MXPA00000910A - 1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Heterocyclic compounds of formula (I), wherein R1 represents a hydrogen atom or a -(CH2)m-Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C3-C7 cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group Y may optionally be substituted by one or more halogen atoms;R2 represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups;and R3 represents a hydrogen or halogen atom or an alkyl group, and pharmaceutically acceptable salts thereof, processes for preparing the same. The compounds are phosphodiesterase 4 inhibitors.

Description

DERIVATIVES OF 1, 2, 4-TRIAZOLO [, 3-B] PIRIDO- [3, 2-D] DIPIRIDACTNA AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.

This invention relates novel therapeutically useful heterocyclic compounds, to the process for their preparations and to the pharmaceutical compositions containing them.

It is known that phosphodiesterase 4 (PDE 4) inhibitors are useful in the treatment of inflammatory and allergic processes such as asthma, gastrointestinal deterioration induced by non-steroidal anti-inflammatory drugs and atopic dermatitis.

EP-A-85,840 discloses a series of triazolo-phthalazine derivatives with formula: REF. : 32557 Which are useful as anxiolytic agents It has been found that the presence of a pyridine ring in place of a benzo ring in the above structure provides new compounds which inhibit cyclic phosphodiesterases, in particular cyclic phosphodiesterases of type 4 and have a very low emetic activity (10- 100 times less active than rolipram in inducing vomiting in dogs).

Accordingly, the present invention provides a compound which is a heterocyclic with formula (I): where: R1 represents a hydrogen atom or a group - (CH2) mY, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl (preferably trifluoromethyl), alkoxy, alkoxycarbonyl, C3-C7 cycloalkyl, norbornyl (preferably 2). -norbornyl) or phenylalkenyl group, or an aromatic group (preferably phenyl or pyridyl) the aromatic group Y can optionally be substituted by one or more halogen atoms; R2 represents an aromatic group (preferably, phenyl, naphthyl or thienyl) these aromatic groups can optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and R3 represents a hydrogen or halogen atom (preferably chlorine) or an alkyl group, and pharmaceutically acceptable salts thereof.

The alkyl, haloalkyl, alkenyl or alkynyl groups and the radicals; such as in the alkoxy groups, mentioned in relation to the groups R1-R3 in the compounds of the invention are usually "lower" alkyl, that is they contain up to 6 and in particular up to 4 carbon atoms, the hydrocarbon chain is branched or straight. Examples of the groups and alkyl radicals are CH3, C2H5, C3H / i-C3H7, n-C Hg, i-C4H9, isoamyl and neopentyl.

When any of the groups, such as R1 or R2, has a chiral center, the compounds of formula (I) exhibit optical isomerism and the isomers are within the scope of the present invention.

Examples of R 1 are the above-mentioned preferred alkyl groups, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl and cyclopentyl ethyl.

Examples of R 2 are phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl and 3-nitrophenyl.

Examples of R are hydrogen, alkyl or chloro, preferably in the 8- or 9- positions.

The most preferred compounds of the invention are 6- (4-fluorophenyl) -3-isobutyl-1,2-triazolo [4, 3-b] pyrido [3,2-d] pyridazine, 3-cyclopropylmethyl-6- ( 3-nitrophenyl) -1,2,4-triazolo [4,3-b] pyrido [3,2-d] pyridazine, 3-cyclopropyl-6-phenyl-1, 2,4-triazolo [4,3-b ] pyrido [3,2-d] pyridazine, and 3-cyclobutylmethyl-6- (3-nitrophenyl) -1,2,4-triazolo [4, 3-b] pyrido [3,2-d] pyridazine.

According to another characteristic of the present invention, the heterocyclic compounds with formula I can be prepared from the corresponding hydrazine derivatives with formula (II): (") wherein R2 and R3 are as defined above, by reaction with a reactive derivative of a carboxylic acid with general formula (III): HOOC (III) wherein R1 is as defined above. The reactive derivative of the carboxylic acid may be, for example, a halide (preferably chloride), an anhydride or a mixed anhydride.

The reaction is preferably carried out in an inert organic solvent such as methylene chloride, dioxane or tetrafuran, in the presence of a base containing organic nitrogen, for example triethylamine and at a temperature between -10 ° C and +60 ° C. In the reaction, the corresponding hydrazide with general formula (IV) is formed first: wherein R1, R2 and R3 are as defined above. A suspension of this hydrazide (IV) in an organic solvent such as dioxane, tetrahydrofuran, isopropanol or n-butanol is heated, for example to the boiling point of the solvent, to give the corresponding heterocyclic compound with formula (I).

