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MX2007006349A - New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same. - Google Patents

New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same.

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Publication number
MX2007006349A
MX2007006349A MX2007006349A MX2007006349A MX2007006349A MX 2007006349 A MX2007006349 A MX 2007006349A MX 2007006349 A MX2007006349 A MX 2007006349A MX 2007006349 A MX2007006349 A MX 2007006349A MX 2007006349 A MX2007006349 A MX 2007006349A
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Mexico
Prior art keywords
pirfenidone
methyl
temperature
pyridone
hours
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MX2007006349A
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Spanish (es)
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Juan Socorro Armendari Borunda
Jose Agustin Rogelio Magana Castro
Laura Vazquez Cervantes
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Cell Therapy And Technology S
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Priority to MX2007006349A priority Critical patent/MX2007006349A/en
Priority to PCT/MX2008/000069 priority patent/WO2008147170A1/en
Publication of MX2007006349A publication Critical patent/MX2007006349A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/63One oxygen atom
    • C07D213/64One oxygen atom attached in position 2 or 6
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/02Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

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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

The present invention concerns a new process for preparation of 5-methyl-l-phenyl-l (H) - pyridone, which consists in three steps which provide greater performance from a high purity product. Pharmaceutical compositions of topical application and use thereof are also described.

Description

NEW SYNTHESIS PROCESS FOR THE OBTAINING OF 5-METHYL-1-PHENYL-2- (1H) -PIRIDONE, COMPOSITION AND USE OF THE SAME FIELD OF THE INVENTION.
The present invention relates to a new synthesis process for obtaining 5-methyl-1-phenyl- (1H) -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 with 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 scars caused by acne, when applied in a suitable pharmaceutical composition.
BACKGROUND OF THE INVENTION 5-methyl-1-phenyl- (1H) -pyridone, of formula; is a drug that has been applied to induce the remodeling of the scar formed in several organs affected by processes that occur with fibrosis, as well as in the prevention of the establishment of different fibrosis, restoration of tissues with fibrotic lesions and for the prevention of injuries fibrotic This compound, called Pirfenidone, is itself a known compound and its pharmacological effects have been described in, for example, the Japanese applications KOKAI Nos. 87677/1974 and 1284338/1976, as an anti-inflammatory agent that includes anti-inflammatory effects. - Pyretic and analgesic. U.S. Patent Nos. 3,839,346, published October 1, 1974, 3,974,281, published August 10, 1976, 4,042,699, published August 16, 1977, and 4,052,509, published October 4, 1977, describe methods for obtaining Pirfenidone, as well as its use as an anti- inflammatory. The anti-fibrotic activity of 5-methyl-1-phenyl- (1H) -pyridone is described in Mexican patent 182,266.
U.S. Patent Nos. 3,974,281 and 3,839,346 describe the preparation of 5-methyl-1-phenyl- (1H) -pyridone starting from 5-methyl-2- (1H) -pyridine in the presence of anhydrous sodium carbonate, copper precipitated with zinc, in iodobenzene, refluxed for 18 hours, from which 5-methyl-1-phenyl- (1H) -pyridone is obtained, which after being crystallized from benzene and petroleum ether, gives a yield of 85%, with a point of fusion at 90 to 104 ° C, which after a recrystallization in hot water melts at 102 ° C. These processes and others existing in the state of the art are difficult, uneconomical and often result in low yields after extensive manipulation of expensive starting materials.
