound of Example 1 and pirfenidone were used in suspension in a 0.5% methylcellulose solution.
  • the solvent group was similarly administered with a 0.5% methylcellulose solution.
  • UV irradiation device (Delmale-200 type A / NB and Dermale-200 type A / B; Terumo Clinical Supply Co., Ltd.).
  • 20 J / cm 2 Irradiance of about 1.4 mW / cm 2 , irradiation for 4 hours) (ultraviolet irradiation animals), and the remaining 5 cases in each group were not irradiated (non-irradiated animals).
  • UV irradiation After completion of UV irradiation (after 0.5, 24, 48 and 72 hours), the degree of erythema and edema that developed on the skin of the auricle was visually observed. Non-irradiated animals were also observed and compared to evaluate the presence or absence of phototoxicity.
  • Example 5 Drug metabolism enzyme CYP induction test using frozen human hepatocytes: A drug metabolizing enzyme CYP induction test using frozen human hepatocytes was carried out, and the inducing action of the compound of Example 1 on the drug metabolizing enzyme CYP was evaluated.
  • a suspension of human frozen hepatocytes was prepared using Hepatocyte Isolation Kit (Xenotech).
  • a 48-well plate was seeded with 1.2 ⁇ 10 5 cells per well and pre-cultured for 48 hours.
  • the compound of Example 1 and pirfenidone were cultured in CP medium (Celsis) containing 10, 100 and 1000 ⁇ mol / L, respectively, for 24 hours.
  • the negative control group was cultured in CP medium (Celsis) containing 0.1 (v / v)% DMSO for 24 hours.
  • Example 2 24 hours after exposure to the compound of Example 1 and pirfenidone, the cells were washed with KHB Buffer (Celsis). After washing, 0.3 mL of 125 ⁇ mol / L Testosterone-containing KHB Buffer was added and reacted at 37 ° C. for 30 minutes. 20 ⁇ L of the supernatant after the reaction was collected and diluted with 180 ⁇ L of ice-cooled KHB Buffer, which was used as a measurement sample.
  • Example 1 has a lower inducing action on the drug metabolizing enzyme CYP than pirfenidone. This suggested that the compound of Example 1 had low liver toxicity.
  • Example 6 Evaluation of Compound Gastrointestinal Disorders in Rats The effects of the compound of Example 1 on the digestive system damage were compared with pirfenidone by a gastric emptying ability test in rats. A single dose of 30 mg / kg of the compound of Example 1 or 30 mg / kg of pirfenidone was orally administered to SD rats (male, 6 weeks old, Charles River, Japan). The compound of Example 1 and pirfenidone were used in suspension in a 0.5% methylcellulose solution. The solvent group was similarly administered with a 0.5% methylcellulose solution.
  • Rats were fasted for 18 hours or more from the day before administration of the test compound.
  • a 0.1% Evans blue solution was orally administered in a volume of 0.2 mL (200 ⁇ g).
  • the rats were euthanized by cervical dislocation, immediately laparotomized, and the stomach was removed.
  • the extracted stomach was immersed in 4 mL of 6.3 mol / L urea solution and shaken. Further acetone 8mL, 20% ZnSO 4 0.4mL, was added in the order of 1N NaOH 0.4 mL, repeated shaking. Thereafter, the stomach was removed from the solution, and the volume of the solution was measured using a graduated cylinder.
  • the solution was filtered through filter paper, and the absorbance at a wavelength of 620 nm was measured with a microplate reader (VersaMax, Molecular Devices Corp.).
  • the concentration of Evans blue dye in the solution was determined using a calibration curve prepared from the standard solution for the calibration curve.
  • the amount of Evans blue pigment contained in the solution was calculated and used as the amount of pigment remaining in the stomach.
  • the amount of pigment remaining in the stomach and the stomach excretion ability were calculated from the following formulas.
  • Gastric residual pigment amount ( ⁇ g) concentration ( ⁇ g / mL) ⁇ volume (mL)
  • Gastric emptying capacity (%) (1 ⁇ Amount of remaining pigment in stomach ( ⁇ g) / Amount of Evans blue administered ( ⁇ g)) ⁇ 100
  • the digestive system damage action of the compound of Example 1 was compared with pirfenidone by a small intestine transportability test in rats.
