FLUORINATED PYRIDAZIN-3-ONES FOR THE USE THEREOF IN THE TREATMENT OF LUNG DISEASES

Abstract

The present invention concerns compounds belonging to the family of fluorinated pyridazin-3-ones, for the use thereof in the treatment of broncho-pulmonary conditions. In compounds having a formula, or a pharmaceutically acceptable salt of the compound, the formula includes R1 representing H, an alkyl, an aryl or a heteroaryl; either E2 and E3 representing, separately from each other, H, an alkyl, an aryl or a heteroaryl, or R2 and R3 being bridged within a same cycle or via several cycles; and F representing CF.sub.3, (CF.sub.2)nCF.sub.3 or CF.sub.2H, with n representing an integer of between 1 and 7.

Claims

1. A compound being in a family of fluorinated pyridazin-3-ones, for treatment of broncho-pulmonary diseases, said compound, or one of its pharmaceutically acceptable salts, comprising a chemical composition having the following formula (I): ##STR00013## wherein: R1 represents H, and alkyl, an aryl or a heteroaryl, R2 and R3 represent either independently of each other, an H, an alkyl, an aryl or a heteroaryl, or R2 and R3 are bridged within a same ring or via several rings; R5 represents CF.sub.3, (CF.sub.2).sub.nCF.sub.3 or CF.sub.2H with “n” representing an integer comprised between 1 and 7.

2. The compound, according to claim 1, wherein: R1 represents H, a linear or branched C.sub.1-C.sub.10 alkyl, or an aryl selected from among the phenyl group C.sub.6H.sub.5, the tolyl group C.sub.6H.sub.4CH.sub.3, the xylyl group C.sub.6H.sub.3(CH.sub.3).sub.2, the naphthyl group C.sub.10H.sub.7, the 4-methoxyphenyl group C.sub.6H.sub.4OCH.sub.3, the 3,4-dimethoxyphenyl group C.sub.6H.sub.3(OCH.sub.3).sub.2, and the group 4-(n-heptyloxyphenyl) group C.sub.6H.sub.4O(CH.sub.2).sub.6CH.sub.3; R.sub.2 and R.sub.3 represent, either independently of each other, H, a linear or branched C.sub.1-C.sub.10 alkyl, and/or functionalized, an aryl selected from the phenyl group C.sub.6H.sub.5, the tolyl group C.sub.6H.sub.4CH.sub.3, the xylyl group C.sub.6H.sub.3(CH.sub.3).sub.2, the naphthyl group C.sub.10H.sub.7, or a heteroaryl selected from among pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl, and oxazolyl, or R.sub.2 and R.sub.3 are bridged within a same ring with 5 or 6 carbon atoms; R.sub.F represents CF.sub.3, (CF.sub.2).sub.nCF.sub.3 or CF.sub.2H with n representing an integer comprised between 1 and 7.

3. The compound, according to claim 1, being selected from among the list of the following compounds: N.sub.2-methyl-4-(trifluromethyl)-6-(4′-methoxyphenyl)-4,5-dihydropyridazin-3(2H)-one 4-(trifluromethyl)-6-(3′,4′-dimethoxyphenyl)pyridazin-3(2H)-one 6-(4′-difluoromethoxy)phenyl)-4-(trifluromethyl)-4,5-dihydropyridazin-3(2H)-one 6-(4′-difluoromethoxy)phenyl)-4-(trifluromethyl)pyridazin-3(2H)-one 2-phenyl-6-(p-tolyl)-4(trifluromethyl)-4,5-dihydropyridazin-3(2H)-one 4-(trifluromethyl)-2-phenyl-6-(p-tolyl)pyridazin-3(2H)-one 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluromethyl)-4,5-dihydropyridazin-3(2H)-one 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluromethyl)pyridazin-3(2H)-one.

4. The compound, according to claim 1, being used as a inhibitory drug of phosphodiesterases of type IV.

5. The compound, according to claim 1, being in the treatment of obstructive chronic obstructive pulmonary diseases.

6. The compound, according to claim 1, being in the treatment of asthma.

7. The compound, according to claim 1, being in the treatment of cystic fibrosis.

8. The compound, according to claim 1, being an active ingredient of a drug against chronic obstructive pulmonary diseases.

9. A method for treating a chronic obstructive pulmonary disease, the method comprising the steps of: forming a compound according to claim 1; and applying the compound for therapeutic use for chronic obstructive pulmonary diseases.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0067] Reference will be made to the appended figures which represent the compounds known in the state of the art for treating chronic obstructive pulmonary diseases and the compounds according to the invention.

[0068] FIG. 1A represents the chemical formula of zardaverine and FIG. 1B represents the chemical formula of an analog of zardaverine, these compounds being known in the state of the art.

[0069] FIG. 2A represents the general chemical formula (I) of the compound belonging to the family of fluorinated pyridazin-3-ones according to the present invention.

[0070] FIG. 2B represents the chemical formula (Ia) corresponding to an embodiment of the compound (I) according to the invention, the latter then consisting in a fluorinated bicyclic pyridazin-3-one.

[0071] FIG. 2C represents the chemical formula (Ib).

[0072] FIG. 2D represents the corresponding chemical formula (Ic) each to another particular embodiments of the compound according to the invention.

[0073] FIG. 3 schematically illustrates a particular embodiment of a method giving the possibility of resulting in a compound (I) according to the present invention, and notably the initial compounds, the intermediate products obtained during the reaction and the reaction conditions.

[0074] FIG. 4 illustrates an example of a method for obtaining the compound (Ib), and notably the initial compounds, the intermediate products obtained during the reaction and the reaction conditions.

