MXPA01003267A - Novel salts of pyridopyrazine compound and crystals thereof - Google Patents

Abstract

A novel salt of a pyridopyrazine compound as represented by general formula (I), and solvates of the same;and crystals of both, which are excellent in solubility and stability.

Description

NEW SALT OF THE COMPOUND OF PIRIDOPIRAZ INA AND ITS CRYSTAL TECHNICAL FIELD This invention relates to the methanesulfonate, which is novel, of a compound of p i r i dop i r a z i na, to be used as a medicament. More particularly, this invention relates to the preparation of the methanesulfonate of 4- [3- (3,5-dichlorobenzoylamino) -phenyl] -2- (3-pyridylmethyl) -3 -oxo-3, 4-di hi dr dr op iri do [2, 3 -b] pirazi na of the following formula (I) [hereinafter, called compound (I)], of a solvate (hydrate, ethanolate, etc.) thereof, of its crystals and to new uses pharmacists thereof. PREVIOUS ART The pyri dop irazi compound of the formula (A), namely 4- [3 (3,5-dichlorobenzoylamino) -phenyl] -2- (3-pyridylmethyl) -3-oxo-3,4-dihydropyrido [2] , 3-b] pyrazine [hereinafter referred to as the free base (A)] and its hydrochloride [hereinafter referred to as the hydrochloride (B)] are described in the Open Specification (laid-op in) PCT WO 96/01825 and, as such, they are known.

DISCLOSURE OF THE INVENTION The free base (A) can not easily be dissolved in water in pharmaceutical production, for example, and the hydrochloride (B) is not as stable as desired, therefore, it is necessary to make certain improvements in terms of solubility and stability. The inventors of the present invention have explored a variety of salts in order to increase the usefulness of the free base (A) as a drug, that is, to improve the solubility and stability of the same and, as a result, they arrived to compound (I), which is the main subject of the present application. They have also discovered that the compound (I), according to this invention, not only exhibits an inhibitory activity of phosph odi asterasa TV (PDE-JV) and an inhibitory activity of the production of tumor necrosis factor (TNF-a). ) of the same order as those of the free base (A), but also exhibits an inhibitory activity of the production of interferons (INF?) and of inter-eucines (IL-2, IL-4, IL- 5, IL-10, etc.) and, on the basis of these activities, inhibits the infiltration of various inflammatory cells, such as macrophages, lymphocytes, eosinophils and neutrophils, at sites of inflammation. This invention has arisen thanks to the aforementioned finding. The compound (1) of this invention is new and has been improved in terms of the solubility in distilled water for injections and physiological saline, compared to the free base (A) and in terms of the crystallinity and stability in the formation of compounds with ethanol, compared with the hydrochloride (B). With respect to the compound (1), up to now six different polymorphs have been identified and the inventors have established processes for the production of the respective polymorphs and have named said polymorphs: A01 crystal, A09 crystal, A16 crystal, A20 crystal, A30 crystal and A43 crystal, respectively. The identification of the respective crystals was based on X-ray powder diffraction patterns (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5 and Fig. 6). Of these crystals, the polymorphic A20 crystal corresponds to the anhydride, the A30 crystal, to the hydrolytic acid and the remaining crystals, to the hydrates. Although those polymorphs are invariably superior to the free base (A) and the hydrochloride (B) in several characteristics, as mentioned above, the most preferred is polymorph A16, which as found, in the evaluation of the stability, the solubility and the absorbability, was the least variable in terms of the structure of the crystal under resting conditions in the solid state or during the formation of compounds, or it was the one that improved the most in terms of the solubility.

The crystal A 16 shows substantially the powder diffraction characteristics by X-rays that are provided in the section Data 3. The diffraction data was generated with an MPD1880 X-ray powder diffraction analyzer from Philip, using radiation whose monochromatic as X-rays. The following data 1-6, obtained from Figs. 1-6, are respectively shown as rearranged in ascending scale of the value 20. It is sufficient that the polymorphs according to this invention substantially satisfy the corresponding diffraction patterns that are provided in Data 1-6, ie, that a strict coincidence.

Data 1: crystal A01 2 T (s) = 2.78, 5.59, 14, 98, 16.73, 19.79, 24, 61, 26.07.

Data 2: crystal A09 2? (s) = 7.72, 10.07, 13.69, 15.23, 20.26, 21.03, 24.74, 25.17.

Data 3: crystal A16 2? (s) = 2.86, 5.63, 20.86, 22.31, 23.88, 25, 93.

Data 4: crystal A20 2? (s) = 12.50, 19.28, 21.50, 23.16, 25.38.

Data 5: crystal A30 2? (s) = 7.72, 10.03, 13.61, 20.05, 24.18e Data 6: crystal A43 2? (s) = 7.08, 12.20, 21.33 The compound (1) of this invention not only exhibits an inhibitory activity of phosph odi asterasa IV (PDE-IV) and an inhibitory activity of the production of tumor necrosis factor (TNF-a) of the same order as those of the free base (A), but also exhibits an inhibitory activity of the production of interferons (INF?) and of inter-and-uc i na s (IL-2, IL-4, IL-5, IL-10, etc. ) and, on the basis of these activities, inhibits the infiltration of various inflammatory cells, such as macrophages, lymphocytes, eosinophils and neutrophils, in the foci of inflammation. In the field of hepatitis, due to its potent inhibitory activity of cell necrosis and its inhibitory activity of inflammatory cell infiltration, the compound (I) of this invention is particularly useful in the treatment of viral hepatitis [types AE, type G, herpetic virus group (herpetic virus 1 and 2, virus goes rice 11 a - zoster, cytomegalovirus, Epstein-Barr virus (EB), adenovirus, etc.), paramyxovirus, etc.], hepatitis (allergic) autoimmune or drug-induced, in the fulminant, acute and chronic stages of hepatic deficiency and hepatitis in the fulminating, acute and chronic stages of hepatic deficiency associated with e 1 in ve ne nami en to (h epa tot ox ici da d induced by overdose of acet ami nofeno, poisoning with the fungus Amanita, poisoning with industrial solvents and other poisonings), ischemia (occlusion of the hepatic veins), hyperthermia, infiltration of malignant cells of the liver, Wilson's disease, severe liver, etc.

