GB2405793A - Pteridine derivatives for treating TNF-alpha related disorders - Google Patents

Abstract

This invention relates to the use of a group of pteridine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, dihydro- and tetrahydroderivatives and enantiomers, for the manufacture of a medicament for the prevention or treatment of TNF- a related disorders. The pterin preferably has an amino, or acetamino in the 2 position; hydroxy, an alkoxy, dialkylamino, dibenzylamino, a N containing heterocycle or an adamantylamino group in the 4 position; a hydrogen, styryl, or optionally substituted phenyl in the 6 position; and hydrogen, methyl or methoxy in the 7-position. The condition K may be septic or endotoxic shock, toxic effects of radiotherapy, TNF- V or chemotherapeutic agents, or cachexia.

Description

PTERIDINE DERIVATIVES FOR THE TREATMENT OF SEPTIC SHOCK

AND TNF-a-RELATED DISEASES.

FIELD OF THE INVENTION

The present invention relates to a novel medical indication of pteridine derivatives for the treatment of side effects of various chemotherapeutic drugs and/or of irradiation in cancer therapy. The present invention also relates to the use of polysubstituted pteridines for the prevention and/or the treatment of pathologic and inflammatory conditions such as septic shock, as well as toxic side effects, disorders and diseases related to or resulting from the exposure of patients to abnormally high levels of tumor necrosis factor-alpha (hereinafter referred as TNF-a) in general, and particularly following the administration of TNF-a in cancer treatment in humans. This invention also relates to the use of polysubstituted pteridines for the prevention and/or the treatment of radiotherapy-induced or chemotherapy-induced disorders such as mucositis, secondary myelodysplastic syndromes and radiation-'nduced graft-versus-host disease, and for the prevention and/or the treatment of injuries in cancer patients such as, but not limited to, apoptosis, radiation necrosis and nephrotoxicity following the administration of certain chemotherapeutic drugs such as cisplatin in cancer treatment. Additionally the invention relates to the treatment of cachexia

BACKGROUND OF THE INVENTION

Several 2,4-diamnopteridine derivatives, including methotrexat, are known in the art (for Instance, see U.S. Patent No. 2,512,572) as being useful as antneoplastic agents Nevertheless, there still is a need in the art for specific and highly therapeutically active compounds, such as, but not limited to, drugs for preventing or treating cell proliferative disorders, including cancer. In particular, there is a need in the art to provide anti-cancer drugs which are active in a minor dose or in minimizing the side effects of other known and efficient anti-cancer drugs or radio-active treatments.

Septic shock is a major cause of death in intensive care units (about 150,000 estimated deaths annually in the United States of America, despite treatment with intravenous antibiotics and supportive care) for which very little effective treatment is available at present. Patients with severe sepsis often experience failures of various systems in the body, including the circulatory system, as well as kidney failure, bleeding and clotting. Lipopolysaccharide (hereinafter referred as LPS) is the primary mediator of Gramm-negative sepsis, the most common form of sepsis, by Inducing the production of a whole array of macrophage-derived cytokines (such as TNF or; interleukins such as IL-1, IL-6, IL-12; interferon-gamma (hereinafter referred IFN=y), etc.).

These cytokines may induce other cells (e.g. T cells, NK cells) to make cytoknes as well (e.g. IF-). In addition, other macrophage products (e.g. nitric oxide, hereinafter referred as NO) may also play a role in the pathogenesis of toxic shock. These substances (e.g. NO) may be induced directly due to microbial interactions or indirectly through the action of pronflammatory cytokines. LPS binds to a serum protein known as LPB and the LPS-LPB complex thus formed is recognized by the CD14 toll-like receptor 4 (hereinafter referred as Tlr 4) complex on mononuclear phagocytes. Tlr4 is a signal transducing unit, the activation of which results in the release of mediators such as TNF-a, IL-1 or, IL-10 and ILK. These cytokines are important for the pathogenesis of shock. Their administration produces the clinical symptoms of septic shock and their blockade partially protects against LPS-induced lethal shock.

Current therapeutic strategies for the treatment of septic shock are directed against LPS (e.g. antibodies against LPS or LBP-34-23) or against the cytokines induced by LPS (e.g. TNF antibodies) or against the receptor for LPS. (.e.a.. CD14) Unfortunately the Initial clinical data of these approaches are very disappointing and illustrate the redundancy of receptors and mediators involved in the pathogenesis of toxic shock. For instance flagellin seems to be another.toxin that plays a role in Gramm-negatve Salmonella shock syndrome and that cannot be prevented or treated by therapeutic strategies directed specifically at LPS.

Clinical teals in humans with TNF blocking antibodies (such as the IL- 1 receptor antagonist or PAP receptor antagonists) have been unsuccessful yet, as have been approaches to down regulate inflammation (e.g. using prednisolone) or to block endotoxins. These products must be administered very early after the onset of the disease, which is in most cases not possible.

The only drug currently approved by health authorities for the treatment of adult patients with the most serious forms of sepsis, including septic shock, is a genetically engineered version of a naturally occurring human protein, Activated Protein C, known as Xigris4D or drotecogin-alpha which shows only moderate efficacy. Furthermore, because Activated Protein C interferes with blood clotting, the most serious side effect associated with Xigris is bleeding, including bleeding that causes stroke Thus Tigris is contra-indicated for patients who have active internal bleeding, or who are more likely to bleed because of certain medical conditions including recent strokes, recent head or spinal surgery or severe head trauma. Beacause treatment with Tigris comes with potentially serious risks, the benefits and risks of treatment with Xigris must be carefully weighed for each individual patient.

Therefore there is a strong need in the art for new medications, either alone or In combination with the currently suggested treatments, for treating the most serious forms of life-threatening illnesses caused by severe infection, such as septic shock.

TNF-a is generally considered to be the key mediator in the mammalian response to bacterial infection. It is a strong pro-inflammatory agent that will affect the function of almost any organ system, either directly or by inducing the formation of other cytokines like IL-1 or prostaglandines TNF-a is also a potent anti-tumor agent. If administered in small quantities to humans, it causes fever, headache, anorexia, myalga, hypotension, capillary leak syndrome, increased rates of lipolysis and skeletal muscle protein degradation (including cachexia). Its use in cancer treatment is therefore very much limited by its severe side effects.

TNF-a, a pleiotropic cytokine produced mainly by activated macrophages, exerts an in vitro cytotoxic action against transformed cells and in viva anti-tumor activities in animal models. However, despite the fact that TNF-a is used in cancer patients especially to treat melanoma and sarcoma, the major problem hampering its use Is toxicity. Indeed, TNF-a induces shock- like symptoms such as bowel swelling and damage, liver cell necrosis, enhanced release of inflammatory cytokines such as IL-1 or ILL, and hypotension probably due to the release of inducers of vessels dilatation such nitric oxide and other proinflammatory cytokines. Cardiovascular toxicity is usually dose-limiting. Hypotenson can be severe with systolic blood pressure below 60 mm Hg. Respiratory compromise is common after treatment with TNF-a and may require mechanical ventilation. Upper as well as lower to digestive tract symptoms are also common in this type of treatment. Nausea and vomiting can be distressing and in some cases dose- limiting. Watery diarrhea is frequently observed. Neurological sequelae of treatment with TNF- a can also occur.

Hence, compounds that inhibit the toxic effects of TNF-a but that do not inhibit TNF-a anti-tumor effect are highly desirable for the treatment of cancer patients. Presently, several clinical trials involving TNF-a are being developed for the cancer of organs such as liver, lung, kidney and pancreas, which are based on a procedure including the steps of organ isolation, injection of TNF- a into the isolated organ, and reperfusion of the treated organ. However, even for isolated organ perfusion, some TNF-a usually escapes to the general blood circulation and leads to the mortality of about 10% of the patients thus treated. Many patients treated by this procedure also require intensive care unit rescue to cope with the toxic side-effects of such TNF-a treatment.

Combined treatment of TNF-a with alkylating drugs in an isolated organ perfusion model has received considerable attention. TNF-a is currently successfully used in Isolated limb perfusion of human cancer patients and, in combination with melphalan and interferon-gamma, against melanoma, sarcomas and carcinomas.

The gastrointestinal mucosa is very sensitive to chemotherapeutic drugs Mucostis caused by chemotherapy usually begins rapidly after initiation of the treatment with Inflammation and ulceration of the gastrointestinal tract and leading to diarrhea. Severe, potentially life threatening, diarrhea may require interruption of the chemotheraputic treatment and subsequent dose reduction of the therapeutic agent. The oral cavity is often the place of severe side effects from cancer therapy that adversely affects the quality of life of the patient and its ability to tolerate the therapy. These side effects can be caused by radiotherapy as well as chemotherapy. A relationship between both serum and mucosal levels of TNFo and IL-1 correlates with nonhematologic toxicities, including mucositis.

Radiation injuries occurring e.g. after a single high-dose irradiation include apoptosis as well as radiation necrosis. Even normal tissues protected by shielding during irradiation may be considerably damaged. It was found in experimental animal models that the radiation injuries after a single high-dose irradiation typically used for the treatment of various malignant tumors consist of radiation necrosis and apoptosis, which were correlated with the expression of TNF-o and TGF-01.

Irradiation may Induce graft-versus-host disease (hereinafter referred as GVHD) in cancer patients. This disease may occur especially in patients receiving allogeneic bone marrow transplantation as a treatment for cancers such as leukemia or Iymphoma and can lead to the death of about 25% of the relevant patients. Before bone marrow transplantation, leukaemia patients for example receive either total body or total Iymphoid irradiation to suppress their immune system. However, such Irradiation induces not only necrosis but also the release of proinflammatory cytokines mainly TNF-a, IL-1 and IL-6 which in turn Induce direct host tissues inflammation and activation of donor cells against host antigens leading to GVHD.

C'splatin is an effective chemotherapeutic agent used in the treatment of a wide variety of both pediatric and adult malignancies, including testicular, germ cell, head and neck (cervical), bladder and lung cancer. Dose dependent and cumulative nephrotoxicity is the major side effect of cisplatin, sometimes requiring a reduction in dose or discontinuation of the treatment.

Other side effects of cisplatin include kidney damage, loss of fertility, harmful effect on a developing baby, temporary drop in bone marrow function causing drop in white blood cell count, anthems, drop in platelets causing bleeding, loss of appetite, numbness or tingling in lmbs7 loss of taste, allergic reactions, and hearing disorders (difficulty in hearing some high-pitched sounds, experiencing ringing in the ears). Blurred vision may also be a side effect with high doses of cisplatin. It was shown that TNF-a is a key element in a network of proinflammatory chemokines and cytokines activated in the kidney by cisplatin. Blockade of TNF-a action would prevent the activation of this cytokine network and would provide protection against cisplatin nephrotoxicity.

Hence, compounds that inhibit the toxic effects of cisplatin but that do not Inhibit cisplatin anti-tumor effects are highly desirable for the treatment of cancer patients.

A surplus of TNF-a also causes a dramatic change of endothelial cells.

In particular, TNF-a is an important mediator of skeletal muscle degeneration associated with cachexia, a debilitating syndrome characterized by extreme weight loss and whole-body wasting. Cachexia is usually a secondary condition whereby there Is excessive tissue catabolism in combination with deficient anabolism. It is frequently seen in patients afflicted with chronic diseases such as cancer, cardiopulmonary diseases, aging, malabsortive disorders, excessive physical stress, easting disorders and acquired immmuno-deficiency syndrome (AIDS). Some authors consider that the elevated TNF-a values found in at least 50% of cancer patients in the active stage of the disease can result in cachexia. TNF-a levels in clinically healthy adults, as well as In adult cancer patients, are well documented, for instance by Nenova et al in Archives of Hellenic Medicine (2000) 17:619421. Serum TNF-a concentrations in healthy children as well as in children with malignancies are documented for instance by Saarinen et al. in Cancer Research (1990) 50:592-595. A very significant proportion of cancer mortalities result from cachexia rather than from tumor burden. Chronic wasting disease (cachexia) may result when excessive cellular damage results in the release of substances (TNF-a, collagenase, hyaluronidase) that further catabolize the so-called healthy tissue resulting in an inability to assimilate nutrients required for anabolic restructuring of associated tissue.

Infants infected with human immunodeficiency virus type 1 (HIV-1) show growth retardation and severe weight loss that can lead to death. The overproduction of certain cytoknes has been implicated as a possible cause for this. For instance according to Rautonen et al. in AIDS (1991) 5:1319 1325, serum IL-6 concentrations are elevated and associated with elevated TNF-a concentrations in children with HIV infection Swapan et al. in Journal of Virology (2002) 76.1 1710-1 1714 have shown that reduction of TNF-a levels by either anti-TNF-a antibodies or human chorionic gonadotropin inhibits the expression of HIV-1 proteins and prevents cachexia and death.

Very few drugs have been suggest at present for the treatment of cachexia. Some high-dose progestins like megestroi acetate, an agent used for the treatment of metastatic breast cancer, and medroxyprogesterone acetate were shown in randomized clinical trials to provide a statistically significant advantage as regards improved appetite and body weight gain Hence, compounds that stimulate appetite and body weight gain without inhibiting the anti-tumor effect or anti-viral effect of co-administered drugs are highly desirable for the treatment of cachexia. More specifically, there is a need In the art for treating cachexa by the administration of compounds that reduce TNF-a levels in the serum of humans.

TNF-a is also suspected to play a role, through a possible dual action in the hematopoietic environment, in the development of hematologic malignancies such as idiopathic myelodysplastic syndromes occurring most often in elderly people but also occasionally in children, these syndromes being currently regarded as the early phase of acute leukemia.