[0075] FIG. 5 illustrates an example of a method for obtaining the compound (Ic), and notably the initial compounds, the intermediate products obtained during the reaction and the reaction conditions.

DETAILED DESCRIPTION OF THE INVENTION

[0076] The compounds of the state of the art have already been mentioned above, notably zardaverine, for which the structure is visible in FIG. 1A, and the analog of the latter, represented in FIG. 1B.

[0077] These compounds in particular have a pyridazin-3-one unit of chemical formula C.sub.4H.sub.4N.sub.2O or preferably a 4,5-dihydropyridazin-3-one unit of chemical formula C.sub.4H.sub.6N.sub.2O including, on the one hand, a pyridazine ring (or 1,2-diazine) consisting in a heterocyclic dinitrogen-containing molecule of chemical formula C.sub.4H.sub.4N.sub.2, therefore including two nitrogen atoms (N) in positions 1 and 2 in an aromatic ring with six members and, on the other hand, a carbonyl function in position 3 on the ring, in other words one has a C═O group in position 3 on the ring.

[0078] However, the inhibitor activity of these compounds towards the PDE4 enzyme further remains to be improved, as well as the selectivity of the compounds towards said enzyme PDE4.

[0079] Indeed, the compounds with a pyridazin-3-one unit act on PDE4, inhibiting its operation.

[0080] The enzyme PDE4 belongs to the large family of phosphodiestrases, and cataylyzes the transformation of AMPc (cyclic 3′5′adenosine mono-phosphate), which is the active form, in AMP, which is the inactive form, by hydrolyzing the phosphate bond present in position 3′ on the AMPc.

[0081] The phosphodiesterases are classified in 11 different families. Because of the large number of isoenzymes phosphodiestrases, the compounds with a pyridazin-3-one unit may interact with enzymes other than PDE4, like for example PDE1.

[0082] Now, PDE4 is the major enzyme of metabolism of AMPc, this enzyme notably intervenes in cells involved in the inflammatory response and the immune cells. The PDE4s therefore are a preferred target and the inhibitors of PDE4 have a very interesting potential for treating the inflammatory response related to broncho-pulmonary pathologies like asthma, COPMs, cystic fibrosis, etc.

[0083] Thus, the inhibitors of PDE4 suppress the release of cytokines and of other inflammatory molecules.

[0084] Accordingly, it is of particular interest to develop compounds which inhibit, in a highly selective way, the PDE4s, by avoiding action on other families of phosphodiesterases.

[0085] A compound belonging to the family of pyridazin-3-ones was therefore developed, notably fluorinated pyridazin-3-ones i.e. including at least one fluorine atom, for its use in the treatment of obstructive pulmonary diseases, and having the general formula (I) illustrated below and in the appended FIG. 2:

##STR00007##

[0086] In this compound of formula (I), the identified radical R.sub.1 represents H, an alkyl, an aryl or a heteroaryl.

[0087] As regards the radicals R.sub.2 and R.sub.3, the latter may represent independently of each other, H, an alkyl, an aryl or a heteroaryl.

[0088] In the case when the dotted line bond connecting the carbon atoms C4 and C5 represent a saturated bond, the compound of the invention belongs to the particular family of fluorinated 4,5-dihydropyridazin-3-one.

[0089] The radicals R.sub.2 and R.sub.3 may also be bridged within a same ring or via several rings, which is illustrated by the dotted lines connecting R.sub.2 and R.sub.3 in the above formula (I). The dotted lines of formula (I) between the radicals R.sub.2 and R.sub.3 represent the possible ring(s) structurally connecting the chemical formula of the invention.

[0090] Now as regards the radical R.sub.F, the latter preferably includes at least two fluorine atoms and may represent CF.sub.3, (CF.sub.2).sub.nCF.sub.3 or CF.sub.2H with n representing an integer comprised between 1 and 7 in (CF.sub.2).sub.nCF.sub.3.

[0091] The fluorinated unit in position 4 on the compound of formula I according to the invention advantageously gives the possibility of increasing the selectivity of said compound towards PDE4.

[0092] From this increased specificity towards PDE4s there results a limitation of the potential undesirable or secondary effects which may result from the taking of these compounds.

[0093] Indeed, a chemical compound inhibiting phosphodiesterases other than the PDE4s may notably cause nauseas, headaches, diarrheas, loss of weight or further signs of anxiety and depression, which may be very unpleasant, or even dangerous for the patient.

[0094] The compound of formula (I) according to the invention therefore gives the possibility of improving the life quality of the patients, by limiting the secondary effects related to the taking of this type of molecule.

[0095] Further, from this selectivity there results that the compound of formula (I) is particularly efficient in the treatment of obstructive pulmonary pathologies, i.e. pathologies affecting the bronchial tubes and/or the lungs.

[0096] Said compound thus causes a reduction in the outbreaks of the disease, like coughing, breathlessness, production of mucus, etc. The deterioration of the respiratory function is then avoided, as well as hospitalization of the patient.

[0097] The compound of formula (I) was mentioned above. However, this is not a limiting embodiment of the invention, and protection is also sought for a pharmaceutically acceptable salt of said compound of formula (I).

[0098] Herein, the term of <<pharmaceutically acceptable salt>> relates to a salt not having any toxicity, irritation, allergic response or other effects having a hazardous effect for the health of the patient.

[0099] The salt of the present compound of formula (I) according to the invention may be obtained by subjecting said compound to an ordinary reaction of salt formation.

[0100] The salt of the present compound of formula (I) may for example be an ammonium salt or a metal salt, such as alkaline metal salt, for example a sodium or potassium salt, or an earth-alkaline metal salt, for example a calcium or magnesium salt.