On the other hand, the compound (I) of this invention is not only effective in stopping the transition from the various types of chronic hepatitis to cirrhosis or hepa touching and in the treatment of primary biliary cirrhosis, but also It is expected that it will be effective as an ophthalmic hepat that should be indicated after surgical intervention in a liver transplant or in a partial hepatectomy (in the case of liver transplants, it is also useful for the premedication of donors). In the ophthalmology department, the compound (I) of this invention is expected to be effective for trachoma (Chlamydia trachomatis infection), in which it is suspected that TNFa is an etiological factor in tissue damage and cyclisation [ In fectionand Imm unity (Infection and Immunity), VOL. 64; (1996), 3273-3279; ibid- Vol, 65 (1997), 1003-1006], in allergic conjunctivitis (inflammatory and atopic), in which it is suspected that inflammatory infiltrating cells -mainly, eosinophils and inflammatory cytokines- perform the main functions, glaucoma, in which it has been reported that pentoxifylline, a non-specific phosphonide inhibitor, generally decreases the intraocular pressure of rabbits and that cAMP is an important factor in regulating blood pressure. infraocular [European Journal of Pharmacology (European Journal of Pharmacology), Vol. 258 (1994), 85-94], and ophthalmitis associated with a herpetic virus, HIV and other viral infections. On the other hand, it is presumed that the compound (I) is effective in the treatment of uveitis, in relation to which it has been demonstrated that the anti-TNFa antibody and the rolipra are effective in the mouse model (u ve orreti ni experimental autoimmune tis) [Inve st igat ive Ophthalmology &; Visual Science (Ophthalmology of Research and Visual Science) Vol. 37 (1996), 221 1-221 8; ibid., Vol. 40 (1999), 942-950]. In recent years, many reports have been prepared indicating that TNFα and TNFα? they play essential roles in the proliferation of the AIDS virus in immune cells and with the aim of suppressing the production of TNFa; Attempts have been made to administer to patients with AIDS for the first time [Journal of Cardiovascular Pharmacology Vol. 25 Suppl.2 (1995), S139-42]. On the other hand, it has been reported that a PDE-IV inhibitor inhibits the HIV's proliferation signal from cytokines [Journal of Virology, Vol. 72 (1998), 4712-20]. mentioned above suggests the possible efficacy of the compound (I) of this invention as a therapeutic drug against AIDS, as well as the other indications, the demonstrated efficacy of the free base (A) in inhibiting the infiltration of eosinophils and in an animal model of late asthma suggests that compound (I) is also effective in asthma and chronic obstructive pulmonary disease (COPD). ) is also useful for the treatment of atopic dermatitis.As compounds that exhibit an inhibitory activity of phosph odi asterasa IV (PDE-IV), an inhibitory activity of the production of tumor necrosis factor (TNF), a The inhibitory activity of the production of interferons and / or an inhibitory activity of the production of i n t e r 1 e u c i n a s - all considered as useful activities for the aforementioned applications - it is possible to mention the following compounds and the compounds described in the US Patents listed below, in addition to the compound of the present invention Compound: Manufacturer: Arofylline Almirall-Prodesfarma Atizoram Pfizer) AWD 12281 ASTA Medica) BAY 198004 Bayer) CDC 801 C e 1 ge) CDP 840 Celltech) Cl 1018 Parke-Davis) Cipamfylline SmithKline Beecham) CP 146523 Pfizer CP 166907 Pfizer CP 220629 Pfizer CP 293121 Pfizer CP 353164 Pfizer CP 77059 Pfizer CP 80633 Pfizer CT 1579 Merck Frosst CT 1786 Merck Frosst D 22888 Medical Asta D 4396 (Ch irosci en ce ) D 4418 (Chiroscience) DWP 205297 (Daewoong) Filaminast (PDA641) (American Home Products GW 3600 (Glaxo Wellcome) KF I 9514 (Kyowa Hakko Kogyo) 0066 (Pielre Fabre) LAS 31025 _ (Almirall-Prodesfarma) LAS 32688 (Almirall-Prodesfarma) LAS 33774 (Almirall-Prodesfarma) MKS 213492 (Novartis) NCS 613 ORG 10325 (Organon, Akzo Nobel) ORG 30029 (Organon, Akzo Nobel) ORG 9731 (Organon, Akzo Nobel) PDB 093 (American Home Products Inhibitors of PDE-IV, Zambón (Zambón) Piclamilast (RP 73401) (Rhon e - P ou 1 a n c Rorer) Roflumilast (Byk Gulden) Rolipram (Shering AG) RPR 116474 - (Rhone-Poulenc Rorer) RPR 132294 (Rh on e - P ou 1 e n c R e r) RPR 132703 (Rhone-Poulenc Rorer) SB 207499 (SmithKline Beecham) SDZISQ 844 (Novartis) SelCI Ds Ce 1 ge ne) SH 636 Schering AG) T 440 Tanabe Seiyaku) Tolafentrine Byk Gulden, Altana) WAY 122331 American Home Products) WAY 127093B American Home Products) WIN 65579 Sanofi Winthrop YM 976 Yamanouchi Pharmaceutical Zardaverine Byk Gulden, Altana) Patent of the United States USP 3896000 USP 4356256 USP 5491147 USP 5580888 USP 5591776 USP 5622977 USP 5674880 USP 5686434 USP 5693659 USP 5710160 USP 5710170 USP 5712282 USP 5728712 USP 5744473 USP 5747506 USP 5753666 USP 5773467 USP 5776958 USP 5780667 The compound (I) of this invention not only has a potent inhibitory activity of phosph odi asterase IV (PDE-IV) and an inhibitory activity of the production of tumor necrosis factor (TNF), but also exhibits an inhibitory activity of TNF production? and from 1L-2, IL-4 and IL-S (compare with test methods A1-A3 described below) and effective in the prophylaxis and / or therapy of various diseases. The utility of compound (I) can be confirmed by the methods described below [compare with test methods B1-B8], by e j emp 1 o.

Test Methods A1-A3: (Al) Inhibitory activity of PDE-IV: [Me all] a crude enzyme was prepared from cells (CHO cells) to which the cDNA had been introduced for the PDE4-B1 isoform human, for the expression of the protein and the inhibitory activity of the PDE4 of the compound (I) of this invention was determined. (A2) Inhibitory activity of TNFa production stimulated with LSP in human peripheral blood monocytes (PBMC): [Method] Isolated monocytes isolated from male adult volunteers, healthy, are they were cultured and stimulated with LPS (1 g / ml) and the amount of TNF in the culture supernatant of 24 hours was determined by ELISA.

(A3) Inhibitory activity of TNFα production stimulated with anti-CD3 / CD2 S antibody in human peripheral blood monocytes (PBMC) [Method] Isolated monocytes isolated from healthy male adult volunteers were cultured and stimulated with anti-CD3 and anti-CD2 8 antibodies and the amounts of TNF, INF, IL-2, IL-4 and IL-10 in the culture supernatant of 24 hours were determined by ELISA.

Research Substance: The compound obtained in Example 2 (hereinafter referred to as the compound of this invention).

RESULTS The results of the A1-A3 tests are presented in the following table.