There is a strong need in the art to improve, or to provide alternatives to, the existing prophylactic or therapeutic solutions to all the aforesaid diseases. Meeting this need In the art constitutes the main goal of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the unexpected funding that a class of pteridine derivatives having the general formula (I): R1x NN R3 R2J(NlNXR4 wherein X represents an oxygen atom or a group with the formula S(O)m wherein m is an integer from O to 2, or a group with the formula NZ and wherein: - R' is a group selected from the group consisting of C,-7 alkyl, C27 alkenyl, C27 aikynyl, C3'0 cycloalkyl, C3,0 cycloalkenyi, aryi, alkylaryl, arylalkyl, heterocyclic, heterocyclic-substituted alkyl and alkyl substituted heterocyclic, each of said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C, 4 alkyl, C,-4 alkoxy, C27 alkenyl, C2 7 alkynyl, halo C, 4 alkyl, C3,0 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C, 7 alkyl, thio C30 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic- substituted alkylthio, formyl, hydroxyl, sulfhydryl, nitro, hydroxylamino, mercaptoamino, cyano, carboxylc acd or esters or thioesters or amides or thioamides or halides or anhydndes thereof, thiocarboxylic acid or esters or thioesters or amides or thioamdes or halides or anhydrides thereof, carbamoyl, thiocarbamoyl, ureido, thio-ureido, amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamno, arylamino, arylalkyl amino, hydroxylalkylam i no, mercaptoalkylamino, heterocyclic am i no, hydrazino, alkylhydrazno and phenylhydrazino; or R. is a carboxyalkyl, carboxyaryl, thiocarboxyaryl or thiocarboxyalkyl group; - Z is a group independently defined as R. or Z is hydrogen or the group NZ together wth R. is either hydroxylamino or an optionally substituted heterocyclic group containing at least one nitrogen atom; - R2 is selected from the group consisting of amino; acylamino; thioacylamino; carbamoyl; thiocarbamoyl, ureido; thioureido, sulfon amdo; hydroxylamino; alkoxyamino; thioalkylamino; mercaptoamino, hydrazino; alkylhydrazino; phenylhydrazino; optionally substituted heterocyclc radicals; C, 7 al kylam i no; arylamino; arylalkylami no; cycloalkylamino; alkenylamino; cycloalkenylamino; heterocyclic amino; hydroxyalkylamno; mercaptoalkylamno; C4-7 alkoxy; C3 0 cycloalkoxy; thio C'-7 alkyl; arylsulfoxide; arylsulfone; heterocyclic sulfoxide; heterocyclic sulfone; thio C3'0 cycloalkyl; aryloxy; arylthio; arylalkyloxy; arylalkylthio; oxyheterocyclic and thioheterocyclc radicals, - R4 is an atom or a group selected from the group consisting of hydrogen; halogen; C' 7 alkyl; C2 7 alkenyl; C2 7 alkynyl; halo C' 7 alkyl; carboxy C, 7 alkyl; acetoxy C' 7 alkyl; carboxyaryl; C1-7 alkoxy; C3,0 cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic substituted alkyloxy; thio C' 7 alkyl; thio C3-'o cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; amino; hydroxylamino; mercaptoamino, acylamino; thioacylamino; alkoxy amino; thioalkylamino; acetal; thioacetal; carboxylic acid; carboxylic acid esters, thoesters, halides, anhydrides, amdes and thioamides; thiocarboxylic acd; thiocarboxylic acid esters, thioesters, halides, anhydrides7 amides and thioamdes; hydroxyl, sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl, ureido; tho-ureido; alkylamino; cycloalkylamno; al kenylamino; cycloalkenylam ino; al kynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkylamino; heterocyclic amino; heterocyclic-substituted alkylamino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; cysteinyl acid, esters, thioesters, halides, anhydndes, amides and thioamides thereof; aryl groups optionally substituted with one or more substituents selected from the group consisting of halogen, C'-7 alkyl, Ci 7 alkoxy, C27 alkenyl, C27 alkynyl, halo C'7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C3,0 cycloalkoxy, aryloxy, arylalkyloxy, oxyhetero-cyclic, heterocyclic-substituted alkyloxy, tho C'-7 alkyl, thio C340 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, uredo, thio-ureido, sulfonamido, hydroxylamino, alkoxyamino, mercaptoamno, thoalkylamino, acyl amino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylam i no, alkenylam ino, cycloalkenylam i no, alkynylam i no, arylamino, arylalkylamino, hydroxyaikylamino, mercaptoalkylamino, heterocyclic am i no, hydrazi no, al kyl-hydrazino and phenylhydrazino; optionally substituted heterocyclc radicals; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the pteridine ring and the aromatic or heterocyclic substituent, whereby said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 4 carbon atoms whch may contain one or more functions, atoms or radicals selected from the group consisting of carbonyl (oxo), thiocarbonyl, alcohol (hydroxyl), thiol, ether, thio-ether, acetal, thio acetal, amino, imino, oximino, alkyloximino, amino-acid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio ureido, carboxylic acid or ester or thioester or halide or anhydride or amde, thocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C' 7 alkyl, thio C3 i0 cycloalkyl, hydroxylamino, mercaptoamno, alkylamino, cycloalkylamino, alkenylamino, cyclo alkenylamno, alkynylamino, arylamino, arylalkylamino, hydroxyalkyl amino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl, sulfonamido and halogen; branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions selected from the group consistng of carbonyl (oxo), thiocarbonyl, alcohol (hydroxyl), thiol, ether, thioether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, amino-acid, cyano, acylamino; thioacylamino; carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C, alkyl, thio C3,0 cycloalkyl, hydroxylamino, mercaptoamino, alkylamino, cyclo alkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylam i no, hydroxyal kylam ino, mercapto-alkylam i no, heterocycl ic amino, hydrazino, alkylhydrazino, phenyl-hydrazino, sulfonyl, sulfinyl, sulfonamido and halogen; and - R3 is an atom or a group defined as R4, or R3 together with R4 forms a homocyclic or heterocyclic radical such as, but not limited to, indolyl, dihydroxypyrimidyl or tetra-methylene, as well as pharmaceutically acceptable addition salts, stereoisomers, mono or di-N-oxides, solvates and/or dihydro- or tetrahydropteridine derivatives thereof, are useful for the manufacture of a medicament for the prevention or treatment of a TNF-o-related disorder in a mammal, the said disorder being selected from the group consisting of: - septic or endotoxic shock, - TNF- mediated diseases, - pathologies and conditions associated with and/or induced by abnormal levels of TNF-u occurring in a systemic, localized or particular tissue type or location in the body of the mammal, - toxic effects of TNF and/or anti-cancer chemotherapeutic agents, - injuries aftemrradiation of a tissue of the mammal by radio-elements, and - cachexia.

The present invention also relates to various processes and methods for making the novel pterdine derivatives defined In general formula (1), as well as their pharmaceutically acceptable salts, N-oxides, solvates, enantiomers and/or dihydro- and tetrahydroderivatives

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 and 2 represent alternative schemes for preparing 2,4,6 trisubstituted pteridine derivatives used In this invention.

Figure 3 represents a scheme for preparing 2,4,7-trisubstituted pteridine derivatives used in this invention.

Figure 4 represents a scheme for preparing unsymmetrical 2,4,6 trsubstituted pteridines and 2,4,7-trisubstituted pteridines used in this invention.

Figure 5 represents a scheme for preparing symmetrical 2,4,6 trisubstituted pteridines and 2,4,7-trisubstituted pteridines used in this invention.

DEFINITIONS

Unless otherwise stated herein, the term " trisubstituted " means that three of the carbon atoms being in positions 2, 4 and 6 or, altematively, in positions 2, 4 and 7 of the pteridine ring (according to standard atom numbering for the pteridine ring) are substituted with an atom or group other than hydrogen. The term " tetrasubstituted " means that ail four carbon atoms being in positions 2, 4, 6 and 7 of the pteridine ring are substituted with an atom or group other than hydrogen.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C,-7 alkyl" or " aliphatic saturated hydrocarbon radicals with 1 to 7 carbon atoms " means straight and branched chain saturated acyclic hydrocarbon monovalent radicals having from 1 to 7 carbon atoms such as, for example, methyl, ethyl, propyl, nbutyl, 1-methylethyl (isopropyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (ter-butyl), 2- methyl butyl, n-pentyl, dmethylpropyi, n-hexyl, 2-methylpentyl, 3- methylpentyl, n heptyl and the like; the term " C, 4 alkyl " designate the corresponding radicals with only 1 to 4 carbon atoms, and so on.

As used herein with respect to a substituting radical, and unless otherwise stated, the term C,-7 alkylene means the divalent hydrocarbon radical corresponding to the above defined C,-7 alkyl, such as methylene, bis(methylene), tns(methylene), tetramethylene, hexamethylene and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C3 in cycloalkyl" and " cycloaliphatic saturated hydrocarbon radical with 3 to 10 carbon atoms " means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or a C7,0 polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3 lo cycloalkylene" means the divalent hydrocarbon radical corresponding to the above defined C3,0 cycloalkyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " aryl " and "aromatic substituent " are interchangeable and designate any mono- or polyaromatic monovalent hydrocarbon radical having from 6 up to 30 carbon atoms such as but not limited to phenyl, naphthyl, anthracenyl, adamantyl, phenantracyl, fluoranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl and the like, including Spiro hydrocarbon radicals and fused benzo - C5 cycloalkyl radicals (the latter being as defined above) such as, for instance, indanyl, 1,2,3, 4 tetrahydronaphtalenyl, fluorenyl and the like.

to As used herein with respect to a substituting radical such as the combination of R3 and R4, and unless otherwise stated, the term " homo cyclc" means a mono- or polycyclic, saturated or mono-unsaturated or polyunsaturated hydrocarbon radical having from 4 up to 15 carbon atoms but including no heteroatom In the said ring.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " heterocyclic " means a mono- or polycyclic, saturated or mono-unsaturated or polyunsaturated monovalent hydrocarbon radical having from 2 up to 15 carbon atoms and including one or more heteroatoms in a 3 to 10 membered ring (and optionally one or more heteroatoms attached to one or more carbon atoms of said ring, for instance in the form of a carbonyl or thiocarbonyl group) and/or to one or more heteroatoms of said ring, for instance in the form of a sulfone, sulfoxide, N oxide, phosphate, phosphonate or selenium oxide, each said heteroatom being independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium and phosphorus, including benzo-fused heterocyclic radicals, such as but not limited to dibenzothiophenyl, dibenzofuranyl, oxazolinyl, oxazolonyl, azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl, pyrimidonyl, thiopyrimidonyl, thiamorpholinyl, azlactonyl, naphtindazolyl, naphtindolyl, naphtothiazolyl, naphtothioxolyl, naphtoxindolyl, naphtotriazolyl, naphtopyranyl, oxabicycloheptyl, azabenzimidazolyl, azacycloheptyl, aza cyclooctyl, azacyclononyl, azabicyclononyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyronyl, tetrahydroqunoleinyl, tetrahydrothienyl and dioxide thereof, dihydrothienyl dioxide,dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl, thioxolyl, thiourazolyl, thotnazolyl, thiopyranyl, thiopyronyl, coumarinyl, quinolenyl, oxyquinoleinyl, quinuclidinyl, xanthinyl, dihydro-pyranyl, benzodhydrofuryi, benzothiopyronyl, benzothopyranyl, benzoxazinyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzothiadiazolyl, benzotriazinyl, benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl (benzothiofuranyl), phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, furyl, dihydrofuryl, furoyl, hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithiinyl, thienyl, indolyl, indazolyl, benzofuryl, quinolyl, quinazolinyl, quinoxalinyl, carbazolyl, phenoxazinyl, phenothiazinyl, xanthenyl, purinyl, benzothienyl, naphtothienyl, thanthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzofuranyl, chromenyl, phenoxathinyl, indolizinyl, quinolizinyl, isoqunolyl, phthalazinyl, naphthiridinyl, cinnolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolinyl, imidazolidinyl, benzimidazolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, piperazinyl, uridinyl, thymidinyl, cytidnyl, azirinyl, azirdinyl, diazirinyl, diaziridinyl, oxiranyl, oxaziridinyl, doxiranyl, thilranyl, azetyl, dihydroazetyl, azetidinyl, oxetyl, oxetanyl, thietyl, thietanyl, diazabicyclooctyl, diazetyl, diaziridinonyl, diaziridinethionyl, chromanyl, chromanonyl, thiochromanyl, thochromanonyl, thiochromenyl, benzofuranyl, benzisothiazolyl, benzocarb- azolyl, benzochromonyl, benzisoalloxazinyl, benzocoumarinyl, thiocoumarinyl, phenometoxazinyl, phenoparoxazinyl, phentriazinyl, thiodiazinyl, thiodiazolyl, indoxyl, thio-indoxyl, benzodiazinyl (e.g. phtalazinyl), phtalidyl, phtalimidinyl, phtalazonyl, alloxazinyl, dbenzopyronyl (i.e. xanthonyl), xanthionyl, isatyl, sopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl, succinyi, succinmido, benzylsultimyl, benzylsultamyl and the like, including all possible isomeric forms thereof, wherein each carbon atom of the said ring may be substituted with a substituent selected from the group consisting of halogen, nitro, C'-7 alkyl (optionally containing one or more functions or radicals selected from the group consisting of carbonyl (oxo), alcohol (hydroxyl), ether (alkoxy), acetal, amino, imino, oximno, alkyloximino, amino-acid, cyano, carboxylic acid ester or amide, nitro, thio C, 7 alkyl, thio C3'0 cycloalkyl, C, 7 al kylam i no, cycloalkylam i no, alkenylam ino, cycloal kenylam i no, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfonamido and halogen), C3-7 alkenyl, C27 alkynyl, halo C,7 alkyl, C30 cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, amino, C,-7 alkylamino, cycloal kylam i no, alkenylam i no, cyclo-al kenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, hetero cyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulflhydryl, C, 7 alkoxy, C30 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic substituted alkyloxy, thio C, 7 alkyl, thio C3,0 cycloalkyl, thioaryl, thioheterocyclic, arylalkyltho, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, thiocarboxylic acid or esters or thioesters or amdes thereof; depending upon the number of unsaturations in the 3 to 10 membered ring, heterocyclic radicals may be sub-divided nto heteroaromatic (or " heteroaryl") radicals and non-aromatc heterocyclic radicals, when a heteroatom of the said non-aromatic heterocyclic radical is nitrogen, the latter may be substituted wth a substituent selected from the group consisting of C, 7 alkyl, C3,0 cycloalkyl, aryl, arylalkyl and alkylaryl.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C, 7 alkoxy ", "C3,0 cycloalkoxy ", " aryloxy", "arylalkyloxy ", " oxyheterocyclic ", "thio C, 7 alkyl", " thio C3'0 cycloalkyl ", "arylthio ", " arylalkylthio " and " thioheterocyclic" refer to substituents wherein a C,-7 alkyl radcal, respectively a C3,0 cycloalkyl, aryl, arylalkyl or heterocyclic radical (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a sngle bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl, cresoxy and the like.

As used heren with respect to a substituting atom, and unless otherwise stated, the term halogen means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " halo C' 7 alkyl " means a C, 7 alkyd radical (such as above defined) In which one or more hydrogen atoms are independently replaced by one or more halogens (preferably fluorine, chlorine or bromine), such as but not limited to difluoromethyl, trifluoromethyl, trifluoroethyl, octafluoropentyl, dodecafluoroheptyl, dichloromethyl and the like; the term "halo C,4 alkyl " designate the corresponding radical with only 1 to 4 carbon atoms, and so on.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C27 alkenyl " and " alphatic unsaturated hydrocarbon radical with 2 to 7 carbon atoms " are interchangeable and designate a straight and branched acyclic hydrocarbon monovalent radical having one or more ethylenical unsaturations and having from 2 to 7 carbon atoms such as, for example, vinyl, 2-propenyl, 3-butenyl, 2- butenyl, 2 pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl, 2-heptenyl, butadienyl, pentadienyl, hexedienyl, heptadienyl, heptatrienyl and the like, including all possible isomers thereof; the term " C3 7 alkenyl " designate the corresponding radical with only 3 to 7 carbon atoms, and so on.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C3-'o cycloalkenyl" and " cycloaliphatic unsaturated hydrocarbon radical with 3 to 10 carbon atoms " are interchangeable and mean a monocyclic mono- or polyunsaturated hydrocarbon monovalent radical having from 3 to 8 carbon atoms, such as for instance cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexedienyl, cycloheptenyl, cycloheptadienyl, cyclohepta- trienyl, cyclooctenyl, cyclooctadienyl and the like, or a C7 40 polycyclic mono- or polyunsaturated hydrocarbon mono-valent radical having from 7 to 10 carbon atoms such as dicyclopentadienyl, fenchenyl (including all isomers thereof, such as a-pnolenyl), bicyclo[2.2 1]hept-2-enyl, bicyclo[2.2.1] hepta 2,5-dienyl, cyclo-fenchenyl and the like.

