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WO2008147170A1 - Nouveau procédé de synthèse pour l'obtention de 5-méthyl-1-phényl-2- (ih) -pyridone, composition et utilisation de celle-ci - Google Patents

Nouveau procédé de synthèse pour l'obtention de 5-méthyl-1-phényl-2- (ih) -pyridone, composition et utilisation de celle-ci Download PDF

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Publication number
WO2008147170A1
WO2008147170A1 PCT/MX2008/000069 MX2008000069W WO2008147170A1 WO 2008147170 A1 WO2008147170 A1 WO 2008147170A1 MX 2008000069 W MX2008000069 W MX 2008000069W WO 2008147170 A1 WO2008147170 A1 WO 2008147170A1
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WO
WIPO (PCT)
Prior art keywords
pirfenidone
methyl
temperature
pyridone
hours
Prior art date
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Ceased
Application number
PCT/MX2008/000069
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English (en)
Spanish (es)
Inventor
José Agustin Rogelio MAGANÃ CASTRO
Laura Vazquez Cervantes
Juan Socorro Armendariz Borunda
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Cell Therapy and Technology SA de CV
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Cell Therapy and Technology SA de CV
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Application filed by Cell Therapy and Technology SA de CV filed Critical Cell Therapy and Technology SA de CV
Publication of WO2008147170A1 publication Critical patent/WO2008147170A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to a new synthesis process for obtaining 5-methyl-l-phenyl- (IH) -pyridone, whose generic name is Pirfenidone, the process object of the present invention consists of three stages, which allow obtain a product of greater purity and better performance, whose characteristics represent an improvement over the other known methods.
  • the compound obtained shows excellent properties in the treatment of atopic dermatosis and actinic keratinosis, hypertrophic scars, keloid scars and acne scars, when applied in a suitable pharmaceutical composition.
  • Pirfe ⁇ i ⁇ one is itself a known compound and its pharmacological effects have been described in, for example, Japanese applications KOKAI Nos. 87677/1974 and 1284338/1976, as an anti-inflammatory agent that includes anti-inflammatory effects. - pyretic and analgesic.
  • a keloid is an overgrowth of dense fibrous tissue that usually develops after healing a skin wound. The tissue extends beyond the edges of the original wound, usually there is no spontaneous regression and tends to recur after being excised when it is altered by the fibroproliferation of human skin.
  • Keloid and hypertrophic scars are the only disorders Fibroproliferative human skin following trauma, inflammation, burn or surgery. The appearance of keloid scar has a familial tendency, and affects sex Arabs equally at an age mostly between 10 and 30 years. In affected individuals, scars that are raised, red and firm can cause itching and pain and create functional and cosmetic problems. Its incidence ranges from 4.5% to 16%, especially in blacks, Hispanics and Orientals.
  • Pirfenidone has demonstrated its effectiveness as an anti-fibrotic agent, in different pathologies and organs, as it has been shown in previous studies, where we have observed an effect on fibroblasts and collagen produced by them, both in experimental models and in clinical trials
  • Pirfenidone (5-methyl-l-phenyl-2- (IH) -pyridone), is an anti-fibrotic agent that has proven effective in preventing and resolving the accumulation of fibrous tissue, both in experimental models of pulmonary fibrosis (2) , uterine leiomyomas (3), renal fibrosis (4) and keloid scars (5); peritoneal adhesions (6), liver fibrosis (7); as well as in clinical trials of idiopathic pulmonary fibrosis (8), and cirrhosis liver (9).
  • a second object of the present invention is to provide a pharmaceutical composition of Pirfenidone, for dermal application.
  • the present invention relates to a three-stage process for obtaining 5-methyl-l-phenyl- (IH) -pyridone which is efficient and direct, in addition to providing high yields.