The hydrazine derivative with formula (II) can be prepared by: 1) reacting a hydrazone of formula (V): wherein R and R are as defined above and R 4 is an alkyl group, with a phosphorus halide or phosphorus oxyhalide (preferably phosphorus oxychloride), to form the intermediate compound of formula (VI): wherein R2 and R3 are as defined above and X is a chlorine or bromine atom; 2) reacting the compound (VI) with an alkyl carbazate (preferably t-butyl carbazate) of formula (VII): H2N-NH-COOR- (VII) wherein R is an alkyl group, to give the alkoxycarbonylhydrazine derivative (VIII): wherein R2, R3 and R5 are as defined above; and 3) treating the compound (VIII) with hydrogen chloride in an anhydrous solvent, such as ethanol.

The reaction between the hydrazone of formula (V) and a phosphorus halide or phosphorus oxyhalide is carried out with an excess of reagent at a temperature of 80 ° C to 120 ° C, then the excess reagent is removed and emptied into water cold In this way, the compound (VI) is obtained.

The reaction of (VI) on the alkyl carbazate of formula (VII) to obtain the corresponding alkoxycarbonylhydrazine derivative (-VIII), is preferably carried out in the presence of an organic solvent such as tetrahydrofuran or dioxane at a temperature of from 60 ° C to boiling point of the reaction medium.

The alkoxycarbonylhydrazine derivative (VIII) can, for example, be transformed into the hydrazine (II) derivative at room temperature in a saturated solution of hydrogen chloride-ethanol.

The hydrazone derivatives of formula (V) are known compounds which can be prepared from the corresponding acylnicotinic acid by means of known methods described in the literature.

Inhibition of the cyclic nucleotide of phosphodiesterase 4 in hearts of guinea pigs was developed using 96-well microtiter plates as described by Verghese et al .; (Molecular Pharmacology, 47, 1164-1171 (1995)).

The results of this test are shown in Table 1.

TABLE 1 ) see structures in Table 2 Compound A is 3-isobutyl-6-phenyl-1,2,4-triazolo [3,4-a] phthalazine, a compound included in EP-A-85,840.

As can be seen from Table 1, the compounds of formula (I) are cyclic phosphodiesterase inhibitors, in particular cyclic AMP phosphodiesterase inhibitors of type 4. The compounds are also capable of blocking the production of some pro-inflammatory cytokines such as , for example, TNFa. Thus, these can be used in the treatment of allergic, inflammatory and immunological diseases, as well as those diseases or conditions where the blocking of pro-inflammatory cytokines or the selective inhibition of PDE 4 could be beneficial.

Disease states include asthma, rheumatoid arthritis, osteoarthritis, osteoporosis, diseases in bone formation, glomerulonephritis, multiple sclerosis, Graves' ophthalmopathy, myasthenia gravis, insulin-dependent diabetes mellitus, graft rejection, gastrointestinal diseases such as ulcerative colitis or Crohn's disease, septic shock, respiratory syndrome by anxiety in adults, and skin diseases such as atopic dermatitis, contact dermatitis, acute dermatomyositis and psoriasis.

These can also be used as substances that improve cerebrovascular function as well as in the treatment of other CNS-related diseases such as dementia, Alzheimer's disease, depression, and as nootropic agents.

The compounds of the present invention are also of benefit when administered in combination with other drugs such as steroids and immunosuppressive agents, such as cyclosporin A, rapamycin or T-cell receptor blockers. In this case the administration of the compounds allows a reduction of the dose of other drugs, thus preventing the appearance of undesirable side effects associated with steroids and immunosuppressants.

The compounds of the invention have also shown their effectiveness in blocking, after preventive and / or curative treatment, the erosive and ulcerogenic effects induced by a variety of etiological agents, such as anti-inflammatory drugs (steroidal or non-inflammatory inti-inflammatory agents). -steroidal), stress, ammonia, ethanol and concentrated acids. These can be used alone or in combination with antacids and / or anti-secretion drugs in the preventive and / or curative treatment of gastrointestinal pathologies such as drug-induced ulcers, peptic ulcers, pyloric-related ulcers, esophagitis, and gastro-esophageal reflux disease .

They can also be used in the treatment of pathological situations when damage to cells or tissues occurs through conditions similar to anoxia or the production of an excess of free radicals. Examples of these beneficial effects are the protection of cardiac tissue after coronary artery occlusion or the prolongation of cell life and tissues when the compounds of the invention are added to preserve the solutions with the intention of storing or transplanting organs or fluids such as blood or sperm. They are also beneficial in tissue repair and wound healing.

The present invention also provides a heterocyclic compound of formula (I) for use in a method of treating the human or animal body by therapy, for use as a PDE 4 inhibitor or to block the production of a cytokine. inflammatory such as TNFa.