[0101] By the term of <<alkyl>> is meant a hydrocarbon radical with a linear or branched chain with an unsaturated bond, which may be functionalized. In other words, the carbon chain may bear one or several chemical functions or <<functional groups>>.

[0102] For the compound (I) according to the invention, advantageous examples of alkyl groups include, without being limited thereto, groups comprising from 1 to 10 carbon atoms (C1 to C10), either linear or branched which may be either functionalized or not. Still more preferentially, this is a lower C.sub.1-C.sub.4 alkyl.

[0103] By the term of <<aryl>> is meant a functional group derived from an aromatic hydrocarbon, generally a phenyl (C6) or naphthyl (bicyclic C10) group and optionally substituted with at least one and up to three group(s) or atom(s) selected from the assembly formed by at least the alkyl, alkyloxy or alkoxy groups (an alkyl group bound to an oxygen group, —O—R), halogen (F, Cl, Br or I) or nitro (—NO.sub.2), alkylthio (—RS), cyano (CN), hydroxyl (—OH), amine (—NH.sub.2), alkylamine (—RNH), dialkylamine (—NR.sub.2), carbonyl (—C═O), ketone (—COR), ester (—CO.sub.2R), amide (—CONRR′).

[0104] Examples of aryl groups include, without being limited thereto, the phenyl groups C.sub.6H.sub.5, the tolyl group C.sub.6H.sub.4CH.sub.3, the xylyl group C.sub.6H.sub.3(CH.sub.3).sub.2, the naphthyl group C.sub.10H.sub.7, the 4-methoxyphenyl group C.sub.6H.sub.4OCH.sub.3, the 3,4-dimethoxyphenyl group C.sub.6H.sub.3(OCH.sub.3).sub.2, and the 4-(n-heptyloxyphenyl) group C.sub.6H.sub.4O(CH.sub.2).sub.6CH.sub.3.

[0105] Preferably, these aryl groups may be substituted with at least an up to three groups, notably alkyl, carbonyl or alkyloxy or another one as indicated above.

[0106] By the term of <<heteroaryl>> is meant a monocylic or polycyclic aromatic ring comprising in the ring carbon (C) and hydrogen (H) atoms, one or several heteroatoms selected independently from notably nitrogen (N), oxygen (O) and sulphur (S), phosphorus (P), and which may have a substitution scheme as described earlier with the term of <<aryl>>.

[0107] By <<heteroatom>>, is meant an atom of an organic molecule having at least one electron doublet but which is neither carbon nor hydrogen, and not a metal. The most frequent heteroatoms are oxygen, nitrogen, sulphur, phosphorus and halogens, like fluorine (F), bromine (Br), chlorine (Cl) and iodine (I).

[0108] Examples illustrating heteroaryl groups include, without however being limited thereto, groups such as pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl and oxazolyl.

[0109] Advantageously, when one of both groups R.sub.2 or R.sub.3 consist in an aryl group or in a heteroaryl group, the second group R.sub.2 or R.sub.3 consist in an alkyl C.sub.1-C.sub.10 group, preferably C.sub.1-C.sub.4 group, or in a hydrogen atom H.

[0110] It has also been mentioned that R.sub.2 and R.sub.3 may be bridged within a same ring or via several rings.

[0111] Preferably, when R.sub.2 and R.sub.3 are bridged, they are bridged via a single homocylic ring only having carbon atoms C and hydrogen atoms H, or via a single heterocyclic ring having at least one atom different from C, H atoms in the ring.

[0112] Advantageously, the bridging between R.sub.2 and R.sub.3 is achieved via a single ring with saturated bonds, having 5 or 6 atoms, preferably a saturated ring with 6 carbon atoms.

[0113] Thus, the compound according to the invention may for example have the formula (Ia) below:

##STR00008##

[0114] The compound (Ia) then consists in a fluorinated bicyclic pyridazin-3-one with: [0115] R.sub.1 represents H, an alkyl, an aryl or a heteroaryl. [0116] R.sub.F represents CF.sub.3, (CF.sub.2)n CF.sub.3 or CF.sub.2H with n representing an integer comprised between 1 and 7.

[0117] According to a particular embodiment, the compound has a formula (I) wherein: [0118] R.sub.1 represents H or a lower C.sub.1-C.sub.4 alkyl [0119] R.sub.2 represents H or a lower C.sub.1-C.sub.4 alkyl [0120] R.sub.3 represents an aryl substituted with a lower alkyl C.sub.1-C.sub.4 group or with one or several alkoxy groups. [0121] R.sub.F represents CF.sub.3 (CF.sub.2)n CF.sub.3 or CF.sub.2H with n representing an integer comprised between 1 and 3.

[0122] In a still further advantageous embodiment of the invention, the compound, or a pharmaceutically acceptable salt of said compound, has a formula (Ib) wherein: [0123] R.sub.1 represents CH.sub.3 [0124] R.sub.2 represents H [0125] R.sub.3 represents the following aryl or p-methoxyphenyl:

##STR00009## [0126] R.sub.F represents CF3.

[0127] This formula corresponds to the formula (Ib) above:

##STR00010##

[0128] The formula (Ib) corresponds to N.sub.2-methyl-4-(trifluoromethyl)-6-(4′-methoxyphenyl)-4,5-dihydroxypyridazin-3(2H)-one.

[0129] In a still further advantageous embodiment of the invention, the compound, or a pharmaceutically acceptable salt of said compound, has a formula (Ic) wherein: [0130] R.sub.1 represents H [0131] R.sub.2 represents H [0132] R.sub.3 represents the following aryl or 3,4-dimethoxyphenyl:

##STR00011## [0133] R.sub.F represents CF.sub.3.

