MXPA97008903A - Xantinas and its use terapeut - Google Patents

Abstract

The xanthine 1, 3-disubtituidas have therapeutic utility by means of the inhibition of TNF or fosfodietera

Description

XANTINAS AND ITS THERAPEUTIC USE DESCRIPTION OF THE INVENTION The present invention relates to novel xanthine compounds and pharmaceutically acceptable eleates thereof, to the processes for their preparation and their formulation and their use as pharmaceutical substances. Xanthine compounds are such as theophylline (The Merck Index, Issue 709?) And PropentoFi 1 ina.The Merck Index, Inc. edition, 7822) have been widely used clinically for the treatment of respiratory tract diseases or dysfunction. of the brain. The main clinical disadvantages of xanthine compounds are severe adverse reactions induced frequently by the administration of these compounds. Examples of adverse reactions are, for example, cardio-excitatorial activity, such as, for example, heart disease or tachycardia; central activity such as, for example, convulsion or headache; and gastrointestinal activity such as nausea or vomiting. Therefore, xanthine compounds without these adverse reactions would provide significant clinical benefits. Related xanthine derivatives have been developed as pesticides and agents with pesticidal activity (U.S. Patent No. 4663601.) In addition, the related xanthine derivatives have been developed as intermediates but without pharmacological activity to be developed for these compounds. European Patent No. 0 369 744, International Patent Application WO 92/05176, European Patent Application No. 0 369 282 and International Patent Application WO 94/00452. Phosphodiesterases regulate the concentrations of cyclic AMPs. that Phosphodiesterase IV is a major regulator of cyclic AP in non-striated respiratory muscle and inflammatory cells (See Torphy and Creslipski, Molecular Pharmacology 37, 206, (1990); Dent et al British Journal oF Pharmacology, 90 163p (1990) Inhibitors of FosFodiesterase IV have been implicated as bropcodiotransmitters and asthma-praPlactic agents and as p-agents. for the inhibition of eosinophil accumulation and the function of eosinophilis (see for example Giembycz and Oent, Clipical and Experimental Allergy 22 337 (1992)), and for the treatment of other diseases and conditions, characterized by, or having an etiology including eosinophil accumulation morbid. Inhibitors of FasFodiesterase IV are also involved in the treatment of inflammatory diseases, prolific skin diseases and symptoms associated with cerebral metabolic inhibition. Excessive or unregulated production of the Dß Necrosis Factor (TNF) has been implicated in regulating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout arthritis, and other arthritic symptoms; sepsis, septic shock, ndotoxic shock, gram-positive sepsis, toxic shock syndrome, respiratory pain syndrome in adults, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion damage, reaction of the rejection host to the graft, rejections to allografts, fevers and myalgias due to infection, such as influenza, secondary cachexia for infection or malignancy, cachexia secondary to humans with acquired immunodeficiency syndrome (AIDS) ARC (Related complex with SI0A) s keloid formation, tissue formation in scars, Crohn's disease, ulcerative colitis, or pyresis, in addition to a large number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and erythematasis of systemic lupus. AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, namely HIV-1, HIV-2, and HIV-3. As a consequence of HIV infection, the regulated immunity of the T cell is damaged ß infects individuals manifesting severe opportunistic infections and / or unusual neoplasms. HIV that enters the T-lymphocyte requires activation of the T lymphocyte. Viruses such as HIV-1 or HIV-2 infect the T lymphocytes after the activation of the T cells and such expression of the virus protein and / or the replication is regulated or maintained by such T cell activation. Once T lymphocyte has been activated, is infected with HIV the T lymphocyte must continue to remain in a state to allow for the expression of the HIV gene and / or replication of HIV. Cytokines, specifically TNF, are involved in the activated T cell of the expression of the regulated dß HIV protein and / or the replication of the virus by an action of maintaining the activation of the T lipfocyte. Therefore, the interference with the activity of the cytokine such as, by inhibiting the production of the cytokine, TNF notably in an individio infected with HIV helps in limiting the maintenance of T cell activation, thereby reducing the progression of the infectivity of HIV to the cells without previously infecting, which results in the decrease or elimination of the progression of the immune dysfunction originated by the HIV infection. Monocytes, macrophages and related cells such as Kupffer and glial cells have also been implicated in maintaining HIV-like infection. These cells similar to T cells are targets for viral replication and the level of viral replication is dependent on the activation state of the cells. (See Rosenberg et al., The Immunospathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989))). Monokines, such as TNF, have shown the activity of HIV replication in monocytes and / or macrophages (See Poli et al, Proc.Nat.Acid.Sci., 67: 782-784 (1990)), therefore the inhibition of the production, of mono? uina or the activity e "yuc's in. l? Limitation of HIV progression as mentioned above for T cells TNF has also been implicated in several roles with other viral infections, such as cytomegalovirus (CMV), influenza virus, adenovirus, and herpes viruses. Similar reasons as mentioned before. TNF is also associated with yeast and fungal infections. Specifically, Candida Albicans has been shown to induce the production of TNF in vitro in human monocytes and in natural dead cells (See Riipi et al., InFection and Immunity, 56 (9); 2750-54, (1990); and JaFari et al., Journal oF InFesctiops Oisease, 164: 389-95 (1991), see also Wasan et al., Aptimicrobial Agents amd Chemootherapy, 35 (10); 2046-46, (1991), and LUke et al. , Jour al oF IpFßctious Diseases, 162: 211-214, (1990) The ability to control the adverse effects of TNF is increased by the use of compounds which inhibit TNF in mammals who are in need of use. Remaining a necessity for the compounds which are useful in the treatment of TNF-regulated disease states, which are exacerbated or caused by the excessive and / or irregular production of TNF.It has been found that novel compounds have the ability to treat disease states, for example disease states associated with proteins that regulate cellular activity, for example, by inhibition of tumor dc necrosis factor and / or by inhibition of phosphodiesterase IV. The novelties are of the formula (i): wherein Q represents aryl, β-β-aryl, cycloalkyl or heterocycle optionally substituted with one or more substituents selected from alkyl of 1-6C (optionally substituted with one or more halogens), alkyl of 1-6C-S (0) -, -C ? H (or alkyl esters of 1-6C thereof or alkyl amides of 1-6C thereof), halogen, alkoxy of 1-6C, CN, NO., Or NR.Ra; R. - R_, which may be the same or different, each represents alkyl of 1-6C (optionally substituted with one or more halogens), alkyl of 1-6C -S (0) -, -C0_H (or alkyl esters) 1-6C thereof or 1-6C alkyl amides thereof), halogen, 1-6C alkoxy, CN, N0_, NR_, Rg or H (with the proviso that they are not all hydrogen simultaneously. , alkyl of 1-6C, -CO pH (or esters of alkyl of 1-6C or alkyl amides of 1-6C thereof), -CN, alkyl of 1-6C optionally substituted by -CO g H (or esters of alkylation of 1-SC thereof, or alkyl amides of 1-6C thereof), alkoxy of 1-6C or -CN, R7 and Rg, which may be the same or different and each represents H, alkyl of 1 -6C, 1-6C-alkylcarbonyl, 1-6C-alkoxycarbonyl, arylsulfonyl, heteroarylsulphonic, heterocyclosulfonyl, arylcarbonyl, betaterocarbonyl, bisterocyclocarbonyl, or alkylsulfonyl 1-6C, or R 7, Rg and nitroge not to which they join, they form a 5- or 6-membered heterocyclic ring (such as morpholine or piperidipa); and n represents 0-2; and the pharmaceutically acceptable salts thereof. Preferred compounds of the invention include those in which they exist independently or in any combination: Q is aryl or heteroaryl (whether it may be optionally substituted with halogen, 1-6C alkyl, CF_, NR-, Rg, alkyl of 1-6C-S (0) n-, alkoxy of 1-6C, -C0-H (or alkyl esters of 1-6C thereof or alkyl amides of 1-6C thereof)); Rj-R5 which can be the same or different, independently are CF3, alkyl of 1-6C, alkyl of 1-6C-S (0) p -CO, H (or alkyl esters of 1-6C thereof or alkyl amides of 1-6C thereof), halogen, alkoxy of 1-6C, N0 ?, NR7 Ra ° H (with the proviso that R - R? 51 are not all H simultaneously); R is H; fí? and Rg, which may be the same or different, are H, alkyl of 1-6C, alkoxycarbonyl dß 1-6C, alkylsulfonyl dß 1-6C or alkyicarboni of 1-6C; or R? , Rg and the nitrogen to which they are attached form a 5 or 6 membered heterocyclic ring such as morpholine or piperdine); and n is 0, 1 or 2. Suitable pharmaceutically acceptable salts are the pharmaceutically acceptable base salts and the pharmaceutically acceptable acid addition salts. Some of the compounds of the formula (i) which contain up acid group form basic salts. Suitable pharmaceutically acceptable basic salts include the metal salts, such as the alkali metal salts, for example the sodium salts, or the organic amine salts, such as those provided with ethylenediamine. Some of the compounds of the formula (i) which contain an amino group form the acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate , benzoate, ascorbate, methane sulfate, alFa-cßtoglutarata, alFa-glyferoeroFosFato and glucose-1-FosFato. The pharmaceutically acceptable salts of the compounds of the Formula (i) are prepared using conventional procedures. It will be known to those skilled in the art that the xanthines of Formula (i) may exist in more than one tautomeric Form. This invention comprises all tautomeric forms. It will be appreciated that the compounds according to the invention may contain one or more asymmetrically substituted carbons and / or sulfur atoms. The presence of one or more of these asymmetric centers in a compound of the formula (i) can give more stereoisomers, and in each case the invention will be understood to comprise all of these stereoisomers, including the enantiomers, and the diastereoisomers and mixtures that include the racemic mixtures thereof. When used herein the term "alkyl", whether used alone or when used as part of another group, includes straight-chain or branched-chain alkyl groups containing up to 6 atoms. The cycloalkyl includes a non-aromatic or multicyclic cyclic ring system of about 3 to about 10 carbon atoms. The alkoxy denotes a group of -O-alkyl in which the alkyl group is as previously described. The alkyl amide comprises both monoalkyl and dialkyl amides, in which the alkyl groups (previously defined) can be the same or different. Alkylcarbonyl means a group of CO-alkyl in which the alkyl group is as previously described. Aryl indicates a multicyclic carbocyclic monocyclic radical containing about 6 to 10 carbon atoms. Hßteroarila means an aromatic manocyclic or a multicyclic hydrocarbon ring system of about 5 to about 10 members, in which one or more of the atoms in the ring system is a carbon-differing element, selected from nitrogen, oxygen or sulfur . Heterocyclic means a saturated or partially saturated or saturated multicyclic hydrocarbon ring system of about 5 to about 10 members, in which one or more of the atoms in the ring system is a non-carbon element, selected from nitrogen, oxygen or sulfur. The arylcarbonyl means up to -CO-aryl group. Heteroarylcarbopyl means up to -CO-hetersar i lo group. Heterocyclocarboni means a group -CO-heteracyclo The arylsulfanyl means a group of aryl-SOj-. Heteroarylsulfani means up to a heteroaryl group i 1-S02 -. The heterocyclasulfani means a heterocyclic group-S0_- The alkylsulfonyl means an alkyl-SOg- group. Halogen means fluorine, chlorine, joke or iodine. "Disease or disease states regulated by TNF" means any and all disease states in which TNF has a role, either through the production of TNF by itself or by ßl TNF originating another cytakine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for example, is a major component, and whose production or action is exacerbated or secreted in response to TNF, so it is considered a disease state regulated by TNF. Like TNF-Beta (also known as lymphotoxin) that has a close structural homology with TNF-alpha (Also known as cacectin), and because each induces similar biological responses and binds to the same receptor cells, both TNF- alpha and TNF-beta are inhibited by the compounds of the present invention and are therefore collectively referred to herein as "TNF" without being otherwise specified. This invention relates to a method for regulating or inhibiting the enzymatic activity or the catalytic activity of PDE IV in a mammal in need thereof, and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to the mammal an effective amount of the compound of the formula (i) a of a pharmaceutically acceptable salt thereof. POE IV inhibitors are useful in the treatment of a variety of inflammatory and allergic diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eye inflammation, allergic responses in the eye, eosinophilic granuloma, psoriasis, Baqußt's disease, eri temßtosis, anaphylactoid purple nephritis, joint inflammation, arthritis, rheumatoid arthritis, and other arthritic diseases, such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion damage, chronic glomerulonephritis, endotoxic attack and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and diseases associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with the disease. Parkinson's disease, depression and dementia of myelin. PDE IV inhibitors are also useful under conditions of improvement by neuroprotective activity, such as cardiac arrest, fulminating attack and intermittent claudication. Additionally, POE IV inhibitors may have utility as gastroprotectors. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma. Viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those that are sensitive to inhibition, such as decrease or replication, directly or indirectly by the TNF inhibitors dβ the formula ( i). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomega-lovirus (CMV), influenza, adenovirus, and the group of Herpes viruses, such as, but not limited to. Herpes zoster and Herpes simplex. This invention more specifically relates to a method of treating upstream mammal, patient with the human immunodeficiency virus (HIV), which comprises administering to said mammal an effective amount of inhibition of TNF of a compound of the formula (i) or a pharmaceutically acceptable salt thereof. The compounds of this invention can also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production. Regulated TNF diseases for treatment, therapeutically or prophylactically, in animals even in disease states such as those not listed above, but in particular viral infections. Examples of such viruses include, but are not limited to, feline immunodeficiency virus (HIV) c from another retroviral infection, such as equine infectious virus, caprine arthritis virus, visna virus, maedi virus and other leptiviruses. The compounds of the invention are also useful in the treatment of infections by parasites, yeasts and fungi, wherein such yeasts and fungi are sensitive to over regulation by TNF or have the production of TNF in vivo.

