MXPA00002203A - 2,3-diaryl-pyrazolo[1,5-b]pyridazines derivatives, their preparation and their use as cyclooxygenase 2 (cox-2) inhibitors - Google Patents

Abstract

The invention provides the compounds of formula (I) and pharmaceutically acceptable derivatives thereof in which:R0 is halogen, C1-6alkyl, C1-6alkoxy, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5;R1 and R2 are independently selected from H, C1-6alkyl, C1-6alkyl, substituted by one or more fluorine atoms, C1-6alkoxy, C1-6hydroxyalkyl, SC1-6alkyl, C(O)H, C(O)C1-6alkyl, C1-6alkylsulphonyl, C1-6alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)nNR4R5, (CH2)nSC1-6alkyl or C(O)NR4R5;with the proviso that when R0 is at the 4-position and is halogen, at least one of R1 and R2 is C1-6alkylsulphonyl, C1-6alkoxy substituted by oneor more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)nNR4R5 or (CH2)nSC1-6alkyl, C(O)NR4R5;R3 is C1-6alkyl or NH2;R4 and R5 are independently selected from H, or C1-6alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring;and n is 1-4. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.

Description

DERIVATIVES OF 2, 3-DIARIL-PIRAZOLO [1, 5-B] PYRIDAZINES, ITS PREPARATION AND ITS USE AS INHIBITORS OF THE CICLOOXYGENASE 2 (COX-2) FIELD OF THE INVENTION This invention relates to pyrazole [1, 5-b] pyridazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

BACKGROUND OF THE INVENTION It has recently been discovered that the enzyme cliclooxigenasa (COX) exists in two isoforms, COX-I and COX-2. COX-1 corresponds to the constitutive enzyme originally identified, while COX-2 can be rapidly and easily induced by a number of agents including mitogens, endotoxins, hormones, cytokines, and growth factors. Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is responsible for important physiological functions such as the conservation of gastrointestinal integrity and blood flow.

REF .: 32939 • A renal. In contrast, it is believed that the form capable of being induced, COX-.2, is responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to said agents, such as inflammatory agents, hormones. , growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, antipyretic and analgesic properties, without the potential side effects associated with the inhibition of COX-1. Now we have found a new group of compounds which are both potent and selective inhibitors of COX-2. The invention thus provides the compounds of formula (I) (I) and pharmaceutically acceptable derivatives thereof, in which: R ° is halogen, alkyl of 1 to 6 carbon atoms, akoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted by • one or more atoms of fluorine, or 0 (CK2) nNR4R5; R1 and R2 are independently selected from H, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by one or more fluorine atoms, alkoxy of the ß carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms carbon, S-alkyl of 1 to 6 carbon atoms, C (0) K, C (O) alkyl of 1 to 6 carbon atoms, alkylsulfonyl of the ß carbon atoms, alkoxy of the ß carbon atoms substituted by one or more fluorine atoms, O (CK2) nC02-alkyl of 1 to 6 carbon atoms, O (CH2) nS- to 1 qui lo of 1 to 6 carbon atoms, (CH2) nNR4R5, (CH2) "S- to the one of 1 to 6 carbon atoms or C (0) NR4R5; with the proviso that when R ° is a halogen and is in the 4-position, at least one of RJ and R 'is alkylsulfonyl of 1 £ carbon atoms, alkoxy of 1 to 6 carbon atoms substituted by one or more fluorine atoms , O (CH2) nC02-alkyl of 1 to 6 carbon atoms, O (CH2) nS-alkyl of the ß carbon atoms, or (CH2) nS-alkyl of the ß carbon atoms, C (0) NR R5; R3 is alkyl of 1 to 6 carbon atoms or NH2; R4 and R are independently selected from H, or alkyl of 1 to 6 carbon atoms or, together with the nitrogen atom to which they are attached, form a saturated ring of 4 to 6 members; and n is a number from 1 to 4. By pharmaceutically acceptable derivative is meant any salt, solvate or ester, or salt or solvate of that ester, pharmaceutically acceptable, of the compounds of formula (I), or any other compound, which upon administration the patient, whether capable of directly or indirectly providing) a compound of formula (I) or an active metabolite or residue thereof. It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may be used, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof. . Suitable pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts formed with organic or inorganic acids, preferably inorganic acids, for example, hydrochlorides, hydrobromides and sulphates. The term halogen is used to represent fluorine, chlorine, bromine or iodine. The term "alkyl" as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl or tert-butyl group. Preferably, R ° is in the 3 or 4 position of the phenyl ring, as defined in formula (I). Preferably, R1 is in the 6-position of the pyridazine ring, as defined in the formula (I) Preferably, R is F, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms, or O (CH2)! -3NR4R5. More preferably R ° is F, alkoxy of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms. Preferably, R1 is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms substituted by one or more fluorine atoms, 0 (CH2)? -3C02-alkyl of 1 to 4 carbon atoms carbon, 0 (CH2)? -3-S-alkyi of 1 to 4 carbon atoms, (CH2) 1_3-NR4R5, (CH2)? -3-S-alkyl of 1 to 4 carbon atoms or C (0) ) NR4R5 or, when R ° is alkyl of the β carbon atoms, alkoxy of 1 to 6 carbon atoms, O (CH2) nNR4R5, can also be H. More preferably R1 is to the 1 sulfonyl of 1 to 4 numbered atoms carbon, alkoxy of 1 to 4 carbon atoms substituted by one or more fluorine atoms or, when R ° is alkyl of the β carbon atoms, alkoxy of 1 to 6 carbon atoms, akoxy of 1 to 6 carbon atoms substituted by one or more fluorine atoms, or O (CH2) nNR R5, can also be H. Preferably, R2 is H. Preferably, R3 is methyl or NH2. Preferably R4 and R5 are independently alkyl of 1 to 3 carbon atoms or, together with the nitrogen atom to which they are attached, form a saturated ring of 5 to 6 members. Preferably, n is a number from 1 to 3, more preferably 1 or 2. Within the invention there is provided a group of compounds of formula (I) (group A) wherein: R ° is F, alkyl of 1 to 3 atoms of carbon, alkoxy of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms, or O (CH2) "NR4R5, R1 is alkylsulfonyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms substituted by one or more fluorine atoms, O (CH2) nC02- to 1 qui 1 or 1 to 4 carbon atoms, O (CH2) nS- to the one of 1 to 4 carbon atoms , (CH2) nNR4R5, (CH2) nS- to cui 1 of the 4 carbon atoms or C (0) NR4R5 or, when R ° is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms , alkoxy of 1 to 3 carbon atoms, substituted by one or more fluorine atoms, or O (CH2) nNR R5, can also be H; R2 is H. R; is metyl NH 2 R 4 V RJ are independently alkyl of 1 to 3 carbon atoms or, together with the nitrogen atom to which they are attached, form a saturated ring of 5 to 6 members; and n is a number from 1 to 3. Within group A, another group of compounds (group Al) is provided wherein R is F, methyl, alkoxy of 1 to 2 carbon atoms, OCHF2, or 0 (CH2) nNR4R5, R1 is methylsulfonyl, OCHF2, 0 (CH2) nC02-alkyl of 1 to 4 carbon atoms, 0 (CH2) nSCH3, (CH2) nNR4R5, (CH2) nSCH3 or C (0) NR4R5 or, when R is methyl, alkoxy of 1 to 2 carbon atoms, OCHF2, 0 (CH2) nN (CH3) 2, can also be H; R2 is H; -R3 is methyl or NH2; R4 and R5 are both methyl or, together with the nitrogen atom to which they are attached, form a saturated ring of 5 to 6 members; and n is a number from 1 to 2. Within group A, an additional group of compounds (group A2) is provided wherein R is F, alkoxy of 1 to 3 carbon atoms or, alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms; R1 is alkylsulfonyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms substituted by one or more fluorine atoms or, when R ° is alkoxy of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms, it can also be H; R is H; and R is methyl or NH2.