[0134] This formula corresponds to the formula (Ib) above:

##STR00012##

[0135] This formula corresponds to the formula (Ic) corresponds to 4-(trifluoromethyl)-6-(3′,4′-dimethoxyphenyl)pyridazin-3(2H)-one.

[0136] Other particularly preferred compounds of the invention are: [0137] 6-(4′-(difluoromethoxy)phenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (Id) [0138] 6-(4′-(difluoromethoxy)phenyl-4-(trifluoromethyl)pyradazin-3(2H)-one (Ie) [0139] 2-phenyl-6-(p-tolyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (If) [0140] 4-(trifluoromethyl)-2-phenyl-6-(p-tolyl)pyradizin-3(2H)-one (Ig) [0141] 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (Ih) [0142] 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Ii)

[0143] These preferred compounds above have the advantage of having large selectivity towards PDE4 and are therefore particularly efficient in the treatment of pulmonary diseases.

[0144] The compound of formula (I) according to the invention, as well as the compound of formula (Ic), may advantageously be obtained by the method schematically illustrated in the enclosed FIG. 3.

[0145] One starts from a fluorinated ketene dithioketal compound of formula (III) with R.sub.F corresponding to CF.sub.3, (CF.sub.2).sub.nCF.sub.3 or CF.sub.2H with n representing an integer comprised between 1 and 7.

[0146] This compound is reactive with a potassium enolate of formula (IV), in the presence of tetrahydrofurane (THF) as a solvent, at a temperature comprised between 0 and 25° C. for a period of the order of 4-10 h.

[0147] Thus the intermediate of formula (V) corresponding to a perfluorinated ketene dithioketal compound illustrated in FIG. 3 is thereby obtained.

[0148] This intermediate of formula (V) is then subject to an acid hydrolysis reaction in the presence of trifluoroacetic acid and water during refluxing with heating. This acid hydrolysis reaction gives the possibility of obtaining a second intermediate of formula (VI).

[0149] The intermediate compound (VI) then undergoes a condensation reaction with hydrazine (R.sub.1NHNH.sub.2). The condensation reaction is carried out in the presence of para-toluenesulfonic acid (PTSA) in a solvent, in a device for refluxing with heating, for a duration of the order of 1 to 5 hours.

[0150] Preferably, this solvent consists in toluene or in glacial acetic acid (AcOH). The condensation reaction gives the possibility of obtaining the compound (I).

[0151] After cooling, the compound (I) according to the invention is then purified. The purification of said compound (I) is either carried out by chromatography on silica gel, advantageously in the presence of a mixture of petroleum ether and of ethyl acetate, or by precipitation of the product (I) by adding water.

[0152] In order to obtain the compound Ic, the compound (I) should then undergo an oxidation reaction in the presence of copper chloride (CuCl.sub.2) in acetonitrile in reflux, for about 4 h.

[0153] The nature of the fluorinated unit, which may notably consist in a group CF.sub.3 or (CF.sub.2).sub.nCF.sub.3 or CF.sub.2H, derived from the fluorinated ketene dithioketal compound (III) gives the possibility, in a particularly interesting way, of modulating the selectivity of the compound (I) according to the invention against the enzyme PDE4.

[0154] Accordingly, when said compound (I) will be administered to a patient for treating a broncho-pulmonary pathology, the potential secondary effects of the compound (I) will be limited, notably as compared with therapeutic molecules already used in the state of the art for treating this type of pathologies.

[0155] The unit R.sub.1 depends on the hydrazine molecule (R.sub.1NHNH.sub.2) used during the condensation step. This unit R.sub.1 gives the possibility of adapting, according to its structure, the interactions with the active site of the PDE enzymes.

[0156] The units R.sub.2 and R.sub.3 are related to the use of different ketones, corresponding to the compound (IV) of FIG. 3, during the preparation of the fluorinated dithioketal intermediate (V). The possibility of a system wherein the units R.sub.2 and R.sub.3 are bridged in order to lead to a bicyclic pyridazin-3-one molecule with 5 or 6 members, notably with 6 members as illustrated in the appended FIG. 2B, was already mentioned.

[0157] Definitively, because of the highly flexible synthesis method of the compound (I) according to the invention, illustrated in FIG. 3, each of the different units, R.sub.1, R.sub.F, R.sub.2 and R.sub.3, form a point for structural variation. This provides accordingly access to many pharmaco-modulations of said compound (I) for obtaining an optimal relationship between the structure, the activity and the selectivity of the compound (I) relatively to PDE4, so that said compound (I) is efficient in the treatment of broncho-pulmonary diseases.

[0158] In particular, the compound according to the invention, whether this is notably the compound (I), the compound (Ia) or the compound (Ib), or a pharmaceutically acceptable salt of one of these compounds, is used for inhibiting the enzymes phosphodiesterases of type IV.

[0159] In a preferential example, the compound according to the invention, whether this is the compound (I), (Ia) or (Ib) notably is used in the treatment of obstructive chronic obstructive pulmonary diseases (OCBP).

[0160] In another exemplary embodiment, said compounds according to the invention which were mentioned above are used for treating asthma.

[0161] The examples below, non-limiting of the invention, illustrate on the one hand the preparation of compounds according to the invention, notably the compounds having the formula (Ic), 4-(trifluoromethyl)-6-(3,4-dimethoxyphenyl)pyridazin-3(2H)-one, (Ig), 4-(trifluoromethyl)-2-phenyl-6-(p-tolyl)pyradizin-3(2H)-one and (Ii), 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one and, on the other hand the activity and interest for these compounds.