As used heren wth respect to a substituting radical, and unless otherwise stated, the term " C2 7 alkynyl " defines straight and branched chain hydrocarbon radicals containing one or more triple bonds and having from 2 to carbon atoms such as7 for example, acetylenyl, 2-propynyl, 3-butynyl, 2- butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl and the like and all possible Isomers thereof.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " arylalkyl " and "heterocyclic-substituted alkyl" refer to an aliphatic saturated hydrocarbon monovalent radical, preferably a C, 7 alkyl or a C3,0 cycloalkyl such as defined above, onto which an aryl radical or respectively a heterocyclic radical (such as defined above) is already bonded, such as but not limited to benzyl, pyridylmethyl, pyridylethyl, 2-(2-pyridyl)isopropyl, oxazolylbutyl, 2-thienylmethyl and 2-furylmethyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " alkylaryl " and "alkyl-substituted heterocyclic" refer to an aryl radical or respectively a heterocyclic radical (such as defined above) onto which is (are) already bonded one or more Emphatic saturated hydrocarbon monovalent radicals, preferably C, 7 alkyl radicals or C3 10 cycloalkyl radicals as defined above such as, but not limited to, o- toluyl, m- toluyl, p-toluyl, mesityl and 2,4,6-trimethylphenyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " alkylamino ", "cycloalkylamino ", "alkenyl amino", " cycloalkenylamino ", " arylamino ", "arylalkylamino", "heterocyclic amino", " hydroxyalkylamino ", "mercaptoalkylamno " and " alkynylamino" mean that respectively one (thus monosubstituted amino) or even two (thus disubstituted amino) C, 7 alkyl, C3,0 cycloalkyl, C2 7 alkenyl, C3-'o cycloalkenyl, aryl, arylalkyl, heterocyclic, mono- or polyhydroxy C' 7 alkyl, mono- or polymercapto C' 7 alkyl or C27 alkynyl radical(s) (each of them as defined herein, respectively) is/are attached to a nitrogen atom through a single bond or, in the case of heterocyclic, include a nitrogen atom, such as but not limited to, anilino, benzylamino, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, propenylamino, n-butylamino, ter-butylamino, dbutylamino, morpholinoalkylamino, morpholinyl, piperidinyl, piperazinyl, hydroxymethylamno, phydroxyethylamino and ethynylamino; this definition also includes mxed dsubsttuted amino radicals wherein the nitrogen atom is attached to two such radicals belonging to two different sub-set of radicals, e.g an alkyl radical and an alkenyl radical, or to two different radicals within the same sub-set of radicals, e.g. methylethylamno; the term " C37 alkyl amno" designates the corresponding radical with only 3 to 7 carbon atoms in the alkyl group(s) attached to nitrogen, for instance di- isopropylamino, and so on; among disubstituted amino radicals, symetrically substituted are usually preferred and more easily accessible.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms "(thio)carboxylic acid ester ", " (thio) carboxylic acid thioester " and " (thio)carboxylic acid amide" refer to radicals wherein the carboxyl or thiocarboxyl group is directly attached to the pteridine ring (e.g. in the 6- and/or 7-position) and wherein said carboxyl or thocarboxyl group is bonded to the hydrocarbonyl residue of an alcohol, a thiol, a polyol, a phenol, a thiophenol, a primary or secondary amine, a polyamine, an amino-alcohol or ammonia, the said hydrocarbonyl residue being selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, alkylaryl, alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, arylamino, arylalkylamino, heterocyclic amino, hydroxyalkylamino, mercapto alkylamino or alkynylamino (such as above defined, respectively).

As used herein with respect to a substituting radical, and unless otherwise stated, the term " amino-acid " refers to a radical derived from a molecule having the chemical formula H2N-CHR-COOH, wherein R is the side group of atoms characterizing the amino-acid type; said molecule may be one of the 20 naturally-occurring amino-acids or any similar non naturally occurring amino-acid.

As used herein and unless otherwise stated, the term " stereoisomer " refers to all possible different isomeric as well as conformational forms which the pteridine derivatives havng the general formula (I) may possess, in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present nvention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

As used herein and unless otherwise stated, the term " enantiomer " means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

As used herein and unless otherwise stated, the term " solvate " includes any combination which may be formed by a pteridine derivative of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.

As used herein and unless otherwise stated, the terms " dihydro pteridine derivative " and " tetrahydropteridine derivative " refer to the hydrogenation products of the pteridine derivatives having the general formula (I), i.e. derivatives wherein two hydrogen atoms are present in positions 5 and 6, or 7 and 8, of the pterdine ring, or respectively wherein four hydrogen atoms are present In positions 5, 6, 7 and 8 of the said ring; such hydrogenated derivatives are easily accessible from the pteridine derivatives of formula (I) by using hydrogenation methods well known in the art.

DETAILED DESCRIPTION OF THE INVENTION

A main object of the invention is to provide a treatment for a class of TNF-a related disorders in a mammal, the said disorders being selected from the group consisting of: - septic or endotoxic shock, TNF-a-mediated diseases, - pathologies and conditions associated with and/or induced by abnormal levels of TNF-a occurring in a systemic, localized or particular tissue type or location In the body of the mammal, - toxic effects of TNF-a and/or other anti-cancer chemotherapeutic agents, - injuries after irradiation of a tissue of the mammal by radio-elements, and - cachexia.

This is achieved by manufacturing a medicament7 or a pharmaceutical composition, including a pteridine derivative having the above mentioned general formula (I) as a biologically active ingredient.

According to the invention, the active pteridine derivatives are as defined in the general formula (I), wherein each of the substituents X, Z. R., R2, R3 and R4 may correspond to any of the defintions given above (and, when X ncludes sulfur, wherein m may be 0, 1 or 2), in particular with any of the individual meanngs (such as illustrated above) of generic terms such as, but not limited to, "C' 7 alkyl ", " C27 alkenyl ", " C27 alkynyl ", " aryl ", "alkylaryl ", "arylalkyl ", "alkylamino", " cycloalkylamino", "alkenylamino ", "alkynylamino", "arylamno", " arylalkylamino ", " C'-7 alkoxy", " C3,0 cycloalkoxy ", "thio C'-7 alkyl ", " thio C3-1O cycloalkyl ", " halo C, 7 alkyl ", "amino-acid " and the like In particular, the pteridine derivatives wherein R2 is C3 7 alkylamino and/or wherein R4 s a heterocyclic radical other than piperidinyl, morpholinyl or pyrrolidinyl (i.e. R4 is for instance selected from the group consisting of dibenzothiophenyl, dibenzofuranyl, oxazolinyl, oxazolonyl, azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thazolidinyl, thiazanyl, pyrimidonyl, thopyrimidonyl, azlactonyl, naphtindazolyl, naphtindolyl, naphtothiazolyl, naphtothioxolyl, naphtoxindolyl, naphtotriazolyl, naphto pyranyl, oxabcycloheptyl, azabenzimdazolyl, azacycloheptyl, azacyclooctyl dihydrothienyl dioxde, dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl, thioxolyl, thiourazolyl, thiotriazolyl, thiopyranyl, thiopyronyl, coumarinyl, quinoleinyl, oxyquinoleinyl, quinuclidinyl, xanthinyl, dihydropyranyl, benzodihydro- furyl, benzothopyronyl, benzothopyranyl, benzoxazinyl, benzoxazolyl, benzodioxolyl, benzodoxanyl, benzothiadazolyl, benzotriazinyl, benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl, phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl, imdazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxediazolyl, pyrrolyl, furyl, dihydrofuryl, furoyl, hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithiinyl, thienyl, indolyl, indazolyl, benzofuryl, quinolyl, quinazolinyl, quinoxalinyl, azacyclononyl, azabicyclononyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyronyl, tetrahydroquinoleinyl, tetrahydrothenyl and dioxide thereof, carbazolyl, phenoxazinyl, phenothazinyl, xanthenyl, purinyl, benzothienyl, naphtothienyl, thianthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzofuranyl, chromenyl, phenoxathiinyl, indolizinyl, quinolizinyl, isoquinolyl, phthalazinyl, naphthiridinyl, cinnolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolnyl, imdazolidinyl, benzimidazolyl, pyrazolinyl, pyrazolidnyi, pyrrolinyl, piperazinyl, uridinyl, thymidinyl, cytidinyl, azirinyl, aziridinyl, diazirinyl, diaziridinyl, oxiranyl, oxaziridinyl, dioxiranyl, thiiranyl, azetyl, dihydroazetyl, azetidinyl, oxetyl, oxetanyl, thietyl, thietanyl, diazabicyclooctyl, diazetyl, diaziridinonyl, diaziridinethionyl, chromanyl, chromanonyl, thiochromanyl, thiochromanonyl, thiochromenyl, benzofuranyl, benzisothazolyl, benzocarbazolyl, benzochromonyl, benzisoalloxazinyl, benzocoumarinyl, thocoumarinyl, phenometoxazinyl, phenoparoxazinyl, phentriazinyl, thodiazinyl, thiodazolyl, indoxyl, thioindoxyl, benzodiazinyl, phtalidyl, phtalimidinyl, phtalazonyl, alloxazinyl, dibenzopyronyl, xanthonyl, isatyl, isopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl, succinyl, succnimido, benzylsultimyl and benzylsultamyl) are novel compounds whch were never suggested for use in medicine.

When a mixture of enantiomers of a pteridine derivative having the general formula (1) accordng to the invention is obtained during synthesis, the said mixture may be separated by means and methods standard in the art, e.g. Iiquid chromatography usng one or more suitable chiral stationary phases. The latter nclude, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases suitable for this purpose are ChiralCelTM CA, OA, OB, OC, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP() and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide-based chiral stationary phases are hydrocarbons such as hexane and the like, optionally admixed with an alcohol such as ethanol, isopropanol and the like. The above mixture of enantiomers may alternatively be separated by forming diastereoisomers, followed by separation of the diastereoisomers, e.g. by differential crystallization or chromatography. The resolving agent may be cleaved from the separated dastereoisomers, e.g. by treatment with acids or bases, in order to generate the pure enantiomers of the compounds of the invention.

Some preferred pteridine derivatives having the general formula (I) according to the invention are more specifically illustrated in the following examples For instance, useful pteridine species disclosed below include these wherein: - R. is selected from the group consisting of methyl, ethyl, isopropyl, pentyl and benzyl, and/or to - R2 is amino, and/or - R4 is hydrogen or methoxy, and/or - R3 Is 3-thienyl or 2-thienyl or a phenyl group with one or more substituents (in the latter case, such substituents are preferably each independently selected from the group consisting of fluoro, methoxy, ethoxy, trifluoromethyl, dimethyl-amino, chloro, cyano, methyl, ethyl, carboxymethyl, methylthio, dimethylcarboxamido, diethylcarboxamido and methylcarboxylate, and/or - X is a sulfur atom (i.e. m is O) or an oxygen atom, or - X is NZ, wherein Z is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and benzyl, or NZ together with R. forms a radical selected from the group consisting of hydroxylamino, tetrahydropyndinyl, morpholinyl, piperidinyl, piperazinyl, N- methylpiperazinyl, 1,2,4-triazolyl and pyrrolidinyl The present invention further provides processes and methods for making the pteridine derivatives having the general formula (I). As a general rule, the preparation of these compounds is based on the principle that, starting from a suitable pteridine precursor, each of the substituents XR,, R2, R3 and R4 may be introduced separately (except, of course, when R3 together with R4forms a homocyclic or heterocyclic radical) without adversely nfluencing the presence of one or more substituents already introduced at other positions on the pteridine ring or the capacity to introduce further substituents later on.

Methods of manufacture have been developed by the present inventors which may be used alternatively to, or may be combined with, the methods of synthesis already known in the art of pteridine derivatives (depending upon the targeted final compound). For instance, methods for simultaneously introducing R3 and R4 in the form of a homocyclic or heterocyclic radical at positions 6 and 7 of the pteridine ring are already known from U.S. Patent No. 2,581,889. The synthesis of mono- and di-N-oxides of the pteridine derivatives of this invention can easily be achieved by treating the said derivatives with an oxidizing agent such as, but not limited to, hydrogen peroxide (e.g. in the presence of acetic acid) or a peracid such as chloroperbenzoic acid. Dihydro and tetrahydropteridine derivatives of this invention can easily be obtained by lO catalytic hydrogenation of the corresponding pteridine derivatives, e.g. by placing the latter in a hydrogen atmosphere in the presence of platinum oxide or platinum. The methods for making the pteridine derivatives of the present invention will now be explained in more details by reference to the appended figures 1 to 5 wherein, unless otherwise stated hereinafter, each of the l5 substituting groups or atoms X, Z. R', R2, R3 and R4 is as defined in formula (I) of the summary of the invention and, more specifically, may correspond to any of the individual meanings disclosed above. The same manufacturing methods may also be applied, if need be, while starting from pteridine derivatives which are already known in the art. In the description of the reaction steps involved in each figure, reference is made to the use of certain catalysts and/or certain types of solvents. It should be understood that each catalyst mentioned should be used in a catalytic amount well known to the skilled person with respect to the type of reaction involved. Solvents that may be used in the following reaction steps include various kinds of organic solvents such as protic solvents, polar aprotic solvents and non-polar solvents as well as aqueous solvents which are inert under the relevant reaction conditions. More specific examples include aromatic hydrocarbons, chlorinated hydrocarbons, ethers, aliphatic hydrocarbons, alcohols, esters, ketones, amides, water or mixtures thereof, as well as supercritical solvents such as carbon dioxide (while performing the reaction under supercritical conditions). The suitable reaction temperature and pressure conditions applicable to each kind of reaction step will not be detailed herein but do not depart from the relevant conditions already known to the skilled person with respect to the type of reaction involved and the type of solvent used (in particular its boiling point).

Figure 1 represents a scheme for the preparation of 2,4,6-trisubstituted pteridines with various R2 and R3 substituents in the 2- and 6-positions of the pteridine ring. In the hrst step (a), a chloropyrimidine 1, wherein R2 may be inter alla am ino, al kylam i no, arylamino, alkoxy, aryloxy, mercaptoalkyl, or mercaptoaryl, is reacted with an appropriate nucleophile R,XH, the said nucleophile being selected from the group consisting of alcohols (e.g. methanol, ethanol, isopropanol or benzylalcohol), thiols, primary amines and secondary amines wherein R' may be inter alla alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl. Introduction of a nitroso group into the pyrimidine intermediate 2 occurs in step (b) under acidic aqueous conditions in the presence of sodium nitrite NaNO2. Reduction of the nitroso functionality of the pyrmidine intermediate 3 into a free amino group in intermediate 4 is then effected in step (c) by means of reducing agents (such as Na2S2O4 or (NH.)2S) in water, or catalytically (PVH2) in the presence of a protic solvent. In step (d), ring closure is performed by treating the diaminopyrimidine 4 with glyoxal in order to form a pteridine ring. In step (e), the nitrogen atom at position 8 of the pteridine ring of compound 5 is oxidized, e.g. using H202 under acidic conditions. In step (f), a chlorine atom is regioselectively introduced on the 6 position of the pteridine ring of compound 6 by treatment with a carboxylic acid choride such as acetyl chloride under acidic conditions.

Then in step (9) the 6-chlorosubstituted pteridine 7 is reacted with a boronic acid having the general formula R3B(OH)2, wherein R3 may be alkyl, cycloalkyl, aryl or heteroaryl, under basic conditions (such as in the presence of an aqueous alcaline solution) and a palladium based catalyst, thus yielding the desired derivative 8 of the present invention.

Figure 2 represents a scheme for the preparation of 2,4,6-trisubstituted pteridines with various R2 and R3 substituents in the 2- and 6-positions of the ptendine ring. In step (a), a nitroso group is ntroduced in position 5 of the pyrimdine ring of a compound 9, wherein R2 may be inter alla amino, alkylamino or arylamino, using sodium nitrite under aqueous acidic conditions.

Reduction of the nitroso group of compound 10 in step (b) is achieved either catalytically (PVH2) in the presence of a protic solvent, or chemically using sodium dithionite or ammonium sulfide In the presence of water. Then In the next step (c), the condensation of the diaminopynmidine 11 with an o ketoaldoxime bearing the group R3, wherein R3 may be alkyl, cycloalkyl, aryl or heteroaryl, under acidic conditions in the presence of a protic solvent such as methanol, regioselectively yields the 6-substituted pteridine derivative 12.