Within the groups A, Al and A2, R preferably occupies the 3- or 4-position of the phenyl ring and R2 preferably occupies the 6-position of the pyridazine ring. It should be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically-acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). Particularly preferred compounds of the invention are: 3 - (4-me t anosul foni 1-feni 1) -2- (-me t oxy-pheni 1) pyrazolo [1, 5-b] pyridazine; 6-difluoromethoxy-2- (4-fluoro-phenyl) -3- (4'-ethanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; 2- (4-Ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; 2- (4-Fluoro-phenyl) -6-methanesulfonyl-3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; 2- (-di-fluoromethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; 4- [2- (4-Ethoxy-phenyl) -pyrazolo [1, 5-b] pyridazin-3-yl] -enzylsulfonamide; 6-difluoromethoxy-2- (3-fluoro-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; and pharmaceutically acceptable derivatives thereof. The compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by its ability to selectively inhibit COX-2 in place of COX-1. In view of their selective inhibitory activity of COX-2, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of pain (both chronic and acute), fever and inflammation of a variety of conditions and diseases. Such conditions and diseases are well known in the art and include rheumatic fever, symptoms associated with influenza or other viral infections, such as the common cold; pain in the lower back and neck; headache, toothache, dislocations and distensions; iositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative diseases in the joints, including osteoarthritis; gout and ankylosing spondylitis; tendonitis; bursitis; conditions related to the skin, such as psoriasis, eczema, burns and dermatitis; injuries, such as injuries caused by sports and those that arise from surgical and dental procedures. The compounds of the invention may also be useful for the treatment of other conditions mediated by the selective inhibition of COX-2. For example, the compounds of the invention can inhibit cellular and neoplastic transformation and tumor growth of tumors and hence may be useful in the treatment of certain cancer diseases, such as colon cancer. The compounds of the invention can also prevent neuronal damage, by inhibiting the generation of neuronal free radicals (and hence oxidative stresses) and can therefore be used in the treatment of apoplexy.; epilepsy; and epileptic seizures (including grand mal, small malignancy, myoclonic epilepsy, and partial apoplectic seizures). The compounds of the invention also inhibit the contraction of smooth muscle induced by prostanoids and hence can be used in the treatment of dysmenorrhea and premature delivery. The compounds of the invention inhibit the inflammatory processes and therefore can be used in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; and inflammations in those diseases such as vascular diseases, migraine, periartis itis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet syndrome, polynes itis , gingivitis, conjunctivitis and myocardial izquemia. The compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and acute injuries to the eye tissue. The compounds of the invention may also be useful in the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's disease), Parkinson's disease and Cr eut z fel dt-Jakob disease), and vascular dementia (including dementia due to multiple infarcts), as well as dementia associated with lesions that occupy intracranial spaces, trauma, infections and related conditions (including HIV infections), metabolism , toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Deterioration of Memory Associated with Age. According to a further aspect of the invention, a compound of formula is provided (I) or a pharmaceutically acceptable derivative thereof, for use in human or veterinary medicine. According to still another aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition that is mediated by the selective inhibition of COX-2. According to a further aspect of the invention, there is provided a method of treating a human or animal subject suffering from a condition that is mediated by the selective inhibition of COX-2 which comprises administering to that subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative. According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the preparation of a therapeutic agent for the treatment of a condition that is mediated by selective inhibition of the COX-2, such as an inflammatory disorder. According to a further aspect of the invention, there is provided a method of treatment for a human or animal subject suffering from an inflammatory disorder, and such method comprises administering to that subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof. It should be understood that when reference is made to treatment, it includes both the treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise. It will be appreciated that the compounds of the invention can advantageously be used together with one or more therapeutic agents. Examples of suitable agents for adjunctive therapy include pain relievers, such as a glycine antagonist, a sodium channel inhibitor (e.g., lamotrigine), a P antagonist (e.g., an NKi antagonist), acetaminophen, or phenacetin.; an inhibitor of matrix metalloproteinase; a nitric oxide synthase (NOS) inhibitor (e.g., an iNOS inhibitor or an nNOS inhibitor); an inhibitor of the release or action of the alpha factor of tumor necrosis; an antibody therapy by (eg, monoclonal antibody therapy); a stimulant, including caffeine; an H2 antagonist, such as ranitidine; a proton pump inhibitor such as omeprazole; an antacid, such as aluminum or magnesium hydroxide; an antiflatulant, such as ethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-deoxyeedrine; an antitussive, such as codeine, hydrocodone, carmifen, carbetapentane, or dextramethorphan; a diuretic; or a sedative or non-sedating antihistamine. It should be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents. The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof, adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in a conventional manner in mixtures with one or more physiologically acceptable carriers or excipients. The compounds of formula (I) and their pharmaceutically acceptable derivatives can be formulated to be administered in any suitable manner. They can be formulated, for example, for topical administration or for administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. The pharmaceutical composition can be of a form such that it can effect the controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives. For oral administration, the pharmaceutical composition can take, for example, the form of tablets (including sublingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For transdermal administration, the pharmaceutical composition may be in the form of a transdermal patch, such as a transdermal iontophoretic patch. For parenteral administration, the pharmaceutical composition can be given as an injection or a continuous infusion (eg, intravenous, intravascular or subcutaneous). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending agents, stabilizers and / or dispersants. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation, preferably with an added preservative. Alternatively, for parenteral administration the active ingredients are in powder form for reconstitution with a suitable vehicle. The compounds of the invention can also be formulated as a depot preparation. These long-acting formulations are administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention are formulated with suitable materials, polymeric or hydrophobic (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. As stated above, the compounds of the invention are used in combination with other therapeutic agents. Thus the invention provides, in a novel aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with an additional therapeutic agent. The combinations referred to above can conveniently be presented for use in the form of pharmaceutical formulations, and thus, pharmaceutical formulations containing a combination as defined, together with a pharmaceutically acceptable carrier or excipient, comprise a novel aspect of the invention. the invention. The individual components of such combinations can be administered, either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound differs from when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. A proposed daily dosage, of a compound of formula (I), for the treatment of man is 0.01 mg / Kg to 500 mg / Kg, such as 0.05 mg / Kg to 100 mg / Kg, eg 0.1 mg / Kg a 50 mg / Kg, which can be conveniently administered in 1 or 4 doses. The precise dose used will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25 mg / Kg to 10 mg / Kg is suitable for systemic administration. The compounds of formula (I) and pharmaceutically acceptable derivatives thereof are prepared by some method known in the art for the preparation of compounds of analogous structure.