Example 1: Preparation of N2-methyl-4-(trifluoromethyl)-6-(4′-methoxyphenyl)-4,5-dihydropyridazin-3(2H)-one of formula (Ib)

[0162] In this example, reference is made to the appended FIG. 4, which illustrates the reaction which gives the possibility of obtaining the compound of formula (Ib).

[0163] A solution of potassium hydride and a solution of 4-methoxyacetophenone is mixed preferably in an argon atmosphere at 0° C., in the presence of a solvent, preferably tetrahydrofurane (THF), this forms the mixture 1.

[0164] To said mixture 1, is added after 10 to 20 mins of stirring, preferably 15 mins, a solution of perfluoroketene dithioacetal solution of formula (III′), this forms the mixture 2.

[0165] Said mixture 2 is stirred, at room temperature for 2 h 45 to 3 h 30, preferably 3 h.

[0166] The current reaction is hydrolyzed occurring within the mixture 2 with water.

[0167] The aqueous phase of the mixture 2, is extracted notably with ether.

[0168] The organic phase of the mixture 2 is dried, preferably on magnesium sulfate.

[0169] The organic phase of the mixture 2 is filtered and evaporated, preferably under reduced pressure.

[0170] A chromatography on a column is carried out for obtaining, advantageously as an oil, the compound (V′) of formula C.sub.16H.sub.19F.sub.3O.sub.2S.sub.2 called 1,1-Bis(ethylsulfanyl)-4-(4′-methoxyphenyl)-2-trifluoromethyl-but-1-ene-4-one and, preferably a silica column is used,

[0171] Said compound (V′) is mixed with water and with trifluoroacetic acid (TFA), this forms the mixture 3.

[0172] The mixture 3 is refluxed, for a period of the order of 10 h.

[0173] After cooling, the mixture 3 is neutralized with a saturated aqueous solution, preferably with NaHCO.sub.3.

[0174] The aqueous phase of the mixture 3, is extracted preferably with methylene chloride.

[0175] The organic phases of the mixture 3 are dried, filtered and evaporated.

[0176] A column chromatography is carried out in order to obtain, advantageously as an oil, the compound (VI′) of formula C.sub.14H.sub.15F.sub.3O.sub.3S called S-ethyl 4-(4′-methoxyphenyl)-2-trifluoromethyl-4-oxo-butanethioate, preferably a silica column is used.

[0177] Said compound (VI′) is mixed with glacial acetic acid and methyl hydrazine, the latter forms the mixture 4.

[0178] The mixture 4 is refluxed, preferably for a period of the order of 1 h.

[0179] After cooling the mixture 4, the product (Ib) present in the mixture 4 is precipitated with water.

[0180] After filtration, washing and drying in vacuo, preferably at a temperature of 100° C. for a period of the order of 16 h, the product (Ib) is obtained, pure in a solid form, of formula C.sub.13H.sub.13F.sub.3N.sub.2O.sub.2 called N2-methyl-4-(trifluoromethyl)-6-(4′-methoxyphenyl)-4,5-dihydropyridazin-3(2H)-one.

Example 2: Preparation of 4-(trifluoromethyl)-6-(3′,4′-dimethoxyphenyl)pyridazin-3(2H)-one of formula (Ic)

[0181] In this example, reference is made to the appended FIG. 5, which illustrates the reaction which gives the possibility of obtaining the compound of formula (Ic).

[0182] A solution of potassium hydride and a solution of 3,4-dimethoxyacetophenone is mixed preferably under an argon atmosphere at 0° C., in the presence of a solvent, preferably tetrahydrofurane (THF), this forms the mixture 1.

[0183] To said mixture 1, after 10 to 20 mins of stirring, preferably 15 mins, is added a solution of perfluoroketene dithioacetal of formula (III″), this forms the mixture 2.

[0184] Said mixture 2 is stirred, at room temperature for 2 h 45 to 3 h 30, preferably 3 h.

[0185] The current reaction occurring within the mixture 2 is hydrolyzed with water.

[0186] The aqueous phase of the mixture 2 is extracted, notably with ether.

[0187] The organic phase of the mixture 2 is dried, preferably on magnesium sulfate.

[0188] The organic phase of the mixture 2 is filtered and evaporated, preferably under reduced pressure.

[0189] A chromatography on a column is carried out for obtaining, advantageously as an oil, the compound (V″) of formula C.sub.17H.sub.21F.sub.3O.sub.3S.sub.2 called 1,1-Bis(ethylsulfanyl)-4-(3′,4′-dimethoxyphenyl)-2-trifluoromethyl-but-1-ene-4-one and preferably a silica column is used.

[0190] Said compound (V″) is mixed with water and trifluoroacetic acid (TFA), this forms the mixture 3.

[0191] The mixture 3 is refluxed, for a period of the order of 10 h.

[0192] After cooling, the mixture 3 is neutralized with a saturated aqueous solution, preferably with NaHCO.sub.3.

[0193] The aqueous phase of the mixture 3 is extracted, preferably with methylene chloride.

[0194] The organic phases of the mixture 3 are dried, filtered and evaporated.

[0195] A chromatography on a column is carried out for obtaining, advantageously as an oil, the compound (VI″) of formula C.sub.15H.sub.17F.sub.3O.sub.4S called S-ethyl 4-(3′,4′-dimethoxyphenyl)-2-trifluoromethyl-4-oxo-butanethioate, preferably a silica column is used.

[0196] Said compound (VI″) is mixed with glacial acetic acid and hydrazine hydrate, this forms the mixture 4.