Biological activity of Pirfenidone The first description of the formation of an abnormal scar in the form of keloids (recorded in a papyrus called Smith) was given in relation to surgical techniques used in Egypt in 1700 BC. Also in the art of Ancient Africa, representations of keloid scars are included. Later in 1806, Alibert coined the term keloid, derived from the Greek chele, or pincers of the crab, to describe the lateral growth of tissue within the unaffected skin. The healing of a wound is a normal process that can suffer two types of alterations: an excess in the formation of granulation tissue (hypertrophic scar) or an abnormal formation of connective tissue with abundant bands of collagen (keloid scar). The first can disappear spontaneously with the passage of time without giving any treatment; however, in many cases the hypertrophic scars do not disappear. Keloid scars are rarely remodeled without any intervention and therefore, do not disappear. A keloid is an excessive growth of dense fibrous tissue that usually develops after healing a wound on the skin. The tissue extends beyond the edges of the original wound, usually there is no spontaneous regression and tends to recur after being excised upon being altered by the fibroproliferation of human skin. Keloid and hypertrophic scars are the only fibroproliferative disorders of human skin that follow to a trauma, inflammation, burn or surgery. The appearance of keloid scar has a familial tendency, and affects both sexes equally at an age comprised mostly between 10 to 30 years. In affected individuals, scars that are elevated, red and firm can cause itching and pain and create functional and cosmetic problems. Its incidence goes from 4.5% to 16%, appearing especially in blacks, Hispanics and Orientals. It is associated with antigens HLA-B14, -B21, HLA-B 16, -BW35, HLA-DR5, DQW3 and blood subjects type A +. Its transmission has been reported as autosomal dominant and autosomal recessive. Different resources and treatments have been used, but to date none of them is really effective. Pirfenidone has demonstrated its effectiveness as an anti-fibrotic agent, in different pathologies and organs, as has been demonstrated in previous studies, where we have observed an effect on the fibroblasts and the collagen produced by them, both in experimental models and in clinical trials Current status of research with Pirfenidone Pirfenidone (5-methyl-l-phenyl-2- (1H) -pyridone), is an anti-fibrotic agent that has been shown to be effective in prevent and resolve the accumulation of fibrous tissue, both in experimental models of pulmonary fibrosis (2), uterine leiomyomas (3), renal fibrosis (4) and keloid scars (5); peripheral adhesions (6), liver fibrosis (7); as well as in clinical trials of idiopathic pulmonary fibrosis (8), and liver cirrhosis (9).
OBJECT OF THE INVENTION It is an object of the present invention to provide a three-step process for obtaining Pirfenidone, which allows to obtain a product of greater purity and with better reaction conditions. A second object of the present invention is to provide a pharmaceutical composition of Pirfenidone, for its dermal application. Also, it is our objective to demonstrate the pharmacological properties of a pharmaceutical composition of Pirfenidone, at the dermal level in patients with hypertrophic or keloid scarring, in order to prevent or improve abnormal healing in those patients undergoing surgery or as a consequence of burns, and with a tendency to form hypertrophic or keloid scars.
SPECIFICATION OF THE INVENTION The present invention relates to a three-step process for obtaining 5-methyl-1-phenyl- (1H) -pyridone which is efficient and direct, as well as providing high yields.
Obtaining 5-methyl-2-pyridone.
The process for 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 means of a diazo reaction in an acidic medium, to obtain 5-methyl-1-phenyl- (1H) -pyridone by reduction with copper in the presence of iodobenzene, carrying out the addition of the aromatic ring in the same stage. The last stage consists in the purification of the 5-methyl-1-phenyl- (1H) -pyridone obtained, which results in a high purity product useful in pharmaceutical compositions.
First stage A mixture of 2-amino-5-methyl-pyridine and water, in an approximate ratio of 1: 8 g / ml, is prepared with acid sulfuric at a temperature between 5 and 10 ° C. Separately, an aqueous solution of sodium nitrite is prepared, which is added slowly to the first mixture maintaining the temperature between 5 and 10 ° C, maintaining the stirring for one hour.
The reaction mixture is slowly heated to a temperature of 90 ° C, which is kept constant for one hour, at the end of this time the reaction mixture is allowed to cool to room temperature. Anhydrous sodium carbonate is added to the reaction mixture until a pH between 7 and 8 is reached. The reaction mixture is heated and distilled in vacuo at 70 ° C. Once the 90¾ of the aqueous phase is eliminated, it is allowed to cool until reaching 50 ° C, temperature at which methanol is added and stirred, to subsequently heat and maintain the reflux temperature for one hour. At the end of the previous step the suspension is filtered, the solid is washed three times with hot methanol. The filtrate and the 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 ° C for 12 hours. The reddish solid is filtered, washed with cold methanol and dried in vacuum for 12 hours. The reaction provides a yield from 98 to 99.5%.
Second stage .