Test Methods B1-B8 (Bl) Rat model with DGalN / LAS induced hepatitis [All] A 12-week-old male Wistar rats were fasted for 24 hours and received an oral dosage of the drug or the vehicle of the solvent in predetermined doses. Immediately after, saline solution was administered by vein to the NORMAL group. D-galactosamine hydrochloride (DGalN) (300 mg / kg) / LPS (0.32 μg / kg) was administered in a similar way to the CONTROL and DRUGS groups. After 2.4 hours of administration of DGalN / LAS, blood was drawn and the liver was isolated. Using the blood, enzymes from the liver (ALT and AST) in plasma were analyzed. The liver was fixed in formalin and some pathological specimens were prepared. The findings were evaluated in 1 or 2 years (infiltration of inflammatory cells and hepatic cell necrosis). [R e ss] The compound of this invention significantly inhibited the increase of ALT and AST in blood in the model used. On the other hand, the compound inhibited hepatic cell necrosis and also liver cell infiltration.

(B2) Rat model with DGalN-induced hepatitis [METHOD] Male 12-week-old Wistar rats were fasted for 24 hours and received oral dosing of the drug or solvent vehicle at predetermined doses. Immediately afterwards, saline solution was administered via the first one 11 to the NORMAL group and D-ga 1 ami na hydrochloride (DGalN), 400 mg / kg, in a similar way, to the control groups and DRUGS After 24 hours. of DGalN administration, blood was drawn and the liver was isolated. Using the blood, enzymes from the liver (ALT and AST) in plasma were analyzed. The liver was fixed in formalin and some pathological specimens were prepared. The findings h i s t op a t o 1 o g i c o s (infiltration of inflammatory cells and hepatic cell necrosis) were evaluated. [R e ss] The compound of this invention significantly inhibited the increase of ALT and AST in this model. On the other hand, it inhibited hepatic cell necrosis and also hepatic cellular infiltration.

(B3) Mouse model with ConA-induced hepatitis (concanavaline-A) [All] Male 9-week-old Balb / c mice were fasted for 20 hours and received oral dosing of the drug or drug. solvent vehicle in predetermined doses. After one hour, saline was administered intravenously to the NORMAL group and concanavaline A, 0.4 mg / mouse, in a similar way, to the CONTROL and DRUG groups. After 18 h. of administration of ConA, blood was drawn and the liver was isolated. Using the blood, enzymes from the liver (ALT and AST) in plasma were analyzed. The liver was fixed in formalin and some pathological specimens were prepared. The findings were evaluated h i s t op a t o 1 o g i c o s (Inflammatory cell infiltration and hepatic cell necrosis). [R e ss] The compound of this invention significantly inhibited the increase of ALT and AST in this model. On the other hand, it inhibited the hepatic cellular necrosis and also the hepatic cellular infiltration.

(B4) Mouse model with hepatitis induced by P_. acnes / LPS [Mé t o do] Propionibacterium acnes (P. acnes) - which was killed by heat treatment - was lyophilized and used in the experiment. Male ICR mice, 7 weeks old, were administered either intravenously saline solution or P. acnes, 0.6 mg / 0.2 ml / mouse. After 7 days, the drug or the vehicle of the solvent was administered orally, in predetermined doses to the animals that had been fasted for 20 hours. At 9 hours after the administration of the drug, the blood was extracted and the enzymes obtained from the liver (ALT and AST) were analyzed in plasma. [R e s u l t s] The compound of this invention significantly inhibited the increase of ALT and AST in blood in this model.

(B5) Model of LEC rat with spontaneous hepatitis It is known that Long Evans Cinnamon (LEC) rats spontaneously develop acute hepatitis with jaundice as a cardinal sign and that 50-70% of them experience a fulminating stage and die. It is also known that almost all the animals that survive go through a clinical stage of chronic hepatitis - hep to t i t i s chronic hepa t i t i s - b ib b i b biliary (cirrhosis) - h ep a t o c a r c i noma.

[Method] A male LEC rats, 9 weeks old, were supplied with the drug or solvent vehicle orally at predetermined doses, once per day, for 23 consecutive weeks. The day after the last day of dosing, the blood was drawn and the liver was isolated. Using the blood, enzymes from the liver (ALT and AST) in plasma were analyzed. The liver was fixed in formalin and some pathological specimens were prepared. The findings were evaluated as to 1 or 2 (infiltration of inflammatory cells, biliary hyperplasia and hepatic cell necrosis). [Results] The compound of this invention significantly inhibited the increase of ALT and AST in this model. On the other hand, it inhibited hepatic cell necrosis and also hepatic cellular infiltration.

(B6) Guinea pig model with delayed asthma [Method] Healthy male Hartley guinea pigs were sensitized by means of a 1-to-one full-time Freund. On the 23rd day after the immunization, the animals were sucked up with an ovalbumin solution from a sonic nebulizer for 3 minutes to provoke an asthmatic response. The drug was administered orally, one hour before exposure to the antigen. The resistance of the special respiratory tract (sRaw) was measured after exposure to the antigen and every time the sRaw value was increased to double or more than the reference value before exposure, in the span of 4-8 hours, it was estimated as a case of late asthma. [R e ss] The compound of this invention inhibited the late asthmatic response that appeared 4-8 hours after exposure to the antigen in this mode.

(B7) Atopia [Mé t o d o 1] Model of ear edema induced by acid to which i c o: In the. left atrium of some mice Balb / c, 2 mg / ear of arachidonic acid was applied to induce inflammation in the skin. After one hour, the thickness of the atrium was measured with a thickness gauge with disc, Peacock, and it was used as an indication of inflammation of the skin. The drug was administered orally, 30 minutes before the application of arachidonic acid. [Result 1] The compound of this invention significantly inhibited ear edema. [Method 2] Model of spontaneous atopic dermatitis: In the mouse model of dermatitis NC / NGa, the drug was administered orally, once a day, for 17 consecutive days. [Result 2] The compound of the present invention indicated a marked effect of improvement in the state of the disease.

(B8) Inhibitory effect on eosinophil infiltration induced by antigens in guinea pigs [Method] Healthy male Hartley guinea pigs were sensitized intravenously with antiserum to n t i - or albumin (OVA) of guinea pigs. After 24 hours, an antigenic induction was carried out by inhalation exposure to a 1% solution of OVA, through a nebulization. Twenty-four hours after the antigenic induction, the bronchial alveolar lavage (BAL) was collected.

Lavage) and the amount of eosinophils was determined, using the peroxidase activity of the eosinophils in BAL as indicators. The drug was administered orally; one hour before induction [Results] The compound of this invention inhibited the infiltration of eosinophils and other inflammatory cells in the bronchial alveoli. The release rates of the compound (I) of this invention and the free base (A) in the Fluid 1 J.P. and the oral absorption rates thereof.