[0197] The mixture 4 is refluxed, preferably for a period of the order of 1 h.

[0198] After cooling the mixture 4, the product (VII′) present in the mixture 4 is precipitated.

[0199] After filtration, washing and drying in vacuo, preferably at a temperature of 100° C. for a period of the order of 16 h, the product (VII″) is obtained pure in a solid form, of formula C.sub.13H.sub.13F.sub.3N.sub.2O.sub.3 called 6-(3′,4′-dimethoxyphenyl)-4-trifluoromethyl-4,5-dihydropyridazin-3(2H)-one.

[0200] The compound (VII″) is mixed under an argon atmosphere in anhydrous acetonitrile with copper chloride, this forming the mixture 5.

[0201] The mixture 5 is refluxed, preferably for a period of the order of 4 h.

[0202] After cooling, the mixture 5 is purified by column chromatography in order to obtain the compound (Ic), in the form of a solid, of formula C.sub.13H.sub.13F.sub.3N.sub.2O.sub.3 called 4-(trifluoromethyl)-6-(3′,4′-dimethoxyphenyl)pyridazin-3(2H)-one.

[0203] The whole of these steps gives the possibility of obtaining the compound (Ib) and (Ic) according to the invention.

Example 3: Preparation of 6-(4′-(difluromethoxy)phenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (Id)

[0204] In this example, reference is made to the compound, having relatively to the structure of the general compound (I), R.sub.1=H, R.sub.F=CF.sub.3, R.sub.2=H, R.sub.3=4-(difluoromethoxy)phenyl.

[0205] A potassium hydride solution and a solution of 4-(difluoromethoxy)acetophenone is mixed, preferably under an argon atmosphere at 0° C., in the presence of a solvent, preferably tetrahydrofurane (THF), this forms the mixture 1.

[0206] To said mixture 1, after 10 to 20 mins of stirring, preferably 15 mins, is added a solution of perfluoroketene dithioacetal of formula (III′), this forms the mixture 2.

[0207] Said mixture 2 is stirred, at room temperature for 2 h 45 to 3 h 30, preferably 3 h.

[0208] The current reaction occurring within the mixture 2 is hydrolyzed with water.

[0209] The aqueous phase of the mixture 2 is notably extracted with ether.

[0210] The organic phase of the mixture 2 is preferably dried on magnesium sulfate.

[0211] The organic phase of the mixture 2 is filtered and evaporated, preferably under reduced pressure.

[0212] A chromatography on a column is carried out in order to obtain, advantageously as an oil, the compound (V′″) of formula C.sub.18H.sub.17F.sub.5O.sub.2S.sub.2 called 1,1-Bis(ethylsulfanyl)-4-(4′-(difluoromethoxy)phenyl)-2-trifluoromethyl-but-1-ene-4-one and, a silica column is preferably used.

[0213] Said compound (V′″) is mixed with water and trifluoroacetic acid (TFA), this forms the mixture 3.

[0214] The mixture 3 is refluxed, for a period of the order of 10 h.

[0215] After cooling, the mixture 3 is neutralized with a saturated aqueous solution, preferably with NaHCO.sub.3.

[0216] The aqueous phase of the mixture 3 is preferably extracted with methylene chloride.

[0217] The organic phases of the mixture 3 are dried, filtered and evaporated.

[0218] A chromatography on a column is carried out for obtaining, advantageously as an oil, the compound (VI′″) of formula C.sub.14H.sub.13F.sub.5O.sub.3S called S-ethyl 4-(4′-(difluoromethoxy)phenyl)-2-trifluoromethyl-4-oxo-butanethioate, preferably a silica column is used.

[0219] Said compound (VI′″) is mixed with glacial acetic acid and hydrazine hydrate, this forms the mixture 4.

[0220] The mixture 4 is refluxed, preferably for a period of the order of 1 h.

[0221] After cooling of the mixture 4, the product (Id) present in the mixture 4 is precipitated with water.

[0222] After filtration, washing and drying in vacuo, preferably at a temperature of 100° C. for a period of the order of 16 h, the product (Id) is obtained pure as a solid, of formula C.sub.12H.sub.9F.sub.5N.sub.2O.sub.2 called 6-(4′-(difluoromethoxy)phenyl)-4-(trifluoromethyl-4,5-dihydropyridazin-3(2H)-one.

Example 4: Preparation of 6-(4′-(difluoromethoxy)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one of formula (Ie)

[0223] In this example, reference is made to the compound, having relatively to the structure of the general compound (I), R.sub.1=H, R.sub.F=CF.sub.3, R.sub.2=H, R.sub.3=4-(difluoromethoxy)phenyl.

[0224] The compound (Id) is mixed in anhydrous acetonitrile under an argon atmosphere with copper chloride, this forms the mixture 5.

[0225] The mixture 5 is refluxed, preferably for a period of the order of 4 h.

[0226] After cooling, the mixture 5 is purified by column chromatography in order to obtain the compound (Ie), in the form of a solid, of formula C.sub.12H.sub.7F.sub.5N.sub.2O.sub.2 called 6-(4′-(difluoromethoxy)phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one.

Example 5: Preparation of 2-phenyl-6-(p-tolyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (If)

[0227] In this example, reference is made to the compound, having relatively to the structure of the general compound (I), R.sub.1=phenyl, R.sub.F=CF.sub.3, R.sub.2=H, R.sub.3=p-tolyl.

[0228] A solution of potassium hydride and a solution of 1-(p-tolyl)ethanone is mixed, preferably under an argon atmosphere at 0° C., in the presence of a solvent, preferably tetrahydrofurane (THF), this forms the mixture 1.

