WO2008147170A1 - New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same - Google Patents

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

_N EUVO SYNTHESIS PROCESS FOR OBTAINING

5-METHYL-1-PHENYL-2- (IH) -PIRIDONE,

COMPOSITION AND USE OF THE SAME

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

The 5-methyl-l-phenyl- (IH) -pyridone, of the formula;

It 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 prevention _l establishment of different fibrosis, restoration of tissues with fibrotic lesions and for the prevention of fibrotic lesions. This compound, called Pirfeπiάone, 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. U.S. Patents 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 agent. Mexican patent 182,266 describes the anti-fibrotic activity of 5-methyl-l-feπil- (IH) -pyridone.

U.S. Patent Nos. 3,974,281 and 3,839,346 describe the preparation of 5-methyl-l-phenyl-

(IH) -pyridone starting from 5-methyl-2- (IH) -pyridine in the presence of anhydrous sodium carbonate, copper precipitated with zinc, in iodobenzene, at reflux during

18 hours, where 5-methyl-l-phenyl- (IH) -pyridone is obtained, which after being crystallized from benzene and petroleum ether, yields 85%, with a melting point of 90 to 104 ⁰ C, which after a recrystallization in hot water melts at 102 ⁰ C.

These processes and others existing in the state of the art are difficult, inexpensive and often result in low yields after extensive Handling 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 B.C. 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 crab pincers, 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 may disappear spontaneously over time without giving any treatment; however, in many cases hypertrophic scars do not disappear. Keloid scars are rarely remodeled without any intervention and therefore do not disappear.

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. It is associated with antigens HLA-B14, - B21, HLA-BWl6, -BW35, HLA-DR5, DQW3 and blood type A + subjects. Its transmission has been reported as autosomal dominant and autosomal recessive.

Different resources and treatments have been used without any of them being really effective to date. 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

Current status of research with Pirfenidone

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).

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 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 healing, in order to prevent or improve an abnormal healing in those patients undergoing surgery or as a sequelae of burns, and with a tendency to form hypertrophic scars or keloids.

SPECIFICATION OF THE INVENTION

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.

Obtaining 5-methyl-2-pyridone.

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. First stage

_S and prepares a mixture of 2-amino-S-methyl- pyridine and water in a ratio of 1: 8 g / ml, with sulfuric acid at a temperature between 5 and 10 ⁰ C. Separately an aqueous solution is prepared of sodium nitrite, which is added slowly to the first mixture keeping the temperature between 5 and 10 ⁰ C, keeping stirring for one hour.

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. At the end of the previous step 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%.

Second stage.

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. At the end of the reaction time the reaction mixture at a temperature between 60 and 70 ⁰ C is cooled, the solid the liquid decanted. 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. Moreover the solution of iodobenzene obtained in the first step of this stage, concentrated by distilling the liquid in vacuo, the suspension obtained is cooled to a temperature between 4 and 10 ⁰ C for 24 hours. The brown crystals are centrifuged. This product meets the one obtained in the previous step, which gives a yield of 84 to 85%.

Third Stage

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.

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 ⁰ C, a solution of 53.8 liters of sulfuric acid is slowly added, maintaining the temperature constant. Once the previous 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 the mixture was homogenised slowly heated to a temperature of 90 ⁰ C, keeping said temperature for 1 hour, after which time is cooled to room temperature. To the mixture obtained, 105.75 kilograms of anhydrous potassium carbonate are slowly added, until a pH between 7 and 8 is achieved. It is slowly heated and distilled under reduced pressure, until 450 liters of liquid. It is cooled to 50 ⁰ C and 300 liters of methanol are added, stirred and the mixture refluxed 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, about 500 liters are concentrated in vacuo until the product begins to crystallize, when the volume is approximately 150 liters. At this point the mixture is passed to a crystallizer and cooled to a temperature between 5 and 10 ⁰ C for 12 hours. Solid bl obtained is centrifuged and washed with 10 liters of cold methanol. The crystals are passed to a tray, dried in vacuum oven at 60 ° C for 12 hours _r. The 5-methyl-2 (H) -pyridone obtained has a weight of 50 Kilograms and is used in the next step.