Activation of the hydroxyl group of the tautomeric form of 12 by a nucleophilic displacement reaction occurs by preparing the 4-[(1,2,4)triazolyl] pteridine derivative 13, using POCI3 or 4-chlorophenyl phosphorodichloridate, and 1,2,4-triazole in the presence of e.g. pyridine as solvent. If R2 is a free amino group, protection of R2 e.g. by means of an acetyl group may be necessary before carrying out the reaction of step (d), followed by a deprotection of the acetyl group during the nucleophilic displacement reaction. The nucleophilic substitution in step (e) may be performed, e.g. in the presence of 1,4-dioxane as a solvent, by mixing the pteridine derivative 13 at room temperature with an appropriate nucleophile R'XH, the said nucleophile being selected from the group consisting of alcohols (e.g. methanol, ethanol, isopropanol or benzylalcohol), thiols, primary amines and secondary amines wherein Rat may be inter alla alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl, thus yielding the desired derivative 14 of the present invention.

Figure 3 represents a scheme for the preparation of 2,4,7-trisubstituted pteridines with various R2 and R4 substituents in the 2- and 7-positions of the pteridine ring. In reaction step (a), a tetreaminopyrimidine 15, wherein R2 may be inter alla amino, alkylamino or arylamino, is reacted with inter alla an alkylglyoxal, arylglyoxal, alkylarylglyoxal, heteroarylglyoxal or alkyl heteroarylglyoxal in water under basic conditions, yielding the 7-substituted pteridine derivative 16 wherein R4 may be inter alla alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl. In step (b), hydrolysis under reflux in the presence of sodium hydroxide 1 N yielded the 4-hydroxy tautomer of pteridne derivative 17. In step (c), a 1,2,4-triazolyl group is introduced in position 4 by reacting 17 with triazole in the presence of 4-chlorophenyl phosphorodichloridate and dry pyridine. Finally in reaction step (d), the 1,2,4 triazolyl group at position 4 of the pteridine derivative 18 is displaced by an appropriate nucleophie R,XH, the said nucleophile being selected from the group consisting of alcohols (e.g. methanol, ethanol,isopropanol or benzylalcohol), thiols, primary amines and secondary amines wherein R. may be inter alla alkyl, cycloalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl, In the presence of a polar aprotc or protic solvent, thus yielding the desired derivative 19 of the present invention.

Figure 4 represents a scheme for the synthesis of unsymmetrical 2,4,6trisubstituted and 2,4,7-tnsubstituted pteridine derivatives with various R2, R3 and R4 substituents in the 2-, 6- and 7-postions of the pteridine ring. In step JO (a), the thiol function on 2-mercapto4,6diaminopyrimidine is methylated, e.g. by reaction with methyl iodide in the presence of a solvent such as ethanol, in order to yield 2-thiomethyl4,6-diamnopyrimdine. Introduction of a nitroso group in the 5-position of the pyrimidine ring is then achieved in step (b) by using sodium nitrite under aqueous acidic conditions. In the next step (c), the methylthio group in the 2-postion is exchanged for a group R2, wherein R2 may be inter alla alkoxy, aryloxy, cycloalkyloxy, heteroaryloxy, mercaptoalkyl, mercaptoaryl, mercaptocyclo-alkyl or mercaptoheteroaryl by reachon with an appropriate nucleophile. Reduction of the nitroso functionality is then achieved in step (d) either catalytically (PVH2) in the presence of a protic solvent or chemically using sodium dithionite or ammonium sulfide in the presence of water. Then in the next step (e), the condensation of the 2-substituted4, 5,6- triaminopyrimidine with an a-ketoaldoxime bearing the group R3, wherein R3 may be inter alla alkyl, cycloalkyl, aryl or heteroaryl, under acdic conditions in the presence of a solvent such as methanol, regioselectively yields a 2,6 substituted4-aminoptendine derivative. The corresponding 2,7-substituted- 4- amnopteridine can be obtained, according to step (i), by reaction of the 2substtuted4,5,6-triaminopyrimidine with a glyoxal bearing the group R4, wherein R4 may be inter alla alkyl, cycloalkyl, aryl or heteroaryl. According to step (f), acidic or basic hydrolysis of the amino group at position 4 of the pteridine ring, performed on the derivative from step (e) or (i), yields the corresponding 4-oxopteridine derivative. In step (9), the hydroxyl group of the tautomeric form of the latter is activated by nucleophilic displacement, e.g. by preparing the 4-[(1,2,4)-triazolyl] pteridine derivative Finally, the nucleophilic displacement in step (h) is performed by mixing the said 4-triazolyl pteridine derivative with the appropriate nucleophile R'XH, wherein R' may be inter alla alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryi.

Figure 5 represents a scheme for the synthesis of symmetrical 2,4,6 trisubstituted and 2,4,7-trisubstituted pteridine derivatives with various R2, R3 and R4 substituents in the 2-, 6- and 7-positions of the pteridine ring. In step (a), the pyrimidine ring is nitrated in position 5 under strongly acidic conditions (HNO3, H2SO4). Then in step (b) both hydroxyl groups (from the tautomeric form) are converted to chloro groups by treatment with a chlorinating agent such as POC13 or SOC12. Both chloro substituents are then displaced in step (c) with an appropriate nucleophile R'XH, wherein R' may be inter alla alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl. The nitro group is reduced in step (d) to an amino group by treatment with a reducing agent (e.g. PVH2). Finally, reaction of the 2,4-substituted-5,6- diaminopyrimidine from step (d) with an a-ketoaldoxime bearing the group R3, wherein R3 may be inter alla alkyl, cycloalkyl, aryl or heteroaryl, regioselectively yields the desired 2,4,6- trisubstituted pteridine derivative in step (e). Altematively, reaction of the 2,4- substituted-5,6-diaminopyrimidine from step (d) with a glyoxal bearing the group R4, wherein R4 may be inter alla alkyl, cycloalkyl, aryl or heteroaryl, yields the desired 2,4,7-trisubstituted pteridine derivative in step (f).

When applicable, and depending upon the specific substituents being present, the pteridine derivatives having the general formula (1) may be in the form of a pharmaceutically acceptable salt. The latter include any therapeutically active non-toxic addition salt which compounds having the general formula (1) are able to form with a salt-forming agent. Such addition salts may conveniently be obtained by treating the pteridine derivatives of the inventon with an appropriate salt-forming acid or base. For instance, pteridine derivatives having basic properties may be converted into the corresponding therapeu-tically actve, non-toxc acid addition salt form by treating the free base form with a suitable amount of an appropiate acid following conventional procedures. Exampies of such appropnate salt-forming acids include, for instance, inorganic acids resulting in forming salts such as but not limited to hydrohalides (e.g. hydrochloride and hydrobromide), sulfate, nitrate, phosphate, diphosphate, carbonate, bicarbonate, and the like; and organic monocarboxylic or dicarboxylic acids resulting in forming salts such as, for example, acetate, propanoate, hydroxyacetate, 2-hydroxypropanoate, 2oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzoate, 2-hydroxybenzoate, 4-amino-2-hydroxybenzoate, benzenesulfonate, p-toluenesulfonate, salicylate, p-aminosalicylate, pamoate, bitartrate, camphorsulfonate, edetate, 1,2-ethanedisulfonate, fumarate, glucoheptonate, gluconate, glutamate, hexylresorcinate, hydroxynaphtoate, hydroxyethane lO sulfonate, mandelate, methylsulfate, pantothenate, stearate, as well as salts derived from ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)2- butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxy-butanedioic, 2-hydroxy- 1,2,3-propanetricarboxylic and cyclohexanesulfamic acids and the like.

Pteridine derivatives having acidic properties may be converted in a smilar manner into the corresponding therapeutically active, non-toxic base addtion salt form. Examples of appropriate salt-forming bases include, for instance, norganic bases like metallic hydroxides such as but not limited to those of alkali and alkaline-earth metals like calcium, lithium, magnesium, potassium and sodium, or zinc, resulting in the corresponding metal salt; organic bases such as but not limited to ammonia, alkylamines, benzathine, hydrabamine, arginine, Iysine, N,N'dibenzylethylenediamine, chloroprocaine, cholne, diethanolamine, ethylenediamine, N-methylglucamine, procaine and the like.

Reaction conditions for treating the pteridine derivatives (I) of this invention with an appropriate salt-forming acid or base are similar to standard conditions involving the same acid or base but different organic compounds with basic or acidic properties, respectively. Preferably, in view of its use in a pharmaceutical composition or n the manufacture of medicament for treating specific diseases, the pharmaceutically acceptable salt will be designed, i.e. the salt-forming acid or base will be selected so as to impart greater water- solubility, lower toxicity, greater stability and/or slower dissolution rate to the pteridine derivaDve of this nvention.

The present invention provides the use of the above-described pteridine deivatives as biologically-active ingredients, '.e. active principles, especially as a medicine or a diagnostic agent or for the manufacture of a medicament or a diagnostic kit for the prevention or treatment of a TNF- a related disorder in a mammal. The class of such disorders include the following: - septic or endotoxic shock or sepsis, especially in patients with a serum level of interleukin-6 above 1,000 pg/ml at start of treatment; - vascular TNF-a- mediated diseases such as, but not limited to, disseminated intravascular coagulation and Kawasaki's pathology; pathologies and conditions associated with and/or induced by abnormal levels of TNF-a (herein defined as exceeding by at least 10 % and at most 500% the TNF-a level present in a normal healthy subject) occurring in a systemic, localized or particular tissue type or location in the body of the mammal; such tissue types include, but are not limited to, blood, lymph, liver, kidney, spleen, heart muscle or blood vessels, brain or spinal cord white matter or grey matter, cartilage, ligaments, tendons, lung, pancreas, ovary, testes and prostate. Abnormal TNF levels can also be localized to specific regions or cells in the body, such as joints, nerve blood vessel junctions and bones Such pathologies Include alcoholinduced hepatitis, neurodegenerative diseases such as extrapyramidal and cerebellar disorders including lesions of the corticospinal system; disorders of the basal ganglia; hyperkinetic movement disorders such as chorea; drug-induced movement disorders; hypokinetic movement disorders, such as Parkinson's disease, spinocerebellar degenerations such as spinal ataxia, multiple systems degenerations (including Dejerine-Klumpke syndrome) and systemic disorders (including Refsum's disease, abetalipoprotemia, ataxia and telangectasia); disorders of the motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Wernicke Korsakoff syndrome; Creutzfeldt-Jakob disease; Hallerrorden-Spatz disease; and primary or secondary myelodysplastic syndromes; - toxic effects of TNF and/or anti-cancer chemotherapeutic agents, especially side effects associated with TNF generation during neoplastic therapy, for Instance following use of cisplatin; - injuries after irradiation of a tissue of a mammal by radio-elements, such as but not limited to radiation-induced graft-versus-host disease; and - cachexia and similar chronic wasting diseases, whether associated with cancer or with other chronic diseases such as malabsortive disorders, excessive physical stress, eating disorders and AIDS.

The medicament of this invention may be for prophylactic use, i.e. where circumstances are such that an elevation in the TNF level might be expected or alternatively, may be for use in reducing the TNF level after it has reached an undesirably high level or as the TNF level is rising.

The medicament according to this invention may be administered orally or In any other suitable fashion. Oral administration is preferred and the preparation may have the form of a tablet, aqueous dispersion, dispersable powder or granule, emulsion, hard or soft capsule, syrup, elixir or gel. The dosing forms may be prepared using any method known in the art for manufacturing these pharmaceutical compositions and may comprise as additives sweeteners, flavoring agents, coloring agents, preservatives and the like. Carrier materials and excipients are detailed hereinbelow and may include, inter alla, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, binding agents and the like. The pharmaceutical composition or combined preparation of this invention may be included in a gelatin capsule mixed with any inert solid diluent or carrier material, or has the form of a soft gelatin capsule, in which the ingredient is mixed with a water or oil medium. Aqueous dispersions may comprise the biologically active composition or combined preparation in combination with a suspending agent, dispersing agent or wetting agent Oil dispersions may comprise suspending agents such as a vegetable oil. Rectal administration is also applicable, for instance in the form of suppositories or gels. Injection (e.g. intramuscularly or intraperiteneously) is also applicable as a mode of administration, for instance in the form of injectable solutions or dispersions, depending upon the disorder to be treated and the condition of the patient.

Usually the medicament of the invention is in the form of a combination of the pteridine derivative active principle and one or more pharmaceutically acceptable carriers or excipients The term " pharmaceutically acceptable carrier or excipient " as used herein refers to any material or substance with which the active principle, '.e the pteridne derivative having the general formula (1) may be formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.

The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, pellets or powders.

Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art.

There is no particular restriction to their selection within the present invention although, due to the usually low or very low water-solubility of the pteridine derivatives of this invention, special attention will be paid to the selection of suitable carrier combinations that can assist in properly formulating them in view of the expected time release profile. Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for Instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10,um, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active Ingredients Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.

to Suitable anionic surfactants Include both water-soluble soaps and water- soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C'O-C22), e.g the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline- earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, eg. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide abducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutylnaphtalenesulphonic acid or a naphtalene-sulphonc acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephaln or lecithin type such as e.a. DhosDhatidvlethanolamine.

phosphatidylserine, phosphatidylglycerine, Iysolecithin, cardiolpin dioctanyl phosphatidylcholine, dipalmitoylphoshatidylcholine and their mixtures.

Suitable non-ionc surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic atones or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as a polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms In the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.

Representative examples of non-'onic surfactants are nonylphenol polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/ polyethylene I oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.

Suitable cationic surfactants Include quaternary ammonium salts, preferably halides, having 4 hydrocarbon radicals optionally substituted with: halo, phenyl, substituted phenyl or hydroxy; for instance quatemary ammonium salts containing as N-substituent at least one C-C22 alkyl radical I (e.g cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further I substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy lower alkyl radicals! A more detailed description of surface-active agents suitable for this purpose may be found for instance in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbuch", 2nd ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants (Chemical Publishing Co., New York, 1981).

Structure-forming, thickening or gel-forming agents may be included into the pharmaceutical compositions of the Invention. Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g., products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle).

Gelling agents which may be included into the pharmaceutical compositions of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arable gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof. Gelatin and modified celluloses represent a preferred class of gelling agents.

Other optional excipents which may be included in the pharmaceutical compositions of the present invention include additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV- absorbers; stabilizers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabsulfte and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as citric acid and acetic acid; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densificaton agents such as magnesium salts; and mixtures thereof.

30Additional ingredients may be included in order to control the duration of action of the biologcaily-active ingredient in the compositions of the invention.

Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino-acids, polyvinyl- pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethyl-cellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on Depending on the route of administration, the pharmaceutical composition of the invention may also require protective coatings.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexng agents such as cyclodextrns and the like, and mixtures thereof.

The present invention further relates to a method for preventing or treating a TNF-related disease, such as above defined, in a subject or patient by administering to the patient in need thereof an effective amount of a pteridine derivative having the general formula (I). The effective amount is usually in the range of 0.01 mg to 20 mg, preferably 0.1 mg to 5 mg, per day per kg bodyweight for humans. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals. The patient to be treated may be any warm-blooded animal such as a mammal, preferably a human being, suffering from said TNF-o-related disease.

The following examples are intended to illustrate several embodiments of the present invention, Including the preparation of the pteridine derivatives, without limiting its scope in any way.

Exa m ale 1 - prenarati on of 2-am i no4-n-pentvioxv-stYrvl oteridine.

A mixture of 1.5 g (5.6 mmoles) 2-amino-6-chloro4-n-pentyloxypteridine (e.g. available following the procedure disclosed by Mohr et al. in Helv. Chem. Acta (1992) 75:2317), palladium acetate (63 mg, 0.28 mmoles), tri-o tolylphosphane (682 mg, 2.24 mmoles), cuprous iodide (53 mg, 0.28 mmoles), styrene (1,3 ml., 11.3 mmoles) and triethylamine 3.1 ml, 22 mmoles) was stirred in dry acetonitrile (50 ml) under reflex for 90 hours. It was evaporated and the residue purified by silica gel column chromatography with chloroform.

The product fraction was evaporated to give 1.37 g (yield: 72%) of an orange powder exhibiting, after recrystallization from a EtOAc/hexane mixture, a lo melting point (m p.) range of 127-128 C.