[0229] To said mixture 1, after 10 to 20 mins of stirring, preferably 15 mins, is added a solution of perfluoroketene dithioacetal of formula (III′), this forms the mixture 2.

[0230] Said mixture 2 is stirred at room temperature for 2 h 45 to 3 h 30, preferably 3 h.

[0231] The current reaction occurring within the mixture 2 is hydrolyzed with water.

[0232] The aqueous phase of the mixture 2, is extracted notably with ether.

[0233] The organic phase of the mixture 2 is dried preferably on magnesium sulphate.

[0234] The organic phase of the mixture 2 is filtered and evaporated, preferably under reduced pressure.

[0235] A chromatography on a column is carried out in order to obtain, advantageously as an oil, the compound (V″″) of formula C.sub.16H.sub.19F.sub.3OS.sub.2 called 1,1-Bis(ethylsulfanyl)-2-trifluoromethyl-4-(p-tolyl)-but-1-ene-4-one and preferably a silica column is used.

[0236] Said compound (V″″) is mixed with water and trifluoroacetic acid (TFA), this forms the mixture 3.

[0237] The mixture 3 is refluxed, for a period of the order of 10 h.

[0238] After cooling, the mixture 3 is neutralized with a saturated aqueous solution, preferably with NaHCO.sub.3.

[0239] The aqueous phase of the mixture 3 is preferably extracted with methylene chloride.

[0240] The organic phases of the mixture 3 are dried, filtered and evaporated.

[0241] A chromatography on a column is carried out in order to obtain, advantageously as an oil, the compound (VI″″) of formula C.sub.14H.sub.15F.sub.3O.sub.2S called S-ethyl 2-trifluoromethyl-4-(p-tolyl)-4-oxo-butanethioate, preferably a silica column is used.

[0242] Said compound (VI″″) is mixed with glacial acetic acid and phenylhydrazine, this forms the mixture 4.

[0243] The mixture 4 is refluxed, preferably for a period of the order of 1 h.

[0244] After cooling the mixture 4, the product (If) present in the mixture 4 is precipitated with water.

[0245] After filtration, washing and drying in vacuo, preferably at a temperature of 100° C. for a period of the order of 16 h, the product (If) is obtained pure in a solid form, with formula C.sub.18H.sub.15F.sub.3N.sub.2O called 2-phenyl-6-(p-tolyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one.

Example 6: Preparation of 4-(trifluoromethyl)-2-phenyl-6-(p-tolyl)pyridazin-3(2H)-one (Ig)

[0246] In this example, reference is made to the compound, having relatively to the structure of the general compound (I), R.sub.1=phenyl, R.sub.F=CF.sub.3, R.sub.2=H, R.sub.3=p-tolyl.

[0247] The compound (If) is mixed under an argon atmosphere in anhydrous acetonitrile with copper chloride, this forms the mixture 5.

[0248] The mixture 5 is refluxed, preferably for a period of the order of 4 h.

[0249] After cooling, the mixture 5 is purified by column chromatography in order to obtain the compound (Ig), as a solid, of formula C.sub.18H.sub.13F.sub.3N.sub.2O called 4-(trifluoromethyl)-2-phenyl-6-(p-tolyl)pyridazin-3(2H)-one.

Example 7: Preparation of 6-(4′-(difluromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one (Ih)

[0250] In this example, reference is made to the compound, having relatively to the structure of the general compound (I), R.sub.1=H, R.sub.F=CF.sub.3, R.sub.2=H, R.sub.3=4-(difluoromethoxy)-3-methoxy-phenyl.

[0251] A solution of potassium hydride and a solution of 4-(difluoromethoxy)-3-methoxy-acetophenone is mixed preferably under an argon atmosphere at 0° C., in the presence of a solvent, preferably tetrahydrofurane (THF), this forms the mixture 1.

[0252] To said mixture 1, after 10 to 20 mins of stirring, preferably 15 mins, is added a solution of perfluoroketene dithioacetal of formula (III′), this forms the mixture 2.

[0253] Said mixture 2 is stirred at room temperature for 2 h 45 to 3 h 30, preferably 3 h.

[0254] The current reaction occurring within the mixture 2 is hydrolyzed with water.

[0255] The aqueous phase of the mixture 2, is notably extracted with ether.

[0256] The organic phase of the mixture 2 is preferably dried on magnesium sulphate.

[0257] The organic phase of the mixture 2 is filtered and evaporated preferably under reduced pressure.

[0258] A chromatography on a column is carried out in order to obtain, advantageously as an oil, the compound (V″″′) of formula C.sub.17H.sub.19F.sub.5O.sub.3S.sub.2 called 1,1-Bis(ethylsulfanyl)-4-(4′-(difluoromethoxy)-3′-m ethoxy-phenyl)-2-trifluoromethyl-but-1-ene-4-one and preferably a silica column is used.

[0259] Said compound (V″″′) is mixed with water and trifluoroacetic acid (TFA), this forms the mixture 3.

[0260] The mixture 3 is refluxed, for a period of the order of 10 h.

[0261] After cooling, the mixture 3 is neutralized with a saturated aqueous solution, preferably with NaHCO.sub.3.

[0262] The aqueous phase of the mixture 3 is preferably extracted with methylene chloride.

[0263] The organic phases of the mixture 3 are dried, filtered and evaporated.

[0264] A chromatography on a column is carried out for obtaining, advantageously as an oil, the compound (VI″″′) of formula C.sub.15H.sub.15F.sub.5O.sub.4S called S-ethyl 4-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-2-trifluoromethyl-4-oxo-butanethioate, preferably a silica column is used.