  • the process of obtaining the 5-methyl-2-pyridone object of the present invention is carried out in three stages which comprise; in the first one, obtain 5-methyl-2 (H) -pyridone from 2-amino-5- methyl-pyridine by a diazo reaction in medium acid, to then obtain 5-methyl-l-phenyl- (IH) -pyridone by reduction with copper in the presence of iodobenzene, carrying out the addition of the aromatic ring at the same stage.
  • the last step consists in the purification of the 5-methyl-l-phenyl- (IH) -pyridone obtained, which results in a high purity product useful in pharmaceutical compositions.
  • the reaction mixture is slowly heated to a temperature of 90 0 C, which remains constant for one hour, at the end of this time is allowed to cool the reaction mixture to reach room temperature.
  • Anhydrous sodium carbonate is added to the reaction mixture until a pH between 7 and 8 is achieved.
  • the reaction mixture is heated and distilled in vacuo at 70 ° C. After removing 90% of the aqueous phase, it is allowed to cool until reach 50 0 C, temperature at which methanol is added and stirred, to subsequently heat and maintain the reflux temperature for one hour.
  • the suspension is filtered, the solid is washed three times with hot methanol.
  • the filtrate and washings are combined and concentrated in vacuo until the crystallization of the product begins.
  • the solution is cooled to a temperature of 5 to 10 0 C for 12 hours.
  • the reddish solid is filtered, washed with cold methanol and dried in vacuo for 12 hours.
  • the reaction provides a yield of 98 to 99.5%.
  • 5-methyl-2 (H) -pyridone obtained in the previous step is mixed with anhydrous potassium carbonate, copper powder and iodobenzene, stirred and refluxed at 160 0 C for 18 to 20 hours.
  • the reaction mixture at a temperature between 60 and 70 0 C is cooled, the solid the liquid decanted.
  • ethyl acetate To the solid is added ethyl acetate, the mixture is stirred and heated under reflux for one hour, after which it is filtered hot, the solid is washed with hot ethyl acetate, the filtrate and the washings are combined, this suspension is distilled in vacuo and allowed to cool for 12 hours.
  • the brown solid obtained is dried and washed with cold ethyl acetate.
  • the Pirfenidone obtained is purified by dissolving it in acetone and adding activated carbon. The mixture is heated at reflux for one hour. The mixture is filtered on celite and washed with hot acetone, The filtrate and washings are combined and distilled to concentrate the solution and promote crystallization of the product. Water is added to the concentrated mixture and all acetone is distilled. The aqueous suspension of a white solid is passed vtn crystallizer and cooled under stirring at a temperature of 5 to 10 0 C for 12 hours. The white solid obtained was filtered and dried at a temperature of 60 0 C for 12 hours. The product obtained has a purity of 99.8%, a max in UV of 316.96, 01830 and a melting point of 109-111 0 C.
  • a mixture is prepared with 50 kilograms of 5-methyl-2 (H) -pyridone, obtained in the previous step, 70 kilograms of anhydrous potassium carbonate, 1 Kilogram of freshly prepared copper powder and 150 liters of iodobenzene.
  • the mixture is heated at reflux, 160 0 C, maintaining stirring. It is left at reflux for 18 to 20 hours. After this reaction time it is cooled to a temperature between SO and 70 0 C. The suspension is allowed to stand and the supernatant is decanted.
  • This is a solution of pirfenidone in iodobenzene, which is treated separately.
  • To the solid 400 liters of ethyl acetate are added, stirred and heated at reflux for 1 hour.
  • Iodobenzene solution is concentrated in vacuo to an approximate volume of 100 liters, it is passed to a crystallizer hot and cooled to a temperature between 4 and 10 0 C for 24 hours. The crystals obtained are filtered in the crentrifuge. You get approximately 40 M
  • Pirfenidone compositions for topical application are Pirfenidone compositions for topical application.
  • the Pirfenidone obtained is used in the manufacture of pharmaceutical compositions of dermatological application as described below: 22