After a suspension of 16 polymorph crystals in 0.5% methylcellulose (hereinafter referred to as the Sample of the invention) and a suspension of the free base (A) in 0.5% methylcellulose, referred to as the Sample of Control) .

Size of the test sample: 32 mg (1) Release test (1-1) Experimental conditions and procedure Test method: JF XIII, Method 2 (paddle method) Test fluid: JP Fluid 1. Volume of the test fluid: 900 ml Rotation speed: 50 rpm. Temperature: 37sC. (1-2) Results The rate of release (%) in each time segment is indicated below. (2) Oral absorption rate (2-1) Méthod Three male beagle dogs, weighing about 10 kg, were fasted from the day before the experiment and the test sample was administered orally. Immediately after the administration, 30 ml of water was delivered by esophageal tube. After the administration of each test sample, about 2.5 ml of blood from the vein was extracted serially in the form of 1. Blood was treated with 25 μl (25 U) of heparin JP, the plasma was separated and the plasma concentration of the drug was determined by HPLC. (2 - 2) Results The plasma concentration (ng / ml) in each time segment is presented below.

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of this invention can be synthesized not only by the process described in PCT Open Specification WO 96/01825, but also from the free base (A), by the processes described in the Preparations and Examples in this application.

For example, the following process can be mentioned as a typical process for the synthesis of crystal A 16. The free base (A) of the formula (A): it is suspended in methanol. After the addition of acid to the ion, the temperature rises to dissolve the crystals and then gradually reduces to allow the crystals to separate. Subsequently, the system is cooled almost to room temperature and stirred to mature at that temperature. Then, the crystals are recovered by filtration to obtain the polymorphic A16 crystals. To demonstrate the usefulness of the compound (I), some studies related to solubility, stability and polymorphism were carried out. (1) Studies on solubility and stability For each sample (ie, free base) (A), the compound (I) (crystal A01), the hydrochloride (B) and the sulfate [hereinafter referred to as sulphate (C)]), the solubility values were studied the changes in the crystallinity before the compound formation with water or ethanol, considering the pharmaceutical procedure. (1) Solubility The solubility in distilled water for injection and physiological saline was studied and the results obtained are shown in Table 1.

Table 1 - Solubility values of each sample It was found that the Crystal compound AOl) had improved in terms of solubility in distilled water for injection and physiological saline, compared to the free base (A). 2) Changes in the crystallinity before the formation of compounds For the compound (I) and the hydrochloride (B), the changes in the crystallinity before the compound formation with ethanol were studied. The results are presented in Table 2.

Table 2-Influence of the formation of compounds with ethanol on the ciris talinity The crystallinity of the hydrochloride was reduced when it was mixed with ethanol. A study of the solid state of this solid that formed compound with ethanol revealed that the residual amount was 91% at 70 ° C., for 9 days. On the other hand, the sample that formed compound with ethanol of compound (1) did not show changes in crystallinity.

(II) Study on the polymorphism of the compound (1) In the study of the polymorphism of the compound (I), six classes of polymorphs were found (the crystals AOI, A09, A16, A20, A30 and A43). For each of these polymorphs, the stability, stability in the solid state, solubility and changes in crystallinity were studied in the formation of compounds with various solvents. However, the A30 crystal was not studied because it contains ethanol. (1) Higroscopicity The crystals A09 and A43 were highly hygroscopic. On the other hand, it appeared that crystals A01, A16 and A20 were less hygroscopic. (2) Stability in solid state The results of stability in solid state are presented in Table 3.

Table 3 - It is solid state ability The AOl crystal indicated a slight reduction in the residual percentage after storage at 70 ° C, for 9 days. On the other hand, both the A16 and A20 crystals, as found, were chemically stable to heat and moisture and exhibited no changes in the shape of the crystals. 3) Solubility The solubility (room temperature, 30 minutes of agitation) of the A16 and A20 crystals in distilled water for injection and physiological saline was determined (Table 4).

Table 4- Solubility values of the API, Al 6 and A20 crystals in various solvents: The A16 crystal exhibited the maximum solubility in distilled water for injection. These results indicate that the compound (I), in particular, its A16 crystal, has improved in terms of solubility and stability, in comparison with the free base (A) and the hydrochloride (B) In this way, it is considered that the crystal A16 is advantageous as the volumetric substance for pharmaceutical production. Finally, this invention provides the compound (1) which represents improvements in the low solubility and stability of the free base (A) and the hydrochloride (B) and, likewise, the crystal A16 of the compound (I), which has no degradation in the solid state and exhibiting no changes in crystallinity during compound formation and also represents an improvement in solubility. The following examples illustrate this invention in greater detail. However, it should be understood that they are not intended to define the scope of the invention.

Preparation 1 2-C 1 -O-3-nitr op-iri-di (50 g), 5-acetyl-m-phenylene-diamine (47.3 g) and anhydrous sodium carbonate (33.4 g) in dioxane were suspended. (250 ml) and the suspension was refluxed with vigorous stirring. After the starting materials were dissolved once, the objective orange crystals were gradually separated. Heating and stirring continued for 6 days, after which the reaction mixture was cooled and the objective crystalline product, as well as the inorganic salt were separated by filtration. The crystals were washed with dioxane, dried and stirred together with water (ΔI). Orange crystals were recovered by filtration and rinsed with water, until the washes were neutralized. The collected crystals were left to dry in the air, in order to obtain 2 - (3-α-amino-1) amino-3-n-t-opy (52.9 g). NMR (DMSO-d6, d) = 2.06 (3H, s), 6.99 (1H, dd, j = 5 Hz, 8Hz), 7.2-7.4 (3H, m), 7.91 (IH, s), 8.5-8.6 (2H, m), 9.93 (IH, s), 9.99 (1H, s).

Preparation 2 A mixture of 2- (3-acetyl-ami-phene-1) -amino-3-nitropyridine (20 g) and 4 N-c-1-oric acid (200 ml) was heated to 90 ° C. , with agitation for two hours. This reaction mixture was cooled and incorporated in portions, in an aqueous solution of sodium hydrogen carbonate (68 g). The crystals that had been separated were recovered by filtration, rinsed with water and allowed to air dry to obtain 2 - (3-ami no f e n i 1) amino-3-n i t r op i r i di n a (17.8 g). NMR (CDCI; 3 d): 3.72 (2H, s), 6.50 (1H, m), 6.80 (1H, m), 6.96 (1H, m), 7.12 (2H, m), 8.48 (2H, m), 10.04 (1H, s).