Suitable methods for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives are described below. In the following formulas, R ° to R5 and n are as defined in formula (I) above unless otherwise stated; Hal is a halogen, such as Br or • I; X ~ is a counterion, such as I ", and alkyl is as previously defined, Thus, according to a first process (A), the compounds of formula (I) can be prepared by the reaction of a compound of formula (II) ) or a protected derivative thereof, with a boronic acid of formula (III) ("I") or a suitable derivative thereof in the presence of a suitable catalyst, based on a transition metal Suitable derivatives of formula (III) include esters of boronic acid, as described in R. Miyaura et al. al, J. Org. Chem., 1995, 60, 7508-7510 Conveniently the reaction is carried out in a solvent, such as an ether (eg, 1,2-dimethoxyethane), in the presence of a base, such as an inorganic base (for example, sodium carbonate), and employing a palladium catalyst, such as tetrakis (triphenylphosphine) palladium (O) .According to another process (B), the compounds of formula (I) wherein R3 is alkyl of the ß carbon atoms, can be prepared by oxidation of a compound of formula (IV) or a protected derivative thereof, under conventional conditions. Conveniently the oxidation is carried out using a monopersulfato compound, such as potassium peroxy onosui fate (known as Oxone ™) and the reaction is carried out in a solvent, such as an aqueous alcohol, (for example aqueous methanol), and a temperature that is between -78 ° C and the ambient temperature. According to another process (C), the compounds of formula (I) wherein R 1 is alkylsulfonyl of 1 to β carbon atoms, can be prepared by oxidation of a compound of formula (V) or a protected derivative thereof, under conventional conditions. Advantageously, the oxidation is carried out in the manner just described for process (B). According to another process (D), the compounds of formula (I) wherein R 1 is akoxy of 1 to 6 carbon atoms substituted by one or more fluorine atoms can be prepared by the reaction of an alcohol of formula (VI) or a protected derivative thereof with a halof luoroalkane under conventional conditions. Conveniently the reaction is carried out in a solvent, such as a polar solvent (for example, N, N-dimethyl formamide) in the presence of a strong base, such as an inorganic hydride (eg, sodium hydride), at room temperature and using the appropriate bromo fluoro alkane to give the desired compound of formula (I). According to another process (E) the compounds of formula (I) can be prepared by interconversion, using other compounds of formula (I) as precursors. The following procedures are illustrative of suitable interconversions. The compounds of formula (I) wherein R 1 and R 2 represent alkyl of 1 to 6 carbon atoms substituted by one or more fluorine atoms can be prepared from the appropriate compounds of formula (I) wherein R or R is hydroxyalkyl of 1 to 6 carbon atoms, C (0) H or C (O) alkyl of the 6 carbon atoms, by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for example, diethylsulfuryl trifluoride. Conveniently the reaction is carried out in the presence of a solvent, such as a halogenated hydrocarbon, (for example, dichloromethane), and at reduced temperatures, such as -78 ° C. The compounds of formula (I) wherein R and R represent C (0) H can be prepared from the corresponding compounds of formula (I) wherein R 1 or R 2 represent CH 2 OH by oxidation. Suitable oxidation agents include, for example, manganese (IV) oxide. Conveniently the oxidation is carried out in the presence of a solvent, such as a halogenated hydrocarbon (for example, chloroform), and at an elevated temperature (for example, at the reflux temperature). The compounds of formula (I) wherein R 1 or R represents hydroxyalkyl of 1 to 6 carbon atoms, and wherein the hydroxy group is attached to the carbon associated with the pyridazine ring, can be prepared by reduction of the compound of formula (I ) where R 1 or R 2 represents the corresponding aldehyde or ketone. Suitable reducing agents include hydrides as reducing agents, such as diisobutylaluminum hydride. Conveniently the reduction is effected in the presence of a solvent, such as a halogenated hydrocarbon (for example, dichloromethane), and at a reduced temperature such as -78 ° C. As those skilled in the art will appreciate, it may be necessary or desirable, at some stage in the synthesis of the compounds of formula (I), to protect one or more sensitive groups in the molecule, in order to prevent undesirable side reactions. Another process E) for preparing compounds of formula (I) thus comprises deprotecting the protected derivatives of the compounds of formula (I). The protecting groups used in the preparation of compounds of the formula (I) can be used in a conventional manner. See, for example, those described in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter GM Wuts, second edition, (John Wiley and Sons, 1991), which also describe methods for the elimination of such groups. compounds of the formula (II) can be prepared by halogenation of the compounds of the formula (VII) through conventional means. Thus, the esters of formula (VI) are first hydrolyzed to their corresponding acids, for example by treatment with a strong base (for example, sodium hydroxide), in the presence of a solvent (for example, ethanol) and at an elevated temperature. The corresponding acid is then treated with a halogenating agent, conveniently at room temperature and in a solvent (eg, a chlorinated hydrocarbon), conditions under which the acid undergoes both halogenation and decarboxylation.

Conveniently, the halogenating agent is a brominating agent, such as a bromide in the presence of a strong acid (for example, hydrobromic acid in acetic acid) or N-bromosuccinimide, to produce the corresponding compound of formula (II) wherein Hal it's bromine. The es: of formula (VII) can be prepared by the reaction of a compound of the formula (VIII) I rent (VIII) with a complex aminopyridazinium of formula (IX) under conventional conditions. Conveniently the reaction is carried out in the presence of a base, such as potassium carbonate, a solvent, such as N, N-dimethyl t-formamide and at room temperature. The boronic acids of formula (III) are both known compounds or can be prepared by methods found in the literature such as those described, for example, in EPA publication No. 533268. The compounds of formula (IV), (V) and (VI) can be prepared by methods analogous to those described for the preparation of the compound of formula (I) from compounds of formula (II). The compounds of formula (VIII) are either known compounds or can be prepared by methods found in the literature, such as those described, for example, in D H Wadsworth et al, J. Org. Chem., (1987), 52 (16), 3662-8 and J. Morris and D.G. Wishka, Synthesis (1994), (1), 43-6. The compounds of formula (IX) are either known compounds or can be prepared by methods found in the literature, such as those described in, for example, Y Kobayashi et al, Chem Pharm Bull, (1971), 19 (10) , 2106-15; T. Tsuchiya, J. Kurita and K. Takayama, Chem. Pharm. Bull. 28 (9) 2676-2681 (1980) and K Novitskii et al, Khim Geterotskil Soedin, 1970 2, 57-62. Certain intermediate compounds described above are novel compounds, and it should be understood that all intermediates found herein, form additional aspects of the present invention. The compounds of formula (II) are key intermediates and represent a particular aspect of the present invention. Conveniently, the. The compounds of the invention are isolated following the manipulation in the form of a free base. The pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared using conventional means. The solvates (for example hydrates) of a compound of the invention can be formed during the process of handling one of the process steps mentioned above. The following examples illustrate the invention although they do not limit the same in any way. All temperatures are in ° C. Flash column chromatography was carried out using Merk 9385 silica. Thin layer chromatography (TLC) was carried out on silica plates. The NMR was carried out on a Brucker 250 MHz spectrometer. The chemical shifts are provided with respect to the t re t ame ti ls i laño as the internal chemical shift reference, d in ppm. The following abbreviations were used: Me = methyl, s = singlet, d = doublet, t = triplet and m = ultiplete.

