MXPA00006223A - Triazine compounds for treatment of cns disorders - Google Patents

Abstract

A compound of formula (I) and pharmaceutically acceptable prodrugs, salts and solvates thereof.

Description

TRIAZINE COMPOUNDS FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM The present invention relates to a triazine compound which is useful in the treatment of diseases and disorders of the central nervous system (CNS) and its pharmaceutically acceptable derivatives, to pharmaceutical compositions containing them, to its use in the treatment of such disorders and methods of preparation. EP-A-0021121 and EP-A-0247892 describe 3,5-diamino triazines, for example 3,5-diamino-6- (2,3-dichlorophenyl) -1,2,4-triazine (lamotrigine) ), which are active in the treatment of CNS disorders and are particularly useful in the treatment of epilepsy. The present invention relates to a 5-amino triazine derivative which is a sodium channel blocker. This compound is a surprisingly potent anticonvulsant which has an increased potency with respect to lamotrigine and an increased selectivity in terms of side effects in the CNS and inhibition of the enzyme dehydrofolate reductase. Therefore, the compound is REF: 121310 useful in the treatment of CNS diseases such as epilepsy. Accordingly, the invention provides a compound of the formula (I) (l) i.e. 5-amino-6- [2, 3, 5-trichlorophenyl] -1,2,4-triazine and pharmaceutically acceptable derivatives thereof. By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of the compounds of the formula (I), or any other compound which during administration to the patient is capable of providing (directly or indirectly) a compound of the formula (I) or an active metabolite or a residue thereof (for example a prodrug). The reference hereinafter to the compounds of the formula (I) includes the compound of the formula (I) and pharmaceutically acceptable derivatives thereof.

Suitable pharmaceutically acceptable salts of the compound of the formula (I) include the acid addition salts formed with organic or inorganic acids, preferably inorganic acids, for example hydrochlorides, hydrobromides and sulfates. Suitable prodrugs are well known in the art and include the N-acyl derivatives, for example in any of the four nitrogens in the compounds of the formula (I), for example the simple acyl derivatives such as acetyl, propionyl and the like , or groups such as RQ-CH2-nitrogen or ROC (O) -nitrogen. The compounds of the formula (I) are particularly useful as anticonvulsants. Therefore, they are useful in the treatment of epilepsy. They can be used to improve the condition of a host, typically a human being, who suffers from epilepsy. They can be used to alleviate the symptoms of epilepsy in a host. The "epilepsy" is proposed to include the following accesses: - simple partial accesses, complex partial accesses, secondary generalized accesses, generalized accesses that include accesses of absence, myoclonic accesses, clonic accesses, tonic accesses, tonic clonic accesses and the atonic accesses. The compounds of the formula (I) are additionally useful in the treatment of a bipolar disorder, alternatively known as a manic depression. Bipolar disorder of type I or II can be treated. In this way, the compounds of the formula (I) can be used to improve the condition of a human patient suffering from a bipolar disorder. They can be used to relieve the symptoms of bipolar disorder in a host. The compounds of the formula (I) can also be used in the treatment of unipolar depression. The compounds of the formula (I) are useful as analgesics. Therefore, they are useful in the treatment or prevention of pain. They can be used to improve the condition of a guest, typically a human being, who suffers from pain. They can be used to relieve pain in a host. Accordingly, the compounds of the formula (I) can be used as a preventive analgesic to treat acute pain such as musculoskeletal pain, post-operative pain and pain by surgery, chronic pain such as chronic inflammatory pain. (for example, rheumatoid arthritis and osteoarthritis), neuropathic pain (for example, postherpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and the pain associated with cancer and fibromyalgia. The compounds of the formula (I) can also be used in the treatment or prevention of pain associated with migraine. The compounds of formula (I) are further useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non-cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterized by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. In this manner, the compounds of the formula (I) can be used to alleviate the pain associated with irritable bowel syndrome. In this way, the condition of a human patient suffering from irritable bowel syndrome can be improved. The compounds of the formula (I) ~ may also be useful in the treatment of neurodegenerative diseases, such as Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, muscle sclerosis, macular degeneration and glaucoma. The compounds of the formula (I) may also be useful in neuroprotection and in the treatment of the neurodegeneration that follows from attacks, cardiac arrest, pulmonary shunt, traumatic brain damage, damage to the spinal cord or the like. The compounds of the formula (I) are also useful in the treatment of tinnitus. Still further, the compounds of the formula (I) are also useful in the prevention or reduction of the dependence of, or for the prevention or reduction of tolerance or inverse tolerance to, a dependency-inducing agent. Examples of dependence-inducing agents include opioids (eg, morphine, CNS depressants (e.g., ethanol), psychostimulants (e.g., cocaine), and nicotine, Therefore, it is further provided by the present invention. , the use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof, for use in human and veterinary medicine.Therefore, it is further provided by the present invention, the use of a compound of the formula I) in the manufacture of a medicament for use in the treatment of a disorder substantially as described hereinabove .. The present invention further comprises a method for the treatment of a patient suffering from, or being susceptible to, a disorder substantially as described herein above, such a method comprises administering to the patient a therapeutically effective amount of a compound of the formula (I). "Attachment" as used herein includes the treatment of established disorders, and also includes the prophylaxis thereof. The precise amount of the compounds of formula (I) administered to a host, particularly a human patient, will be the responsibility of the attending physician. However, the dose used will depend on several factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration. The compound of the formula (I) can be administered in a dose from 0.1 to 10 mg / kg of body weight per day and more particularly 0.3 to 3 mg / kg of body weight per day, calculated as the free base. The dose range for adult humans is generally from 8 to 1000 mg / day, such as from 35 to 800 mg / day, preferably 10 to 200 mg / day or 20 to 200 mg / day, calculated as the free base. The compounds of the formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Accordingly, in another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the 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 a mixture with one or more physiologically acceptable carriers or excipients. Although it is possible for the compounds of formula (I) to be administered as the unrefined chemical, it is preferable to present them as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of the formula (I) thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carrier (s) must be "acceptable" in the sense that they are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, parenteral (including subcutaneous, e.g., injection or by depot, intradermal, intrathecal, intramuscular, e.g., deposit and intravenous), rectal and topical (including dermal, buccal or sublingual) administration although the The most appropriate route may depend, for example, on the condition and disorder of the patient or recipient. The formulations can be conveniently presented in a unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, sachets or tablets (for example chewable tablets in particular for pediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary or paste. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, a dispersing agent or surfactant, lubricant . The molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be coated or labeled and may be formulated to provide a slow or controlled release of the active ingredient therein. Formulations for parenteral administration include sterile, aqueous and non-aqueous injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the proposed patient's blood; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in unit dose or multiple dose containers, for example ampoules and flasks, and can be stored in a freeze-dried condition (lyophilized) requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, solid fat or polyethylene glycol. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and lozenges comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. The compounds of the invention can also be formulated as depot preparations. Such long-acting formulations can be administered by the implant (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly salt soluble. In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art which have been considered with respect to the type of the formulation in question, for example those suitable for oral administration may include flavoring agents. Preferred unit dosage formulations are those containing an effective daily dose, as mentioned hereinbefore, or an appropriate fraction thereof, of the active ingredient. Conveniently those which can be from 5 mg to 1000 mg, such as from 8 mg to 1000 mg, more conveniently 35 mg to 800 mg, and even more conveniently 10 to 200 mg or 20 to 200 mg, calculated as the free base. The compounds of the formula (I) can be used in combination with other therapeutic agents, for example other anticonvulsants. When the compounds of the formula (I) are used in combination with other therapeutic agents, the compounds can be administered either sequentially or simultaneously by any convenient route. In this manner, the invention provides, in a further aspect, a combination comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof with an additional therapeutic agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and therefore pharmaceutical formulations comprising a combination as defined above, together with a pharmaceutically acceptable carrier or excipient, comprise a further aspect of 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 the formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. The appropriate doses will be readily appreciated by those skilled in the art. The present invention provides a process for preparing the compounds of the formula (I) and pharmaceutically acceptable derivatives thereof.