Example 2 - preparation of 2-amino-6-(1.2-dibromophenethYl)-4-n-Pent pteridine.

To a solution of the derivative of example 1 (1.0 9, 2.94 mmoles) in chloroform (50 ml) was added a 2 M bromine solution in chloroform (2.2 ml. , 4.4 mmoles) and then the mixture was stirred at room temperature for 7 hours.

It was diluted with chloroform (50 ml), washed with a saturated aqueous Na2SO3 solution (100 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue was treated with toluene, filtered, washed with ether and dried in a vacuum desiccator to give 0.84 9 (yield: 57%) of a yellow powder.

Example 3 - preparation of 2-amino-4.7-dimethoxv-6-stvrYInteridine.

A suspension of the derivative of example 2 (0.3 9, 0.6 mmoles) is methanol (10 ml) was treated with 1 M methanolic sodium methoxide (3 ml, 3 mmoles) and then reflexed for 4 hours. It was diluted with chloroform (100 ml), washed with a saturated aqueous ammonium chloride solution and water and then the solution was dried over sodium sulfate. The filtrate was evaporated and the residue was purified by silica gel column chromatography while using chloroform as the eluent. The product fraction was evaporated to give 50 mg (yield: 26%) of a yellow powder with a melting point range of 197-198 C.

Example 4 - preparation of 04-methYI-blopterin (2-amino4-methoxY-6-(12dihYdroxvoropyl) pteridine) To a solution of N2, 1', 2'-O-triacetylbiopterin (1,0 9, 2.75 mmoles), triphenyl-phosphane (12,08 9, 4.13 mmoles) and methanol (0.15 ml, 3.7 mmoles) in dry dioxane (30 ml) was added diisopropyl azodicarboxylate (0.81 9, 4.1 mmoles). After stirring for 1.5 hour at room temperature, the mixture was evaporated to dryness. The residue was purified by silica gel column chromatography while using an ethylacetate/CHCI3 (1:4) mixture as the eluent. The product fraction was evaporated and dried in vacuum to give 0.4 9 (yield: 38%) of N2, 1',2'-O-triacetyl-04-methylbiopterin. Deacetylation of this reaction product (0.28 9, 0 74 mmole) was done by stirring it in absolute methanol (20 ml) and triethylamine (4 ml) for 24 hours. Evaporation to dryness, treatment of the residue with ether, filtration and drying gave 0.172 9 (yield: 83%) of 04-methyl-biopterin with a melting point range of 160-161 C.

Example 5 - preparation of 2-amino-4-hvdroxYlamino-6-phenYlpteridine.

A suspension of 2,5,6-tnamino-4-methoxypyrimidine dihydrochloride (1 9, 4 mmoles) in methanol (40 ml) was heated to boiling and then a solution of phenylglyoxalmonoxime (1 9, 6.6 mmoles) in methanol (10 ml) was added dropwise. A clear solution is obtained from which on reflux for 2 hours a precipitate was separated out. The solid (hydrochloride salt) was filtered off, suspended in water (30 ml) and then neutralized to pH 8 by concentrated ammonia. The resulting precipitate was collected, washed with water and ethanol and dried at 100 C to give 0.84 9 of a yellow powder (yield: 82%).

Examples 6 to 53 - synthesis of 2-amino4-dialkvlamino4-arYIPteridines' 2 amino4-di(arylalkyl)amlno-6-arylpteridines, 2-amino-4-alkYlamino-6arYInten dines, 2-amino4-(N-containinn heterocyclic amino)-6arYInteridines and 2 amino4-alkoxy-6-arvlpteridines The procedure for the synthesis of the following 2-amino4-dialkylamino-6 arylpteridines, 2amino-4-dialkylamino-6-arylpteridines, 2-amino4-alkylamino 6-arylpteridines, 2-amino-4-(N-containing heterocyclic amino)-6arylpteridines and 2-amino4-alkoxy-6-arylpteridines proceeds in three steps: a) a solution of 2,6-diamino4-chloro-5-p-chlorophenylazopyrimidine (a compound known from British Patent No. 677,342) (5.0 9, 16.6 mmoles) in DMF (50ml) and 0.12 mole of the appropriate reactant, being selected from the group consisting of secondary alkylamines and arylalkylamines (e. g. dimethyl-amne in ethanol (50%), diethylamine, di-n-propylamine or dibenzylamine), primary amines (e.g. an adamantanamine), heterocyclic amines (e.g. morpholine, piperidine, pyrrolidine, piperazine or N-methyl piperazine) and alcaline metal alkoxides (e.g. sodium ethoxide or sodium isopropoxide), were heated in an oil bath at 70 C for 5 hours. Then water (50 ml) was added, cooled and the yellow precipitate collected, washed with water and dried. Recrystallization from ethanol or a DMF/water mixture provided the relevant 2,6-diamino4-dialkylamino-5-p-chloro phenylazopyrimidine, 2,6-diamino4-di(arylalkyl)amino-5-p-chlorophenylazopyrimidine, 2,6-dIamino-4-alkyl-amino-5-p-chlorophenylazopyrimidine, 2,6-diamino-4-(N-containing hetero-cyclic amino)-5-p-chlorophenylazo pyrimidine or 2,6-diamino4-alkoxy-5-p-chlorophenylazopyrimidine with a yield ranging from 55 to 90% b) a suspension of the pyrimidine compound (3.28 g, 10 mmoles) resulting from step (a) in methanol (70 ml) and concentrated ammonia (10 ml) was reduced in a shaking apparatus under a hydrogen atmosphere in the presence of a Raney nickel catalyst (3.5 g) for 2 days. The catalyst was filtered off under argon atmosphere and then the filtrate evaporated in vacuo to dryness. The residue was treated with ether to remove p chloroanilne, filtered and then the solid stirred in methanolic HCI (10%, 50 ml) overnight. The dhydrochloride salt (obtained with a yield ranging from to 90%) of the relevant 2,5,6-triamino-4dialkylaminopyrimidine, 2,5,6 triamino-4-alkoxypyrimidne, 2,5,6-tnamino-4di(arylalkyl)aminopyrimidine, 2,5,6-triamino-4-alkylaminopyrimidine or 2,5,6-triamino-4-(N-containing heterocyclic amino) pyrimidine, was collected and dried in a vacuum desiccator over KOH c) to a boiling solution of the 2,5,6-triamino-4- substituted pyrimdine dihydrochloride salt (5 mmoles) from step (b) in methanol (20 ml) was added a solution of the relevant arylglyoxalmonoxime (7 5 mmoles) in methanol (10 ml) dropwise and then the mixture was heated under reflux for 3 hours. After cooling, the suspension or solution was made alkaline by means of concentrated ammonia up to pH 9 and the resulting precipitate was filtered off, washed with water and dried. Recrystallization was done from ethanol and a DMF/water mixture, respectively, such as to provide a yellow solid with a yield ranging from 50 to 85%.

The following compounds were prepared according to the above general procedure: 2-amino-4-dimethylamino-6-phenylpteridine (example 6); 2-amino4-dimethylamino-6-(4-tolyl) pteridine (example 7); 2-amino4-dimethylamno-6-(4-methoxyphenyl)pteridine (example 8); 2-amino4-diethylamino-6-phenylpteridine (example 9); 2-amno4-diethylamino-6-(4-chlorophenyl)pteridine (example 10); 2-amino-4-diethylamino-6-(4-methoxyphenyl)pteridine (example 11); 2-amIno-4-diethylamino-6-(3,4-dimethoxyphenyl)pteridine (example 12); 2-amno-4-dibenzylamino-6-phenylpteridine (example 13); 2-amino-4-dibenzylamino-6-(4-chlorophenyl)pteridine (example 14); 2-amino-4-dibenzylamino-6-(4-methoxyphenyl)pteridine (example 15); 2-amino-4-dibenzylamino-6-(3,4-dimethoxyphenyl)pteridine (example 16); 2-amno-4-dipropylamino-6-phenylpteridine(example 17); 2-amino4-dipropylamino-6-(4-chlorophenyl)pteridine (example 18); 2-amino4-dipropylamno-6-(4-methoxyphenyl)pteridine (example 19); 2-amino-4-dipropylamino-(3,4-dimethoxyphenyl)pteridine (example 20); 2-amino-4-morpholino-6-phenylpteridine (example 21); 2-amino4-morpholino-6-(4-chlorophenyl)pteridine (example 22), 2-amino4-morpholino-6-(4-methoxyphenyl)pteridine (example 23); 2-amino4-morpholno-6-(3,4-dimethoxyphenyl)pteridine (example 24); 2-amino-4-piperidino-6-phenylpteridne (example 25); 2-amino-4-piperidino-6-(4-chlorophenyl)pteridine (example 26); 2-amino4-pipendino-6-(4-methoxyphenyl)pteridine (example 27); 2-amino4-pipendino4-(3,4-dimethoxyphenyl)pteridine (example 28); 2-amino-4-N-methylpiperazino-6-phenylpteridine (example 29); 2-amino-4-N-methylpperazino-6-(4-chlorophenyl)pteridine (example 30); 2-amno-4-N-methylpiperazno-6- (4-methoxyphenyl) pteridine (example 31); 2-amino-4-methylpiperazino-6- (3, 4-dimethoxyphenyl) pteridine (example 32); 2-amino-4-pyrrolidino-6- (4-methoxyphenyl) pteridine (example 33); 2-amino-4-piperazino-6-phenylpteridine (example 34); 2-amino-4-piperazino-6- (4-chlorophenyl) pteridine (example 35); 2-amino-4-piperazino-6- (4-methoxyphenyl) pteridine (example 36); 2-amino4-piperazino-6- (3, 4-dimethoxyphenyl) pteridine (example 37); 2-amino-4-dibenzylamino-6-(3, 4,5-trimethoxyphenyl) pteridine (example 38) ; 2-amino4-morpholno-6- (3, 4, 5-trimethoxyphenyl) pteridine (example 39); 2-amino-4-(3-adamantylamino)-6-(3,4,5-trimethoxyphenyl) pteridine (example 4o); 2-amino4-(3-adamantylamno)-6-naphtylpteridne (example 41); 2-amino-4-(4-adamantylamino)-6-(3,4,5-trimethoxyphenyl) pteridine (example 42); 2-amino-4-(4-adamantylamno)-6-naphtylpteridine (example 43); 2-amino4-morpholino-6-(3,4-formylidene-3,4-dihydroxyphenyl)pteridine

(example 44);

2-amino4-dimethylamino-6-(3,4-formylidene-3,4-dihydroxyphenyl)pteridIne

(example 45);

2-amino-4-pyrroldino-6-(3, 4-dimethoxyphenyl) pteridine (example 46); 2-amino4-dimethylamino-6-(3, 4-dimethoxyphenyl) pteridine (example 47); 2-amino-4-dimethylamino-6-methylpteridne (example 48); 2-amino4-ethoxy-6-phenylpteridine (example 49); 2-amino-4-propylamino-6-phenylpteridine (example 50); 2-amino-4-propylamino-6-(3, 4-dimethoxyphenyl) pteridine (example 51); 2-acetamdo-4-isopropoxy-6-(3,4-dimethoxyphenyl) pteridine (example 52); and 2-amino4-ethoxy-6-(3,4-dimethoxyphenyl)pteridine (example 53); Example 54 - synthesis of 2,6-diamino4-ethoxY-nYrimidine To a solution of sodium (1. 05 9) in ethanol (50 ml) was added 4-chloro 2,6-diaminopyrimidne (6 9, 41 4 mmoles). The resulting solution was heated in a reactor for 6 hours at 160 C. The reaction mixture was cooled down and the precipitated sodium chloride was filtered off. The filtrate was concentrated and precipitated from ethanol (two times), affording the pure title compound as a white solid (4.53 9, 72% yield). The spectral data are identical to those described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961) 94, 12 Example 55 - synthesis of 2,6-diamino- 4-isoProPoxY-Pyrimidine The same procedure as in example 54 was followed using isopropanol instead of ethanol. The filtrate was pure enough for further reaction without purification The spectral data are identical to those described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961) 94, 12.

Example 56 - synthesis of 5-nitroso-2,6-diamino-4-ethoxv-ovrimidine To a solution of the compound of example 54 (6.13 9, 39.8 mmoles) in % aqueous acetic acid (57 ml) was added dropwise a solution of NaNO2 (3.29 9) in water (13 ml) at 80 C. A pink precipitate was formed which was stirred at 80 C for an additional 2 hours. The reaction mixture was cooled down in the refrigerator overnight and the resulting precipitate was filtered off, yielding the title compound as a pink powder (4 98 9, yield 68 %). Spectral data are identical with those described e.g. by W. Pfleiderer et al. in Chem. Ber(1961)94, 12.

Example 57 - synthesis of 5-nitroso-2,6-diamino-4-isoPronoxv-nYrimidine The same procedure was followed as In example 56 but starting from the compound of example 55. The product has identical spectral data to those described by W. Pfleiderer et al. (cited supra).

Example 58 - synthesis of 2.5,6-triamino-4-ethoxY-pvrimidine To a suspension of the compound of example 56 (7.12 9, 38.9 mmoles) in water (150 ml) at 60 C was added sodium dithionite (46.7 mmol, 8.12 9).

Additional sodium dithionite was added till the pink colour completely disappeared and a yellow solution was formed. The solution was stirred at 60 C for another 4 hours. Water was evaporated and the resulting residue was precipitated from a small amount of water, providing the title compound as a yellow powder (4.02 9, yield 61 %) Spectral data are identical with literature data (W. Pfleiderer et al cited supra).

Example 59 - synthesis of 2,56-triamino4-isopropoxy-pyrimidine The procedure of example 58 was followed, however using the compound of example 57 as the starting material. The spectral data of the product obtained are identical with the literature data (W. Pfleiderer et al. cited supra).

Example 60 - synthesis of 2-amino4-ethoxy-pteridin To a solution of 2,5,6triamino-4-ethoxy-pyrimidine (10.54 9, 62.37 mmoles) in ethanol (160 ml) was added glyoxal (40 % solution in water, 2.7 ml, 18.6 mmoles). The reaction mixture was refluxed for 4 hours. Some insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica, using a CH30H/CH2C12 mixture (5:95) as the eluent), providing the pure title compound (7.34 9, yield: 62 %) The spectral data of the product are identical with the literature data (W. Pfleiderer et al. cited supra) Exa mole 6 1 - synthesis of 2-am ino4- isopronoxy-pterid in The procedure of example 60 was repeated, however using isopropanol as the solvent instead of ethanol. The spectral data of the product obtained are identical with the literature data (W. Pfleiderer et al. cited supra).

Example 62 - synthesis of 2-amino4-ethoxypteridine-N8-oxide To a cooled (0 C) solution of the compound of example 60 (2.47 9, 12.9 mmoles) in trifluoroacetic acid (53 ml) was added dropwise 2.53 ml of a % aqueous H202 solution. The reaction mixture was kept at 4 C for two days in the refngerator, whereby another 1.25 ml of the same H2O2 solution was added after 1 day. The solution was concentrated in vacua. The residue was suspended in water and neutralized by the addition of a concentrated ammonia solution. Evaporation of the solvent in vacuo and purification of the residue by flash chromatography (silica, using a CH30H/CH2CI2 mixture (6:94) as the eluent) provided the title compound as a yellow powder (861 mg, yield: 32 %). Mass spectrum data are as follows: m/z (%) 230 ([M+Na]+, 30), 208 ([M+H]+7 100), 180 [(M+H-ethene)+, 10].