  • Pirfenidone serum levels were assessed after 21 days of daily topical dermal application to albino rabbits, which were divided into four groups, of 9 rabbits each, and were topically medicated with graduated doses (200 to 5000 mg / kg / day) Pirfenidone hydrophilic ointment 10%, blood samples were taken for the Pirfenidone test before starting the application and again on day 22. Rabbits that received doses equal to or greater than 2000 mg / kg showed quantifiable levels in serum, of the order of 1.10 ⁇ 0.39 micrograms / ml. These levels are not toxicologically or pharmacologically significant, even after repeated massive topical doses of ointment with 10% Pirfenidone.
  • Topical cytoprotective activity of concentrations of 0.0% (control) r 1.0%, 2.5%, 5.0% and 10.0% of Pirfenidone in ointments were determined in albino mice according to the WaIz method. Ten mice were used for each dose. Dermal inflammation lesions were generated by the subcutaneous injection of 0.03 ml of a 0.05 M hydrochloric acid solution in a shaved area, centrally located in the ventral abdominal skin of each mouse. Each mouse received a topical application of 70 mg of ointment and was applied to a circle with a diameter of 20 mm, above the induced skin lesion.
  • Each rabbit's dorsal was pinched by an electric clamp. Twenty-four hours later, an ultraviolet lamp was suspended 9 inches above the rabbits' backs. Before exposure, the lamp was heated for a minimum of 10 minutes.
  • Each rabbit was prepared for exposure to dorsal radiation by covering its back with an aluminum foil in which 4 circular holes of 1.0 cm had been cut. From two of these holes, the aluminum cover was removed to allow penetration of DV radiation to the dorsal skin; the other two remained covered. They were exposed for 25 minutes in groups of three, 10 min after exposure, 0.5 grams of the respective cream preparations were applied. The animals were restricted until the erythema had been evaluated at 4 hours.
  • Readings were made after 24, 48 and 72 of the initial exposure. The complete resolution of the irritation occurred at 72 hours. In contrast, areas not treated with Pirfenidone cream showed marked irritation (grade 2 or 3) at 72 hours. The difference i s were statistically significant (P ⁇ 0.05).
  • the effect of 5.0% vs 10.0% pirfenidone ointment was evaluated in a study with 10 pregnant mares, in which inflammatory dermal neck injuries were experimentally induced by subcutaneous injection of 5.0 ml of sodium alginate followed by 5.0 ml of chloride of calcium within the same site.
  • the ointments were applied once a day starting 24 hours after the subcutaneous injection of the irritants and was continued for 5 days. Measurements in centimeters, length and width of the lesions were made daily. The peak inflammatory reaction was achieved between 48 and 72 hours.
  • Keloid human tissue weight in transplanted xenografts within nude mice Keloid human tissue weight in transplanted xenografts within nude mice.
  • Tissues of surgically obtained human keloids were transplanted into groups of nude mice, of which two series of groups were obtained. One series served as a control and did not receive Pirfenidone. The second series received Pirfenidone mixed in the. food. Subsequently, the measurement of transpiated keloids was performed at 30, 60 and 90 days after the transplant procedure. After the transplants were removed from their subcutaneous sites, wet and dry weights were determined and expressed as percentages of the original weights. Clearly the administration of Pirfenidone in the diet significantly reduced the weight of keloid transplants without altering the ratio of chondroitin sulfate. In addition, the final weight of the animals fed with Pirfenidone was comparable to that of the controls.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé pour la préparation de 5-méthyl-1-phényl-1 (H) - pyridone, qui comprend trois étapes permettant d'obtenir des rendements supérieurs d'un produit de haute pureté, ainsi que des compositions pharmaceutiques à administrer par voie topique et l'utilisation de celles-ci.
PCT/MX2008/000069 2007-05-29 2008-05-29 Nouveau procédé de synthèse pour l'obtention de 5-méthyl-1-phényl-2- (ih) -pyridone, composition et utilisation de celle-ci Ceased WO2008147170A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXMX/A/2007/006349 2007-05-29
MX2007006349A MX2007006349A (es) 2007-05-29 2007-05-29 Nuevo proceso de sintesis para la obtencion de 5-metil-1-fenil-2-(ih)-piridona, composicion y uso de la misma.

