Derivatives of 1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, the method of production thereof, pharmaceutical composition and method of inhibiting phosphodiesterase-4

 

Describes new derivatives of 1,2,4-triazolo [4,3-b] pyrido [3,2-d] pyridazine General formula I, where R¹denotes a hydrogen atom or -(CH₂)_m-Y group, in which m denotes an integer from 0 to 4 and Y represents C₁-C₆alkyl, C₁-C₆halogenation,₁-C₆alkoxy group, alkoxycarbonyl group having up to 7 carbon atoms, With₃-C₇cycloalkyl, norbornylene, phenylalaninol group having up to 12 carbon atoms, phenyl group, optionally substituted by one halogen atom, or 4-pyridyloxy group; R²denotes a phenyl group optionally substituted by one or more halogen atoms or With₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkane, methylenedioxy, nitro, di(C₁-C₆alkyl)amino or triptoreline groups, naftalina or thienyl group; R³denotes a hydrogen atom or halogen or₁-C₆alkyl group, and pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition and method of inhibiting phosphodiesterase-4. The described compounds can be used to treat inflammatory is always;">

The invention relates to new therapeutically useful heterocyclic compounds, method of their production and pharmaceutical compositions containing them.

It is known that inhibitors of phosphodiesterase-4 (PDE-4) used in the treatment of inflammatory and allergic diseases such as asthma, damage to the intestine caused by non-steroidal anti-inflammatory drugs, and atopic dermatitis.

In EP-A-85840 revealed series triazolo-phthalazinone derivatives of the formulaused as an anxiolytic drug.

Currently, we have found that the presence of pyridine rings in this structure instead of the benzene ring provides new compounds that inhibit cyclic phosphodiesterase, in particular 4 cyclic phosphodiesterase, and are characterized by a very low ability to cause vomiting (from the point of view of inducing vomiting in dogs that are 10-100 times less active than rolipram).

Thus, the present invention relates to a connection that is heterocyclic and has the formula (I)in which R¹denotes a hydrogen atom or -(CH₂)_m-Y group, in which m train is hydroxy, alkoxycarbonyl,₃-C₇cycloalkyl, norbornylene (preferably 2-norbornyl) or phenylalaninol group, or an aromatic group (preferably phenyl or pyridyloxy), with the specified aromatic group, Y may be optionally substituted by one or more halogen atoms; R²denotes an aromatic group (preferably phenyl, naftalina or thienyl), with the specified aromatic group may be optionally substituted by one or more halogen atoms or alkyl, alkoxy, C₃-C₆cycloalkane, methylenedioxy, nitro, dialkylamino or triptorelin groups; and R³denotes a hydrogen atom or halogen (preferably chlorine) or alkyl group, and its pharmaceutically acceptable salts.

Alkyl, halogenation, Alchemilla or Alchemilla groups and their part in groups such as alkoxy groups mentioned in the context of the description of the groups R¹-R³in the compounds of the present invention, are usually "inferior" to alcelam, i.e. containing up to 6 and especially up to 4 carbon atoms, while the hydrocarbon chain can be branched or linear. Examples of the alkyl GRU is ISO-C₄H₉isoamyl and neopentyl.

When any of the groups, such as R¹or R²have a chiral center, the compounds of formula (I) exhibit optical isomerism, and such isomers are also included in the scope of the present invention.

Examples R¹are preferred, the above alkyl groups, and cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl and cyclopentylmethyl.

Examples R²are phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-forfinal, 4-forfinal and 3-nitrophenyl.

Examples R³are hydrogen, alkyl or chlorine, preferably in positions 8 or 9.

The most preferred compounds of the present invention are 6-(4-forfinal)-3-isobutyl-1,2,4-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]pyridazin.

The present invention also relates to the production of heterocyclic compounds of the formula (I) by reaction of the corresponding hydrazine derivatives of the formula (II)in which R²and R³defined above, with reacn above. Specified reactive carboxylic acid derivative can represent, for example, a halide (preferably chloride), anhydride or mixed anhydride.

The reaction is carried out preferably in an inert organic solvent such as methylene chloride, dioxane or tetrahydrofuran, in the presence of organic nitrogen-containing base, such as triethylamine, at temperatures from -10 to +60^oC. during the reaction is a first corresponding hydrazide of General formula (IV)

where R¹, R²and R³defined above. The suspension is specified hydrazide (IV) in an organic solvent, such as dioxane, tetrahydrofuran, isopropanol or n-butanol, heated to the boiling point of the solvent to obtain the corresponding heterocyclic compounds of the formula (I).