The 5-methyl-2 (H) -pyridone obtained in the previous step is mixed with anhydrous potassium carbonate, copper powder and iodobenzene, stirred and heated at reflux at 160 ° C for 18 to 20 hours. At the end of the reaction time the reaction mixture is cooled to a temperature between 60 and 70 ° C, the solid is decanted from the liquid. Ethyl acetate is added to the solid, the mixture is stirred and refluxed for one hour, after which it is filtered hot, the solid is washed with hot ethyl acetate, the filtrate is collected and the washes are washed. The suspension is distilled under vacuum and left to cool for 12 hours. The obtained brown solid is dried and washed with cold ethyl acetate. On the other hand, the iodobenzene solution obtained in the first step of this stage is concentrated by distilling the liquid in vacuo, the suspension obtained is allowed to cool at a temperature between 4 and 10 ° C for 24 hours. The brown crystals are centrifuged. This product meets with the one obtained in the previous step, with which it has a yield of 84 to 85%.
Third Stage.
The obtained Pirfenidone is purified by dissolving it in acetone and adding activated carbon. The mixture is heated to reflux for one hour. The mixture is filtered on celite and this is washed with hot acetone, the filtrate and the washings are combined and distilled to concentrate the solution and promote the crystallization of the product. To the concentrated mixture water is added and all the acetone is distilled. The aqueous suspension of a white solid is passed to a crystallizer and cooled under stirring at a temperature of 5 to 10 ° C, for 12 hours. The white solid obtained is filtered and dried at a temperature of 60 ° C for 12 hours. The product obtained has a purity of 99.8%, a UV max of 316.96, 01830 and a melting point of 109-111 ° C.
Example .
Synthesis of 5-methyl-2 (H) -pyridone.
To a mixture of fifty kilograms of 2-amino-5-methyl-pyridine and 410 liters of deionized water, cooled to a temperature between 5 and 10 ° C, is slowly added a solution of 53.8 liters of sulfuric acid, keeping the temperature constant. Once the above mixture is obtained, a solution of 36.2 kilograms of sodium nitrite in 97.5 liters of water is added slowly and with stirring, keeping the temperature constant. The reaction mixture is allowed to stir for one hour. Once homogenized the mixture is slowly heated to a temperature of 90 ° C, maintaining said temperature for 1 more hour, after this time it is allowed to cool to room temperature. To the obtained mixture, 105.75 kilograms of anhydrous potassium carbonate are added slowly, until a pH between 7 and 8 is reached. It is slowly heated and distilled under reduced pressure, until 450 liters of liguido are separated. Cool to 50 ° C and add 300 liters of methanol, stir and reflux the mixture for one hour. The suspension is filtered hot through a "sparkler" filter, the solid is washed twice with 100 liters each of hot methanol. The potassium salts are discarded, the filtrate and the washings, around 500 liters are concentrated in vacuum until the product begins to crystallize, when the volume is approximately 150 liters. At this point the mixture is transferred to a crystallizer and cooled to a temperature between 5 and 10 ° C for 12 hours.
The solid obtained is centrifuged and washed with 10 liters of cold methanol. The crystals are transferred to a tray, dried under vacuum in the oven at 60 ° C, for 12 hours. The 5 methyl-2 (H) -pyridone obtained has a weight of 50 Kilograms and is used in the next step.
Preparation of precipitated zinc copper catalyst. 100 grams of cupric sulfate pentahydrate are dissolved in 350 ml of distilled water, the mixture is heated slightly to achieve total dissolution of the copper compound, around 30 °. At this temperature and stirring, zinc powder is slowly added until the total discolouration of the solution, approximately between 20 and 35 grams. Copper in the form of a heavy, reddish brown powder is separated from the liquid by decantation and washed three times with approximately 350 ml of 5% hydrochloric acid (pH = 1), separating the washes by decanting. It is filtered in a Büchner, washing with water until a neutral pH and stored without drying in an amber bottle.
Obtaining Raw Pirfenidone.