Example 1 β-Difluoromethoxy-2- (4-fluoro-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [i, 5-b] pyridazine (i) 6-Methoxy-2- (- fluoro-) methyl ester phenyl-pyrazolo [1, 5-b] pyridazin-3-carboxylic acid 1,8- Diazabicyl [5.4.0] undec-7-ene (3.39 ml) is added to a mixture of 3- (4-fluoropheni-1) -prop-2-yl-co-methyl ester (3.36 g) and sulfonate. of l-amino-3-methoxy-pyridazin-1-io mesitylene (6.1419 g) in acetonitrile (125 ml) and the mixture is stirred at room temperature for 48 hours. During the first two hours a stream of air is passed through the reaction. The mixture is concentrated in vacuo, dissolved in ethyl acetate (150 ml), washed with water (3 x 25 ml), dried (MgSO 4), filtered and evaporated in vacuo to give the title compound. as a brown solid (4.77 g). XH NMR (CDCl,): 8.4 (d, 1H, J = 10Hz) 7.85-7.90 (m, 2H) 7.1-7.2 (, 2H) 6.9-7.0 (d, 1H, J = 10Hz) 4.1 (s, 3H) 3.9 (s, 3H) MH * 302 Ref: 1 T. Tsuchiya, J. Kurita and K. Takayama, Chem. Pharm. Bull. 28 (9) 2676-2681 (1980). (ii) 6-Methoxy-2- (4-fluoro-phenyl-pyrazolo [1,5-b3-pyridazine-3-carboxylic acid] A mixture of 6-methoxy-2- (4-fluoro-phenyl-pyrazolo [1,5-b] pyridazine-3-carboxylic acid methyl ester (4469 g), sodium hydroxide is heated under reflux for 2 hours. 2N (50 ml) and methanol (90 ml) The cooled solution is added to 2N hydrochloric acid (200 ml) and the title compound isolated by filtration as a beige or yellowish solid. (3.639 g). 1U NMR (DMSO-dβ): 12.8 (br.s, 1H), 8.4 (d, 1H, J = 10Hz) 7.8-7.9 (, 2H) 7.21-7.32 (m, 2H) '7.15-7.2 (d, 1H , J = 10Hz) 4.0 (s, 3H). MH + 288 (iii) 2- (4-Fluoro-fenii) -3- (4-methanesulfonyl-phenyl) -6-methoxy-pyrazolo [1,5-b] pyridazine Treat a mixture of 6-methoxy-2- (4-fluoro-phenyl-pyrazolo [1, 5-b] pyridazine-3-carboxylic acid (869 mg) and sodium bicarbonate (756 mg) in dimethylformamide (10 ml) with N-bromosuccinimide (587 mg) and stirred at room temperature for 1 hour, then added to water (50 ml) and extracted with ethyl acetate (3 x 50 ml), dried (MgSO4), and evaporated in vacuo The resulting brown solid (1612 g) is dissolved in 1,2-dimethoxyethane (20 ml), 2N aqueous sodium carbonate solution (10 ml) is added together with 4- (methanesulfonyl) phenylboronic acid (660 mg). and tetrakis (triphenylphosphine) palladium (0) (100 mg) and the mixture is refluxed for 20 hours.The reaction is poured into water (50 ml), extracted with dichloromethane (3 x 100 ml). dry (MgSO *) and evaporate in vacuo to give a brown solid (1116 g) which is purified by flash column chromatography on silica, eluting with cyclohexane / acetic acid. the (4: 1 then 2: 1), to give the title compound as a yellow solid (390 mg). Tic, Si02, Rf 0.3 (cyclohexane / ethyl acetate, 1: 1), detection TJV MH + 398 iv) 2- (4-Fluoro-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazin-6-ol A mixture of 2- (4-fluoro-phenyl) -3 - (4-methanesulfonyl-phenyl) -6-methoxy-pyrazolo [1, 5-blpiridazine (321 mg) and pyridine hydrochloride (1.4 g) is heated to and at 200 ° C in a sealed container (Reactivial ™) for 3 hours. The cooled reaction is poured into water (20 ml), and extracted with ethyl acetate (3 x 30 ml). The combined organic extracts are dried (MgSO4), filtered and evaporated in vacuo to give a solid which is triturated with diethyl ether to give the title compound as a beige or yellowish solid (119 g). Tic, Si02, Rf 0.07 (cyclohexane / ethyl acetate 1: 2) UV detection MH * 384 . v) 6-Difluoromethoxy-2- (4-fluoro-pheiyl) -3- (-metanesulfonyl-phenyl) -pyrazolo [1,5-b-3-pyridazine] Treat a solution of 2- (4-fluorophenyl) -3- (4-methansulfonyl-phenyl) -pyrazolo [1, 5-b] pyridazin-6-ol (0.2 g) in anhydrous dimethylformamide (5 ml) with sodium hydride (0.046 g, 60% dispersion in mineral oil), after the effervescence is stopped a stream of bromodifluoromethane gas is passed through the mixture, at room temperature for 30 minutes. The reaction mixture is then poured into water (50 ml) and extracted with ethyl acetate (50 ml), the organic extract is washed with water (3 x 50 ml), dried and concentrated in vacuo. The residue is purified by chromatography to give the title compound as a white solid (0.17 g). MH * = 434 1 H NMR. { CDCl »): d 8.05- 8.0 (d, J = 1 OHz, 2H) 8.0-7.95 (d, J = 10Hz, 1H) 7.6-7.5 (m, 4H) 7.8-7.2 (t, J = 70Hz, 1H) 7.1-7.05 (t, J = llHz, 2H) 6.9-6.85 (d, J = 10Hz, 1H) 3.15 (s, 3H) Tic, Si02 f 0.35 (cyclohexane / ethyl acetate (l / l)) Example 2 3- (4-Methanesulfonyl-phenyl) -2- (4-methoxy-pheny1) -pyrazolo [1,5-b] pyridazine (i) 2- (4-Methoxy-phenyl) -pyrazoloic acid methyl ester [1, 5-b] pir i da zin- 3 -carbox i lico Add, dropwise, diazabicyclo [5.4.0] undec-7-ene (22.76 ml, 2 eq) to a solution of methyl 3- (4-methoxy-phenyl) -prop-2-ynoic acid (14.46 g, 76 M) and 1-aminopyridazinium iodide (2 eq) in acetonitrile, lower nitrogen, and stir for 6 hours. Purification by chromatography on silica gel eluting with toluene, then toluene: ethyl acetate (9: 1) affords the title compound (2.76 g) as a brown solid. MH + 284 XH NMR (CDCls) d 3.87 (3H, s) 3.9 (3H, s) 7.0 (2H, d, J = 9Hz) 7.25 (1H, dd, J = 9 & amp;; 4Hz) 7.90 (2H, d, J = 9Hz) 8.45 (1H, dd, J = 4 &2Hz) 8.55 (1H, dd, J = 9 &2Hz) Ref: 1 J. Morris and D.G. Wishka, Synthesis (1994), (1), 43-6 Ref: 2 Kobayashi et al. Chem. Pharm. Bull. (1971), 19 (10), 2106-15 (ii 3- (4-Methanesulfonyl-phenyl) -2- (4-methoxy-phenyl) -pyrazolo [1,5-b] pyridazine A mixture of 2- (4-methoxy-phenyl) -pyrazolo [1,5-b] pyridazine-3-carboxylic acid methyl ester (2.76 g) and hydroxyethyl ester is refluxed under nitrogen for 2 hours. aqueous sodium (2N, 30 ml) in ethanol (30 ml). The cooled mixture is acidified with hydrochloric acid (2N) and the resulting white solid (2.53 g) is isolated by filtration. This solid is dissolved in DMF and sodium bicarbonate (2.67 g, 3.3 eq) is added, followed by N-bromosuccinimide (1.88 g, 1.1 eq) in portions. After stirring for 1 hour under nitrogen, water is added and extracted into ethyl acetate (2 x 25 ml). The dried organic phase is concentrated and the resiis taken up in DME (60 ml). Aqueous sodium carbonate (2N, 15 ml) is added followed by 4-met ansul foni 1-phenylboronic acid (3.12 g) and tetrakis (tri-f-foldils) palladium (0) (250 mg). The mixture is refluxed under nitrogen for 18 hours, cooled, poured into water and extracted into ethyl acetate (2 x 25 ml). The combined organic phases are dried and concentrated on silica gel. Chromatography on silica gel eluting with toluene: ethyl acetate (8: 1) gives, by concentration, the title compound (3.58 g) as a cream solid. lH NMR (DMSO) d 3.25 (3H, s) 3.75 (3H, s) 6.95 (2H, d, J = 8.5Hz) 7.25 (1H, dd, J = 9 &5Hz) 7.45 (2H, d, J = 8.5Hz) 7.60 (2H, d, J = 8Hz) 7.9 (2H, d, J = 8.5Hz) 8. 15 (1H, dd, J = 9 -i 2Hz) 8.49 (1H, dd, J = 5 &2 Hz) Example 3 2- (4-Ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine (i) 4- [3- (4-Me tansulfoni-l-phenyl) -pyrazolo [1, 5-b] pyridazin-2-yl] -phenol Boron tribromide (1M solution in CH2C12, 2.1 eq) is added to '3- (4-methanesulfonyl-phenyl) -2- (4-methoxy-phenyl) -pyrazolo [1,5-b] pyridazine (3.58 g) in CH2C12 at -70 °. The mixture is stirred for 10 minutes, then warmed to ~ 0 ° and stirred at 0 ° overnight. The reaction mixture becomes alkaline with potassium carbonate and then acidified with hydrochloric acid (2M), poured into water and extracted into CH2C12. The organic phase is dried, filtered and concentrated to give the title compound (1.87 g) as a yellow solid.