Preparation of the precipitated copper catalyst. of zinc

100 grams of pentahydrate cupric sulfate are dissolved in 350 ml of distilled water, the mixture is slightly heated to achieve the total dissolution of the copper compound, around 30 °. At this temperature and stirring, zinc powder is slowly added until the solution is completely discolored, approximately 20 to 35 grams. Copper in the form of 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 washings by decantation. It is filtered in a Büchner, washing with water to a neutral pH and JO

Store without drying in an amber jar.

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 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. 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, it is passed hot to a crystallizer. The solution is cooled and allowed to stand for 12 hours. A reddish brown powder crystallizes, which is filtered by centrifugation and washed with 10 It of cold ethyl acetate. About 30 Kilograms of raw Pirfenidone is obtained.

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

kilograms of raw Pirfenidone.

Purification of raw 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 by heating the mixture at reflux and with stirring for one hour. A "sparkler" filter with cotton canvas disks and 50 kilograms of celite is prepared. The hot acetone solution is filtered and the residue is washed with approximately 100 liters of hot acetone. The filtrate and washings are concentrated in vacuo to a volume of 100 liters, to which 300 liters of water is added and the rest of acetone is distilled in vacuo. The concentrated aqueous solution is passed to a crystallizer and cooled under stirring at a temperature of between 5 and 10 ⁰ C for 12 hours. Let it stand in the cold for 24 hours, obtaining a fine white powder, which is filtered in a centrifuge. The product is passed to drying trays and left in the oven at 60 ⁰ C, under vacuum for 12 hours. Pure Pirfenidone with a melting point 109-11 ⁰ C, a maximum UV of 316.96, 018300, is obtained with a purity of

Pirfenidone compositions for topical application.

The Pirfenidone obtained is used in the manufacture of pharmaceutical compositions of dermatological application as described below: 22

* Sorbitan monostearate

Example

An example of a composition which can be prepared by methods known in the state of the art and which are known to any pharmaceutical chemist:

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 the direct application of Pirfenidone ointment to skin lesions. This was done by direct application of Pirfenidone ointment to dermal lesions, such as mild to moderate lacerations, which do not cause scarring of the skin or was minimal when Pirfenidone ointment was directly and quickly applied to the lesions. This reflects both the anti-fibrotic and cytoprotective activities analogous to the systemic effects cited in other studies.

Preliminary clinical trial of Pirfenidone ointment 7.0% in keloids.

In a preliminary clinical trial using 7.0% Pirfenidone ointment in keloids, three patients with keloid scarring had re-developed keloids after surgery; a case developed Keloid scar in the surgical wound after surgery for carpal tunnel syndrome. After five years the patient began to complain of severe pain at the site, which was severe even with the use of an analgesic. Subsequently Pirfenidone ointment was applied. After a month a clear improvement was observed, although the pain persisted. However, when a mixture of Pirfenidone and DMSO was applied, signs of subsequent 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 after 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, comparing the lesions at baseline, after topical application of Pirfenidone hydrophilic ointment to 10% {30 patients), No incidence of undesirable (systemic or local) side effects 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 to placebo, a statistically significant improvement was shown in 4 of 5 clinical parameters (erythema, pruritus, desquamation, vesicles), remarkable results because in these patients the eczema lasted from 2 to S years.

Topical dermal cytoprotective (anti-TNF-a) activity in patients:

1 Contact dermatitis {8 cases) treated by the local application of 5% or 10% Pirfenidone ointment, which resulted in a rapid release of pruritus, redness, inflammation and edema, and the lesions disappeared within a few days. Dermatitis was attributed to various detergents, poison ivy (poisons) and personal care preparations.