The present invention further provides a pharmaceutical composition comprising, an active ingredient, at least one heterocyclic compound of formula (I), and a pharmaceutically acceptable carrier or diluent.

Preferably the compositions are in a form suitable for oral, inhalation, rectal, transdermal, nasal, topical or parenteral administration.

The pharmaceutically acceptable carriers or diluents that are mixed with the active compound or compounds to form the compositions of this invention are well known intrinsically and the current excipients used depend inter alia on the method of administration proposed for the compositions.

The compositions of this invention are preferably adapted for oral administration. The compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention. These preparations can be made by methods well known in the art, for example by mixing the heterocyclic compound of formula (I) with the pharmaceutically acceptable carrier or diluent.

The diluents that can be used in the preparation of the compositions include those liquid and solid diluents that are compatible with the active ingredient, together with coloring or flavoring agents if desired. The tablets or capsules can conveniently contain from 1 to 100 mg and preferably from 5 to 50 mg of active ingredient. The compounds can also be incorporated into granules coated with suitable natural or synthetic polymers known in the art to produce constant release characteristics or incorporated with polymers in the form of tablets to produce the same characteristics.

Liquid compositions adapted for oral use may be in the form of solutions, suspensions or aerosols. The solutions may be aqueous or aqueous-alcoholic solutions in association with, for example, sucrose or sorbitol to form a syrup. The suspensions may comprise an insoluble or microencapsulated form of an active compound of the invention in association with water and other acceptable solvents together with an agent for the formation of the suspension or flavoring agent.

The compositions for administration by inhalation may be in the form of solutions, suspensions or micronized powder, contained within an appropriate inhaler.

Compositions for parenteral injection can be prepared, which may or may not be freeze dried and which may be dissolved in water or in an appropriate parenteral injection fluid.

In human therapy, the doses of the heterocyclic compound depend on the desired effects and duration of the treatment; adult doses are generally from 1 mg to 100 mg per day. In general, the doctor will decide the posology, taking into account the age and weight of the patient who will be treated.

The following examples further illustrate the invention EXAMPLE 1 a) a mixture of t-butoxycarbonylhydrazone of 2-benzoylnicotinic acid (45 g, 13.2 moles) in phosphorus oxychloride (500 ml) was boiled under reflux for one hour, then The excess phosphorus oxychloride was removed under reduced pressure, the residue was treated with ice water and extracted twice with methylene chloride. The organic solution was washed with 4% aqueous sodium carbonate solution, with brine and then dried (Na2SO4), the solvent was removed in vacuo. The solid obtained was collected with a mixture of diethylether-petroleum ether 1: 1 to give 5-chloro-8-phenylpyrido [2,3-d] pyridazine as a red solid (25.4 g, yield 80%). b) t-butyl carbazate (10.0 g, 0.075 mol) was added to a suspension of the above compound (18.2 g, 0.075 mol) in anhydrous tetrahydrofuran (180 ml) and the mixture was boiled under reflux for one hour. After cooling the crystallized solid was collected by filtration when 5-t-butoxycarbonylhydrazin-8-phenylpyrido [2,3-d] pyridazine (28.5 g) was obtained. This compound was dissolved in ethanol (150 ml), hydrogen chloride was added in saturated ethanol solution (100 ml) and the resulting mixture was stirred at room temperature for 15 hours. A solid formed which was collected by filtration and washed with diethylether to give 5-hydrazin-8-phenylpyrido [2,3-d] pyridazine dihydrochloride (21.6g, 92% yield). c) triethylamine (1.9 ml, 0.013 mol) was added to a suspension of 5-hydrazin-8-pheinlpyrido [2,3-d] pyridazine dihydrochloride (1.24 g, 0.004 mol) in methylene chloride (30 ml), then it was stirred at room temperature for 15 minutes and pivaloyl chloride (0.5 ml, 0.0044 mol) was slowly added. After stirring at room temperature for two hours, water (30 ml), the yellow solid, was added by filtration and washed with diethylether to give the hydrazide intermediate. This compound was suspended in n-butanol (30 ml), boiled under reflux for 15 hours and on cooling, a white solid crystallized which was collected by filtration and washed with diethyl ether. The solid obtained was purified by flash column chromatography with silica gel and as eluent 200: 8: 1 methylene chloride-ethanol-ammonium hydroxide. There was obtained 3-t-butyl-6-phenyl-1,2,4-triazolo [4, 3-b] pyrido [3,2-d] pyridazine (0.83 g, 69% yield), p. F. 188.1 ° C (determined by Differential Scanning Calorimetry, Perkin-Elmer DSC-7 (compound 8 in Table 2).

The heterocyclic compounds of formula (I) in Table 2 were prepared according to the processes set forth in this example, but with the appropriate raw materials.