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 to reflux, 160 ° C, maintaining the stirring. It is left to reflux for 18 to 20 hours. After this reaction time it is cooled to a temperature between 60 and 70 ° C. The suspension is allowed to settle and the supernatant liquid is decanted. This is a solution of pirfenidone in iodobenzene, which is treated separately. To the solid is added 400 liters of ethyl acetate, stirred and refluxed for 1 hour. It is filtered hot through a "sparkler" filter. It is washed with 50 liters of hot ethyl acetate, the mother liquor and the washings are combined, concentrated in vacuo to a volume of 200 liters, heated to a crystallizer. The solution is cooled and left to stand for 12 hours. A reddish-brown powder crystallizes, which is filtered by centifugation and washed with 10 l of cold ethyl acetate. Approximately 30 kilograms of crude Pirfenidone is obtained.
The iodobenzene solution is concentrated in vacuo to an approximate volume of 100 liters, heated to a crystallizer and cooled to a temperature between 4 and 10 ° C for 24 hours. The obtained crystals are filtered in the crentrifuge. Approximately 40 kilograms of crude Pirfenidone is obtained.
Purification of crude Pirfenidone.
To the crude Pirfenidone obtained in the previous step, approximately 70 kilograms, they are dissolved in acetone and 10 kilograms of activated carbon are added, heating the mixture to reflux and stirring for one hour. A "sparkler" filter is prepared with cotton canvas discs and 50 kilograms of celite. The hot acetone solution is filtered and the residue is washed with approximately 100 liters of hot acetone. The filtrate and the washings are concentrated in vacuo to a volume of 100 liters, to which 300 liters of water are added and the remaining acetone is distilled in vacuo. The concentrated aqueous solution is transferred to a crystallizer and cooled under stirring to a temperature of between 5 and 10 ° C for 12 hours. It is left to rest in cold for 24 hours, obtaining a white fine powder, which is filtered in a centrifuge. The product is transferred to drying trays and left in the oven at 60 ° C, vacuum for 12 hours. Pure Pirfenidone is obtained from fusion 109-11 ° C, a UV maximum of 316.96, 018300, with a purity of 98.
Pirfenidone compositions for topical application.
The Pirfenidone obtained is used in the manufacture of pharmaceutical compositions for dermatological application such as the one described below: * Sorbitan monostearate Employ An example of composition which can be prepared by methods known in the state of the art and which are known to any pharmaceutical chemist: Component Quantity Pirfenidone 8 gr Propylene glycol 15 gr Liquid petroleum jelly 6 gr Cetyl alcohol 4 gr Stearyl alcohol 4 gr Tween 60 2 gr SPA 2 gr Nipagin 147 mg Nipazol 66 mg Citric acid 1 mg Purified water c. c .p.
Pilot clinical trials at the dermal level with Pirfenidone.
Inhibition of excessive scar formation by Topical pirfenidone.
Previous results have been obtained related to the inhibition of excessive scar formation by Direct application of ointment with Pirfenidone to skin lesions. This was done through the direct application of Pirfenidone ointment to skin lesions, as they are mild to moderate lacerations, which do not generate scarring on the skin or was minimal when the ointment Pirfenidone was directly and rapidly applied to the injuries This reflects both the anti-fibrotic and cytoprotective activities analogous to the systemic effects cited in other works.
Preliminary clinical trial of Pirfenidone ointment at 7.0% in keloids.
In a preliminary clinical trial using Pirfenidone ointment at 7.0% on keloids, three patients with keloid scarring had re-developed keloids after surgery; One case developed keloid scar in the surgical site after surgery for carpal tunnel syndrome. After five years the patient began to complain of severe pain in the site, which was severe even with the use of analgesic. Subsequently Pirfenidone ointment was applied. After one month, a clear improvement was observed, although the pain persisted. However, when a mixture of Pirfenidone and DMSO was applied, signs of further improvement and pain dissipation appeared. The conditions of improvement were maintained during the year of follow-up. In the other two cases, one after a hysterectomy and the other a gangliostomy, the surgical wounds effectively healed with the application of Pirfenidone ointment and the keloid scars did not reappear during the 12-month follow-up.
Topical dermal cytoprotective activity In a double-blind, controlled trial, in 60 patients with skin disorders such as neurodermatitis (atopic dermatitis), a statistically significant improvement was demonstrated, when comparing the lesions at baseline, after the topical application of pirfenidone hydrophilic ointment. 10% (30 patients), No incidence of undesirable side effects (systemic or local) was found after one and two weeks. The response obtained did not differ significantly from that observed with betamethasone valerate ointment (30 patients).