A preferred disease state for treatment is fungal meningitis. The compounds of the formula (i) are preferably in the pharmaceutically acceptable form. By pharmaceutically acceptable form it will be understood inter alia, of a pharmaceutically acceptable purity level excluding normal pharmaceutical additives, such as diluents and carriers, and not including material considered toxic at normal dosage levels. A pharmaceutically acceptable level of purity will be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90%, and even more preferably 95%. The invention further provides a process for the preparation of a compound of the formula ( i) in which R - R are as defined. It will be appreciated that the functional groups such as the amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such examples, the removal of the protection group may be the final step in a particular reaction. Suitable protection groups for such fupcionability will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Iterscience, TW Greene. Therefore, the process required for the preparation of the compounds of the formula (i) in which Rg is -CO "comprises the deprotection (for example by hydrolysis) of a compound of the formula (i) in which Rg is -COpR wherein R represents a suitable protection group (eg, methyl) It will be appreciated that where a particular stereoisomer of the formula (i) is required, it can be obtained by conventional resolution techniques such as chromatography of high-resolution liquids, or the synthetic methods described herein can be performed using the appropriate homochiral starting material.Approach for the preparation of a compound of the formula (i) comprises a cyclization dehydration of up to the compound of the formula ( ii): - where R.a represents R, as defined in relation to formula (i) or a group that can be converted to R. and R_-R_ to ca or similarly represent R_-R_ or groups that can be converted to R-, H-respectively; A. represents -NC or -NHCHO and A_ represents -NHCH 3 or -NH_, providing that when A. is -NO then A - is NHCH-, and when A, is NHCHO then A- is NH p; and then, if required, convert any group from R ^ / or R ^ to R., and / or R3ga R3 and / or R4aa R ^ and / or R5ga R5 and / or R6aa R6 'The dehydration cyclization of a compound of the formula (ii) can be carried out under any of the suitable conditions known to those skilled in the art. Favorably the selected conditions are those in which the water formed is removed from the reaction mixture, thus the reaction is generally carried out at an elevated temperature in the range of 100 ° C., To 200 ° C, such as in the range of 180 ° C. at 190 ° C. In one aspect of the process, especially when A, is - NO and A_ is -NHCH_, the reaction is carried out in a solvent immiscible with water, such as toluene, at the reflux temperature of the solvent, the water being removed using a water separator. A compound of the formula (ii) wherein A. represents -NHCHO and A _ represents -NH_, can be prepared from dβ. a 6-amipouration of the formula (iii) according to the following reaction scheme Civ) 3a NO to plo (ü) Cv) ßn where R, - R_ are as defined in relation to the formula 6a (ii). Suitably, the reaction conditions used in the above reaction scheme are appropriate conventional conditions known to those skilled in the art. In up preferred aspect of the procedure, the conversion of the 6-amipaurate (iii) via (iv) and (v) to the corresponding compound of the formula (ii) and the cyclization of the compound of the formula (ii) to the compound of the formula (i) are brought to in situ, suitably by the use of a procedure analogous to that of H. Bredereck and A. Edenhofer, Chem. Bericht? 88 1306-1312 (1955). The 6-amiparides of formula (iii) can be prepared by the method of V.Papesch and E .F. Schroder, J. Org. Chem. 16 1879-90 (1951), or Yozo Ohtsuka, Bull. Chem. Soc.