Example 63 - synthesis of 2-amino4-isopropoxYpteridine-N8-oxide The procedure as described in example 62 was followed, however using the compound of example 61 as the starting material. Mass spectrum data are as follows: m/z (%): 222 ([M+H]+, 100), 180 ([M+H-propene]+, 60) Example 64 synthesis of 2-amino-6-chloro4-ethoxYnteridine A suspension of the compound of example 62 (460 mg, 2.22 mmoles) in acetyl chloride (5.5 ml) was stirred at -40 C. Trifluoroacetic acid (1.69 ml) was then added dropwse. The resulting solution was slowly warmed up to O C and stirred for an additional 4 hours at 0 C. Reaction was carefully quenched with ice, followed by neutralization with a concentrated ammonia lS solution (pH = 8). The aqueous phase was extracted with CH2CI2 (five times).

The combined organic layers were concentrated in vacua and the residue was purified by flash chromatography (silica, using a CH30H/CH2CI2 mixture (1:99) as the eluent), thus providing the title compound as a yellow powder (360 mg, yield: 72 %). This compound was further characterized as follows: - mass spectrum: m/z (%): 226 ([M+H]+, 100), - 'H-NMR (200 MHz, DMSO-d6): 0 1.42 (3 H. t), 4.52 (2 H. q), 7.42 (2 H. d) and 8.85 (1 H. s) ppm, - '3C-NMR (50 MHz, DMSO-d6): o 14.19, 63.58, 121.74, 140.22, 150.99, 156.13, 161.98 and 165.97 ppm.

Example 65 - synthesis of 2-amino-6-chloro-4-isooropoxYnteridine The procedure as described in example 64 was followed, however starting from the compound of example 63 The mass spectrum data of the resulting compound are as follows: m/z (%): 240 ([M+H]+, 55), 198 ([M+H propane]+, 100).

Examples 66 to 83 - synthesis of 2-amino-6-arvl4-ethoxvpterldines and 2 amino-6-heteroarvl4-ethoxYpteridines The general procedure used for preparing 2-amino-6-aryl-4-ethoxy pteridines is as follows. to a degassed solution of the compound of example 64 (50 mg, 0.22 mmole) in THE (5 ml) was added a degassed solution of sodium carbonate (5 ml of a 0.4 M solution in water), tetrakis(triphenyl phosphine) palladium (0.013 mmole, 14 mg) and an arylboronic or (examples 72 and 73) heteroarylboronic acid (0.22 mmole). The solution was refluxed for 4 hours Solvents were concentrated in vacuo and the residue was purified by flash chromatography (silica) with an appropriate CH3OH/CH2CI2 mixture (2:98 or 3:97) as the eluent (except for the compound of example 82, which was eluted with an acetone/CH2CI2 (7:3) mixture). This procedure provided, with a yield ranging from 16 % to 60 % depending upon the aryl or heteroaryl group (from the arylboronic or heteroarylboronic acid) introduced at the 6position of the pteridine ring, the following pure final compounds which were characterized by their mass spectrum MS and optionally by their 'HNMR (200 MHz, DMSO-d6) spectrum: 2-amino-6-(p-methoxyphenyl)4-ethoxy-pteridine (example 66): MS 298 ([M+H]+, 100), 270 ([M+H-ethene]+, 55); 2-amino-6-(o-methoxyphenyl)4-ethoxy-pteridine (example 67): MS 298 ([M+H]+, 100), 270 ([M+H-ethene]+, 30); 2-amino-6-(m-methoxyphenyl)-4-ethoxy-pteridine (example 68): MS 298 ([M+H]+, 100), 270 ([M+H-ethene]+, 35); 'H-NMR: 1.46 (3 H. t), 3.85 (3 H. s), 4 58 (2 H. q), 7.06 (1 H. dd), 7.33 (2 H. br s), 7.46 (1 H. t), 7.68 (1 H. m) and 9 43 (1 H. s) ppm; 2-amino-6-(3,4-difluorophenyl)4-ethoxy-pteridine (example 69): MS 304 ([M+H]+,100), 270 ([M+H-ethene]+, 35); 'H-NMR: 1.45 (3 H. t)7 4.57 (2 H. q), 7.42 (2 H. br s), 7.60 (1 H. q), 7.98 (1 H. d), 8.16 (1 H. t) and 9.42 (1 H. s) ppm; - 2-amino-6-(p-dimethylaminophenyl)-4-ethoxy-pterldine (example 70): MS 311 ([M+H]+, 100), 283 ([M+H-ethene]+, 35); 2-amino-6-(p-trifluoromethylphenyl)4-ethoxy-pteridine (example 71): MS 336 ([M+H]+, 100), 308 ([M+H-ethene]+, 50); 2-amino-6-(2-thienyl)4-ethoxy-pteridine (example 72): MS 274 ([M+H]+, 100), 246 ([M+H-ethene]+, 40); - 2-amino-6-(3-thienyl)4-ethoxy-pteridine (example 73): MS 274 ([M+H]+, 100), 246 ([M+H-ethene]+, 45); 2-amino-6-(3,4-dichlorophenyl)-4-ethoxy-pteridine (example 74): MS 337 ([M+H]+, 100); H-NMR: 1.46 (3 H. t), 4.59 (2 H. q), 7.42 (2 H. br s), 7.81 (1H, d), 8.14 (1 H. dd), 8.37 (1 H. d) and 9.47 (1 H. s) ppm; 2-amino-6-(p-cyanophenyl)4-ethoxy-pteridine (example 75): MS 293 ([M+H]+, 100), 265 ([M+H-ethene]+, 65); 2-amino-6-(p-ethoxyphenyl)-4-ethoxy-pteridine (example 76): MS 312 ([M+H]+, 100), 284 ([M+H-ethene]+, 70); 2-amino-6-(p-fluorophenyl)-4-ethoxy-pteridine (example 77): MS 286 ([M+H]+, 100), 258 ([M+H-ethene)+, 45); 2-amino4-(p-ethylphenyl)-4-ethoxy-pteridine (example 78): MS 296 ([M+H]+, 100), 268 ([M+H-ethene)+, 45); 2-amino-6-(p-acetylphenyl)-4-ethoxy-pteridine (example 79): MS 310 ([M+H]+, 100), 282 ([M+H-ethene]+, 60); 2-amino-6-(3-methyl-4-fluorophenyl)4-ethoxy-pteridine (example 80): MS 300 ([M+H]+, 100), 272 ([M+H-ethene]+, 30); 2-amino-6-(p-thiomethylphenyl)-4-ethoxy-pteridine (example 81): MS 314 ([M+H]+, 100), 286 ([M+H-ethene]+, 35); 2-amino-6-(p-N,N-dimethylbenzamido)4-ethoxy-pteridine (example 82) MS 338 ([M+H]+, 100), 311 ([M+H-ethene]+, 15), and 2-amino-6-(3,4-dimethoxyphenyl)-4-ethoxy-ptendine (example 83): MS 328 ([M+H]+, 100), 300 ([M+H-ethene]+, 40).

Examples 84 to 98 - synthesis of 2-amino-6-arvl4-isoPronoxYPteridines and 2 amino-6-heteroarY14-isopropoxypteridines The procedure as described in examples 66-83 was followed while using 2-amino-6-chloro-4isopropoxypteridine as the starting material, except that longer reaction times were needed (refluxing overnight instead of 4 hours). This procedure provided, with a yield ranging from 10 % to 70 % depending upon the aryl or heteroaryi group introduced at the 6-position of the pterdine ring, the following pure final compounds which were characterized by their mass spectrum: - 2-amino-6-(3-methyl-4-methoxyphenyl)4-isopropoxypteridine (example 84): MS 326 ([M+H]+, 100), 284 ([M+H-propene]+, 30); 2-amino-6-(3,4-dimethylphenyl)-4-isopropoxypteridine (example 85): MS 310 ([M+H]+, 100), 268 ([M+H-propene]+, 60); 2-amino4-(3-chloro4-trifluoromethylphenyl)4-isopropoxypteridine (example 86). MS 384 ([M+H]+, 20), 342 ([M+H-propene]+, 50); 2-amino-6-(3-chloro4-fluorophenyl)-4-isopropoxypteridine (example 87): MS 334 ([M+H]+, 20), 292 ([M+H-propene]+, 50); - 2-amino-6-(p-N, N-diethylbenzamido)4-isopropoxypteridine (example 88): MS 381 ([M+H]+, 100); - 2-amino4-(p-trifluoromethylphenyl)4-isopropoxypteridine (example 89): MS 350 ([M+H]+, 100), 308 ([M+H-propene]+, 30); 2-amino-6-(3,4-difluorophenyl)-4-'sopropoxypteridine (example 90): MS 318 ([M+H]+, 100), 276 ([M+H-propene]+, 50); 2-amino4-(p-methoxyphenyl)4-isopropoxypteridine (example 91): MS 312 ([M+H]+, 100), 270 ([M+H-propene]+, 50); 2-amino-6-(p-ethoxyphenyl)-4-isopropoxypteridine (example 92). MS 326 ([M+H]+, 55), 284 ([M+H-propene]+, 100); 2-amino4-(p-dimethylbenzamido)-4-isopropoxypteridine (example 93): MS 353 ([M+H]+, 75), 311 ([M+H-propene]+, 100); 2-amino4-(3-thienyl)4-isopropoxypteridine (example 94): MS 288 ([M+H]+, 55), 246 ([M+H-propene]+, 100); 2-amino4-(p-cyanophenyl)-4-isopropoxypteridine (example 95): MS 307 ([M+H]+, 40), 265 ([M+H-propene]+, 100); - 2-amino-6-(p-benzoic acid methyl ester)-4-isopropoxypteridine (exam- ple 96): MS 340 ([M+H]+, 75), 298 ([M+H-propene]+, 100); 2-amino4-(p-acetylphenyl)-4-isopropoxypteridine (example 97) MS 324 ([M+H]+, 55), 282 ([M+H-propene]+, 100); and 2-amino4-(3,4-dimethoxyphenyl)4-'sopropoxypteridine (example 98): MS 342 ([M+H]+, 100), 300 ([M+H-propene]+, 60).

Example 99 - synthesis of 2,6-diamino-5-nitroso4-hYdroxYpvrimidine To a solution of 2,6-diamino-4-hydroxypyrimdine (12.9 9, 102.2 mmoles) in 200 ml of a 10% acetic acid solution in water at 80 C was added dropwise a solution of NaNO2 (7.05 9, 102.2 mmoles) in 20 ml water. A pink precipitate was formed, which was further stirred for 1 hour at 80 C. The reaction mixture was cooled down in the refrigerator overnight. The precipitate was filtered off and dried over P205, providing the title compound as a pink powder (15.43 9, yield: 97%). The spectral data are In accordance with literature data (Landauer et al. in J. Chem. Soc. (1953) 3721-3722).

Example 100 - synthesis of 2 5.6-triamino4-hvdroxvpvrimidine A suspension of the compound of example 99 (15 9, 96.7 mmoles) in an ammonium sulfide solution (20 % in water, 200 ml) was stirred overnight at C The reaction mixture was cooled down in the refrigerator and the precipitate was filtered off, providing the title compound as a yellow powder (11.33 9, yield: 83 %). The spectral data are identical with literature data (Landauer et al. cited supra).

Example 101 - synthesis of 2-amino-6-(3,4-dimethoxvPhenvl)pterine To a boiling solution of the compound of example 100 (2.4 9, 17 mmoles) in methanol (100 ml, with 0.9 N HCI) was added dropwise a solution of 3,4dimethoxyphenylglyoxal mono-oxime (3.8 9, 18 mmoles) in methanol (100 ml). The reaction mixture was heated under reflux for 4 hours. The precipitate formed was filtered off, washed with water, then ethanol and diethyl ether, and dried over P205 under vacuum, providing the title compound as a yellow powder (4.33 9, yield: 85 %). This compound was further characterized by the following spectra: - 'H-NMR (500 MHz, TFA): 0 4.11 (3 H. s), 4.07 (3 H. s), 7.21 (1 H. d), 7.78 (1 H. dd), 7.81 (1 H. d) and 9.32 (1 H. s) ppm; - '3C-NMR (125 MHz, TFA): o 56.39, 56.7, 111.94, 113.21, 123.22, 127.41, 127.91, 145.92, 149.39, 150.46, 15247, 153.15, 155.13 and 161.59 ppm.

Example 102 - synthesis of 2-acetvlamino-6-(3.4-dimethoxvPhenYI)pterine A suspension of the compound of example 101 (10.46 9, 35 mmoles) in acetic anhydride (600 ml) and acetic acid (200 ml) was reflexed for 1 hour until a clear solution was formed By cooling down the reaction mixture in the refrigerator, the precipitate formed was filtered off, washed with ethyl acetate and dethyl ether, and then dried over P205 under vacuum, providing the title compound as a yellow powder (9.19 9, yield: 77 %). This compound was further characterized by the following spectra: - MS: m/z (%): 300 ([M+H]+, 100); to - 'H-NMR (200 MHz, DMSO-d6): 0 2.22 (3 H. s), 3.84 (3 H. s), 3.87 (3 H. s), 7.14 (1 H. d), 7.75 (2 H. m) and 9.51 (1 H. s) ppm.

Example 103 - synthesis of 2-acetvlamino-4-(1,2,4-triazolYI)-6-(3.4dimethoxY phenvl)pteridine To a solution of phosphorus oxychloride (1.68 ml, 18 mmoles) and 1,2,4-trazole (4.96 9, 72 mmoles) in dry pyridine (110 ml) was added the compound of example 102 (2.45 9, 7.18 mmoles). The suspension was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with pyridine, toluene and diethyl ether. The resulting solid was dried over P205 under vacuum, providing the title compound as a yellow powder (2 9, yield: 80 %) which afforded the following mass spectrum 392 ([M+H]+, 100).

Examples 104 and 105 - synthesis of 2-amino-4-mercantoethvl4-(3.4 dimethoxvphenyl)pteridine and 2-amino-4-mercaPtoisopronvl-(34 dimethoxvphenyl) pteridine To a suspension of the compound of example 103 (0.25 mmole, 100 mg) in dioxane (5 ml) was added 1 mmole of either ethanethiol (example 104) or sopropanethiol (example 105) and sodium (12 mg, 0.5 mmole). The suspension was stirred for 24 hours at room temperature. The solvent was concentrated in vacua and the residue purified by flash chromatography (silica, using a CH30H/CH2C12 mixture (5:95) as an eluent), followed by purification by preparative TLC, providing the pure title compounds as yellow powders with yields ranging from 20 to 30%. Both compounds were characterized by their mass spectrum as follows: - 2-amino-4-mercaptoethyl-6-(3,4-dimethoxyphenyl) pteridine: 344 ([M+H], 100); - 2-amino-4-mercaptoisopropyl-6-(3,4-dimethoxyphenyl) pteridne 357 ([M+H], 100).

Example 106 - synthesis of a mixture of 2,4-diamino-6-(p-methoxvPhenYl) pteridine and 2,4-diamino-7-(P-methoxvPhenvl)pteridine 2,4,5,6-tetra-aminopyrimidine (10 mmoles, 1.4 g) was dissolved in water (50 ml) and the pH was adjusted to 9 with ammonium hydroxide. A solution of 4 methoxyphenylglyoxal (11 mmoles, 1.8 g) In ethanol (10 ml) was added dropwise and the solution was reflexed for 1 hour. The yellow precipitate formed was filtered off and washed with water, ethanol and diethyl ether. NMR analysis reveals the obtention of a mixture (1 2 9, 45 % yield) consisting of 87 % of 2,4-diamino-7-(p-methoxyphenyl)pteridine and 13 % of 2,4-diamino-7- (p methoxy-phenyl)pteridine. 'H-NMR (500 MHz, TEA): o 4.04 (3 H. s), 4.08 (3 H. s), 7.15 (2 H. d), 7.25 (2 H. d), 8.19 (2 H. d), 8.30 (2 H. d), 9. 27 (1 H. s) and 937 (1 H. s) ppm Example 107 - synthesis of a mixture of 2-amino-6-(P- methoxvPhenvl)pterin and 2-amino-7-(-methoxvphenvl)pterin The mixture obtained in example 106 (1.2 9, 4.5 mmoles) was suspended in NaOH 1 N (80 ml) and reflexed till a solution was obtained The hot solution was treated with acetic acid till pH 5, then cooled down and the resulting precipitate was filtered off and washed with water, ethanol and diethyl ether, providing a mixture of 2-amino-6-(p-methoxyphenyl)pterin and 2- amino-7-(p-methoxyphenyl) pterin as a yellow powder (1 9, yield. 82 %). Mass spectrum: 270 ([M+H]+, 100).