Double-blind, placebo-controlled study in dermal eczema In a double-blind, placebo-controlled trial of 9 patients (average 46 years of age) with long-term dermal eczema, in which 10% Pirfenidone ointment was used compared with placebo, a statistically significant improvement was shown in 4 patients. 5 clinical parameters (erythema, pruritus, desquamation, vesicles), remarkable results because in these patients the eczema lasted from 2 to 8 years.
Topical non-blinded dermal (anti-TNF-a) cytoprotective activity in patients: 1 Contact dermatitis (8 cases) treated by the local application of 5% or 10% Pirfenidone ointment, which produced an early release of pruritus, erythema, inflammation and edema, and the lesions disappeared in a few days. Dermatitis was attributed to various detergents, poison ivy (poisons) and preparations for personal care. 2 Neurodermatitis (2 cases) medicated with 10% Pirfenidone ointment, which obtained an early release of pruritus and the lesions disappeared in a few days. 3 Fungal dermatitis (10 cases) the pruritus of fungal infections (eg, athlete's foot) was terminated by applying 5% or 10% Pirfenidone ointment, and the lesions were quickly cleansed. 4 Herpes Simplex Dermatitis-1 (7 cases). The amps, sensitivity and pruritus of herpetic lesions affecting the lips, including dermal areas around the mouth, were promptly eliminated with the topical application of 10% Pirfenidone ointment and the lesions disappeared in 5 to 7 days. 5 Acute reactions with musculoskeletal injuries in humans (local or systemic medication). A double-blind controlled clinical trial (14 randomly selected patients) conducted in Argentina demonstrated the different cytoprotective actions of Pirfenidone topical ointment at 10.0%, when it was applied to soccer players with acute traumatic injuries. The edema and pain were quickly and sharply relieved with Pirfenidone ointment. No undesirable effects were reported.
Inhibition of excessive scar formation by the direct application of Pirfenidone ointment to skin lesions.
Lacerations or mild to moderate skin lesions failed to cause scarring of the skin, or caused only minimal scarring, when Pirfenidone ointment It was promptly and directly applied to the injuries. This action probably reflects both topical anti-fibrotic and cytoprotective activity (anti-TNF-a), activities analogous to the systemic effects cited at several sites. Several open and controlled human clinical trials have explored the cytoprotective properties of Pirfenidone. They are included primarily as a background that supports the relative safety of Pirfenidone in human subjects.
Additional experiments of excretion (clearance) and Biotransformation with Pirfenidone Serum Pirfenidone levels after 21 days of topical dermal application to albino rabbits: Serum pirfenidone levels were evaluated 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 gradual doses (from 200 to 5000 mg / kg / day) of 10% Pirfenidone hydrophilic ointment, blood samples were taken for the Pirfenidone test before starting the application and again to day 22. The rabbits received doses equal to or greater than 2000 mg / kg showed quantifiable serum levels, of the order of 1.10 ± 0.39 micrograms / ml. These levels are not toxicologically or pharmacologically significant, even after repeated topical doses of ointment with Pirfenidone at 10¾.
Topical effect on dermal reaction induced in dogs by Bordetella intradermal endotoxin The effect of Pirfenidone on 10 hid hydrophilic ointment applied topically to dorsal skin lesions in dogs (thoracolumbar region of the back), induced by intradermal injections of Bordetella endotoxin (0.3 ml), with careful measurements of the diameter of the lesions compared with equivalent placebo ointment, once a day for 3 consecutive days. Although the measurements of edema, bleeding and pain were not significantly different from controls, the diameter of the indurated area (within the lesion) had a distinctive reduction by the fourth day, as a result of the topical application of Pirfenidone in ointment. .
Topical cytoprotective activity against skin lesions induced with dilute hydrochloric acid in mice.
The topical cytoprotective activity of 0.0% (control), 1.0%, 2.5%, 5.0% and 10.0% of Pirfenidone in ointments were determined in albino mice according to the Walz 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 lesion induced in the skin.