Jap. 46 (3) 506-9 (1973) or the modifications of these methods. A compound of the formula (ii) in which A "represents -NO and A2 represents -NHCH3 can conveniently be prepared from the 6-chlorouracy or the formula (vi) according to the following reaction scheme: where R. - R_ are as defined in relation to the formula 6a (ii). Suitably, the reaction conditions used ßp the above scheme are the appropriate conventional conditions, for example those used in the method of H. Goldner, G. Oietz and E. Carsteps, Liebigs Annalen der Chemie 691 142-158 (1965). The 6-chlorosuration of formula (vi) can also be prepared according to the procedure of Dietz et al. Alternatively, the compounds of the formula (i) can be prepared according to the following reaction scheme: ep where Rja-Rga are as defined sß pa in relation to formula (ii) and X is an appropriate displaceable group such as bromine. Suitably the reaction conditions used in the above reaction scheme are normal conditions known to those skilled in the art. Another method for the preparation of some compounds of the formula (i) ("married on a method described by CEMuller, D. Shi, M. Manning and JW Daly in J. Md.Che 36 3341 (1993)) is shown in the following scheme wherein R 1, a-RC ° aa are comma defined in relation to formula (ii) and W represents up removable group such as bromine. It will be appreciated by those skilled in the art that this method will not be applicable if any of R. FL represents fluorine. The compounds of the formula (i) can also be prepared by the interconversion of other compounds of the formula (i). Thus, for example, up compueeta of the formula (i) in which R, ea NH _ can be prepared by reducing a compound of the formula (i) in which R is -NO 1 2 A compound of the formula (i) or wherein a suitable pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable salvatore thereof, can be administered per se, preferably as a Pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the formula (i) or wherein the pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier. The active compound can be formulated by administration by any suitable route, the preferred route depends on the disease for which the treatment is required, and is preferably in the unit dosage form or in the form that can be administered to the patient. up human patient in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral or through the respiratory tract administration. The preparations can be formulated to provide slow release of the active ingredient. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-external or infusion techniques. In addition to the treatments in warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans. The compositions of the invention may be in the form of tablets, capsules, creams, vials, powders, granules, tablets, suppositories, reconstituiblße powders, or liquid preparations such as sterile oral or parenteral solutions, or suspensions. Topical formulations are also understood when appropriate. In order to obtain the consistency of administration it is preferred that a composition of the invention be in the form of a unit dose. The unit dosage forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents for example syrup., acacia, gelatin, sorbitol, tragacanth, or pi 1 i vinylpyrrole idopa, fillers for example microcrystalline cellulose, lactose, sugar, corn starch, calcium phosphate, sorbitol and glycine, lubricants for the rattle, for example magnesium stearate, disintegrants , for example starch, pol ivipi lpirrol idona, sodium starch glycollate or inacrochietal cellulose ina; or pharmaceutically acceptable wetting agents such as lauryl sodium sulfate. The solid oral compositions can be prepared by conventional methods of mixing, filling, tapping or the like. The repeated mixing operation ee can be used to distribute the active agent through the compositions used in large quantities of replenishers. Such operations are of the conventional order in the art. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be present as a dry product for re-addition with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sarbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum gel stearate, hydrogenated edible fats, emulsification agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oil esters, such as esters of glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if conventional coloring or flavoring agents are desired. The compositions may also suitably be present for administration to the respiratory tract as a product for aspiration or an aerosol, or solution for a nebulizer, or as a microfine powder for aspiration, alone or in combination with an inert carrier such as lactose.

In such a case, the particles of the active compound suitably have diameters of less than 50 microns, such as 0.1 to 50 microns, preferably less than 10 microns, for example 1 to 10 microns, 1 to 5 microns or 2 microns 5 microns. When appropriate, small amounts of other anti-asthmatics and brancodi-latars are for example sympatamimetic amines such as isoprenal ina, isaetarin, salbutamal, fßpilefripa, and ephedrine; Caerticosteroids, such as Prednisolsna and adrenal stimulants such as ACTH can be included.