Example 108 - synthesis of 2-acetvlamino-6-(P-methoxvPhenvl)Pterin and 2acetvlamino-7-(p-methoxyphenyl)pterin A suspension of the mixture obtained in example 107 (7.43 mmoles, 2 9) was suspended in a mixture of acetic anhydride (50 ml) and acetic acid (50 ml). The suspension was refluxed for 4 hours till a clear solution was obtained.

Some insoluble material was filtered off and the solution was partly evaporated till precipation starts. Further precipitation was achieved overnight in the refrigerator. The resulting precipitate was filtered off and washed with ethyl acetate and diethyl ether, providing a mixture of 2acetylamino4-(p methoxyphenyl)pterin and 2-acetylamino-7-(p-methoxyphenyl) pterin as a yellow powder (2.1 9, 91 % yield). Mass spectrum: 312 ([M+H]+, 100).

Example 109 - synthesis of 2-acetvlamino-4-(1.2,4-triazolvl)-6-(p-methoxv phenvl) pteridine and 2-acetVlamino4-(1,2.4-triazolvl)-7-(P-methoxvphenvl) pteridine To a suspension of the mixture obtained in example 108 (1.5 9, 4 mmoles) in dry pyridine (100 ml) was added 1,2,4-triazole (830 mg, 12 mmoles) and 4-chlorophenyl phosphorodichloridate (1 ml, 6 mmoles). The suspension was stirred for 2 days at room temperature under nitrogen. The solvents were removed in vacua. The solid material was suspended in dichloromethane and washed with 2 % HCI. Evaporation of the solvents provided a mixture of 2-acetylamino4-(1,2,4-triazolyl)-6-(p-methoxyphenyl) pteridine and 2-acetylamino-4-(1,2,4-triazolyl)-7-(p-methoxyphenyl) pteridine.

Example 110 - synthesis of 2-amino-4-isooropoxv-7-(P-methoxvphenvl) Pteridlne To a suspension of the mixture obtained in example 109 (180 mg, 0.50 mmole) in isopropanol (8 ml) was added sodium (23 mg, 1 mmole). The suspension was stirred at room temperature overnight. The solvents were evaporated and the residue was purified by preparative TLC (silica, using a methanol/CH2CI2 (7:93) mixture as the eluent). At this stage, both regio isomers obtained were separated, thus providing the pure title compound as a yellow powder (yield 45 %) which was further characterized by its mass spectrum: 312 ([M+H]+, 65), 270 ([M+H-propene]+, 100).

Example 111 - synthesis of 2-amino4-lsopropoxy-7-(3,4-dimethoxyphenYl) pteridine The sequence of reactions described in examples 106 to 110 was followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4 methoxyphenylglyoxal in the first step. This provided 2-amino-4isopropoxy-7- (3,4-dimethoxyphenyl) pteridine, a compound which was further characterized by its mass spectrum: 342 ([M+H]+, 55), 300 ([M+H-propene]+, 75).

Example 112 - synthesis of 2-amino-4-ethoxY-7-(3,4-dimethoxYphenvl) 1 0 ptendine The sequence of reactions described In examples 106 to 110 was followed, however staring from 3,4-dimethoxyphenylglyoxal instead of 4methoxyphenylglyoxal in the first step, and from ethanol instead if sopropanol in the last step. This provided 2-amino-4-ethoxy-7-(3,4dimethoxyphenyl) pteridine, a compound which was further characterized as follows - MS: 328 ([M+H]+, 100), 300 ([M+H-ethene]+, 40); - 'H-NMR (500 MHz, DMSO-d6): o 1.44 (3 H. t), 3.86 (3 H. s), 3.88 (3 H. s) , 4.54 (2 H. q), 7.13 (1 H. d), 7.16 (2 H. br s), 7.85 (1 H. d), 7.88 (1 H. dd) and 9.06 (1 H. s) ppm; - 43C-NMR (125 MHz, DMSO-d6): 0 14.25, 5567, 55.76, 63.06, 110.39, 111.89, 121.13, 121.25, 128.24, 136.87, 149.28, 151.62, 155.82, 156.72, 162 03 and 166.70 ppm.

Example 113 - synthesis of 2-amino-4-methoxY-7-(3.4-dimethoxYPhenvl) pteridlne The sequence of reactions described in examples 106 to 110 was followed, however starting from 3,4-dimethoxyphenylglyoxal instead of 4methoxyphenylglyoxal in the first step, and from methanol instead if isopropanol in the last step. This provided 2-amino4-ethoxy-7-(3,4 dimethoxyphenyl) pteridine, a compound which was further characterized by its mass spectrum: 314 ([M+H]+, 100), 300 ([M+H-methane]+, 20).

E)(AMPLE 114 - synthesis of 3,4-dimethoxyPhenYInIYoxalmonoxime SeO2 (0.33 mole) was heated to 50 C in a mixture of dioxane (250 ml) and water (10 ml) After dissolution of SeO2, 3,4-dimethoxyacetophenone (0.3 mole) was added and the mixture heated under reflux for 16 hours. The hot solution was filtered in order to remove selenium, the filtrate was evaporated, the oily residue dissolved in CHC13 (300 ml), then washed with saturated NaHCO3 solution (100 ml) and water. The organic phase was dried over Na2S2O4, filtered and evaporated. The yellow oil was distilled in vacuum, the resulting 3,4-dimethoxyphenylglyoxal was dissolved in methanol (50 ml) and water (200 ml), then acetonoxime (0.25 mole) was added and the pH adjusted to to 4 by 2 N HCI. The solution was heated to 50 C for 2 hours, then cooled to 0 C and the resulting crystals collected. After washing with cold water and drying in a vacuum desiccator, 3,4-dimethoxyphenylglyoxalmonoxme was obtained with a yield of 71 %, optionally recrystallized from CHCI3 or acetone, and characterized by H-NMR (200 MHz, DMSO-d6) showing peaks at 3. 84 (3 H. s), 7.06 (1 H. d), 7.51 (1 H. s), 7.75 (1 H. d), 8.10 (1 H. s) and 12.51 (1 H. s) ppm.

Example 115 - alternative synthesis of 2-amino4-isooroPoxy-6-(34 dimethoxYphenYl)pteridine To a suspension of the compound of example 59 (1.16 9, 6.34 mmole) in isopropanol (1.25 M HCI, 30 ml) was added the compound of example 114 (6.34 mmole, 1 32 9). The reaction mixture was refluxed for 5 hours, then cooled down and the pH was adjusted to 9 by the addition of an aqueous concentrated solution of NH3 The precipitate was filtered off and further purified by flash chromatography over silica gel, using a isopropanol/CH2CI2 (1:99 to 3:97) mixture as the eluent, thus providing as a yellow powder 1. 34 9 of 2-amino-4-isopropoxy-6-(3,4-dimethoxyphenyl)pteridine, i.e. the compound of example 98 (yield: 62 %).

Example 116 - synthesis of 2.6-diamino4-(1,2.3.6-tetrahYdroPYridinYl) pyrimidine To a suspension of 6-chloro-2,4-diaminopyrimidine (6 9, 41mmole) in toluene (50 ml) was added 1,2,3,6-tetrahydropyridine (8.23 ml, 91 mmole). The resulting suspension was heated to reflex until a solution was obtained, then the solution was reflexed for 5 hours The reaction mixture was cooled down and water was added. The precipitate formed was filtered off and washed with toluene, providing 2,6-diamino-4-(1,2,3,6tetrahydropyridinyl)-pyrimidine as a white powder (7.4 g, yield 94 %).

Example 117 - synthesis of 5-nitroso-2,6-diamino-4-(1,2,3,6-tetrahYdro pyridinyl)pyrimidine To a solution of the compound of example 116 (7.4 g, 38.7 mmole) in water (80 ml) and acetic acid (3.87 ml) was added a solution of sodium nitrite (2 94 g, 42.6 mmole) in water. The pink precipitate formed was filtered off and washed with water, providing 5-nitroso-2,6-diamino-4-(1,2,3,6- tetrahydro pyridinyl)pyrimidine (7.83 g) with a yield of 92 %.

Example 118 - synthesis of 2,5,6-triamino4-(1,2,3.6-tetrahYdroPyridinyl) pyrimidine To a suspension of the compound of example 117 (4 g, 18 mmole) In water (40 ml) was added sodium dithionite (7.9 g, 45 mmole). The suspension was heated to 90 C until a solution was obtained. After cooling down, the 2,5,6-trIamino-4-(1,2,3,6-tetrahydropyridinyl)pyrimidine precipitate formed was filtered off and used as such for further reaction.

Example 119 - synthesis of 2-amino-4-(1,2,3,6-tetrahYdronYridinvl)-6-(34 dimethoxyphenyl)pteridine To a solution of the reaction product of example 118 (2.22 g, 10.8 mmole) in methanol (with 1 N HCI, 50 ml) was added the compound of example 114 (2.26 g, 10.8 mmole). The solution was refluxed for 3 hours. The pH of the reaction was adjusted to 8 by the addition of an aqueous concentrated ammonia solution. The resulting precipitate was filtered off and further purified by flash chromatography over silica gel, using a CH30H/CH2CI2 mixture (3:97) as the eluent. This provided a yellow powder (2.56 g, yield 65 %) of 2-amino 4-(1,2,3,6-tetrahydropyridinyl)-6-(3,4-dimethoxyphenyl)pteridine which was characterized by the following spectra H-NMR (200 MHz, DMSO-d6) 0 3, 84-3.88 (3 H. s), 4.45 (2 H. s), 4.75 (2 H. s), 5.85-5.94 (1 H. m), 7.12 (2 H. d), 7.40 (2 H. s), 7.66 (1 H. s), 7.72 (2 H. d) and 9.39 (1 H. s) ppm; MS: 365 ([M+H]+, 100).

Example 120 - TNF-a and IL-1 assays Peripheral blood mononuclear cells (herein referred as PBMC), in response to stimulation by lipopolysaccharide (LPS), a gram-negative bacterial endotoxin, produce various chemokines, in particular human TNF-a and IL-1 if. The inhibition of the activation of PBMC can be measured by the level of suppression of the production of TNF-a or IL-1,3 by PBMC in response to stimulation by LPS Such inhibition measurement was performed as follows: PBMC were isolated from heparinized peripheral blood (Huffy coat) by density gradient centrifugation. LPS is then added to the PMBC suspension in complete medium (106 cells /ml) at a final concentration of 1,ug/ml. The pteridine derivative to be tested was added at different dilution levels, and the cells were incubated at 37 C for 72 hours. The supernatants were collected, and TNF-a or IL-1 concentrations were measured with respectively an anti-TNF antibody or an anti-lL-1 antibody in a sandwich ELISA (Duo Set ELISA human TNFa, commercially available from R&D Systems, United Kingdom).

The calorimetric reading of the ELISA was measured by a Multiskan RC plate reader (commercially available from ThermoLabsystems, Finland) at 450 nm (reference wavelength 690 nary). Data analysis was performed with Ascent software 2.6. (also from ThermoLabsystems, Finland): a standard curve (recombinant human TNFa) was drawn and the amount (pg/ml) of each sample on the standard curve was determined.

The % inhibition of human TNF-a production or human IL-1,3 was calculated using the formula: % inhibition = (pg/ml in sample - pg/ml min.) / (pg/ml max. - pg/ml min.) -1 wherein: - min. pg/ml in culture medium without test compound, and - max.: pg/ml in culture medium + LPS without test compound.

Tables 1 and 2 hereinafter show the IC50 values (expressed in,uM) of the tested compounds, being represented by the general formula (I), in these TNF-o and IL-1 assays.

TABLE 1

Example n TNF-3IL 1

24 o41 5.5 6.7> 40 98 3.5> 40 119 0.515

TABLE 2

Example n TNF-a Example n TNF-u 59 1 8.0 83 6.6 63 4.0 85 6.7 9.1 1 87 7.5 66 4.5 89 9.1 67 10 0 go 1 6.6 68 10.0 91 6.2 72 8.5 92 10.0 77 8.1 94 7.6 78 8.5 95 6.3 6 8 97 9.1 81 10.0 3 5 Example 121 - protection anainst lethal toxic shock.

When a control group of 14 sham treated (saline injection) C3H mice are injected ntraperitoneously with 100 lug LPS per mouse, all animals die within 1-3 days after injection. However when a group (16 animals) of the same C3H mice were treated for 2 days with the ptendine derivative of example 24 ('ntraperitoneous administration of 20 mg/kg/day; a hrst injection at the same time as the LPS injection, a second Injection 24 hours later), all mice were significantly protected from acute shock related mortality: - 14 animals permanently survived the challenge of a LPS lethal dose, and - 2 animals showed a significantly prolonged survival (5 days).

Thus it can be concluded that treatment with a pteridine derivative of the Invention provides an unexpectedly nearly complete protection against lethal toxic shock.

Example 122 - protection against a lethal dose of TNF-a A model of TNF-a Induced shock in C57BL/6 male mice was performed as l O follows. Animals from the control group received an intravenous administration of a lethal dose of TNF-a (10 lug) in the tail. Animals from the test group received three intraperitoneous injections of a pteridine derivative (20 mg/kg/day) respectively 48 hours, 24 hours and immediately before an intravenous injection of TNF-a (10 lug).

Body temperature, a clinical sign of TNF-induced shock, was followed for 48 hours in control mice and in mice receiving the pteridine derivative of example 24: the body temperature of control mice dropped significantly (28.2 C) when compared to mice receiving the test compound (30.1 C).

The survival rate (at least 50%) of mice that received the pteridine derivatives of the invention In addition to the TNF-a dose (10 p9) was quite substantial, as shown in table 3.

TABLE 3

Example n Total number of Animals surviving 48 hours animals after TNF-a administration control 24 9 7 98 6 3 119 6 3 This model therefore demonstrates that in viva treatment with a pteridne derivative of this invention provides substantial and significant protection against a lethal dose of TNF-a.

Example 123 - reduction of tumor growth while inhibiting TNF-a toxicity A tumor model of melanoma (B16BL/6) in C57BL6 (B6) mice was performed as follows. On day 1, a group of 18 Be mice were injected with 1.5 x 106 B16BL/6 melanosarcoma cells. The group was further divided into the following sub-groups 3 days after the tumor cells injection: - a first control sub-group of 6 mice received vehicle (physiological solution) 3 times a week starting on day 3; - a second control sub-group of 5 mice received TNF-a (15,ug) on day 5 and, for surviving animals, TNF-a was again administered 3 times a week for 2 weeks; - a test sub-group of 7 mice ntraperitoneously received the pteridine derivative of example 24 at a dose of 20 mg/kg on each of days 3, 4 and 5; the latter third injection on day 5 occurred 2 hours before a first TNF- a intravenous injection (15 lug). Then the test compound (20 mg/kg/day) and TNFa (15,ug/day) were administered each subcutaneously 3 times a week for 2 weeks.

Substantial protection against TNF-a toxicity was achieved by the pteridine derivative of the invention in tumor bearing mice: 5 out of 7 animals of the test sub-group survived, compared to none of the second control group (which all died during day 5).