2 Neurodermatitis (2 cases) medicated with 10% Pirfenidone ointment, which obtained an early release of pruritus and the lesions disappeared within a few days.

3 Fungal dermatitis (10 cases) the pruritus of fungal infections (eg, athlete's foot) was terminated by the application of 5% or 10% Pirfenidone ointment, and the lesions were quickly cleaned. 4 Herpes Simplex-1 dermatitis (7 cases). The ampules, tenderness 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 within 5 to 7 days.

5 Acute reactions with musculoskeletal wounds 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 topical Pirfenidone ointment at 10.0%, when applied to soccer players with acute traumatic wounds. Edema and pain were quickly and acutely relieved with Pirfenidone ointment. No undesirable effects were reported.

Inhibition of excessive scar formation by direct application of Pirfenidone ointment to skin lesions.

Mild to moderate lacerations or lesions of the skin failed to cause skin scarring, or caused only minimal scarring, when Pirfenidone ointment was prompt and directly applied to the lesions. This action probably reflects both topical anti-fibrotic and cytoprotective activity (anti-TNF-a), activities analogous to the systemic effects cited at various sites. Several open and controlled human clinical trials have explored the cytoprotective properties of Pirfenidone. They are n

included primarily as a background that supports the relative safety of Pirfenddone in human subjects.

Additional excretion experiments (clearance) and Biotransformation with Pirfenidone

Serum levels of Pirfenidone after 21 days of topical dermal application to albino rabbits:

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 effect on the dermal reaction induced in dogs by intradermal Bordetella endotoxin

The effect of Pirfenidone on 10% hydrophilic ointment applied topically to dorsal skin lesions in dogs (thoraco-lumbar region of the back), induced by intradermal injections of Bordetella endotoxin

(0.3 mi), with careful measurements of the diameter of the ¡8

lesions compared with equivalent placebo ointment, once a day for 3 consecutive days. Although the measurements of edema, redness and pain were not significantly different from the controls, the diameter of the indurated area (within the lesion) had a distinctive reduction for the fourth day, as a result of topical application of Pirfenidone in ointment.

Topical cytoprotective activity against dermal lesions induced with dilute hydrochloric acid in mice.

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.

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 surface 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).

Topical cytoprotective activity against edema of equine limbs, induced by dermoplasty; A clinical pharmacological study.

In order to generate experimentally induced inflammatory lesions, six horses were punctured bilaterally on the inner surface of their limbs by an equine veterinarian. Each limb was treated with either ointment 10.0% modified Pirfenidone hydrophilic USP, 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 every 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 edema peak appeared on the fourth day. The measurements showed that topical applications of Pirfenidone were clearly effective in reducing edema and the improvement was statistically significant vs placebo.

Comparison of 5.0% and 10.0% Pirfenidone ointment against experimentally induced dermal reactions in pregnant mares:

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. The measurements of the surface area of the lesions on the final day (day 5) showed a reduction of 71.6 ± 6.3% in the measurement of 5.0% ointment injury; and a reduction of 80.4 ± 3.2% in the area of the lesion with the ointment of 10.0%. However, the difference between the responses at both concentrations was not statistically significant (P> 0.20).

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.