For parenteral ad instration, fluid unit dosage forms are prepared using the compound and up sterile vehicle and depending on the concentration used, they may be either suspended or dissolved in the vehicle. In the preparation of the solutions the compound can be dissolved in water for injection and sterilized and filtered before filling in a suitable vial or ampoule and sealed. Advantageously, adjuvants such as local anesthetics, a preservative or regulating agents can be dissolved in the vehicle. To increase stability, the composition can be frozen after filling in the vial and removing the water under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and the esterization can not be performed by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% to 99% by weight, preferably 10-60% by weight of the active material depending on the method of administration. The compounds of the formula (I) or if the pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, can also be administered as a topical formulation in combination with the conventional topical excipients. Topical formulations can be present as, for example, upguentoe, cremae or locianee, impregnated toilet product, gels, gel sticks, sprays and aerosols, and can contain conventional additives, talee as preservatives, solvents, to help the penetration of the drug and emollients in the unguentoe and creams. The formulations may contain conventional carriers compatible, such as creams or ointment bases, and ethanol or oleyl alcohol for lotions. Suitable creams, lotion, gel, stick, ointment, spray or aerosol formulations that can be used for the compounds of the formula (i) or if the pharmaceutically acceptable salt thereof, are conventional formulations well known in the art, for example as described in normal textbooks such as Harry's Cosmetalogy published by Leopard Hill Books, Remipton's Pharmaceutical Sciences, and British and US Pharmacopoeias Suitably, the compound of the formula (i) or if the pharmaceutically acceptable salt thereof, which will comprise from about 0.5 to 20% by weight of the formulation, from about 1 to 10%, for example from 2 to 5%. The dose of the compound used in the treatment of the invention will vary in the usual manner with the seriousness of the disorders, the weight of the patient, and the relative efficacy of the compound. However, as a general guide of the appropriate unit dosages can be from 0.1 to 1000mg, such as from 0.5 to 200, 0.5 to 100, 0.5 to 10mg, for example 0.5, 1, 2, 3.4, or 5 m. , and such unit doses can be administered more than once a day, for example 2, 3, 4, 5, or 6 times a day, although preferably 1 or 2 times per day, so that the total daily dose for a adult 70K. , is in the range of approximately 0.1 to 1000 mg. , this is on the scale of approximately 0.001 to 20 mg / kg / day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg / kg / day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1, 0.2 mg / kg / day and such therapy ee It can extend for a certain number of weeks or months. When used in the preamble, the term "pharmaceutically acceptable" includes materials suitable for both human and veterinary use. The following illustrates the invention. Intermediate Compound 1 2- (METHYLTHO) PHENYLISOCYANATE The 2-methylmercaptoani 1 ina (69.5g) is dissolved in ethanol and treated at 0 ° C, in portions with concentrated hydrochloric acid (75 ml). The resulting solid is obtained by filtration, washed with isopropanol and dried in vacuo. This solid is finely ground, suspended in dry dioxane (500 ml.) And treated with trichloromethylchloroformate (27 ml.) And the mixture is refluxed for 18 hours under nitrogen. The solvent is carefully removed under vacuum and the product is obtained by distillation. Yield = 24.14 g. p. of e. 116-118 ° C. (15 mm Hg) Intermediate 2 2- (METHYLTHO) BENZYLAMINE A solution of 2- (meth i It) benzonitrile (29.8 g) in dry ether (150 ml) is added in portions to a stirred hydrolysis solution. of aluminum and lithium (11.6g.) in ether aeco (360ml.) under nitrogen. A thick gum that forms is dissolved by the addition of dry THF (100 ml.). The mixture is stirred at room temperature for 2 hours. Then carefully add water (12ml.) Followed by a 15% aqueous solution of sodium hydroxide (36 ml.), And more water (12ml.) The mixture is filtered, the filtrate is washed with water, dried and evaporated in vacuo, the residue is dissolved in vacuo to obtain a colorless oil, yield = 20.9 g from e, 139-141 ° C. (15 mm Hg), intermediate compound 3, 1-BENCIL 3-Í 3- (ETHYLTHY) PHENYL) UREA Method A Dissolve the 3- (meth i t) ani 1 ina (22.24 g) in dry toluene (300 ml) and add benzyl isocyanate (19.95 g) to this. .) with agitation. Very soon a thick deposit is formed and stirred as much as possible. The resulting mixture is allowed to stand overnight at room temperature and then hexapo (250ml *) is added. The product is filtered and washed with toluene-hexane 1: 1. Performance = 38.89g. F. 127-129 ° C. Intermediate 4 l-BENCIL-3- (3-CL0R0FENI) UREA Method B Dissolve 3-chloro-phenyl-1-isocyanate (30.7g ») in dry toluene (400ml) and add benzylamine (23.54g) in a single portion with agitation. The mixture is stirred for 30 minutes at room temperature and the product is filtered and washed with toluene and then with hexane. Performance = 47.53g. F. 172-174 ° C. Intermediate 5 l-BENCIL-3- (4-CL0R0FENIL) UREA Method C Dissolve the benzylamine (26.75 g) in dry toluene (800 ml.) And to this is added 4-chloro-phenyl isocyanate (38.38 g) with agitation. After the exotherm has been precipitated, the mixture is heated to boiling and then left overnight at room temperature. The product is filtered and washed with toluene. Performance = 64g. p. of F. 202-204 ° C.