[0265] Said compound (VI″″′) is mixed with glacial acetic acid and with hydrazine hydrate, this forms the mixture 4.

[0266] The mixture 4 is refluxed, preferably for a period of the order of 1 h.

[0267] After cooling of the mixture 4, the product (Ih) present in the mixture 4 is precipitated with water.

[0268] After filtration, washing and drying in vacuo, preferably at a temperature of 100° C. for a period of the order of 16 h, the product (Ih) is obtained pure as a solid, with formula C.sub.13H.sub.11F.sub.5N.sub.2O.sub.3 called 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl-4,5-dihydropyridazin-3(2H)-one.

Example 8: Preparation of 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one of formula (Ii)

[0269] In this example, reference is made to the compound, having relatively to the structure of the general compound (I), R.sub.1=H, R.sub.F=CF.sub.3, R.sub.2=H, R.sub.3=4-(difluoromethoxy)-3-methoxy-phenyl.

[0270] The compound (Ih) is mixed under an argon atmosphere in the anhydrous acetonitrile with copper chloride, this forms the mixture 5.

[0271] The mixture 5 is refluxed, preferably for a period of the order of 4 h.

[0272] After cooling, the mixture 5 is purified by column chromatography in order to obtain the compound (Ii), as a solid, of formula C.sub.13H.sub.10F.sub.5N.sub.2O.sub.3 called 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl-4-(trifluoromethyl)pyridazin-3(2H)-one.

Example 9: Evaluation of the action of 4-(trifluoromethyl)-6-(3′,4′-dimethoxyphenyl)-4,5-dihydropyridazin-3(2H)-one of formula (Ic), of 4-(trifluoromethyl)-2-phenyl-6-(p-tolyl)pyradizin-3(2H)-one (Ig) and of 6-(4′-(difluoromethoxy)-3′-methoxy-phenyl)-4-(trifluoromethyl)pyridazin-3(2H)-one of formula (Ii)

[0273] In order to evaluate the action of the compounds (Ic), (Ig) and (Ii) according to the invention, the activity of different sub-types of phosphodiesterases, either of type 4 or not, was tested in vitro by using a kit adapted to the recombinant isoforms of human phosphodiesterases PDE4B2 and PDE4D coded by Escherichia coli. The activity of the PDE1 and PDE10 enzymes was also monitored.

[0274] The principle of the test is based on the cleavage of AMPc by the enzymes phosphodiesterases. The nucleotide-5′ which is sorted out during the reaction is itself cleaved by an enzyme 5′-nucleotidase into a nucleoside and a phosphate, the latter being quantified by using the reagent Biomol Green™.

[0275] The PDE enzymes are incubated on microplates in the presence of AMPc, 5′-nucleotidase, in the presence of an inhibitor, more particularly corresponding to the compound (Ic), (Ig) or (Ii) according to the invention, or in the absence of any inhibitor (control), and this for a period of the order of 60 mins.

[0276] The reaction is stopped by adding an amount of 100 microliters of the reagent Biomol Green™ and the plate is incubated for further 30 mins in order to allow development of the colour before reading the absorbance by means of a micro-plate reader.

[0277] The compounds (Ic), (Ig) or (Ii) according to the invention are dissolved in dimethylsulfoxide (DMSO) so as to obtain a final DMSO concentration of 2%, this concentration not significantly affecting the activity of the PDE enzymes.

[0278] The study of the inhibition of the PDE enzymes by the compound (Ic), (Ig) or (Ii) according to the invention was carried out by testing five different concentrations (500 μM, 50 μM, 5 μM and 0.5 μM) of said compounds (Ic), (Ig) or (Ii).

[0279] The CI.sub.50 values, for “inhibitory concentration 50”, corresponding to the amount, in μM, of compounds (Ic), (Ig) or (Ii) required for allowing inhibition of half of the activity of the PDE enzymes were then calculated by non-linear regression.

[0280] The CI.sub.50s which were calculated represent the average value of three determinations which were achieved independently of each other.

[0281] A non-specific inhibitor of the PDE enzymes, 3-isobutyl-1-methylxanthin (IBMX) corresponds to the control.

[0282] The results gave the possibility of showing that the compound (Ic) has a CI.sub.50 of 8.1 μM, that the compound (Ig) has a CI.sub.50 of 15 μM and that the compound (Ii) has a CI.sub.50 of 250 nM. As a comparison, the zardaverine molecule showed a CI.sub.50 of 2 μM.

[0283] Further, it was also shown that said compounds (Ic), (Ig) or (Ii) are particularly selective against PDE4, relatively to PDE1. Indeed, the inhibition percentage of PDE4 by the compound (Ic) is 74% at a concentration of 50 μM of compound (Ic), 45% for (Ig) and 56% at a 5 μM concentration of compound (Ii). On the contrary, the compounds (Ic), (Ig) and (Ii) do not allow any inhibition of PDE1. The inhibition of PDE1 is actually 0% at a concentration of 50 μM of compound (Ic), (Ig) and (Ii). Further, the compound (Ii) has a selectivity towards PDE10 since it has a percentage of inhibition of 9% towards this enzyme at 50 μM.

[0284] The compounds (Ic), (Ig) or (Ii) therefore have on the one hand good inhibitory efficiency towards the therapeutic target, the enzyme PDE4, and, on the other hand increased specificity towards this target, relatively to other isoforms of the enzyme, notably PDE1 or PDE10.

[0285] Of course, the invention is not limited to the examples illustrated and described earlier which may have alternatives and modifications without however departing from the scope of the invention.