Furthermore, histological studies after two weeks treatment show that administration of the pteridine derivative of example 24 together with TNF-a leads to a significant reduction of tumor growth: the average tumor size (tumor size was measured as the largest diameter multiplied by the smallest diameter) in the test sub-group was 144 mm2, whereas the average tumor size in the first control group was 439 mm2. These data clearly demonstrate that the pteridine derivative of example 24 effectively protects mice against the toxicity of TNF-a while preserving its antitumor effects.

Claims (10)

1. ClAIMS 1. Use of a pteridine derivative for the manufacture of a

   medicament for the prevention or treatment of a disorder in a mammal, the said disorder being selected from the group consisting of: - septic or endotoxic shock, - TNF-a- mediated diseases, - pathologies and conditions associated with and/or induced by abnormal levels of TNF-a occurring In a systemic, localized or particular tissue type or location in the body of the mammal, - toxic effects of TNF-a and/or anti-cancer chemotherapeutic agents, - injuries aftemrradabon of a tissue of the mammal by radio-elements, and - cachexia, the said pteridine derivative having the general formula (1): R' x 1 5 R2lNiN:R4 wherein X represents an oxygen atom or a group with the formula S(O)m wherein m is an integer from O to 2, or a group with the formula NZ and wherein: - R. is a group selected from the group consisting of C,-7 alkyl, C2 7 alkenyl, C27 alkynyl, C3,0 cycloalkyl, C3-jo cycloalkenyl, aryl, alkylaryl, arylalkyl, heterocyclic, heterocyclic-substituted alkyl and alkyl-substituted heterocyclic, each of said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, C, 4 alkyl, C, 4 alkoxy, C2 7 alkenyl, C2 7 alkynyl, halo C,-4 alkyl, C3-'o cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C,-7 alkyl, thio C3-'o cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic- substituted alkyltho, formyl, hydroxyl, sulfhydryl, nitro, hydroxylamino, mercaptoamino, cyano, carboxylic acid or esters or thioesters or amdes or thioamdes or halides or anhydrides thereof, thiocarboxylic acid or esters or thioesters or amides or thioamides or halides or anhydrides thereof, carbamoyl, thiocarbamoyl, ureido, thio ureido, amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxylalkylamino, mercaptoalkyl-amino, heterocyclic amino, hydrazino, alkylhydrazino and phenyl-hydrazino; or R. is a carboxyalkyl, carboxyaryi, thiocarboxyaryl or thiocarboxyalkyl group; - Z is a group independently defined as R. or Z is hydrogen or the group NZ together with R. s either hydroxylamno or an optionally substituted heterocyclic group containing at least one nitrogen atom; - R2 is selected from the group consisting of amino; acylamino; thioacylamino, carbamoyl; thiocarbamoyl, ureido; thioureido, sulfon-amido; hydroxylamino; alkoxyamno; thioalkylamino; mercaptoamino, hydrazino; alkylhydrazi no; phenyl hydrazi no; optionally substituted heterocycl ic radicals, C'7 alkylamino, arylamino; arylalkylamino; cycloalkylamino; alkenylamino; cycloalkenylamino; heterocyclic amino; hydroxyalkylamino; mercaptoalkylamino; C, 7 alkoxy; C3'0 cycloalkoxy; thio C, 7 alkyl; arylsulfoxide; arylsulfone; heterocyclic sulfoxide; heterocyclic sulfone; thio C3,0 cycloalkyl; aryloxy; arylthio; arylalkyloxy; arylalkylthio; oxyheterocyclic and thioheterocyclic radicals, - R4 is an atom or a group selected from the group consisting of hydrogen; halogen, C,-7 alkyl; C27 alkenyl; C27 alkynyl; halo C, 7 alkyl; carboxy C, 7 alkyl; acetoxy C,-7 alkyl; carboxyaryl; C'-7 alkoxy; C3 '0 cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic- substituted alkyloxy; thio C, 7 alkyl, thio C3,0 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; amino; hydroxylamino; mercapto-amino; acylamino, thioacylamino, alkoxyamino; thioalkylamino; acetal; thioacetal; carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides, thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl, sulfhydryl; ntro; cyano; carbamoyl; thiocarbamoyl, ureido; thio-ureido; alkylamino; cycloalkylamino; alkenylamino; cycloalkenylamino; alkynyl amino; arylamino; arylalkylamino; hydroxyalkylamino; mercapto alkylamino; heterocyclic amino; heterocyclic-substituted alkylamino, oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; cysteinyl acid, esters, thioesters, halides, anhydrides, amides and thioamides thereof; aryl groups optionally substituted with one or more substituents selected from the group consisting of halogen, C,-7 alkyl, C,-7 alkoxy, C27 alkenyl, C27 alkynyl, halo C, 7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C3,0 cycloalkoxy, aryloxy, arylalkyloxy, oxyhetero-cyclic, heterocyclcsubstituted alkyloxy, thio C' 7 alkyl, thio C3'0 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thio-ureido, sulfonamido, hydroxylamino, alkoxyamino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylc acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amdes thereof, alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amno, hydrazino, alkyl-hydrazino and phenylhydrazino; optionally substituted heterocyclic radicals; aromatic or heterocyclic substituents substituted wth an aliphatic spacer between the pteridine ring and the aromatic or heterocyclic substituent, whereby sad aliphatic spacer is a branched or straight, saturated or unsaturated alphatic chain of 1 to 4 carbon atoms which may contain one or more functions, atoms or radicals selected from the group consisting of carbonyl (oxo), thiocarbonyl, alcohol (hydroxyl), thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximno, alkyloximino, amino acid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-uredo, carboxylic acd or ester or thioester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, ntro, thio C'-7 alkyl, thio C3, 0 cycloalkyl, hydroxylamino, 3 0 mercaptoam i no, alkylam ino, cycloalkylam ino, alkenylam i no, cycloalkenyl amino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl, sulfonamide and halogen; branched or straight, saturated or unsaturated Emphatic chains of 1 to 7 carbon atoms optionally containing one or more functions selected from the group consisting of carbonyl (oxo), thiocarbonyl, alcohol (hydroxyl), thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyl-oximino, amino acid, cyano, acylamino; thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C, 7 alkyl, thio C3'0 cycloalkyl, hydroxylamino, mercapto-amino, alkylam i no, cycloal kylam ino, alkenylamino, cycloalkenylam i no, alkynyl amino, arylamno, arylalkylamino, hydroxyalkylamno, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl, sulfonamido and halogen; and - R3 is an atom or a group defined as R4, or R3 together with R4 forms a homocyclic or heterocyclic radical; and/or a pharmaceutically acceptable addition salt thereof and/or a stereoisomer thereof and/or a mono- or a di-N-oxide thereof and/or a solvate and/or a dihydro- or tetrahydropteridne derivative thereof.
2. 2. Use according to claim 1, wherein R. is selected from the group consisting of methyl, ethyl, isopropyl and pentyl
3. 3. Use according to claim 1, wherein R3 s 3-thienyl, 2-thienyl or a phenyl group
4. 4. Use according to claim 1, wherein R3 is a phenyl group with one or more substituents each independently selected from the group consisting of fluoro, methoxy, ethoxy, trifluoromethyl, dimethylamino, chloro, cyano, methyl, ethyl, carboxymethyl, methylthio, dimethylcarboxamido, diethylcarboxamido and methyl carboxyl ate.
5. 5. Use according to claim 1, wherein: - XisNZ, - Z is selected from the group consisting of hydrogen, methyl, ethyl, n- propyl and benzyl, and R' is selected from the group consisting of methyl, ethyl, n-propyl and benzyl.
6. 6. Use according to claim 1, wherein X is NZ and wherein the group NZ together with R' is selected from the group consisting of tetrahydropyridinyl, hydroxylamino, morpholinyl, piperidinyl, piperazinyl, 1,2,4-triazolyl and N methylpiperazinyl.
7. 7. Use according to claim 1, wherein the pteridine derivative is a compound selected from the group consisting of.

   - 2-amino-4-ethoxypteridine - 2-amino-4-ethoxy-6-chloro-pteridine 2-amino-4-ethoxy-6-(4-methoxyphenyl)-pteridine 2-amino-4-ethoxy-6-(2-methoxyphenyl)-pteridine 2-amino-4-ethoxy-6-(3-methoxyphenyl)-pteridine 2-amino-4-ethoxy-6-(3,4-difluorophenyl)-pteridine 2-amino-4-ethoxy-6-(4-dimethylamnophenyl)-pteridine 2-amino-4-ethoxy-6-(4-trifluoromethylphenyl)-pteridIne 2-amno4-ethoxy-6-(2-thienyl)-pteridine 2-amino-4-ethoxy-6-(3-thienyl)-pteridine 2-amino4-ethoxy-6-(3,4-dichlorophenyl)-pteridine 2-amino-4-ethoxy-6-(4-cyanophenyl)-pteridine 2-amino4-ethoxy-6-(4-ethoxyphenyl)-pteridine 2-amino-4-ethoxy-6-(4-fluorophenyl)-pteridine 2-amino4-ethoxy-6-(4-ethylphenyl)-pteridine 2-amino4-ethoxy-6-(4-acetylphenyl)-pteridine 2-amino-4-ethoxy-6-(3-fluoro-4-methylphenyl)-pteridine 2-amino-4-ethoxy-6-(4-methylthiophenyl)-pteridine 2-amino-4-ethoxy-6-(4-N, N-dimethylbenzamido)-pteridine 2-amino-4-isopropoxypteridine - 2-amino4-isopropoxy-6-chloropteridine 2-amino-4-isopropoxy-6-(3-methyl4-methoxyphenyl)-pteridIne 2-amino-4-isopropoxy-6-(3,4-dimethylphenyl)-pteridine 2-amino-4-isopropoxy-6-(3-chloro-4-trifluoromethylphenyl)-pteridine 2-amino-4-isopropoxy-6-(3-chlorol4-fluorophenyl)-pteridine 2-amino4-isopropoxy-6-(4-N, N-diethylbenzemido)-pteridine l O - 2-amino4-Isopropoxy-6-(4-trifluoromethylphenyl)-pteridine 2-amino-4-isopropoxy-6-(3,4-difluorophenyl)-pteridine 2-amino-4-isopropoxy-6-(4-methoxyphenyl)-pterldine 2-amno-4-isopropoxy-6-(4-ethoxyphenyl)-pteridine 2-amino-4-isopropoxy-6-(4-N, N-dimethylbenzamido)-pteridine l 5 - 2amino-4-isopropoxy-6-(3-thienyl)-pterdine 2-amino-4-isopropoxy4-(4-cyanophenyl)-pteridine 2-amino-4-isopropoxy-6-(4-benzoic acid methyl ester)-pteridine 2-amino4-isopropoxy-6-(4-acetylphenyl)-pteridine 2-amino-4-'sopropoxy-6-(3,4-dimethoxyphenyl)-pteridine 2-amino-4-ethyltho-6-(3,4-dimethoxyphenyl)-pteridine 2-amino-4-isopropyltho-6-(3,4-dimethoxyphenyl)-pteridine 2-amino-4-pentoxy-6-styrylpteridine, 2-amino-4-n-pentoxy-6-(1,2-dibromo-2-phenylethyl)-pteridine, 2-amino-4-methoxy-6-styryl-7-methoxypteridine, 2,4-diamino-6-phenyl-7-methylpteridine, 2-amino4-dimethylamino-6-phenylpteridine, 2-amino-4-dimethylamino-(4-tolyl)pteridine, 2-amino-4-dimethylamino-6-(4-methoxyphenyl)pteridine, 2-amino4-dethylamino-6-phenylpteridine, 2-amino-4-diethylamino-6-(4-chlorophenyl)pteridine, 2-amino-4-diethylamino-6-(4-methoxyphenyl)pteridine, 2-amIno-4-diethylamino-6-(3,4-dimethoxyphenyl)pteridine, - 2 - a m i n o 4 - d i b e n z y I a m i n o - 6 - p h e n y I p t e r i d i n e, 2-amino4-dibenzylamino-6-(4-chlorophenyl)pteridine, 2-amino4-dibenzylamino-6-(4-methoxyphenyl)pteridine, S - 2-amino4dibenzylamino-6-(3,4-dimethoxyphenyl)pteridine, 2-amino-4-dipropylamino-phenylpteridine, 2-amino-4-dipropylamno-6-(4-chlorophenyl)pteridine, 2-amino-4-dipropylamino-6-(4-methoxyphenyl)pteridine, 2-amino-4-dipropylamino-6-(3,4-dimethoxyphenyl)pteridine, l O - 2-amino4-morpholino-6-phenylpteridine, 2-amino-4-morpholino-6-(4-chlorophenyl)pteridine, 2-amino-4-morpholino-6-(4-methoxyphenyl)pteridine, 2-amino-4-morpholino-6-(3,4-dimethoxyphenyl)pteridine, 2-amino-4-pperidino-6-phenylpteridne, 2-amino-4-piperidino-6-(4-chlorophenyl) pteridine, 2-amino-4-piperidino-6-(4-methoxyphenyl)pteridine, 2-amino4-piperidino-6-(3,4-dimethoxyphenyl)pteridine, 2-amno4-N-methylpiperazino-6-phenylpterdine, 2-amIno-4-N-methylpiperazino-(4-chlorophenyl)pteridine, 2-amIno-4-N-methylpiperazno-6-(4-methcxyphenyl)pteridine, 2-amino-4-methylpiperazino-6-(3,4-dimetnoxyphenyl)pteridine, 2-amino-4-pyrrolidino-6-(4-methoxyphenyl)pteridine, 2-amino-4-pperazino-6-phenylpteridine, 2-amino-4-pperazino-6-(4-chlorophenyl)pteridine, 2-amino-4-piperazino-6-(4-methoxyphenyl)pteridine, 2-amino-4-piperazino-6-(3,4-dimethoxyphenyl)pteridine, 2-amino-4-dibenzylamino-6-(3,4,5-trimethoxyphenyl)pteridine, 2-amino-4-morpholino-6-(3,4,5-trimethoxyphenyl)pteridine, 2-amino-4-(3-adamantylamino)-6-(3,4,5-trimethoxyphenyl)pteridine, 2-amino4-(3-adamantylamino)-6-naphtylpteridine, 2-amino4-(4-adamantylamno)-6-(3,4, 5-trimethoxyphenyl)pteridine, 2-amino4-(4-adamantylamino)-6-naphtylpteridine, 2-amino-4-morpholino-6-(3,4-formylidene-3,4-dihydroxyphenyl)pteridine, 2-amino-4-dimethylamino-6-(3,4-formylidene-3,4-dihydroxyphenyl) pteridine, - 2-amino-4-pyrrolidino-6-(3,4, dimethoxyphenyl)pteridine, 2-amino-4-dimethylamino-6-(3,4-dimethoxyphenyl)pteridine, 2-amino4-dimethylamino-6-methylptendine, 2-amino-4-ethoxy-6-phenylpteridine, 2-amino4-propylamino-6-phenylpteridine, l 0 - 2-amino-4-propylamino4-(3, 4-dimethoxyphenyl)pteridine, 2-acetamido4-hydroxy-6-(3,4-dimethoxyphenyl)pteridine, 2-acetamido-4-'sopropoxy-6-(3,4-dimethoxyphenyl)pteridine, 2-amIno-4-ethoxy-6-(3,4-dimethoxyphenyl)pteridine, and - 2-amino4-( 1,2,3,6-tetrahydropyridinyl)-6-(3,4-dimethoxyphenyl) pteridine. l5
8. 8. Use according to claim 1, wherein the said disorder is septick shock and the medicament is for the treatment of a mammal with a serum level of interleukin-6 above 1,000 pg/ml at start of treatment.
9. 9. Use according to claim 1, wherein the said TNF-mediated disease is selected from the group consisting of neurodegenerative diseases, myelodysplastic syndromes and alcohol-'nduced hepatitis.
10. 10. Use according to claim 1, wherein the abnormal levels of TNF are levels exceeding by at least 10 % and at most 500% the TNF level present in a normal healthy subject.