Intermediate 6-BENClL-3- (3- (METOXYCARBONYL) PHENYL) UREA Method A, page F. 148-151 ° C. Intermediate compound 7 1 -BENCIL-3- (-METDXIFENIL) UREA Method B, p. F. 164-167 ° C. Intermediate Compound 8 l-BENCIL-3- (4-FLU0R0FENIL) UREA Method B, page F. 181-183 ° C. Intermediate Compound 9 l-BENCIL-3- (3-FLU0R0FENIL) UREA Method B, page F. 158-160 ° C. Intermediate Compound 10 1-BENCIL-3-C ((METHYLTH) FENI) UREA Method A, p. of F.173-176 ° C. Intermediate 11 l-BENCIL-3- (-MET0XIFENI) UREA Method A, p. of F.159-161aC. Intermediate compound 12 l-BENCIL-3- (3-BR0M0FENIL) UREA Method A, page F. 173-175 ° C. Intermediate 13 l-BENCIL-3- (3-NITR0FENI) UREA Method A, p. of F. 193-195 ° C. Intermediate compound 14 1- (THEN-2-IL) -3- (2-METHYLPHENI) UREA Method B, p F. 188-190 ° C. Intermediate 15 1 -FURRURIL-3- (2-METHYLPHENYL) UREA Method B, p. of F. 117-119 ° C. Intermediate compound 16 1- (2-FLU0R0BENCIL) -3- (-CL0R0-PHENYL) UREA Method B, p. of F. 195-198 ° C. Intermediate 17 1- (2-TRIFLUOROMETHYL) BENCI) -3- (2-METHYL-PHENYL) UREA Method A, page F. 190-192 ° C. Intermediate 16 1-BENCIL-3- (2-methylphenyl) UREA Method A, page F. 189-190 ° C. Intermediate compound 18 1- (2-FLU0R0BENCIL) -3- (2-FLU0R0-PHENYL) UREA Method B, page F. 160-163 ° C. Intermediate 19 l- (2-FLU0R0BENCIL) -3- (2- (METHYLTH) - PHENYL) REA Method B, page F. 135-137 ° C. Intermediate compound 50 1- (2-FLU0R0BENCIL) -3- (2-TRI-FLUOROMETI) -FENIL) UREA Method A, p. of f. 178-181 ° C. Intermediate Compound 21 1 - (2-FLU0R0BENCIL) -3- (2-NITRO-PHENYL) UREA Method A, p. of f. 169-172 ° C. Intermediate 22- (2-METHYLPHENYL) -3- (2-METHYL-TIO) -BENCIL) UREA Method A, p. of f. 214-216 ° C Intermediate compound 23 l-BENCIL-3- (3-CL0R0FENIL) -1- (CYANOACETIL) UREA A mixture of 1-benzyl 1-3- (3-chloro eni 1) urea (44.78g) and acid The cyanoacetic acid (16.11 g) is ground together and then acetic anhydride (48 ml.) is added.The resulting mixture is heated and stirred at 75-80 ° C, for 16 hours. It is then allowed to cool, is diluted with ether and the filtrate is washed cop ether. This is then recrystallized with toluene, with a hot filtration. Performance = 20.15g. p. of f. 122-123 ° C. The intermediate compounds are prepared using the above procedure. Intermediate Compound 24 1 -BENCIL-1 - (CYANO-OZETHYL) -3- (3- (METOXYCARBONYL) PHENYL) UREA The crude material is dissolved in hot toluene and treated with activated charcoal. The carbon is removed by filtration and the product recrystallized with toluene. p. of f. 134-137 ° C. Intermediate compound 25 l-BENCIL-3- (4-CL0R0FENIL) -1- (CYANOACETIL) UREA p. of f. 100-104 ° C. Intermediate Compound 26 1-BENCIL-l- (CYANO-OZYLTHYL) -3- (3- (METHYLTHO) FENIU] UREA P. of 113-116 ° C. Intermediate 27 1 -BENCIL-1- (CIANOACETI) -3- (- METOXYPENYL) UREA The raw material is dissolved in hot toluene and treated with activated charcoal.The activated carbon is removed by filtration and the product is recrystallized with toluene / hexapa, pp. 114-117aC. 1-BENZYL- 1- (cyanoacetyl) -3- (3- FLUOROPHENYL) UREA p.f of 97-99 ° C. Intermediate Compound 29 1-BENCIL-1-CYANOACETIL) -3- (4- (METHYLTH) PHENYL ) UREA p. of f. 128-130 ° C. Intermediate 30 1 -BENCIL- 1- (CYANO-OZETHYL) -3- (3-METOXYPENYL) UREA The crude material is dissolved in hot toluene and treated with activated charcoal. The activated carbon is removed by filtration and the product recrystallized with toluene, e.g. of f. 127-130 ° C. Intermediate 31 l-BENCIL-3- (3-BR0M0FENI) -1- (cyanoacetyl) UREA The crude material is dissolved in hot toluene and treated with activated charcoal. The activated carbon is removed by filtration and the product recrystallized with toluene / hexane. p. of f. 108-121 ° C. Intermediate compound 32 L- (THEN-2-IL) -3- (2-METHYLPHEN) - 1 - (CYANO-ACETYL) UREA p. of f. 127-130 ° C. Intermediate 33 1 -FURRURIL-3- (2-METHYLPHENYL) -1 - (ClANAN-ACETYL) UREA p. of f. 117-119 ° C. Intermediate compound 34 1 - (2-FLU0R0BENCIL) -3- (4-CL0R0-PHENYL) -1- (CYAN0ACETIL) UREA The product is washed with ethanol. p. of F. 125-134 ° C. Intermediate 35 6-AMIN0-3-BENCIL-I- (3- (METHYLTHY) - PHENYL) URACIL L-benzyl-1- (cyanoacetyl) -3- (3-methylthia) phenyl) urea (14.9g *) is suspended in ethanol (150 ml), and to this is added a solution of sodium hydroxide (2.34g »), in water (30ml *). This is stirred for 1 hour and then allowed to stand overnight at room temperature. The mixture is filtered to remove dark impurities and the filtrate is treated with charcoal. The solution is then evaporated to remove the ethanol, then diluted with water. This is extracted with ethyl acetate (150 ml.) And the extract is washed with water (2 x 75 ml.) Then dried and evaporated with which it gives a foam. Eata ee is empty in a 1: 1 mixture of ethyl acetate and toluene (100 ml.). Then the product that has precipitated is allowed to stand for 1 hour. It is filtered and washed with toluene / hexane 1: 1 (50 ml) then dried to have a constant weight. Performance = 9.06g. p. DEF.168-170 ° C. Intermediate 36 6-AMIN0-3-BENCIL- 1- (3- (METOX I-CARBONYL) -FENIL) RACILO. The 1-benzyl 1-1 - (cyanaacetyl) -3- (3- (methocarbaryl) phenyljurea (3.51 g) is dissolved in dichloromethane (50 ml.), And triethylamine (1.52 g.) Is added thereto. The mixture is stirred for 1 hour at room temperature and the product is filtered and washed with dichloromethane, Yield = 3.16 g of F. 208-210 C. The following intermediate compounds are prepared using the above procedure. -AMIN0-3-BENCIL-1 - (-METOXIFENI) URACILO, P. of F. 219-221 ° C. Intermediate compound 38 6-AMIN0-3-BENCIL-1- (4-CL0R0FENIL) URACIL P. of f. 246-248 ° C. Intermediate compound 39 6-AMIN0-3- (TEN-2-I) -1- (2- METHYLPHENYL) URACIL P. of F. 253-256 ° C. Intermediate 40-AMIN0-3 -FURFURIL-l- (2-METHYL-PHENYL) URICHL P. pp.241-244 ° C. Intermediate compound 41 6-AMIN0-3- (2-FLU0R0BENCIL) - 1- (4- CHLOROPHENYL) URACIL The raw material It is dissolved in hot etapol and treated with activated charcoal.The activated charcoal is removed by filtration and the product rec crystallizes with ethanal. p. of F. 192-212 ° C. Intermediate compound 42 6-AMIN0-3-BENCIL- 1 - (3-FLU0R0- -36- FENIL) URACIL. p. of F. 22ß-230 ° C. Intermediate compound 43 6-AMIN0-3-BENCIL-1- (4-METHODIUM) FENIL) URACIL. p. of F. 132-133 ° C. Intermediate compound 44 6-AMIN0-3-BENCIL-1- (3-METOXIFE-NIL) URACIL. The product is recrystallized with ethanol. p. of F. 211-214 ° C. Intermediate compound 45 6-AMIN0-3-BENCIL-1- (4-FLU0R0-PHENYL) URACIL. L-benzyl-l- (cyanoacetyl) -3- (4-Fluoro-Efei-1-urea) is prepared from the appropriate benzylurea using the procedure described in the preparation of intermediate 22. The product in the form of oil obtained is used in the above procedure (intermediate 36) whereby the title compound is obtained is recrystallized with ethyl acetate, The following starting compounds are prepared using the above procedure: intermediate compound 46 6-AMIN0-1 - (2-methylphenyl) -3- (2- (TRIFLURO-METHYL) BENCIL URACILO.