Publications (1)

Publication Number Publication Date
WO2008147170A1 true WO2008147170A1 (fr) 2008-12-04

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MX (1) MX2007006349A (fr)
WO (1) WO2008147170A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482255A (zh) * 2009-06-03 2012-05-30 英特姆尼国际公司 用于合成吡非尼酮(pirfenidone)的改良方法
CN102558040A (zh) * 2011-12-28 2012-07-11 辰欣药业股份有限公司 一种吡非尼酮的制备方法
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
CN105330598A (zh) * 2015-12-02 2016-02-17 新发药业有限公司 一种吡非尼酮的制备方法
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
WO2017072216A1 (fr) 2015-10-29 2017-05-04 Procos S.P.A. Procédé de synthèse de pirfénidone
US9770443B2 (en) 2014-01-10 2017-09-26 Genoa Pharmaceuticals, Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
WO2018178996A1 (fr) 2017-03-28 2018-10-04 Natco Pharma Limited Procédé amélioré pour la préparation de pirfénidone
US10092552B2 (en) 2011-01-31 2018-10-09 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10105356B2 (en) 2011-01-31 2018-10-23 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US11066368B2 (en) 2016-01-14 2021-07-20 Laurus Labs Limited Process for the preparation and particle size reduction of pirfenidone

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016775A1 (fr) * 1998-09-18 2000-03-30 Mepha Ag Formulation topique a base d'alkyl-, phenyl-pyridone
CN1386737A (zh) * 2002-06-11 2002-12-25 中南大学湘雅医学院 抗纤维化吡啶酮药物及其生产工艺方法
WO2003014087A1 (fr) * 2001-08-06 2003-02-20 Asahi Glass Company, Limited Procede de preparation de 5-methyl-1-phenyl-2(1h)-pyridinone
CN1817862A (zh) * 2006-03-15 2006-08-16 浙江省医学科学院 一种抗纤维化药物吡非尼酮的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016775A1 (fr) * 1998-09-18 2000-03-30 Mepha Ag Formulation topique a base d'alkyl-, phenyl-pyridone
WO2003014087A1 (fr) * 2001-08-06 2003-02-20 Asahi Glass Company, Limited Procede de preparation de 5-methyl-1-phenyl-2(1h)-pyridinone
CN1386737A (zh) * 2002-06-11 2002-12-25 中南大学湘雅医学院 抗纤维化吡啶酮药物及其生产工艺方法
CN1817862A (zh) * 2006-03-15 2006-08-16 浙江省医学科学院 一种抗纤维化药物吡非尼酮的制备方法

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] 16 August 2006 (2006-08-16), Database accession no. (2006:843808) *
DATABASE CAPLUS [online] 2006, "Synthesis of pirfenidone", Database accession no. (2007:889612) *
DATABASE CAPLUS [online] 25 December 2002 (2002-12-25), Database accession no. (2003:935146) *
ISMAIL ET AL.: "Novel pirfenidone analogs as antifibrotic agents", MEDICAL CHEMICAL RESEARCH, vol. 14, 2005, pages 382 - 403 *
LI C-S. ET AL.: "An efficient copper-catalyzed coupling reaction of pyridin-2-ones with aryl and heterocycle halides nased on Buchwald's protocol", TETRAHEDRON LETTERS, vol. 45, 2004, pages 4257 - 4260, XP002464514 *
ZHONGGUO YIYAO GONYE ZAZHI, vol. 37, no. 6, pages 372 - 373 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
CN102482255A (zh) * 2009-06-03 2012-05-30 英特姆尼国际公司 用于合成吡非尼酮(pirfenidone)的改良方法
US8519140B2 (en) 2009-06-03 2013-08-27 Intermune, Inc. Method for synthesizing pirfenidone
AP3630A (en) * 2009-06-03 2016-03-08 Intermune Inc Improved method for synthesizing pirfenidone
EP2440543A4 (fr) * 2009-06-03 2012-11-21 Intermune Inc Procédé de synthèse amélioré de la pirfénidone
US10105356B2 (en) 2011-01-31 2018-10-23 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10092552B2 (en) 2011-01-31 2018-10-09 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
CN102558040A (zh) * 2011-12-28 2012-07-11 辰欣药业股份有限公司 一种吡非尼酮的制备方法
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US9770443B2 (en) 2014-01-10 2017-09-26 Genoa Pharmaceuticals, Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US10028966B2 (en) 2014-01-10 2018-07-24 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
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
WO2017072216A1 (fr) 2015-10-29 2017-05-04 Procos S.P.A. Procédé de synthèse de pirfénidone
US10472325B2 (en) 2015-10-29 2019-11-12 Procos S.P.A. Process for the synthesis of pirfenidone
CN105330598B (zh) * 2015-12-02 2017-11-14 新发药业有限公司 一种吡非尼酮的制备方法
CN105330598A (zh) * 2015-12-02 2016-02-17 新发药业有限公司 一种吡非尼酮的制备方法
US11066368B2 (en) 2016-01-14 2021-07-20 Laurus Labs Limited Process for the preparation and particle size reduction of pirfenidone
WO2018178996A1 (fr) 2017-03-28 2018-10-04 Natco Pharma Limited Procédé amélioré pour la préparation de pirfénidone

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