Preparation 3 2- (3-Aminophenyl) amino-3-nitropyridine (17.8 g) was dissolved in dioxane (180 ml) under heating. After the addition of triethylamine (10.8 ml) a solution of sodium chloride was added dropwise. 3,5-dichlorobenzoyl (16.2 g), in dioxane (20 ml) with constant stirring. After completion of the drop incorporation, the mixture was further stirred at room temperature for 1 hour. This reaction mixture was diluted with water and the resulting crystals were recovered by filtration. The crystals were rinsed with water and methanol and allowed to air dry overnight to obtain crystals of 2- (3 - (3, 5-dec-1-benzoi-1-ami-no) -phen-1-ami-no) -3- ni tr op iri di na (27.5 g). NMR (CDCl 3, ¿): 7.00 (1H, m), 7.37 (1H, dd, J = 8 Hz, 8 Hz), 7.45 (1H, m), 7.55 (1H, m), 7 , 88 (1H, m), 7.99 (2H, s), 8.10 (1H, m), 8.53 (2H, m), 9.98 (1H, s), 10.45 (1H, s). P. of f: 237-242 sC.

Preparation 4 A mixture of 2 - (3 - (3,5-di c 1 or obemz oi 1) -amino) f enylammo-3-nitropyridine (25 g), acetic acid (99.4 ml) and ethanol (300 ml) ) was heated under agitation. When the temperature of the oil bath reached 50 ° C, iron powder (17.3 g) was added, after which it was continued to warm up. The reflux started after around 20 minutes, accompanying by the separation of white crystals of iron acetate. The reflux continued for 2 hours, after which the reaction mixture was cooled and the objective crystals and the inorganic salt were recovered by filtration. This mixture was extracted with N, N-dimethoxymethyl (DMF) and the insoluble inorganic salt was removed by filtration. The DMF solution obtained in this way was diluted with water, after which white crystals were separated. This crystal production was collected by filtration, rinsed with water and allowed to air dry overnight to obtain crystals of 3-amino-2- (3- (3, S-di c 1 or ob in zoi 1 ami no) feni 1 ami no) piri di na (19.6 g). NMR (DMSO-d6, d); 5.09 (2H, s), 6.62 (1H, dd, J = 8 Hz, 5 Hz), 6.90 (1H, m), 7.20 (2H, m), 7.41 (1H, m), 7.50 (1H, m), 7.78 (1H, s), 7.86 (1H, s), 7.99 (28, s), 8.05 (1H, s).

Preparation 5 To a suspension of 60% sodium hydride (1.49 g) in ether (1 ml) was added dropwise a solution in ethyl ester mixture of N, N-dime thi 1 glycol (7.9 ml) and 3-pyridine n-car box 1 hour (2.0 g) in ether (4 ml) under stirring. When about one fifth of the amount had been incorporated by dripping, the reaction started and the ether went to reflux. Cooling was then started with ice water and the speed of incorporation by dripping was adjusted (for a period of approximately 30 minutes) so that the reaction proceeded to an internal temperature of 20-30 ° C. When the aggregate is finished by dripping, the reaction mixture is stirred at room temperature for 24 hours. Once the hydrogen gas stopped producing, the reaction mixture was cooled with ice and more ice was added (1 g). The exothermic reaction raised the temperature to 35 ° C and the system solidified. After cooling to an internal temperature of 1 8, C, water (13 ml) and ether (20 ml) were added, and then stirred. The ether layer was separated and the aqueous layer was extracted twice with 10 ml of ether at each opportunity. The layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure (4.6 g). The residue was subjected to distillation under reduced pressure. With a vacuum pump connected directly, the distillate was collected up to a bath temperature of 140 ° C., in order to obtain 3- (2-dimethylamimo-2- (ethoxycarbonyl) ethenyl) -pyridine (3.1). (p.of e.12OsC). NMR (CDCl 3, d): 1.25 (3H, t, J = 7 Hz), 2, 60 (6H, s), 4.22 (2H, q, J = 7), 6.70 (1H, s ), 7, 40 (1H, m), 7, 96 (1H, m), 8.45 (1H, m), 8, 69 (1H, m Preparation 6 In 2N-sodium hydroxide, 3- (2-dimetho-1-ami-2-yl) was suspended (3 x 1 g) and the suspension was subjected to reflux for 6 hours. This reaction mixture was washed with ethyl acetate (6 ml) and the aqueous layer was filtered by suction, in order to eliminate both the oil and the precipitate that formed in smaller amount. The aqueous solution was adjusted to a pH of 3.0, with concentrated hydrochloric acid (about 1.5 ml) and allowed to stand, under cooling with ice, whereby the target crystals were separated. The system remained at rest overnight and the crystal production was collected by filtration, rinsed with water and allowed to air dry to obtain 3 - (3-pyridium) pyriform (1.1). g) as light yellow crystals.

NMR (D20, d): 7.90 (1H, m), 8.40 (1H, ml,, 58 (2H, m).

Preparation 7 3-ami no-2 - (3 - (3, 5 -di c 1 or ob enzoi 1 ami no) f in i 1 ami no) piri di na (18.6 g) and 3 - acid were suspended. 3-pipera di 1) pi r ú vi co (8.23 g) in ethanol (370 ml) and the suspension was refluxed for 8 hours. This reaction mixture was cooled and the resulting crystals were recovered by filtration. The crystals obtained in this way were rinsed with ethanol and dried to obtain crystals of 4- (3 - (3,5-di c 1 or ob enzoi 1 ami no) -pheni 1) -2- (3-pyridyl) methyl 3-oxo-3, 4-dihydroxypyrido [2,3-bipyrazine (21.2 g). NMR (DMS0-d6, d): 4.27 (2H, s), 7.12 (1H, d, J = -8 Hz), 7.3-7.45 (2H, m), 7.56 ( IH, t, J = 8 Hz), 7.75-7.85 (3H, m), 7.88 (IH, t, J = 2 Hz), 7.98 (2H, d, J = n 2Hz) , 8.21 (1H, dd, J2Hz, 8Hz), 8.41 (1H, d, J = 5Hz), 8, 48 (1H, d, J = S Hz), 8.60 (1H, d, J = 2 Hz).

EXAMPLE 1 4- (3- (3,5-Dichlorobenzoylamino) phenyl) -2- (3-pyridyl) methyl-3-oxo-3, 4-dihydrogen oxidi [2] was suspended in methanol. 3-b] pirazi na (12 g) and the suspension was warmed up to approximately 60sC. After the addition of methanesulfonic acid (2.29 g), the system was cooled and the resulting crystals were recovered by filtration, rinsed with methanol and allowed to air dry overnight to obtain 4- (3-methanesulfonate. (3,5-dichlorobenzoyl-amino) phenyl) -2- (3-pyridyl) methyl-3-oxo-3,4-di-hydropyrido [2,3-b] pyrazine (13.3 g) as crystals. NMR (DMSO-d6, d): 2.32 (3H, s), 4.47 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.41 (1H, dd,) = 8Hz, 5Hz), 7.57 (1H, dd,] = 8Hz, 8Hz), 7.77 (1H, d, 3 = 8Hz), 7.89 (2H, m), 7.98 (2H, m ), 8.01 (1H, dd,] 8Hz, 5Hz), 8.15 (1H, d, J = 8Hz), 8.43 (1H, d, J = SHz), 8.53 (1H, d, J = 8Hz), 8.83 (1H, d, J = 5 Hz), 8.93 (1H, d, J = 2 Hz), 10.64 (1H, s). p. of f. : 158-166sC.