A derivative of hydrazine of the formula (II) can be obtained:
1) in the interaction of the hydrazone of the formula (V)

where R²and R³defined above and R⁴represents an alkyl group, with a halide compound of phosphorus or oxyhalogenation phosphorus (preferably with phosphorus oxychloride) with formation of an intermediate coat a chlorine atom or bromine;
2) in the interaction of the compound (VI) with allylcarbamate (preferably t-BUTYLCARBAMATE) of the formula (VII)
H₂N-NH-COOR⁵(VII)
where R⁵denotes alkyl group, to obtain the derived alkoxycarbonylmethyl (VIII)

where R², R³and R⁴defined above, and
3) by treating compound (VIII) with hydrogen chloride in an anhydrous solvent, such as ethanol.

The reaction between the hydrazone of the formula (V) with a halide compound of phosphorus or phosphorus oxychloride is carried out with an excess of the reagent at a temperature of from 80 to 120^oWith, and then remove the excess reagent, and poured into cold water. Thus obtained compound (VI).

The reaction of the compound (VI) with alkalicarbonate formula (VII) to obtain the corresponding derivative of alkoxycarbonylmethyl formula (VIII) is preferably carried out in the presence of an organic solvent, such as tetrahydrofuran or dioxane, at a temperature of from 60^oC to the boiling point of the reaction medium.

Derived alkoxycarbonylmethyl formula (VIII) may be, for example, transformed into a hydrazine derivative of the formula (II) at room temperature in a saturated solution of hydrogen chloride Testwuide 2-allnegative acid by known methods, described in the literature.

Inhibition of cyclic nucleotidyltransferase 4 from the hearts of Guinea pigs performed using 96-well plates for micrometrology described Verghese et al. (Verghese et al., Molecular Pharmacology, 47, 1164-1171 (1995)).

The results of such testing are shown in table 1.

Table 1
Connection* - PDE-4, IR₅₀,micron
A - 10
6 - 2
7 - 0,3
12 - 3
31 - 0,2
47 - 0,7
55 - 0,2
60 - 0,1
61 - 2
109 - 0.04
112 - 0,7
113 - 0,2
* Cm. the patterns in table 2.

The compound a is a 3-isobutyl-6-phenyl-1,2,4-triazolo[3,4-a] phthalazine connection, included in the EP-A-85840.

As can be seen from table 1, the compounds of formula (I) are inhibitors of cyclic phosphodiesterase, in particular inhibitors of cyclic AMP phosphodiesterase type 4. These compounds also have the ability to block the formation of certain inflammatory cytokines, such as TNF. Thus, they can be used in the treatment of allergic, inflammatory and immunological diseases, such diseases and conditions that can have a positive effect blockade of inflammatory cytokines or selective inhibition of PDE-ia bone formation, glomerulonephritis, multiple sclerosis, graves ' ophthalmopathy, severe pseudoparalysis the gravis, insulin-dependent diabetes mellitus, reaction, transplant rejection, diseases of the gastrointestinal tract, such as ulcerative colitis, or Crohn's disease, septic shock, respiratory distress syndrome of adults and skin diseases such as atopic dermatitis, contact dermatitis, acute dermatomyositis and psoriasis.

They can also be used in connection with an inherent ability to improve the function of the cardiovascular system, in the treatment of other diseases LTP, such as dementia, Alzheimer's disease, depression, as well as a nootropic drugs.

Compounds of the present invention also have a positive effect when put together with other drugs, such as steroids and immunosuppressants, including cyclosporine a, rapamycin or blockers receptor T cells. In this case, the introduction of the considered compounds can reduce the dose of other medications that prevents the occurrence of undesirable side effects, determined by steroids and immunosuppressants.

The compounds of the present invention demonstrates the ability of blokirovannom etiological agents, such as anti-inflammatory agents (steroidal or non-steroidal anti-inflammatory drugs), stress, ammonia, ethanol and concentrated acids. They can be used alone or in combination with antacids and/or protivozachatochnye tools for the preventive and/or therapeutic treatment of pathologies of the gastrointestinal tract, such as ulcers drug origin, peptic ulcers, ulcers associated with exposure to N.pylori, esophagitis, and gastroesophageal reflux.