The resulting residue is subjected to a column of cracking on silica eluting with ethyl acetate to obtain the title compound, Intermediate 47 6-AMIN0-3-BENCIL-1- (2-METHYLPHENYL) URACIL. The raw material is dissolved in hot ethanol and treated with activated charcoal. The activated carbon is removed by filtration and the product is recrystallized with ethanol. p. of f. 194-197 ° C. Intermediate Compound 48 6-AMIN0-3-C2-FLU0R0BENCIL) -1- (2- FLUOROFENYL) URACIL. p. of f. 207-208 ° C. Intermediate Compound 49 6-AMIN0-3- (2-FLU0R0BENCIL) -l- (2- (METHYLTHY) -FENIL) URACIL. p. of f. 214-216 ° C. Intermediate Compound 50 6-AMIN0-3- (2-FLU0R0BENCIL) -1- (2- (TRIFLUORO-METHYLPHENYL) URECILO, pp. 259-263 ° C. Intermediate 51 51-AMIN0-3- (2- (FLU0R0BENCIL) -l- (2- NITROFENIL) URECILL Intermediate Compound 52 6-AMIN0-3-BENCIL-1- (3-NITROPHENYL) URACIL L-bßncyl-3- (3-nitrophenyl) urea (32.53g. ) and the cysapaacetic acid (11.24g) are ground together and acetic anhydride (34ml) is added.The mixture is stirred and heated at 78-80 ° C for 30 hours. Boiling toluene is treated with activated charcoal.The activated charcoal is removed by filtration.The resulting solution is allowed to cool and left overnight at room temperature.The resulting solid is filtered and washed with ether.This solid is dissolved in dichloromethane (100 ml.) and triethylamine (3.57 g.) is added. The filtrate is also treated with triethylamine (8.55 g.) These two solutions are allowed to stand overnight and the precipitated solids they are filtered, washed with dichloromethane and combined with which the title compound (11.32 g) is obtained. p. of f. 256-260 ° C. Intermediate Compound 53 6-AMIN0-1- (2-METHYLPHENYL) -3- (2- (METHYLTHY) -BENCIL) URACIL0. The l- (2-me ilphenyl) -3- (2- (me thio) benzyl) urea (23.47g.) And ßl cyanoacetic acid (7.66g) are ground together and acetic anhydride (23ml.) Is added. The mixture is stirred and heated at 75-80 aC for 30 hours. Then, toluene (20 ml.) Is added and the heating is continued for an additional 16 hours. The reaction is cooled and filtered. The filtrate is heated to boiling and treated with activated charcoal. The solid is removed by filtration and the filtrate is evaporated in vacuo. The product in the form of oil is dissolved in dichloromethane (300 ml.) And triethylamine (8.15%) is added. The mixture is stirred for 5 hours at room temperature and the solvent is removed in vacuo. The residue is purified by column chromatography on silica gel eluting with ethyl acetate and the product is recrystallized from ethyl acetate. Performance = 2.60g. p. of f. 21ß-221 ° C. EXAMPLE 1 l-BENCIL-3- (3-METXYXIFENYL) XANTIN A mixture of 6-amino-3-benzyl-l- (3-methoxypheni-1) uracil (5.52 g), formic acid (3.2 ml.) And Sodium nitrite (1.45g.) in formamide (130ml.), gradually warm to 100 ° C, with stirring, then add dithioxide of aodium (4.83g.) in portions in a period of 10 min. temperature is maintained at 100 ° C. The temperature then rises to 190 ° C, and the mixture is stirred at this temperature for 30 minutes. Allow to cool and then extract chloroform. The chloroform solution is extracted with a 2M sodium hydroxide solution and this is washed with ether. The aqueous layer is acidified with concentrated hydrochloric acid, whereby a solid is obtained which is filtered and washed with water. The rcrcr istalization with ethanol gives us the title compound. (1.55g.) TLC R_ 0.33 (5% methanol / dichloromethane) This general procedure is used for all the following xantheas Example 2 1 -BENCIL-3- (3-CL0R0FENIL) XANTHIN 6-amino-3-l - (3-chlorophenyl) uraci is prepared using the procedure described for intermediate 36. The foam produced is used in the procedure of example 1 whereby the title compound is obtained TLC Rf 0.33 (5% methanal / dichloromethane) mp 245-248 ° C. Example 3 1 -BENCIL-3- (FLUOROPHENYL) XANTIN, recrystallized from ethanol, TLC R f 0.51 (5% methanol / dichloromethane) mp 203- 204 ° C Example 1 -BENCIL-3- (3-METHYLTH) PHENYL) XANTIN. It is recrystallized with ethanol. TLC Rp 0.44 (5% methanol / dichlorometapa) p. of f. 191-193 ° C. EXAMPLE 5 1-BENZYL-3- (4-METXYXYPENYL) XANTIN, Recrystallized with TLC ethanol Rp 0.30 (5% methanol / dichloromethane) p. of F. 242-244 ° C. Example 6 l-BENCIL-3- (4-FLU0R0FENIL) XANTIN. It is recrystallized with etapol. TLC Rjr 0.30 (5% methanal / dichloromethane) p. of F. 252-255 ° C. EXAMPLE 7 l-BENCIL-3- (4-METHTHYL) PHENYL) XANTIN It is recrystallized with ethanol / DMF TLC R 0.44 (5% methanol / diclsromtan) p. of F. 260-264 ° C. Example 8 1 -BENCIL-3- (3-BR0M0FENIL) XANTIN. The 6-amino-l- (3-bromoFeni 1) -3-bep-luraci is prepared using the procedure described in the preparation of intermediate 36. The foam produced is used in the procedure of Example 1, whereby the title compound is obtained. It is recrystallized with ethanol. TLC Rp 0.49 (5% methanol / dichloromethane) p. of F. 253 - 256 ° C. EXAMPLE 9 l-BENCIL-3- (3-NITROPHENYL) XANTIN. It is recrystallized with acetanitrile. TLC R 0.42 (5% methanol / diclaramine) Example 10 1-TEN-2-IL) -3- (2-METHYLPHENJL) XANTIN It is recrystallized from ethanol. TLC R_ 0.35 (ethyl acetate) p. of F. 258-262 ° C. Example 11 1 - (2-FLUROBENCIL) -3- (4-CL0R0FENIL) - XANTIN. It is recrystallized with acetoni tr i lo / DMF. TLC Rp 0.41 (ethyl acetate) p. of F. 329-331 ° C.

E. Example 12 l-BENCIL-3- (2-METHYLPHENYL) XANTHIN. Recrystallize with Ethanal TLC Rf 0.33 (ethyl acetate) p. of F. 266-269 ° C. Example 13 1- (2-FLUR0BENCIL) -3- (2-FLU0R0FENIL) - XANTIN.

It is recrystallized with ethanol. TLC Rf 0.35 (ethyl acetate) p. of F. 253-256 ° C. Example 14 l-BENCIL-3- (4-CL0R0FENIL) XANTIN. Recrystallize with acentnitride / OMF TLC Rf 0.41 (ethyl acetate) p. of F. 310-313 ° C. Example 15 1- (2-TRIFLUR0METIL) BENCIL) -3- (2-METHYL-PHENYL) XANTIN. It is recrystalized with ethanal. TLC Rf 0.36 (ethyl acetate). p. of F. 282-285 ° C. Example 16 1- (2-FLU0R0BENCIL) -3- (2-METHTHYL) PHENYL) XANTIN. It is recriatalized with acetonitrile. TLC Rp 0.31 (ethyl acetate). p. of F. 274-279 ° C. Example 17 1- (2-FLU0R0BENCIL) -3- (2- (TRIFLU0R0METIL) - PHENYL) XANTIN. It is recriatalized with ethanol.