EXAMPLE 2 4 - (3 - (3, 5-di c 1 or oben zoi 1 -amino) phenyl) -2- (3-pyridyl) methyl-3-oxo-3,4-dihydr opiid was suspended [2 , 3-b] pi razi na (20.0 g) in methanol (MeOH) 98% (200 ml). Methanesulfonic acid (MsOH) (3.83 g) was then added and the temperature raised to 60-65 ° C. After confirming the dissolution of the crystals, the system gradually cooled to allow the crystals to separate. The system was cooled further, at 20-25 ° C and stirred at the same temperature to ripen. After maturation, the crystals were recovered by filtration to obtain methanesulfonate dihydrate of 4- (3- (3,5-dichlorobenzoylamino) phenyl-2- (3-pyridyl) methyl-3-oxo-3,4-dihydropyrido [ 2,3-b] pyrazine (16.76 g) as light yellow crystals The crystallographic morphology of the crystals obtained in this manner, as confirmed, was the polymorph A16, according to X-ray powder diffraction analysis. NMR (DMSO-d6, d): 2.32 (3H, s), 4.47 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.41 (1H, dd, J = 8Hz, SHz), 7.57 (1H, dd, J = 8Hz, 8Hz), 7.77 (1H, d, J = 8 Hz), 7.89 (2H, m), 7.98 (2H, ), 8.01 (1H, dd, J = 8 Hz, 5 Hz), 8.15 (1H, d, J = 8H z), 8, 43 (1H, d, J = 5Hz), 8, 53 (1H, d, J = 8Hz), 8.83 (1H, d, J = 5 Hz), 8.93 (1H, d, J = 2 Hz), 10.64 (1H, s).

EXAMPLE 3 4 - (3 - (3,5-Dichlorobenzoylamino) phenyl) -2- (3-pyridyl) methyl-3-oxo-3, 4-di-hi-op-opy [2, 3-b] pirazi was suspended Na (5.0 g) in 95% ethanol (EtOH) (50 ml). Then, the temperature was raised to 70-75 ° C and MsOH (0.96 g) was added. When it was confirmed that the crystals had dissolved, the system gradually cooled to allow the crystals to separate. The system was further cooled to 20-25 ° C and stirred at the same temperature to mature. After maturation, the crystals were recovered by filtration, to obtain 4- (3- (3, 5-dichlorobenzoylamino) -phenyl) -2- (3-pyridyl) methyl-3-oxo-dihydropyrido- [2, methanesulfonate. 3-b] pyr-azine (4.84 g) as light yellow crystals. The crystallographic morphology of the crystals obtained in this manner, as confirmed, was polymorph A30, in accordance with X-ray powder diffraction analysis. NMR (DMSQ-d6, d): 2.32 (3H, s) , 4.47 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.41 (1H, dd, J = 8Hz, 5Hz), 7.57 (1H, dd, J = 8Hz , 8Hz), 7.77 (1H, d, J = 8 Hz), 7.89 (2H, m), 7.98 (2H, m), 8.01 (1H, dd, J = 8Hz, 5Hz) , 8,15 (1H, d, J = 8Hz), 8,43 (1H, d, J = 5Hz), 8,53 (1H, d, J = 8Hz), 8,83 (1H, d, J = 5 Hz), 8.93 (1 H, d, J = 2 Hz), 10.64 (1 H, EXAMPLE 4 The methanesulfonate of 4- (3- (3, 5-dichlorobenzoylamino) phenyl) -2- (3-pyridyl) methyl-3-ox or -3,4-dihydric acid was suspended [2, 3 -b] pirazi na (0.5 g) (polymorph A16) in EtOH (5 ml). Then, the temperature rose to 70-75 ° C and the dissolution of the crystals was confirmed. This system gradually cooled, after which the crystals separated. The system was further cooled to 20-25 ° C and stirred at the same temperature to ripen. After maturation, the crystals were recovered by filtration in order to obtain 4- (3 - (3,5-di c 1 or obe nzoi 1 ami no) -phenyl) -2- (3-pyridyl) methyl methanesulfonate. 3-oxo-3, 4-dihydro-p iri do [2, 3-b] pirazi na (0.43 g) as light yellow crystals. The crystallographic morphology of the crystals obtained in this way, as confirmed, was polymorph A01, in accordance with X-ray powder diffraction analysis.

NMR (DMSQ-d6, d): 2.32 (3H, s), 4.47 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.41 (1H, dd, J = 8 Hz, S Hz) 7.57 (1H, dd, J = 8 Hz, 8 Hz), 7.77 (1H, d, J = 8 Hz), 7.89 (2H, m), 7, 98 (2H, m), 8.01 (1H, dd, J = 8 Hz, 5 Hz), 8.15 (1H, d, J = 8Hz), 8, 43 (lHd, J = 5Hz), 8.53 (1H, d, J = 8Hz), 8.83 (1H, d, J = 5Hz), 8, 93 (1H, d, J = 2 Hz), 10, 64 (1H, s).

EXAMPLE 5 The methanesulfonate of 4- (3- (3,5-dichlorobenzoylamino) -phenyl) -2- (3-pyridyl) methyl-3-oxo-3 was suspended, 4-dihydropyrido [2,3-b-pyrazine (1.0 g) (polymorph A30) in 95% EtOH (10 ml). This suspension was stirred until mature at 20-25, C. After maturation, the crystals were recovered by filtration, in order to obtain 4- (3- (3,5-dichlorobenzoylamino) phenyl) -2- methanesulfonate. (3-pyridyl) methyl-3-oxo-3,4-dihydric acid [2, 3-b] pyrazole (0.86 g) as light yellow crystals. The crystallographic morphology of the crystals obtained in this way, as confirmed, was polymorph A09, in accordance with X-ray powder diffraction analysis.