TABLE 2 The following examples illustrate the pharmaceutical compositions according to the invention.

EXAMPLE 2 3,000 inhalation flasks each were prepared each containing 40 mg of 3-t-butyl-6-phenyl-1,2-triazole [4, 3-b]? Irido [3,2-d] pyridazine (active compound) as follow: Active Compound 120 g Sorbitan trioleate 4 g Substance diff. Cant.sufic. 60 g Process The microcrystalline suspension was prepared with these ingredients was introduced into the inhalation flasks with a volume of 20 ml per flask with a filling machine. The flasks were supplied with an appropriate valve which released 0.2 ml of the suspension for each activation (0.4 mg of active compound).

Example 3 ,000 capsules were prepared each containing 20 mg of 3-t-butyl-6-phenyl-1,2,4-triazolo [4,3-b] pyrido [3,2-d] pyridazine (active compound) as follows: Active compound 300 g Sodium Carboxymethyl starch 330 g Talc 195 g Hydrogenated Castor Oil 165 g Corn starch 495 g Process The above ingredients were sieved through a 60 mesh screen, then mixed in a suitable mixer and filled into 15,000 gelatin capsules.

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 invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (12)

1. A compound with formula (I characterized in that; R1 represents a hydrogen atom or a group - (CH2) mY, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C3-C cycloalkyl, norbornyl, or phenylalkenyl group, or a aromatic group the aromatic group Y may optionally be substituted by one or more halogen atoms; R2 represents an aromatic group; these aromatic groups may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and R3 represents a hydrogen or halogen atom or an alkyl group, and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, characterized in that the alkyl, haloalkyl and alkoxy groups have up to 6 carbon atoms, the alkoxycarbonyl groups have up to 7 carbon atoms and the phenylalkenyl groups have up to 12 carbon atoms.

3. A compound according to claim 1, characterized in that R1 represents - (CH2) m-Y where m is 0 or 1 and Y represents C6-6 alkyl or C3- cycloalkyl.

. A compound according to any of the preceding claims, characterized in that R 2 represents a phenyl group, naphthyl group or thienyl group in this group R 2 may be optionally substituted by one or more halogen atoms, methyl groups, methoxy groups, cyclopentoxy groups, groups nitro or dimethylamino groups.

5. A compound according to claim 4, characterized in that R 2 represents a phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl or 3-nitrophenyl group.

6. A compound according to any one of the preceding claims, characterized in that R3 represents a hydrogen atom, a Cx_6 alkyl group or a chlorine atom in the 8- or 9- position of the 1,2,4-triazolo skeleton [4, 3-b] pyrido [3,2-d] pyridazine.

7. A compound according to claim 1, characterized in that it is 6- (4-fluorophenyl) -3-isobutyl-l, 2,4-triazolo [4,3-b] pyrido [3,2-d] pyridazine, 3- cyclopropylmethyl-6- (3-nitrophenyl) -1,2-triazolo [4, 3-b] pyrido [3,2-d] pyridazine, 3-cyclopropyl-6-phenyl-1, 2,4-triazolo [4 , 3-b] pyrido [3,2-d] pyridazine and 3-cyclobutylmethyl-6- (3-nitrophenyl) -1,2,4-triazolo [4,3-b] pyrido [3,2-d] pyridazine.

8. A process for the preparation of a compound with formula (I) wherein R1 represents a hydrogen atom or a group - (CH2) mY, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C3-C cycloalkyl, norbornyl, or phenylalkenyl group, or an aromatic group the aromatic group Y can optionally be substituted by one or more halogen atoms; R2 represents an aromatic group; these aromatic groups may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and R3 represents a hydrogen or halogen atom or an alkyl group, this process is characterized in that it comprises the formulation of the 1,2-triazine ring present in the formula (I) by forming the cyclic compound of a hydrazide with formula (IV) ) where R1, R2 and R3 are as defined above.

9. A composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, characterized in that it is mixed with a pharmaceutically acceptable diluent or carrier.

10. A compound according to any one of claims 1 to 7 or pharmaceutically acceptable salt thereof or a composition according to claim 9 for use in a method of treating the human or animal body.

11. The use of a compound according to any of claims 1 to 7 or the pharmaceutically acceptable salt thereof or a composition according to claim 9 for the manufacture of a medicament for the treatment of a condition whose known treatment is inhibiting phosphodiesterase 4 including allergic reaction and disease states, inflammation, ulcers and immune disease.

12. A method for treating a condition whose known treatment is to inhibit phosphodiesterase 4, characterized in that it comprises administering to a human or animal subject in need of this treatment an effective amount of the compound according to any of claims 1 to 7 or the salt of This pharmaceutically acceptable or a composition according to claim 9.