TLC RF 0.31 (ethyl acetate) p. of F. 273-277 ° C. Example 18 1- (2-FLU0R0BENCIL) -3- (2-NITROFENIL) XANTIN. TLC Rf 0.31 (ethyl acetate) p. of F. 210-255 ° C. Example 19 1 - (2-FLU0R0BENCIL) -3- (2- (TRIFLUOROMETHYL) PHENYL) XANTIN. It is recrystallized with ethanol. TLC Rp 0.34 (ethyl acetate) p. of F. 220-233 ° C. The following two compounds are prepared using the general procedure with a modified work as follows: Example 20 1 -BENCIL-3- (3- (MET0XICARB0NIL) PHENYL) XANTIN. With cooling, the reaction mixture is extracted with chloroform. The extracts are washed with water, aeecan and evaporate. The resulting residue is subjected to a chromatography column over silica eluting with ethyl acetate with which the title compound is obtained. TLC Rp 0.33 (5% methanol / dichloromethapa). p. of f. 230-232 ° C. Example 21 1 -FURFURIL-3- (2-METHYLPHENYL) XANTIN. It is recrystallized with ethanol. TLC Rp 0.35 (ethyl acetate) p. of f. 257-260aC. Example 22 3- (3-AMINOFENIL) -1-BENCIL XANTIN. L-benzyl-3- (3-nitroFepi 1) xanthine (lg.) Is added to a solution of the stannous chloride dihydrate (2.51 g.) In concentrated hydrochloric acid (5 ml.), And the mixture is heated to 60- 70 ° C., With stirring and kept at this temperature for 20 minutes. The reaction mixture is allowed to cool and 40% aodium hydroxide is added (llrr.l.). The mixture is cooled and the solid is filtered and washed with water (10 ml.). It is poured into 2M sodium hydroxide (10 ml.), Treated with activated charcoal, filtered, and the filtrate is acidified with glacial acetic acid. The product is filtered and washed with water. Yield 0.44g. TLC Rp 0.24 (5% methanol / diclaromantana). p. of f. 320-323 ° C. EXAMPLE 23 3- (2-AMINOPHENYL) -1- (2-FLU0R0BENCIL) XANTHINE. The title compound is prepared using the above procedure. It is recrystallized with acetoni r i la. TLC Rf 0.23 (ethyl acetate). p. of f. 316-319 ° C. (d) Example 24 3- (3-ACETAMIDOFENIL) -1-BENCILXANT INA. The 3- (3-aminopheni 1) -l-bepci 1 xanthine (0.68g.) Is suspended in glacial acetic acid (30ml.). To this is added acetic anhydride (0.25 g.), And the mixture is stirred at reflux for 1 hour. Then add water (30ml.), And the product is filtered and then washed with water (30ml.). Performance 0.55g. TLC RF 0.19 (5% methanol / dichloromethane) p. of f. 300 ° C. Example 25 1 - (2-FLU0R0BENCIL) -3- (2-methylsulfonyl) -phenyl) Xantin. A solution of 1- (2-fluorobenz 1) -3- (2- (methyl-1) phenyl) xanthine (2.8 g) in chloroform (600 ml.) And methanol (15 ml.), Are stirred and kept below from 10 aC, during the addition of 3-chloroperbenzoic acid (3.45 y of the 80% material). The mixture is stirred for 4 h at room temperature and then added with 3-chloroperbenzoic acid (0.7 g of the 80% material). The reaction is stirred overnight and then treated with sodium bicarbonate (2.1 g.) In water (100 μl). The mixture is stirred for 1 hour, filtered and the filtrate evaporated in vacuo. The residue is formed in a slurry with water, filtered and the solid washed with water. It is recrystallized with ethanol / DMF. Performance = 1.44g. TLC Rp 0.19 (ethyl acetate). p. of f. 264-270aC. Example 26 1- (2-FLU0R0BENCIL) -3- (2- (METILSULFINIL) - PHENYL) XANTIN.

A solution of 1- (2- luorobenz 1) -3- (2-methyl-1-ic) phenyl) xanthipa (1.15 g), in chloroform (200 ml.) And methanol (5 ml.) Is stirred and maintained at 0 -2 C. during the addition of 3-chloroperbenzoic acid (0.65g of the 80% material). The mixture is stirred for 4 hours at 0 ° C. and then more 3-chloroperbenzoic acid (0.06 g of the 80% material) is added. The reaction mixture is stirred for 1 hour at 0 ° C, and then overnight at room temperature. The mixture is treated with calcium hydroxide (0.3 g). The mixture is stirred for 1 hour, filtered and the filtrate evaporated in vacuo. The residue is poured into dichloromethane, washed with an aqueous solution of sodium bicarbonate and then extracted with a 1M aqueous sodium hydroxide solution (2 × 100 mg). The extracts are diluted with dichloromethane and the aqueous layer is acidified with concentrated hydrochloric acid with which a product is obtained in the form of an oil. The product in the form of oil is extracted with dichloromethane, dried, filtered and the filtrate is evaporated, whereby an aolide is obtained. The solid is triturated with ether and obtained by filtration. Performance = 0.53g. TLC R 0.05 (ethyl acetate). p. def 230-233 ° C. (deecompoeición) Example 27 1- (2-FLU0R0BENCIL) -3- (2-METHYLPHENYL) - XANTIN. The ortho-toluene isocyanate (4.95 ml) is added to a solution of 2-fluorobenzyl (4.56 ml.), In toluene (50 ml.) Under a nitrogen atmosphere at 5 ° C, for rapid production of the formation of a white solid. Heptane is added, the solid is broken and filtered with which it is obtained l- (2- (f lurobenz 1) -3- (2-met i lfepi 1) urea (9.5 g), as a white aolide. Urea (.g.) And cyanoacetic acid (2.9g.) Are ground together and heated in acetic anhydride (15ml.) At 80. After cooling, the reaction mixture at room temperature is added. diethyl ether and washed with water, the separated ether phase is dried over magnesium sulfate, filtered and evaporated in vacuo, whereby a crude solid residue (8.9 g) is obtained. dichloromethane (120 ml.), triethylamine (5.7 ml.) is added, and the mixture is stirred at room temperature for 3 days.Filtration of the precipitate gives the desired uracil as a white solid (2.6 g.) The compound of the The preparation is prepared from this uracil, following the general procedure with a working method, then the reaction mixture is allowed to cool to the ura environment and extracted in dichloromethane. The extraction is carried out with an aqueous sodium bicarbonate solution providing any product. However, the product is precipitated with a dichloromethane solution and collected by filtration, whereby a white solid (273 mg.) P. of f. 276-277 ° C. TLC R 0.11 (50% ethyl acetate in hexane) Test Methods The methods used to confirm the inhibitory activity of phosphideterase IV of the compounds of the formula (i) are normal test procedures as developed Schilling et al. Anal. Biochem 216 154 (1994), Thompson and Strada Adv. Cycl. Nucí Res. 8 119 (1979) and Gristwood and Owen Br. J. Phar acal 87 91P (1986). The compounds of the formula (i) have level inhibitory activity consistent with those which are believed to be useful in the treatment of disease states related to phospholipid IV in these tests.