MH + 366 1E NMR (DMSO) d 3.30 (3H, s) 6.80 (2H, d, J = 8.5Hz) 7.30 (1H, dd, J = 9 &5Hz, 7.35 (2H, d, J = 8.5Hz) 7.60 (2H, d, J = 8Hz) 8.0 (2H, d, J = 8.5Hz) 8.20 (1H, dd, J = 9 &2Hz) 8.55 UH, dd, J = 5 & 2Hz) 9.75 (1H, s). (ü 2- (4-Ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) pyrazolo [1,5-b] pyridazine The mixture is refluxed under nitrogen for 18 hours 4 - [3- (4 -Metansul fonil-feni 1) -pyrazolo 1, 5-b] pyr idazin-2-yl] -phenol (663 mg, 1.82), iodoethane (1 eq) and potassium carbonate (2 eq) in acetonitrile (30 ml). The cooled reaction mixture is partitioned between water (30 ml) and ethyl acetate (30 ml). The organic phase is combined, dried and purified by chromatography to give the title compound (547 mg) as a cream colored foam. MH * 394 XH NMR (DMSO) d 1.45 (3H, t, J = 7Hz) 3.10 (3H, s) 4.1 (2H, quartet, J = 7Hz) 6.87 (2H, d, J = 9Hz) 7.08 (1H, dd , J = 9 &5Hz) 7.55 (4H, t, J = 9Hz) 7.92 (1H, dd, J = 9 &2Hz) 7.95 (2H, d, J = 9Hz) 8.20 (1H, dd, J = 9 &2Hz) 8.32 (1H, dd, J = 5 &2Hz) Example 4 2- (4-Fluoro-phenyl) -6-methanesulfonyl-3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine (i) 2- (4-Fluoro-phenyl) methyl ester 6-Methylsulfanyl-pyrazolo [1,5-b] pyridazine-3-carboxylic acid To the mixture, with stirring, solid 1-t-butoxycarboni 1-ethylhexyl fonylhydroxylamine (7.8 g) is added to TFA (25 ml) over 10 minutes, then stirred for an additional 20 minutes. The solution is poured onto ice (approximately 200 ml) and left until the ice melts. The resulting white solid is separated by filtration, washed with water, and dissolved in DME (100 ml). The solution is dried over 4A molecular sieves for 1.5 hours, it is filtered and then it is added to a solution of 3-met il t io-piridaz ina2 (2.6 g) in dichloromethane (35 ml) and the reaction is stirred at room temperature for 20 hours. The intermediate salt is isolated by filtration as light brown crystals (3.87 g), suspended in acetonitrile (100 ml) and methyl 3- (4-fluoro-phenyl) -prop-2-inoi co (2.02 g) is added. ). 1,8-Diazabicyclo [5 .0] undec-7-ene (2.1 ml) is added dropwise and the reaction is stirred at room temperature for 20 hours. The resulting crystalline precipitate is filtered off, washed and dried (770 mg). The concentration of the filtrate provides a second collection (430 mg). The residues are partitioned between water and ethyl acetate (100 ml each time) and the aqueous layer is extracted with ethyl acetate (20 ml). The combined organic compounds are washed with water, brine and dried. Removal of the solvent gives a brown oil which is purified by flash chromatography on silica (300 g) eluting with cyclohexane / ethyl acetate (3: 1) to give an additional amount of the product (247 mg). The three collections are combined to give the title compound (1.45 g) as a light brown solid. MH * 318 aH NMR (CDCls) d 2.70 (3H, s), 3.88 (3H, s) 7.08-7.18 (3H, m) 7.84 (2H, m) 8.31 (1H, d, J = 10Hz) Ref: 1 K Novitskii et al, Khim Geterotskil Soedin, 1970 2, 57-62 Ref: 2 Barlin GB, Brown, W V. J Chem Soc (1968), (12) 1435-45 (ii 2- (4-Fluoro-phenyl) -3- (4-methanesulfanyl-f-enyl) -6-methylsulfonyl-pyroxy [1,5-b] pyridazine A mixture of 2- (4-fluoro-phenyl) -6- (methylthio) -pyrazolo [1 5-b] pyridaz-3-carboxylic acid methyl ester (1.45 g), potassium carbonate (690 mg) ) in metabolite (40 ml) and water (14 ml), stirred and heated under reflux for 20 hours, under nitrogen. The solvents are removed and the resulting solid is partitioned between ethyl acetate (50 ml) and water (250 ml). The aqueous layer is acidified to pH 1 (2M HCl) and separated or solid by filtration (1.0 g, MH * 304). A mixture of the solid (1.0 g), sodium bicarbonate (557 mg) and NBS (594 mg) was stirred at room temperature for 4 hours. The reaction is poured into water (150 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts are washed with water (50 ml), brine (20 ml), dried and concentrated. The resulting solid (1015 g, MH * 338, 340), 4 - (meth ansulfoni 1) phenyleboronic acid (902 g), sodium carbonate (740 mg) and tetrakis (triphenylphosphine) palladium (0) (175 mg) they are stirred and heated under nitrogen, under reflux, in DME (30 ml) and water (15 ml) for 48 hours. The reaction is poured into water and extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried and the solvent is removed to give a brown solid. This is purified on silica (300 g) eluting with cyclohexane, ethyl acetate (1: 1) to give the title compound (0.713 g) as a yellow solid. MH * 414 XH NMR (DMSO) d 2.65 (3H, s) 3.28 (3H, s) 7.20-7.30 (3H, m) 7.55 (2H, m) 7.62 (4H, d, J = 8.5Hz) 7.95-8.05 ( 3H,) (iii 2- (4-Fluoro-phenyl) -6-methanesulfonyl-3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine A suspension of 2- (4-fluoro-phenyl) -3- (4-methanesulfonyl-phenyl) -6- (methylthio) -pyrazolo [1,5-b] pyridazine (60 mg, 0.145) in MeOH (5%) is stirred. ml) and water (2 ml), with oxone (196 mg, 0.32) for 20 hours. The resulting solution is poured into water (50 ml) and extracted with chloroform. (3 x 20 ml). The combined extracts are dried and the solvent is removed. Crystallization of the residue from methanol gives the title compound (60 mg) as a white solid. , 1H NMR (DMS0-d6) d 3.34 (3H, s) 3.53 (3H, s) 7.33 (2H, t, J = 9Hz) 7.62 (2H,) 7.68 (1H, d, J = 8.5Hz) 8.04 (1H, d, J = 10Hz) 8.52 (1H, d, J-9Hz) Tic Si02 hexane: ethyl acetate (1: 1) Rf 0.24 UV Example 5 2- (4-Difluoromethoxy-phenyl) -3- (-metanesulfonylphenyl) -pyrazolo [1,5-b] pyridazine Sodium hydride (48 mg, 60% dispersion in oil, 1.2 mmol) is added to a solution of 4- [3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazin-2. il] -phenol (200 mg, 0.55 mmol) in anhydrous dimethylformamide (5 ml). Bubodi f luoromet ano gas is gently bubbled through the solution, for 20 minutes, then diluted with CH2C12 (30 ml). Aqueous manipulation followed by chromatography on silica gel with CH2C12: ethyl acetate (3: 1) as eluent, and then chromatography with CH2C12: ethyl acetate (10: 1) as eluent, afforded the title compound (63 mg, 28 o) as a white solid. MH * 416 NMR (CDC13) d 8.38 (lH, dd, J = 4Hz), 8.01 (2H, d, J = 8.5Hz). 7.94 (1H, dd, J = 9 &2Hz), 7.65 (2H, d, J = 8.5 Hz) 7.57 (2H, d, J = 8Hz), 7.10 (3H, m), 6.87-6.27 (1H, t , J = 7.4 Hz) 3.15 (3H, s) E xemployment 6 4- [2- (4-? Toxi-phenyl) -pyrazolo [1, 5-b] pyridazin-3-yl] benzenesul fonamide (i) Methyl ester of 2 - (4-E-t-oxy) acid f eni 1) -pyrazolo [1, 5-b] pyridazine-3-carboxylic acid Di az abicyclo [5.4.0] undec-7-ene (1.47 ml, 2 eq) was added, dropwise, to a solution of methyl 3 - (4-ethoxyethyl) -propionate. 2-inoic (1.0 g) and 1-aitinopi ridaz ini o2 iodide (2.19 g) in acetonitrile (10 ml) under nitrogen, and stir for 5 hours. Concentration and aqueous workup yield the title compound (1.2 g) as a brown, sticky solid.