NMR (DMSO-d6, d): 2.32 (3H, s), 4.47 (2H, s), 7.10 (1 H, d, J = 8 Hz), 7.41 (1H, dd, J = 8Hz, 5Hz), 7, 57 (1H, dd, J = 8Hz, 8Hz), 7.77 (1H, d, J = 8 Hz), 7.89 (2H, m), 7.99 (2H , m), 8.01 (1H, dd, J = 8 Hz, 5 Hz), 8.15 (1H, d, J = 8Hz), 8.43 (1H, d, J = 5Hz), 8.53 (1H, d, J = 8Hz), 8.83 (1H, d, J = 5 Hz), 8.93 (1H, d, J = 2 Hz), 10.64 (1H, s).

EXAMPLE 6 The methanesulfonate of 4- (3- (3,5-dichlorobenzoylamino) -phenyl) -2- (3-pipdyl) methyl-3-oxo-3,4-dihydro-pyrido [2, 3 - b] pyrazi na (3.5 g) (polymorph A30) in 86% EtOH (38.5 ml). Then, the temperature was increased to 70-75 ° C and the dissolution of the crystals was confirmed. Then, the system gradually cooled, whereby the crystals were separated. This system was further cooled to 20-25 ° C and allowed to mature under agitation at the same temperature. After maturation, the crystals were recovered by filtration, in order to obtain 4 - (3 - (3, 5-di c 1 or obe nzoi 1 ami no) -phenyl) -2- (3-pyridyl) methyl methanesulfonate. -3-oxo-3, 4-dihydro-p iri do [2, 3-hpirazi na (2.73 g) as light yellow crystals.

The crystallographic morphology of the crystals obtained in this way, as confirmed, was polymorph A43, in accordance with X-ray powder diffraction analysis. NMR (DMSO-d6, d) = 2.32 (3H, s) , 4.47 (2H, s), 7.10 (1H, d, J = 8Hz), 7.41 (1H, dd, J = 8 Hz, 5 Hz), 7.57 (1H, dd, J = 8Hz, 8 Hz), 7.77 (1H, d, J = 8Hz), 7.89 (2H, m), 7.98 (2H, m), 8.01 (1H, dd, J = 8Hz, 5Hz ), 8,15 (H, d, J = 8Hz), 8,43 (1H, d, J = 5Hz), 8,53 (1H, d, J = 8Hz), 8,83 (1H, d, J = 5Hz), 8.93 (1H, d, J = 2 Hz), 10.64 (1H, s).

EXAMPLE 7 The methanesulfonate of 4- (3- (3,5-di c 1 or ob enzoi 1 ami no) phenyl) -2- (3-pyridyl) methyl-3-oxo-3,4-dihydropyrido [2] was suspended. , 3'-b] pyrazine (1.0 g) (polymorph A30) in isopropyl alcohol (IPA) (20 ml). Then, the temperature was raised to 75-80 ° C and water (1.23 ml) was added. When confirming that the crystals had been dissolved, 50 mg of seed crystals were added at 70-75sC. Then the system cooled gradually, to let the crystals separate. The system was cooled further, at 20-25 ° C and left to mature under agitation, at the same temperature. After maturation, the crystals were recovered by filtration, to obtain 4- (3 - (3, 5-di c 1 or ob in zoi 1 ami) -phenyl) -2- (3-pyridyl) methyl methanesulfonate. 3-oxo-3, 4-dihydro-p iri do [2, 3-b] pirazi na (4.84 g) as light yellow crystals. The crystallographic morphology of the crystals obtained in this manner, as confirmed, was polymorph A20, in accordance with X-ray powder diffraction analysis. NMR (DMSQ-d6, d): 2.32 (3H, s) , 4.47 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.41 (1H, dd, J = 8Hz, 5Hz), 7.57 (1H, dd, J = 8Hz , 8Hz), 7.77 (1H, d, J = 8 Hz), 7.89 (2H, m), 7.98 (2H, m), 8.01 (1H, dd, J = 8 Hz, 5 Hz), 8,15 (1H, d, J = 8Hz), 8,43 (1H, d, J = 5Hz), 8,53 (1H, d, J = 8Hz), 8,83 (1H, d, J = 5 Hz) 8.93 (1H, d, J = 2 Hz), 10.64 (1H, s) .0 REFERENCE EXAMPLE 1 4 - (3 - (3,5-di c 1 or obe nzoi 1 -amino) phenyl) -2- (3-pyridyl) methyl-3-oxo-3,4-dihydro-pyrido was suspended. 2, 3-b] pi raz ina (5 g) in methanol (50 ml), followed by the addition of sulfuric acid (0.98 g). The mixture was warmed to a temperature of about 60 C to dissolve. The solution was allowed to stand overnight and the resulting crystals were recovered by filtration, rinsed with methanol and dried, to obtain 4- (3- (3,5-dichlorobenzoylamino) phenyl) -2- (3) sulfate. -pyridyl) methyl-3-o-xo-3,4-dihydropyrido [2, 3-b] pyrazine (5.15 g). p. of f. : 215-22 IsC. NMR (DMSO-d6, d): 4.45 (2H, m), 7.10 (1H, d, J = 8 Hz), 7.40 (1H, dd, J = 8Hz, 5Hz), 7.55 (1H, dd, J = 8Hz, 8Hz), 7.77 (1H, d, J = 8Hz), 7.89 (1H, m), 7.99 (3H, m), 8.17 (1H, d) , J = 8Hz), 8.43 (lH, m), 8.49 (lH, d, J = 8 Hz), 8.80 (1H, d, J = 5 Hz), 8.90 (1H, s ), 10.63 (1H, s).

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a powder diffraction pattern by X-rays of the polymorph AOI crystal of the compound (I). Fig. 2 is a powder diffraction pattern by X-rays of the polymorph A09 crystal of the c ompue s (I). FIG. 3 is a powder diffraction pattern by X-rays of the polymorphic crystal A16 of the cell (I).

Fig. 4 is a powder diffraction pattern by X-rays of the polymorph A20 crystal of the c omp u e s t o (I). FIG. 5 is an X-ray powder diffraction pattern of the polymorph A30 crystal of the atom (I). Fig. 6 is a powder diffraction pattern by X-rays of the polymorph A43 crystal of the c ompue s (I).