Claims (2)

1. R E I V I N A C I O N E S 1.- The compounds of the general formula (i) (i) wherein Q represents aryl, heteroaryl, cycloalkyl, or optionally substituted heterocycle with one or more substituents selected from 1-6C alkyl (optionally substituted with one or more halogens), 1-6C-S alkyl ( Q) n where (n is 0, 1 or 2), -CO H (or alkyl esters of 1-6C thereof or alkyl amides of 1-6C thereof), halogen, 1-6C alkoxy, CN , N02 and NF ^ Rg; R, - R5 which are the same or different, each represents alkyl of 1-6C (optionally substituted with one or more halogens), alkyl of 1-6C-S (0) - (wherein n is 0.1, or
2. 2), -CO H (or 1-6C alkyl esters thereof or 1-6C alkylamides thereof), halogen, 1-6C-alkoxy, CN, N0-, NR_R_ or H (with the proviso that R - R not all are H 7 8 H 1 6 simultaneously); R represents H, alkyl of 1-6C, -CO H (or esters of 2-C6 alkyl thereof, or 1-6C alkyl amides thereof], -CN, 1-6C alkyl optionally substituted by -CO H (or C 1-6C alkyl ester thereof, or amides) of alkyl of 1-C thereof), alkoxy of 1-6C or -CN and R7 and Rg which may be the same or different, each represents H, alkyl of 1-6C, alkylcarbonyl of 1-6C, alkoxycarbopi of 1- 6C, arylsulfonyl, heteroaryl sulfonyl, heteroaryl sulfonyl, arylcarbonyl, heteroarylcarbopyl, heterocyclecarbapyl, or alkylsulfonyl of 1-6C, or R, Rg and the nitrogen to which they are attached form a heterocyclic ring of 5 or 6 members (such as morpholine or piperidine); and the pharmaceutically acceptable salts thereof. 2. A compound according to clause 1, wherein R and Rg are independently selected from H, alkyl, alkylcarbonyl, alkoxycarbonyl, arylsulphonyl, arylcarbonyl, and alkylsulfonyl, or NR7Rg is up ring. 3. A compound according to clause 1 or 2, wherein Q is aryl or heteroaryl, whether they are optionally substituted by halogen, alkyl, CFj, NR7 Rg, alkyl-S (Q), alkoxy or COOH (or ethers or amides thereof). 4. A compound according to any of the preceding clauses, wherein R-R are independently selected from CF, alkyl, alkyl-S (O), COOH (or esters or amides thereof), halogen, alkoxy, NO, NR R and H). 2 7 8 5. A compound according to clause 2, wherein Q is phenyl; R-R are independently selected from alkyl S (0), COOH (or esters or amides thereof), halogen, alkoxy, NO, NR R and H: and FL and R are 2 7 8 7 J 8 independently selected from H, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl sulphonic, arylcarbonyl, and alkylsulfopyl. S.- A compound according to any of the preceding clauses wherein R is H. ^ 6 7. A compound according to clause 1, e-electrocytion of l-benzyl-3- (3-methoxyphenyl) xaptine, l-benzyl-3- (3-chlorophenyl) xaptin; l-benzyl-3- (3-fluorophenyl) xanthine, l-benzyl-3- (3-methylthio) phenyl) xanthine, 1-benzyl-3- (4-methoxyphenyl) xanthine, 1-benzyl 1-3- ( 4-fluorofeni l) xaptine, 1-benzl-3- (4- (methylthia) phenyl) xapt ina; l-benzyl-3- (3-brornophenyl) xanthine, l-benzyl-3- (3-nitroflynyl) xaptine and l-benzyl-3- (3- (m -thoxycarbanyl) -phenyl) xanthine. 8. A compueeta according to clause 1, selected from l-benzyl-3- (2-methylphenyl) xaptipa and l- (2-f luorobepci 1) -3- (2-methylphenyl) xaptipa. 9. - A compound according to clause 1, selected from l- (ten-2-yl) 3- (methylphenyl) xanthine, 1- (2-fluorobenzyl) -3- (4-chlorophenyl) xanthine, 1- (2-fluorobenzyl) -3- (2-fluorophenyl) xanthine, l-bepcyl-3- (4-chlorophenyl) xanthine, l- (2- (trifluoromethyl) benzyl) -3- (2-met i lfeni 1) xanthine, l- (2 -fluorobenzyl) -3- (2- (methylthio) phenyl) xanthine, 1- (2-fluorobenzyl) -3- (2- (l-trifluoromethyl) phenyl) xanthine, 1- (2-fluorobenzyl) -3- (2 -nitrophenyl) xanthine, l- (2-fluorobenzyl) -3- (2- (trifluromethyl) pheni 1) xanthine, l-furfuryl-3- (2-methylphenyl) xanthine, 3- (3-aminophenyl) -l-benzylxanthine , 3- (2-aminaphenyl) -l- (2-fluorobenzyl) xaptin, 3- (3-acetamidaphenol) -l-benzylxaptin1- (2-fluorobenzyl) -3- (2- (methylsulfonyl) phenyl] xanthine and l- (2-fluorobenzyl) -3- (2- (methylsulfinyl) fepyl) xanthine 10.- A compound according to any of the above clauses, in the form of an enantiomer or diastereomer, or any mixture of any 11. 11. A pharmaceutical composition containing a compound according to any of clauses 1 to 10, as an active ingredient in combination with suitable excipients. A method for the treatment of a disease state that is regulated by the production of phosphodiesterase IV inhibition, which comprises supplying a patient suffering from the disease with an effective amount of a compound according to any of the clauses 1 to 10. 13. The method according to clause 12, wherein the disease condition is a pathological condition associated with a function of phenaheadcase IV, accumulation of easino-phylum or a function of eosinophil. the c lauule 13, where the pathological disease is selected from asms, chronic bronchitis, atopic dermatitis, urticaria, rhinitis ^ allergic, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic respueetae in the eye, granuloma eosinif 1 ico, psoriasis, rheumatoid arthritis , arthritis of gout, and other arthritic diseases, ulcerative colitis, Crohn's disease, adult reepirate malaise syndrome, diabetes insipidue, keratoeus, atopic dermatitis, atopic eczema, cerebral senility, dementia of mui tiinfartoe, senile dementia, memory damage associated with Parkinson's disease, depression, heart attack, fulminating attack and intermittent claudication. 15. The method according to clause 14, where the pathological disease is asthma. 16. A method for the treatment of a disease state capable of being modulated by the inhibition of TNF, which comprises administering to a patient suffering from the disease an effective amount of a compound according to any of clauses 1 to 10. 17. The method according to clause 16, wherein the condition of the disease is an inflammatory disease or an autoinfect disease. 18. The method according to clause 17, wherein the disease state is selected from joint inflammation, arthritis, rheumatoid arthritis, rheumatoid epondilitis and osteoarthritis, eepsis, septic shock, endotoxic shock, gram-negative sepei a toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, asthma, oozing resorption disease, reperfusion injury, graft rejection reaction, rejection of the allograft, fever and myalgia, HIV, AIDS, ARC, cachexia, keloid formation, scars tissue formation, Crohn's disease, ulcerative colitis, pyreals, erythemal erythematosus lupus, multiple sclerosis, type 1 diabetes mellitus, psoriasis, Bechet's disease, purple nephritis Lactoid anaphylaxis, chronic glomerulane, inflammatory bowel disease and leukemin. 19. The method according to clause 18, wherein the disease state is inflammation of the joint. 20. The method according to claw 12, or claw 16, where the disease condition is late disquiecy. 21. The method according to clause 16, wherein the disease state is a yeast or fungal infection. 22. A method for gaetroprotection comprising the administration to a patient of an effective amount of a compound according to any of clauses 1 to 10. RESUME 1, 3-disubstituted xanthines have therapeutic utility by inhibiting TNF or phosphodiesterase.