MH * 298 (ii 3- (3-carboxylic acid) 3- (4-Ethoxy-phenyl) -pyrazolo [1,5-b] pyridic acid A mixture of 2- (4-ethoxy-phenyl) -pyrazolo [1,5-b] pyridazine-3-carboxylic acid methyl ester (1.2 g), ethanol (10 ml) is heated at 80 ° for 1.5 hours. and 2N sodium hydroxide (10 ml). The mixture is allowed to cool and acidified to pH 1 with 2N hydrochloric acid. The title compound is isolated by filtration as a brown solid (716 mg, 63 >) MH * 284 (Üi) 2- (4-Ethoxy-phenyl) -3-iodo-pyrazolo [1, 5-b] pyr ida zine A mixture of 2- (4-ethoxy-phenyl) -pyrazolo [1,5-b] pyridazine-3-carboxylic acid (710 mg), N-iodosuccinimide (678 mg) and sodium bicarbonate is stirred for 4 hours. sodium (717 g) in DMF (8ml). An additional amount of N-iodosuccinimide (100 mg) is added and stirring is continued for 2 hours. The manipulation in aqueous medium produces a dark brown solid which is purified by SPE with dichloromethane as eluent. This produces the title compound as an orange-brown solid (429 mg, 47%). MH * 366 (iv; 4- [2- (4-Ethoxy-phenyl) -pyrazolo [1, 5-b] pyridazin-3-yl] -benzenesulfonamide A mixture of 4-iodobenzenesulphonamide (0.311 g), dipinacoldiborane (0.279 g), potassium acetate is heated under nitrogen at 80 ° for 2 hours. (486 mg) and [1,1'-bi s (di-phenyl-fos complex) -ferrocen] palladium (II) chloride complex with dichloromethane (1: 1) (0.45 g) in dimethylformamide (8 ml). The reaction mixture is concentrated in vacuo and the residue is suspended in 1,2-dimethoxyethane (10 ml), 2- (4-ethoxy-phenyl-1) -3-iodo-pi is added just [1, 5-b] pyridazin (0.4 g) together with 2N sodium carbonate (4 ml) and tetrakis (triphenyl phosphine) palladium (0) (20 mg) and the mixture is refluxed under nitrogen for 18 hours. The cooled reaction mixture is poured into water (60 ml) and the suspension is extracted with ethyl acetate (3 x 60 ml). The organic extracts are combined, dried (Na2SO4) and concentrated. The residue is purified by chromatography eluting with dichloromethane / ethyl acetate (3: 1) to give the title compound as a yellow solid (0.116 g, 27%). MH * 395 NMR (CDCls) d 8.32 (1H, dd, J = 4 &2Hz), 7.97 (2H, d, J = 8Hz), 7.89 (1H, dd, J = 9 &2Hz), 7.54 (4H , m), 7.04 (1H, dd, J = 9 &4Hz), 6.88 (2H, d, J = 9Hz), 1.43 (3H, t, J = 7Hz) Ref: 1 R. Miyaura et al J. Org . Chem., 1995, 60, 7508-7510.