Effect of Pirfenidone cream on dermal erythema induced by ultraviolet radiation in albino rabbits: Twelve albino rabbits were assigned to four groups by a random distribution system. The dorsal surface of each rabbit was clamped by an electric clamp. Twenty-four hours later, an ultraviolet lamp was suspended 9 inches above the rabbits' backs. Before the exposure, the lamp was heated for a minimum of 10 minutes. Each rabbit was prepared for exposure to dorsal radiation when covering his back with an aluminum sheet in which 4 circular holes of 1.0 cm had been cut. From two of these holes, the aluminum cover was removed to allow the penetration of UV radiation to the dorsal skin; the other two remained covered. They were exposed for 25 minutes in groups of three, 10 minutes 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. Subsequent readings were made at 24, 48 and 72 of the initial exposure. The complete resolution of the irritation occurred at 72 hs. In contrast, the areas not treated with Pirfenidone cream showed marked irritation (grade 2 or 3) at 72 hs. The differences were statistically significant (P <0.05).
Topical cytoprotective activity against edema of equine extremities, induced by dermoplasty; a clinical-armacological study.
In order to generate experimentally induced controlled inflammatory lesions, six horses were punctured bilaterally on the internal surface of your extremities by an equine veterinarian. Each limb was treated either with 10.0% modified USP Pirfenidone hydrophilic ointment or the control ointment (USP modified hydrophilic ointment without Pirfenidone). Ten grams of ointment was applied to the lesions, three times a day, for 7 days, starting 24 hours after the punctures. Each limb was measured each day in three locations through the points located at 2, 4, and 6 inches above the ergot. Daily measurements of the circumference of the legs were made. The peak of edema appeared on the fourth day. The measurements showed that the topical applications of Pirfenidone were clearly effective in reducing edema and the improvement was statistically significant vs placebo.
Comparison of Pirfenidone ointment at 5.0% and 10.0% against experimentally induced dermal reactions in pregnant mares: The effect of pirfenidone ointment at 5.0% vs 10.0¾ was evaluated in a study with 10 pregnant mares, in which inflammatory dermal neck lesions were experimentally induced by subcutaneous injection of 5. 0 ml of sodium alginate followed by 5.0 ml of calcium chloride in the same place. The ointments were applied once a day starting 24 hours after the subcutaneous injection of the irritants and was continued for 5 days. The measurements in centimeters, throughout the length and width of the injuries were made daily. The peak inflammatory reaction was achieved between 48 and 72 hs. Measurements of the surface area of the lesions on the final day (day 5) showed a reduction of 71.6 + 6.3% in the extent of the lesion with the 5.0% ointment; and a reduction of 80.4 ± 3.2 ¾ in the area of the lesion with the 10.0% ointment. However, the difference between the responses to both concentrations was not statistically significant (P> 0.20).
Weight of keloid human tissues in transplanted xenografts within nude mice.
Surgically obtained human keloid tissues were transplanted into groups of nude mice, of which two sets of groups were obtained. One series served as control and did not receive Pirfenidone. The second series received Pirfenidone mixed in the food.
Subsequently, the measurement of transplanted keloids was performed 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.