Claims

1.- A process for obtaining 5-methyl-l-phenyl- (IH) -pyridone, characterized by said process because it comprises the following three stages: first stage: obtaining 5-methyl-2 (H) -pyridone from 2-amino-5-methyl-pyridine by a diazo reaction in acid medium; second stage; obtain 5-methyl-l-phenyl- (IH) -pyridone by reduction with copper in the presence of iodobenzene, by adding the aromatic ring at the same stage; and third stage; Purify the 5-methyl-l-phenyl- (IH) -pyridone obtained, which results in a high purity product useful in pharmaceutical compositions. 2. The process according to claim 1, characterized in that the first step consists in: preparing a mixture of 2-amino-5-methyl-pyridine and water, in an approximate ratio of 1: 8 gr / ml, with sulfuric acid a a temperature between 5 and IQ ⁰ C; separately prepare an aqueous solution of sodium nitrite; slowly add to the first mixture keeping the temperature between 5 and 10 ⁰ C, keeping stirring for one hour; warm slowly to a temperature of 90 ⁰ C, which remains constant for one hour; cool the reaction mixture to room temperature; add anhydrous sodium carbonate until a pH between 7 and 8 is achieved; heating the reaction mixture and distilled under vacuum at 70 ⁰ C, removed 90% of the aqueous phase is allowed to cool to reach 50 ⁰ C; add methanol and stir, to subsequently heat and maintain the reflux temperature for one hour, filter the suspension, wash three times with hot methanol; concentrate the filtrate and washings in vacuo until crystallization of the product begins; cool the solution at a temperature between 5 to 10 ⁰ C for 12 hours, wash the reddish solid and filter; wash with cold methanol and dry in vacuo for 12 hours, a yield of 98 to 99.5% is obtained. 3. The process according to claim 1, characterized in that the second stage consists of: mixing the 5-methyl-2 (H) -pyridone obtained in the previous stage with anhydrous potassium carbonate, copper powder and iodobenzene, stirring and heating to reflux at 160 ⁰ C for 18 to 20 hours; cooling the reaction mixture to a temperature between 60 and 70 ⁰ C, decanting the solid , the liquid; add ethyl acetate, stir the mixture and heat at reflux for one hour; hot filter, wash the solid with hot ethyl acetate; distil the filtrate and washings in vacuo, 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 solution of iodobenzene obtained in the previous step second, concentrated by distilling the liquid vacuum and allowed to cool to a temperature between 4 and 10 ⁰ C for 24 hours. 5. The process according to claim 4, characterized because the brown crystals obtained are centrifuged. 6. The process according to claim 3, characterized in that the yield is from 84 to 85%. 7 - The process according to claim 1, characterized in that the third stage consists in dissolving the Pirfenidone obtained in the second stage in acetone and adding activated carbon; heat at reflux for one hour; filter on celite and wash the celite with hot acetone; concentrate the filtrate and washings by distillation, until the product crystallizes; add water and distill all acetone; go to a crystallizing the aqueous suspension of the white solid and cool under stirring to a temperature 5 to 10 ° C for 12 hours _r; filtering and drying the white solid at a temperature of 60 ⁰ C for 12 hours. 8. The process according to any of the preceding claims, characterized in that the 5-methyl-l-phenyl-1 (H) -pyridone obtained has a purity of 99. 8%, a max in UV of 316.96, 01830 and a melting point of 109-111 ° C. 9.- A pharmaceutical composition comprising: P

10. The use of pirfenidone for the manufacture of a medicament, characterized in that said medicament has the composition described in claim 9 and also has topical cytoprotective activity in mammals. 11. The use of pirfenidone for the manufacture of a medicament according to claim 10, wherein the cytoprotective topical activity consists in inhibiting the formation of hypertrophic scars, keloid scars, atopic dermatosis and actinic keratinosis. 12. The use of pirfenidone for the manufacture of a medicament according to claim 10, wherein the topical cytoprotective activity consists of preventing 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 cytoprotective topical activity consists in treating hypertrophic scars, keloid scars, atopic dermatosis and actinic keratiπosis. 14. The use of pirfenidone according to any of claims 11 to 13, wherein the atopic dermatosis is selected from the group consisting of contact dermatitis, neurodermatitis, fungal dermatitis; Herpes Simple-1 dermatitis and acute reactions with musculoskeletal wounds. 15. The use of pirfenidone according to any of claims 11 to 13, wherein actinic keratinosis is selected from the group consisting of excessive scar formation or keloid scarring; Erythema, pruritus, peeling, vesicles.