Example 7 ß-Difluoromethoxy-2- (3-fluoro-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine (i) 1- (2,2-Dibromo-vinyl) -3-fluoro-benzene To a stirred, cooled solution (ice / salt, 0 °) of carbon tetrabromide (48.82 g) in anhydrous CH2C12 (200 ml) is added, in portions, for 3 minutes, triphenylphosphine (77.1 g), maintaining the temperature below 10 °. The resulting orange suspension is stirred at 0 ° C for 1 hour before adding 3-fluorobenzaldehyde (7.8 ml) thereto. After the addition is complete, the suspension is stirred at 0 ° for 1 hour and then quenched by the addition of water (75 ml). The organic phase is separated and washed with brine (75 ml), dried (Na 2 SO 4) and evaporated to dryness. The residual gum is poured into cyclohexane (1 L) and stirred for 30 minutes. The organic phase is decanted and the residue is taken up in CH2C12 and poured into cyclohexane (1 L). This procedure is repeated twice more and the combined organic phases are concentrated to approximately 100 ml and passed through silica gel. The filtrate is concentrated to give the title compound as a changeable yellow oil (24 g, 100%). MN * 280, MH "279 NMR (CDC13) d 7.05 (1H, tm, J = 9Hz) 7.3 (3H, m) 7.45 (1 H, s) 11 Methyl ester of the acid (3-Fluorofeni 1, > -propmoi co To a stirred solution of l- (2,2-dibro o-vinyl) -3- f luoro-benzene (23.8 g) in anhydrous THF (350 ml), cooled to -78 °, is added dropwise during 30 minutes, n-butylithium (2: 2 eq, 1.6 M in hexanes). The mixture is stirred for an additional 30 minutes at -78 ° before adding methyl chloroformate (11.6 g, 9.5 ml) and the resulting mixture is allowed to warm to 0 ° for 1 hour before being diluted with saturated aqueous sodium bicarbonate solution or: ammonium chloride, 1: 1, (100 ml) and extracted. in ether (2 x 100 ml). The combined organic extract is washed with brine (25 ml), dried (Na2SO4) and evaporated to dryness to give the title compound as a brown oil (16.7 g, 100%) MH "173 NMR (CDCls) d 7.4-7.1 (4,) 3.85 (3H, s, C02Me) (iii) 2- (3-Fluoro-phenyl) -6-methoxy-pyrazolo [1, 5-b] pyridazine-3-carboxylic acid methyl ester 1,8- Diazabicyclo [5.4.0] undec-7 was added NaOH (5 ml) was added to a stirred and cooled mixture of (3-fluoro-phenyl) -propynoic acid methyl ester (2.67 g) and 1-amino-3-methoxy-pyridazin-1-io (4,89 g) mesitylene sulfonate. ) in acetonitrile (80 ml) and the mixture is stirred at 0 ° for 1 hour and then at room temperature for 18 hours. The mixture is concentrated in vacuo and partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous phase is separated and extracted further with ethyl acetate (2 x 100 ml). The combined organic extracts are washed with water (2 x 50 ml), brine (25 ml), dried (MgSO 4), filtered and evaporated in vacuo to give a solid which is triturated with anhydrous ether: petroleum ether ( 1: 0.5) to give the title compound as a brown solid (2.4 g, 53). MH * 302 X H NMR (CDCl ») d 12.8 (1H, broad s); 8.4 (1H, d, J = 10Hz) 7.7-7.6 (2H, m) 7.42 (1H, quartet, J = 8Hz) 7.15 (1H, td, J = 8 &3Hz) 6.95 (1H, d, J = 10Hz ) 4.1 (3H, s) 3.88 (3H, s) (iv: 2- (3-Fluoro-phenyl) -methoxy-pyrazolo [1,5-b] pyridazine-3-carboxylic acid 2N sodium hydroxide (50 ml) is added to a solution of 2- (3-Fluoro-phenyl) -6-methoxy-pyrazole [1, 5-b] pyridazine-3-carboxylic acid methyl ester (2.3 g. ) in absolute ethanol (50 ml) and the resulting mixture is refluxed for three hours. The cooled reaction mixture is slowly poured into a stirred solution of 2N hydrochloric acid (300 ml). The resulting suspension is stirred at room temperature for 1 hour and then filtered and the filter cake is washed with water and dried in vacuo at 60 ° to give the title compound as an off-white solid (2.0g, 91%). MH * 288 X H NMR (DMSO) d 8.45 (1H, d, J = 10Hz); 7.67 (2H,); 7.5 (1H, quartet, J = 7Hz); 7.3 (1H, td, J = 7 &2Hz); 7.21 (1H, d, J = 10Hz); 4.0 (3H, s) (v) 3-Bromo-2- (3-fluoro-phenyl) -6-methoxy-pyrazolo [1, 5-b] pyridazine To a stirred solution of 2- (3-fluoro-phenyl) -6-methoxy-pyrazolo [1, 5-b] pyridazine-3-carboxylic acid (2.0 g) in anhydrous DMF (20 ml) is added n-bromosuccinimide ( 1.78 g) and the resulting solution is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate (800 ml) and sequentially added with water (10 x 100 ml) and saturated brine ml), concentrated Na2SO4) to give the title compound as a solid light yellow (2.1 g, 93%). MH * 323, MH "321 XE NMR (CDC13) d 7.9 (2H, m) 7.8 (1H, d, J = 10Hz); 7.45 (1H, m); 7.1 (1H, td, J = 8 &2Hz) 6.78 (1H, d, J = 10Hz); 4.1 (3H, s) vi 6-Difluoromethoxy-2- (3-fluoro-phenyl) -pyrazolo [1,5-b] pyridazine Portions of 3-bromo-2 - (3-fluoro-phenyl) -6-methoxy-pyrazolo [1,5-b] pyridazine are placed. (400 mg, 2.1 g total) in individual reaction flasks equipped with a magnetic stir bar. Pyridine hydrochloride (10 eq) is added to each bottle, the bottles are sealed, and heated to 200 ° for 3 hours. The bottles are allowed to cool to approximately 140 ° before opening and the contents are poured into ice / water. The resulting mixture is extracted into ethyl acetate (3 x 100 ml) and the combined organic extracts are washed with water (7 x 75 ml), dried (Na2SO4) and evaporated to give the des-bromo phenol as a coffee color (1.0 g, MH * 230). This solid is dissolved in anhydrous DMF (10 ml) and added, in portions, sodium hydride (60% dispersion in ineral oil, 200 mg). After stirring for 20 minutes at room temperature, the solution is transferred to a small cooled autoclave and brodix fluoromethane (5 ml, xs, condensed at -30 °) is added. The autoclave is then sealed, heated to room temperature and stirred for 36 hours. The resulting solution is diluted with ethyl acetate (200 ml), washed with water (10 x 20 ml), dried (Na 2 SO 4), concentrated and the residual gum purified by flash column chromatography with cyclohexane: ethyl acetate. (4: 1) as eluent. This produces the title compound as a solid (652 mg, 60 l). MH * 280 MH "278 NMR (DMSO) d 8.42 (1H, d, J = 10Hz) 7.85 (1H, d, J = 8Hz) 7.78 (1H, t, J = 70Hz) 7.55 (1H, q, J = 8Kz ) 7.38 (1H, s) 7.25 (1H,) 7.17 (1H, d, J = 10Hz) (vii 3-Bromo-6-difluororneto i- 2- (3-fluoro-phenyl) -pyrazolo [1,5-b 3 -pyridazine] N-bromosuccinimide (195 mg) is added to a solution of 6-difluoromethoxy-2- (3-phorophenyl) -pyrazolo [1,5-b] pyridazine (251 mg) and sodium bicarbonate (185 mg) in anhydrous DMF ( 10 ml) and stirred for 18 hours. The reaction mixture is diluted with ethyl acetate (300 ml) and washed with water (10 x 20 ml), brine (20 ml), dried (Na2SO4) and concentrated to give the title compound as a solid ( 293 mg, 91%) MH * 359, MH "356/357 NMR (DMSO) d 8.36 (1H, d, J = 10Hz) 7.88 (1H, d, J = 8Hz) 7.78 (1H, t, J = 70Hz, 0CHF2) 7.77 (1H, DM, J = 10Hz) 7.62 (1H, dt, J = 8 &6Hz) 7.38 (1H, dt, J = 9 &2HZ) 7.3 (1H, d, J = 10Hz) (viii) 6-Difluoromethoxy-2- (3-fiuoro-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine To a stirred solution of 3-bromo-d-difluoromethoxy-2- (3-fluoro-phenyl) -pyrazolo [1,5-b] pyridazine (286 mg) in DMF (20 ml) is added 2N aqueous solution of sodium carbonate. sodium (10 ml). To this mixture is added 4-methanesulphonyl phenylboronic acid (180 mg) and tetrakis triphenylphosphine palladium (0) (34 mg). The resulting mixture is stirred and heated to reflux for 18 hours. The cooled reaction mixture is diluted with ethyl acetate (300 ml) and the organic solution is washed with water (10 x 30 ml) and brine (30 ml), dried (Na2SO) and evaporated to give a gum which it is purified by flash column chromatography "with chloroform: ethyl acetate (50: 1 to 5: 1) as eluent The combination of the appropriate fractions and the concentration affords the title compound as an off-white solid (132 mg, 37%). %) .MH * 434 XH NMR (CDCl ») d 8.02 (1H, d, 9Hz), 7.95 (2H, d, J = 10Hz), 7.58 (1H, d, 9Hz), 7.52 (1H, t, = 70Hz) ); 7. 32 (3H, m); 7.08 (1H, m); 6.9 (1H, d, J = 9Hz); 3.15 (3 H, s) Biological Data The inhibitory activity against human COX-l and C0X-2 was evaluated in COS cells that had been stably transfected with cDNA for human COX-1 and human COX-2. 24 hours before the experiment, the COS cells were transferred from the 175 cm2 flasks in which they had grown, onto plates for 24-well cell culture, using the following procedure. The incubation medium (Dulbecco's modified Eagle's medium (DMEM) supplemented with fetal calf serum, thermally inactivated (10 9o v / v), penicillin (100 IU / ml), streptomycin (10 μg / ml) and geneticin (600 μg / ml)) was removed from a bottle of confluent cells (1 vial at the confluence contains approximately 1 x 107 cells). To wash the cells 10 ml of phosphate-buffered saline (PBS) were added to the bottle. After discarding the PBS, the cells were rinsed in 10 ml of tripcin for 20 seconds, after which the tripcin was removed and the flask was placed in an incubator (37 °) for a time of 1 to 2 minutes until the cells disengaged from the bottle. The flask was then removed from the incubator and the cells were resuspended in 10 ml of fresh incubation medium. The contents of the bottle were transferred to a sterile 250 ml container and the volume of the incubation medium was subsequently completed to 100 ml. 1 ml of the cell suspension was pipetted into each well of the plates for 4 x 24 well cell culture. The plates were then placed in an incubator (37 ° C, 95% air 5 or C02) overnight. If more than 1 vial of cells was required. The cells of the individual flasks were combined before being placed in the 24-well plates. After incubation overnight, the incubation medium was completely removed from the plates for 24-well cell culture and replaced with 250 μL fresh DMEM (37 ° C). The test compounds were concentrated 250 times the concentration of analysis required, in DMSO, and were added to the wells in a volume of 1 μL. The plates were then gently mixed by whirling and then placed in an incubator for 1 hour (37 ° C, 95% air / 5 po of C02). After the incubation period, 10 μL of arachidonic acid (750 μM) was added to each well, to give a final concentration of arachidonic acid of 30 μM. The plates were then incubated for an additional 15 minutes, after which time the incubation medium was removed from each well of the plates and stored at -20 ° C, before determination of prostaglandin E2 (PGE2) levels using the immunoassay with enzymes. The inhibitory potency of the test compound was expressed as an IC50 value which is defined as the concentration of the compound required to inhibit the release of PGE2 from the cells, by 50%. The selectivity ratio for the inhibition of COX-l versus C0X-2 was calculated by comparing the respective IC 50 values. For the compounds of the invention the following IC 50 values were obtained for the inhibition of C0X-2 and COX-1: It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (13)