Claims (1)

  1. RE IVINDICATIONS 1. - A process for obtaining 5-methyl-l-phenyl- (1H) -pyridone comprising three stages which are: first step: obtain 5-methyl-2 (H) -pyridone from 2-amino-5 -methyl 1-pyridine by a diazo reaction in an acid medium; second stage; obtaining 5-methyl-1-phenyl- (1H) -pyridone by reduction with copper in the presence of iodobenzene, carrying out the addition of the aromatic ring in the same step; and a third step to purify the 5-methyl-1-phenyl- (1H) -pyridone obtained, which results in a high purity product useful in pharmaceutical compositions. 2. The process according to claim 1, wherein the first step consists in: preparing a mixture of 2-amino-5-methyl-pyridine and water, in an approximate ratio of 1: 8 g / ml, with sulfuric acid to a temperature between 5 and 10 ° C; prepare separately an aqueous solution of sodium nitrite; add slowly to the first mixture maintaining the temperature between 5 and 10 ° C, keeping the stirring for one hour; heat slowly to a temperature of 90 ° C, which remains constant for one hour; cool the reaction mixture to room temperature; add anhydrous sodium carbonate until achieving a pH between 7 and 8; heat the reaction mixture and distill in vacuo at 70 ° C, remove 90% of the aqueous phase and allow to cool to 50 ° C; add methanol and stir, then heat and maintain the reflux temperature for one hour filter the suspension, wash three times with hot methanol; Concentrate the filtrate and wash in vacuum until the crystallization of the product begins; cool the solution at a temperature of between 5 to 10 ° C for 12 hours, wash the reddish solid and filter; wash with cold methanol and dry in vacuum for 12 hours, a yield of 98 to 99.5% is obtained. 3. The process according to claim 1, wherein the second step consists of: mixing the 5-methyl-2 (H) -pyridone obtained in the step above with anhydrous potassium carbonate, copper powder and iodobenzene, stirring and heating at reflux at 160 ° C, for 18 to 20 hours; cool the reaction mixture at a temperature between 60 and 70 ° C, decant the solid from the liquid; add ethyl acetate, stir the mixture and heat at reflux for one hour; filter hot, wash the solid with hot ethyl acetate; vacuum distill the filtrate and washings, allow to cool for 12 hours; Dry and wash the brown solid with cold ethyl acetate. 4. - The process according to claim 3, wherein the iodobenzene solution obtained in the second step above, is concentrated by distilling the liquid in vacuum and allowing it to cool at a temperature between 4 and 10 ° C for 24 hours. 5. The process according to claim 4, wherein the brown crystals obtained are centrifuged. 6. - The process according to claim 3, wherein the yield from 84 to 85%. 7. - The process according to claim 1, wherein the third stage consists of: dissolve the Pirfenidone obtained in the second stage in acetone and add activated carbon; heat at reflux for one hour; filter over celite and wash the celite with hot acetone; concentrate the filtrate and the washings by distillation, until the crystallization of the product; add water and distill all the acetone; pass the aqueous suspension of the white solid to a crystallizer and cool under stirring at a temperature of 5 to 10 ° C, for 12 hours; filter and dry the white solid at a temperature of 60 ° C for 12 hours. 8. - The process according to any of the preceding claims wherein the 5-methyl-l-phenyl-1 (H) -pyridone obtained has a purity of 99.8%, a UV max of 316.96, 01830 and a melting point of 109-111 ° C. 9. - A pharmaceutical composition comprising: Component Pirfenidone 1-10 Propylene Glycol 1.8-19 Petroleum jelly 0.5-5 Cetyl alcohol 0.5-5 Stearyl alcohol 0.5-5 Tween 60 0.25-2.5 SPAN * 0.25-2.5 Nipagin 0.01-0.23 Nipazol 0.0002-0.0013 Citrus acid 0.0002-0.0013 DMSO 0-90 Purified water c. c .p. 11. - The use of pirfenidone for the manufacture of a medicament according to claim 10, wherein said The drug has topical cytoprotective activity in mammals. 12. - The use of pirfenidone for the manufacture of a medicament according to claim 10, wherein the topical cytoprotective activity consists in inhibiting the formation of hypertrophic scars, keloid scars, Atopic dermatosis and actinic keratinosis. 13. - The use of pirfenidone for the manufacture of a medicament according to claim 10, wherein the Topical cytoprotective activity consists in preventing hypertrophic scars, keloid scars, atopic dermatosis and actinic keratinosis. 14. - The use of pirfenidone for the manufacture of a medicament according to claim 10, wherein the Topical cytoprotective activity consists in treating hypertrophic scars, keloid scars, atopic dermatosis and actinic keratinosis. 15. The use of pirfenidone according to any of claims 12 to 14, wherein the atopic dermatosis is selected from the group consisting of contact dermatitis, neurodermatitis, fungal dermatitis; Herpes simplex-1 dermatitis and acute reactions with musco-skeletal wounds. 16. The use of pirfenidone according to any of claims 12 to 14, wherein the actinic keratinosis is selected from the group consisting of excessive scar formation or keloid scarring; erythema, pruritus, desquamation, vesicles.
MX2007006349A 2007-05-29 2007-05-29 New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same. MX2007006349A (en)

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