They can also be used in the treatment of pathological conditions in which damage cells or tissues caused by such adverse conditions, such as hypoxia or the formation of excessive free radicals. Examples of such favorable effects are protective effect on cardiac tissue after occlusion of the coronary artery or prolonging the viability of cells or tissue that is observed in those cases where the compounds of the present invention is added to the preservative solutions, which are designed for storage of transplants of organs or fluids, such as blood or semen. They also have a good effect on tissue repair and the healing of wounds.

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In addition, the present invention relates to a pharmaceutical composition, which comprises as active ingredient an effective amount of at least one heterocyclic compound of the formula (I) and a pharmaceutically acceptable carrier or diluent.

Preferably the composition is in a form suitable for oral, inhalation, rectal, percutaneous, nasal, local or parenteral administration.

Pharmaceutically acceptable carriers or diluents, which are mixed with the active compound or compounds with obtaining compositions of the present invention, are well known in the art, the choice of the specifically used fillers depends, among others, from the applied method of administration of the compositions.

The compositions of the present invention is preferably adapted for insertion through the mouth. Compositions for oral administration may be in the form of tablets, capsules, candies, as well as effervescent granules, or they may represent a liquid preparations, such as alasannya drugs can be obtained using known methods, for example, when mixing heterocyclic compounds of the formula (I) with a pharmaceutically acceptable carrier or diluent.

Diluents which can be used in the preparations on the basis of the present compositions include those liquid and solid diluents which are compatible with the active ingredient, if desirable, they can be added colourings or flavourings. Moreover, tablets and capsules can contain from 1 to 100 mg and preferably from 5 to 50 mg of active ingredient. The considered compounds can also be incorporated into the beads coated with the appropriate natural or synthetic polymers, which are known that they have properties to facilitate extended release, or you can enter together with the polymer in the composition of the tablets to generate the same characteristics.

Liquid compositions adapted for oral use may be in the form of solutions, suspensions or aerosols. The solution can be an aqueous or aqueous-alcoholic solutions, in combination with, for example, sucrose or sorbitol to obtain syrup. Suspension may include insoluble or microencapsulating form an active link in the op

Compositions for inhalation may be in the form of solutions, suspensions or micronized powder entered in the appropriate inhaler.

Can also be prepared composition or the last freeze drying, or not suitable for parenteral injection, which is then dissolved in water or another liquid that is acceptable for parenteral injection.

In the case of treatment of people of injected dose heterocyclic compounds depend on the desired outcome and duration of treatment; dosage for adult patients typically range from 1 to 100 mg per day. In the General case, the attending physician will decide the dosage, taking into account the age and weight of the patient to be treated.

The following examples illustrate the present invention.

EXAMPLE 1
a) a Mixture of t-butoxycarbonylamino 2-benzoylamino acid (45 g, 13,2 mol) in phosphorus oxychloride (500 ml) is boiled in a flask with reflux condenser for one hour, then at reduced pressure to remove the excess of phosphorus oxychloride, the residue is treated with ice water and extracted twice with methylene chloride. Then the organic solution was washed with 4% aqueous sodium bicarbonate solution, a saturated solution is given by a mixture of diethyl ether-petroleum ether (1:1), receiving 5-chloro-8-phenylpyrimido[2,3-d] pyridazin as a red solid (25.4 g, 80% yield).

b) To a suspension of the above compound (18.2 g, 0,075 mol) in anhydrous tetrahydrofuran (180 ml) is added t-BUTYLCARBAMATE (10.0 g, 0,075 mol) and the mixture is boiled in a flask with reflux condenser for one hour. After cooling, is collected by filtration vegascasinoonline solid, while receiving 5-t-butoxycarbonylamino-8 fenspiride[2,3-d] pyridazin (28.5 g). The specified connection is dissolved in ethanol (150 ml), add a saturated solution of hydrogen chloride in ethanol (100 ml) and the resulting mixture was stirred at room temperature for 15 hours. The resulting solid is collected by filtration followed by washing with diethyl ether, to obtain the dihydrochloride 5-hydrazino-8 fenspiride[2,3-d]pyridazine (21,6 g, 92%).