1. The compounds of the Formula (I and pharmaceutically acceptable derivatives thereof, characterized in that: R ° is halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of the β carbon atoms substituted by one or more fluorine atoms, or O (CH2) nNR * R5; R1 and R2 are independently selected from H, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by one or more fluorine atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 atoms of carbon, S-alkyl of 1 to 6 carbon atoms, C (0) H, C (O) alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted by one or more fluorine atoms, O (CH2) nC02-alkyl of 1 to 6 carbon atoms, O (CH2) nS-alkyl of 1 to 6 carbon atoms, (CH2) nNR4R5, (CH2) nS-alkyl from 1 to 6 carbon atoms or C (0) NR R5; with the proviso that when R ° is a halogen and is in the 4-position, at least one of R1 and R2 is alkylsulfonyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted by one or more carbon atoms. fluorine, O (CH2) nC02-alkyl of 1 to 6 carbon atoms, O (CH2) nS-alkyl of 1 to 6 carbon atoms, (CH2) nNR (RNi (CH2) nS-alkyl of 1 to 6 carbon atoms carbon, C (0) NR R; R, 3"is alkyl of 1 to 1 carbon atoms or NH2; R4 and R5 are independently selected from H, ~ or alkyl of 1 to 6 carbon atoms or, together with the atom of nitrogen to which they are attached, form a saturated ring of 4 to 8 members, and n is a number from 1 to 4.

2. The compounds according to claim 1, characterized in that R ° is F, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms substituted by 1 or more fluorine atoms , or 0 (CH2) NR4R5; R1 is alkylsulfonyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms substituted by one or more fluorine atoms, 0 (CH2) nC02-alkyl of 1 to 4 carbon atoms, O (CH2) nS-alkylated from 1 to 4 carbon atoms, (CH2) "NR4R5, (CH2) nS-alkyi of 1 to 4 carbon atoms or C (0) NR4R5 or, when R ° is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms, or O (CH2) "NR4RS, can also be H; R2 is H; R3 is methyl or NH2; R4 and R5 are independently alkyl of 1 to 3 carbon atoms or, together with the nitrogen atom to which they are attached, form a saturated ring of 5 to 6 members; and n is a number from 1 to 3.

3. The compounds according to claim 1 or 2, characterized in that R ° is F, methyl, alkoxy of 1 to 2 carbon atoms, 0CHF2, or O (CH2) nNR4Rs, R1 is methylsulfonyl, 0CHF2, O (CH2) nC02-alkyl of 1 to 4 carbon atoms, 0 (CH2) nSCH3, ( CH -) "NR4R5, (CH2) nSCH3 or C (0) NR R5 or, when R ° is methyl, alkoxy of 1 to 2 carbon atoms, 0CHF2, or O (CH2) nN (CH3) 2, may also be H; R2 is H; R3 is methyl or NH2; R4 and R5 are both methyl or, together with the nitrogen atom to which they are attached, form a saturated ring of 5 to 6 members; and n is a number from 1 to 2.

4. The compounds according to any one of claims 1 to 3, characterized in that R ° is F, alkoxy of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms; R1 is alkylsulfonyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms substituted by one or more fluorine atoms or, when R ° is alkoxy of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms substituted by one or more fluorine atoms, it can also be H; R2 is H; and R3 is methyl or NH2.

5. The compounds according to any one of claims 1 to 4, characterized in that R ° is in the 3 or 4 position of the phenyl ring.

6. The compounds according to any one of claims 1 to 5, characterized in that R1 is in the 6-position of the pyridazine ring.

7. The compounds characterized in that they are: 2- (4-Ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; 6-Difluoromethoxy-2- (3-fluoro-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine; and the pharmaceutically acceptable derivatives thereof.

8. A process for the preparation of the compound of Formula (I) and pharmaceutically acceptable derivatives thereof, according to the definition of any one of claims 1 to 7, characterized in that it comprises: (A) reacting a compound of Formula (II) or a protected derivative of the same with a compound of Formula (III) or a protected derivative thereof; or (B) wherein R3 represents alkyl of 1 to 4 carbon atoms, reacting a compound of Formula (IV) or a protected derivative thereof, with an oxidizing agent; or (C) where R1. is alkylsulfonyl of 1 to 6 carbon atoms, oxidizing a compound of Formula (V) or a protected derivative. (D) wherein R 1 is alkoxy of 1 to 6 carbon atoms substituted by one or more fluorine atoms, reacting an alcohol of Formula (VI) or a protected derivative thereof, with a fluoroalkane halo. (E) The interconversion of a compound of Formula (I) into another compound of Formula (I); or (F) deprotecting a protected derivative of the compound of formula (I); and optionally converting the compounds of formula (I) prepared by any of the processes of (A) to (F) into pharmaceutically acceptable derivatives thereof.

9. A pharmaceutical composition characterized in that it comprises a compound of Formula (I) or a pharmaceutically acceptable derivative thereof, according to the definition of any one of claims 1 to 7, mixed with one or more physiologically acceptable carriers or excipients.

10. A compound of Formula (I) or a pharmaceutically acceptable derivative thereof, in accordance with the definition of any one of claims 1 to 7, for use in human veterinary medicine.

11. A compound of formula (I) or a pharmaceutically acceptable derivative thereof, in accordance with the definition of any one of claims 1 to 7, for use in the treatment of a condition that is mediated by selective inhibition of the COX-2.

12. A method of treating a human or animal subject suffering from a condition that is mediated by selective inhibition of COX-2, characterized in that it comprises administering to that subject an effective amount of a compound of Formula (I) or a derivative pharmaceutically acceptable, according to the definition of any of claims 1 to 7.

13. The use of a compound of Formula (I) or a pharmaceutically acceptable derivative thereof, in accordance with the definition of any one of claims 1 to 7, for the manufacture of a therapeutic agent for the treatment of a condition that is mediated by selective inhibition of COX-2, such as an inflammatory disorder.