  • a single dose of 30 mg / kg of the compound of Example 1 or 30 mg / kg of pirfenidone was orally administered to SD rats (male, 6 weeks old, Charles River, Japan).
  • the compound of Example 1 and pirfenidone were used in suspension in a 0.5% methylcellulose solution.
  • the solvent group was similarly administered with a 0.5% methylcellulose solution.
  • Rats were fasted for 18 hours or more from the day before administration of the test compound. 60 minutes after administration of the test compound, 5% carbon powder suspension (liquid obtained by suspending carbon powder (Wako Pure Chemical Industries) at a ratio of 5% in 10% gum arabic (Wako Pure Chemical Industries)) in a volume of 1 mL. Orally administered. Thirty minutes after administration of the 5% carbon powder suspension, the rats were euthanized by cervical dislocation and immediately laparotomized, and the stomach and intestinal tract were excised while removing the mesentery.
  • 5% carbon powder suspension liquid obtained by suspending carbon powder (Wako Pure Chemical Industries) at a ratio of 5% in 10% gum arabic (Wako Pure Chemical Industries)
  • the intestinal tract was stretched, and the entire length of the small intestine (from the stomach pylorus to the cecal opening) and the distance from the stomach pylorus to the tip of the carbon powder suspension were measured using a measure.
  • the transfer rate of 5% carbon powder suspension with respect to the entire length of the small intestine was calculated as the small intestine transport ability (%) by the following formula.
  • Small intestine transportability (%) distance from stomach pylorus to tip of carbon powder suspension / total length of small intestine x 100
  • Table 2 shows the results of the gastric emptying ability test and the small intestine transport ability test.
  • “Solvent” in the table indicates a group (solvent group) orally administered with a 0.5% methylcellulose solution
  • Compound of Example 1 indicates a group orally administered with 30 mg / kg of the compound of Example 1
  • “Pirfenidone” indicates a group to which 30 mg / kg of pirfenidone was orally administered.
  • Example 1 had less influence on gastric excretion ability and small intestine transport ability than pirfenidone. This suggested that the compound of Example 1 had a low digestive system disorder action.
  • the novel lactam derivative of the present invention has an excellent antifibrotic effect, does not have phototoxicity, and has reduced liver toxicity and gastrointestinal disorders. Therefore, it can be used as a highly safe pharmaceutical. In particular, it can be used as a therapeutic or prophylactic agent for fibrosis.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un agent thérapeutique ou un agent prophylactique à utiliser dans le cadre d'une fibrose, lequel est très sûr, ne présente pas de phototoxicité et une hépatotoxicité réduite, et provoque peu de troubles digestifs. La présente invention concerne ainsi un dérivé de lactame représenté par la formule chimique (I).
PCT/JP2012/069119 2011-07-29 2012-07-27 Dérivé de lactame et son utilisation à des fins médicales WO2013018685A1 (fr)

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US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
CN105906558A (zh) * 2016-05-04 2016-08-31 河南师范大学 抗纤维化药物吡非尼酮晶型及其制备方法
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones

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JPS504669B1 (fr) * 1969-01-27 1975-02-22

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JPS504669B1 (fr) * 1969-01-27 1975-02-22
US3843608A (en) * 1971-07-27 1974-10-22 Ceskoslovenska Akademie Ved Preparing polyamides by anionic polymerization of lactams

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CANNIZZO,L.F. ET AL.: "Reactions of ''Cp2Ti:CH2'' sources with acid anhydrides and imides", J. ORG. CHEM., vol. 50, no. 13, 1985, pages 2316 - 23 *
HIROYUKI TANIGUCHI: "IPF no Chiryo 1) Pirfenidone", KOKYUKINAIKA, vol. 19, no. 6, June 2011 (2011-06-01), pages 568 - 74 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones
CN105906558A (zh) * 2016-05-04 2016-08-31 河南师范大学 抗纤维化药物吡非尼酮晶型及其制备方法

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