(C) To a suspension dihydrochloride 5-hydrazino-8 fenspiride[2,3-d]pyridazine (1.24 g, 0,004 mol) in methylene chloride (30 ml) was added triethylamine (1.9 ml, of 0.013 mol), then it was stirred at room temperature for 15 minutes and slowly add pualeilani (0.5 ml, 0,0044 mol). After stirring at room temperature for two hours, add water (30 ml), phim obtaining the intermediate hydrazide. The specified connection is suspended in n-butanol (30 ml), boiled in a flask under reflux for 15 hours, cooled vegascasinoonline white solid is collected by filtration and washed with diethyl ether. The obtained solid is purified flash chromatography on a column of silica gel, using as eluent a mixture of methylene chloride-ethanol-ammonium hydroxide (200: 8: 1). Get this 3-t-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazin (0,83 g, yield 69%). So pl. 188,1 (determined by the method of differential scanning calorimetry, Perkin-Elmer DSC-7 (compound 8 in table 2).

Heterocyclic compounds of the formula (I) listed in table 2, obtained using the method disclosed in this example, but using the appropriate starting materials.

The following examples illustrate how the pharmaceutical compositions of the present invention.

EXAMPLE 2
3000 sprays for inhalation, each of which contains 40 mg of 3-t-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine (active connection), is made as follows:
Active connection - 120g
Sorbitan trioleate - 4 g
Propellant (enough) - 60 l
Procedure
Get microcr the tion volume of 20 ml each. The spray can supply the appropriate valve that allows you to release 0.2 ml of the suspension at each pressure (0.4 mg of active compound).

EXAMPLE 3
15,000 capsules, each containing 20 mg of 3-t-butyl-6-phenyl-1,2,4-triazolo[4,3-b] pyrido[3,2-d]pyridazine (active connection), is made as follows:
Active connection - 300 g
Sodium carboxymethyl-starch - 330 g
Talc - 195 g
Hydrogenated castor oil - 165 g
Corn starch - 495
Procedure
The above ingredients are passed through a sieve with openings 60 mesh and then mixed in a suitable mixer and use the mixture to fill 15000 gelatin capsules.

Claims

1. Derivatives of 1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine formula (I):

in which R¹denotes a hydrogen atom or -(CH₂)_m-Y group, in the office m denotes an integer of 0 to 4 and Y represents C₁-C₆alkyl, C₁-C₆halogenation, C₁-C₆alkoxygroup, alkoxycarbonyl group having up to 7 carbon atoms, With₃-C₇cycloalkyl, norbornylene, phenylalaninol the groups of 4-pyridyloxy group;
R²denotes a phenyl group optionally substituted by one or more halogen atoms or C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₆cycloalkane, methylenedioxy, nitro, di(C₁-C₆)alkyl)amino or triptoreline groups, naftalina or thienyl group;
R³denotes a hydrogen atom or halogen, or C₁-C₆alkyl group,
and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R¹refers to a group -(CH₂)_m-Y, where m is 0 or 1 and Y represents C₁-C₆alkyl or C₃-C₇cycloalkyl.

3. Connection under item 1 or 2, in which R²denotes a phenyl group which may be optionally substituted by one or more halogen atoms, methyl groups, methoxypropane, Cyclopentasiloxane, nitro groups or dimethylaminopropane, or R²is naftalina group or thienyl group.

4. Connection on p. 3 in which R²denotes phenyl, 3-chloraniline, 4-chloraniline, 3-florfenicol, 4-florfenicol or 3-nitrophenyl group.

5. The compound according to any one of the preceding paragraphs, in which R

6. Connection on p. 1, which is 6-(4-forfinal)-3-isobutyl-1,2,4-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]pyridazin.

7. The method of obtaining the compounds of formula (I) as defined in any of paragraphs.1-6, characterized in that the hydrazide of formula IV

where R¹, R²and R³defined above,
is subjected to cyclization in the medium of organic solvent at the boiling point.

8. Pharmaceutical composition having inhibitory activity against cyclic nucleotidyltransferase 4, comprising the compound according to any one of paragraphs.1-6 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

9. The compound according to any one of paragraphs.1-6 or its pharmaceutically acceptable salt or composition under item 8 as an inhibitor of phosphodiesterase-4.

10. Method of inhibiting phosphodiesterase-4 in the subject, which is man or animal, including the introduction of a specified subject an effective amount of the Messiah.