Claims (14)

1. CLAIMS 1.- Compound of the following formula or a solvate thereof:
2. 2. Compound according to claim 1, characterized in that it has the following formula: CH3S03H-2H20
3. 3. Crystal of the compound according to claim 1 or 2, which substantially shows the following X-ray powder diffraction values:
4. Diffraction angles: 20 (?) = 2, 78, 5, 59, 14, 98, 16, 73, 19, 79, 24, 61, 26, 07; 2 T (?) = 7, 72, 10, 07, 13, 69, 15, 23, 20, 26, 21, 03, 24, 74, 25, 17; 2 ? (?) = 2, 86, 5, 63, 20, 86, 22, 31, 23, 88, 25, 93; 2 T (?) = 12, 50, 19, 28, 21, 50, 23, 16, 25, 38; 2 ? (?) = 7, 72, 10, 03, 13, 61, 20, 05, 24, 18; or 26 »(?) = 7, 08, 12, 20, 21, 334. Crystal as claimed in claim 3, which shows the following X-ray diffraction values. Diffraction angles: 2? (?) = 2.86,5,63,20,86,22,31,23,88,25,93.
5. 5. Process for the production of the crystal as claimed in claim 4, characterized in that it comprises; suspension crystals of the compound of the following formula (A) in methanol; the addition thereto of methanesulfonic acid; the increase in the temperature of the system to dissolve the crystals; the gradual cooling of the system in order to let the crystals separate; it also cools the system to a temperature close to room temperature; and the agitation of the system at the same temperature, for maturation.
6. 6. Therapeutic composition for hepatitis, which comprises a compound having an inhibitory activity of phosphodiesterase IV, an inhibitory activity of the production of tumor necrosis factor, an inhibitory activity of the production of interferons or an inhibitory activity of the production of 1, the use for the manufacture of a medicament for treating hepatitis, or a method for the treatment of hepatitis comprising administering the compound to a human or animal
7. 7. The therapeutic composition for hepatitis, the use of the compound for the manufacture of a medicament for treating hepatitis, or the method for the treatment of hepatitis comprising administering the compound to a human or animal, as claimed in claim 6, wherein the hepatitis is viral, autoimmune or induced by drugs or hepatitis in the fulminating, acute and chronic stages of liver deficiency associated with poisoning to, ischemia, hyperthermia, infiltration of malignant cells of the liver, ilson's disease, or fatty liver.
8. 8. A therapeutic composition to inhibit the transition of the various types of chronic hepatitis to cirrhosis or hepatocarcinoma, a therapeutic composition for primary biliary cirrhosis or a hepa t op rotective composition to indicate in the process po st-ope rat or io of liver transplantation or in partial hepatectomy, which comprises a compound that has an inhibitory activity of phosph odi asterasa IV, an inhibitory activity of the production of tumor necrosis factor, an inhibitory activity of interferon production or an activity inhibitory of the production of inter 1 euc i na s.
9. 9. Use of a compound that has an inhibitory activity of phosph odi asterasa IV, an inhibitory activity of the production of tumor necrosis factor, an inhibitory activity of the production of interferons or an inhibitory activity of the production of inter 1 euines, for the manufacture of a medicament intended to inhibit the transition of the various types of chronic hepatitis to cirrhosis or hepatocarcinoma or to treat primary biliary cirrhosis, to be used as a hepatectomy to indicate in the postoperative process of liver transplantation or in partial hepatectomy.
10. 10. Method to inhibit the transition from various types of chronic hepatitis to cirrhosis or hepatocarcinoma, to treat primary biliary cirrhosis or to protect hepatocytes, to be indicated in the post-operative process of liver transplantation or in partial hepatectomy, which comprises the administration of a compound having an inhibitory activity of phosph odi asterasa IV, an activity inhibitory of the production of the tumor necrosis factor, an inhibitory activity of the production of interferons or an inhibitory activity of the production of inter-eucines, to a human being or to an anima 1.
11. 11. Therapeutic composition for trachoma, a therapeutic composition for allergic conjunctivitis (inflammatory and atopic), glaucoma, ophthalmitis associated with HIV infection, AIDS, chronic obstructive pulmonary disease comprising a compound, which has an inhibitory activity of phosphine asterasa IV, an inhibitory activity of the production of tumor necrosis factor, an inhibitory activity of the production of interferons or an inhibitory activity of the production of inter kinase, use of the compounds for the preparation of a drug to treat diseases, or a method for the treatment of said disease which comprises administering the compound to a human or animal.
12. 12. The therapeutic composition claimed in any of claims 6, 8 and 11, the use of the compound for the manufacture of a medicament for treating the diseases claimed in any of claims 6-7,9 and 11, or the method for the treatment of said diseases. diseases which comprises the administration of the compound in a human or animal claimed in any of claims 6-7, 10 and 11, wherein the compound has inhibitory activity phosphodiesterase IV, inhibitory activity for the production of tumor necrosis factor, inhibitory activity of interferon production or inhibitory activity of production of inter 1 eu si na s is the following compound: F or rmu la: o F or rmu la: CH3S03H-2H20
13. 13. The therapeutic composition claimed in any of claims 6-8 and 11, the use of the compound for the manufacture of a medicament for treating the diseases claimed in any of claims 6-7,9 and 11, or the method for treating said diseases which comprises the administration of the compound in a human or an animal claimed in any of the above indications 6-7, 10 and 11, wherein the compound has inhibitory activity phosphodiesterase IV, inhibitory activity for the production of tumor necrosis factor , inhibitory activity of interferon production or inhibitory activity of inter-eosin production is the following compound described in the following North American Patents. 3896000, 4356256, 5491147, 5580888, 5591776, 5622977, 5674880, 5686434, 5693659, 5710160, 5710170, 5712282, 5728712, 5744473, 5747506, 5753666, 5773467, 5776958, 5780667, 5786354, 5787215, 5792774, 5798373, 5804588, 5834485, 5849770, 5859008, 5859034, 5866593, 5889014, 5891878, 5891896, 5919801, 5922557, 5922740, 5922751, 5925636 and 5935977.
14. 14. The therapeutic composition claimed in any of the above indications 6-8 and 11, the use of the compound for the manufacture of a medicament for treating the diseases claimed in any of claims 6-7,9 and 11, or the method for the treatment of said diseases which comprises the administration of the compound in a human or animal claimed in any of claims 6-7, 10 and 11, wherein the compound has inhibitory activity phosphodiesterase IV, inhibitory activity for the production of necrosis factor Tumor, inhibitory activity of interferon production or inhibitory activity of interleukin production is any of the following compounds described in the following North American Patents. Arofylline, Atizoram, A D12281, BAY 198004, CDC 801, CDP 840, Cl 1018, Cipamf ylline, CP146523, CP 166907, CP 220629, CP 293121, CP 353164, CP 77059, CP 80633, CT 1579, CT 1786, D 22888 , D 4396, D 4418, DP 205297, Filaminast (PDA 641), GW 3600, KF 19514, L 0066, LAS 31025, LAS 32688, LAS 33774, MKS 213492, NCS 613, ORG 10325, ORG 30029, ORG 9731, PDB 093, inhibitors of PDE-IV, Zambon, Piclamilast (RP 73401), Roflumilast, Rolipram, RPR 116474, RPR132294, RPR 132703, SB 207499, SDZISQ 844, SelCIDs, SH636, T 440, T or 1 afentrine, WAY 122331, WAY 127093B, WIN 65579, TM 976 and Zardaverine.