The compounds of the formula (I) can be prepared by the methods described below which form a further aspect of the invention. According to a general procedure (A), which forms a further aspect of the invention, a compound of the formula (I) can be prepared under suitable reaction conditions from a compound of the formula (II) (ll) for example, by reduction, preferably using a reduction metal, such as Raney nickel, and a source of hydrogen, such as hydrazine monohydrate, in a suitable solvent, such as ethanol, preferably at elevated temperature, for example between 70-75 ° C. According to another process (B), which forms a further aspect of the invention, a compound of the formula (I) can be prepared under suitable reaction conditions by reacting a compound of the formula (III) (Hl) where n can be one or two, with a reducing agent. Suitable reducing agents include borohydrides, preferably sodium borohydride. The reaction can be carried out in a mixture of solvents, such as an ether, preferably tetrahydrofuran and an alcohol, preferably t-butanol and at room temperature. A compound of the formula (III) can be prepared under suitable reaction conditions by reacting a compound of the formula (II) with an oxidizing agent, such as a permeate, for example potassium peroxymonosulfate or m-chloroperbenzoic acid and at reduced temperature , for example, < 5 ° C and this forms a further aspect of the invention. A compound of the formula (II) can be suitably prepared by reacting the 2,3,5-trichlorobenzoyl cyanide with a salt of S-methylthiosemicarbazide, preferably hydroiodide, in the presence of a dilute mineral acid, preferably a dilute sulfuric acid and this forms a further aspect of the invention. A compound of the formula (II) can alternatively be prepared under suitable reaction conditions by photolysis of a solution of a compound of the formula (IV), at between 320 and 750 nm (IV) in a suitable solvent, such as an alcohol, preferably propan-1-ol and at an elevated temperature, for example the reflux temperature of the solvent and this forms a further aspect of the invention. The 2, 3, 5-trichlorobenzoyl cyanide and S-methylthiosemicarbazide can be prepared according to conventional procedures and this forms a further aspect of the invention.

A compound of the formula (IV) can be prepared under suitable reaction conditions by reacting a compound of the formula (V) (V) with a dehydrating agent, preferably diphosphoryl chloride and this forms a further aspect of the invention. A compound of the formula (V) can be suitably prepared by the reaction of a compound of the formula (VI) (SAW) with a salt of S-methylthiosemicarbazide, preferably hydroiodide, in a suitable solvent, for example ethanol, and at an elevated temperature, for example 50 ° C and this forms a further aspect of the invention.

A compound of the formula (VI) can be prepared under suitable reaction conditions by reacting the 2,3,5-trichlorobenzoyl cyanide with a strong aqueous acid, preferably concentrated hydrochloric acid, which forms a further aspect of the invention. The prodrugs of the compounds of the formula (I) can be prepared according to conventional procedures. The following Examples, which are not to be construed as constituting a limitation thereto, are provided to illustrate the invention.

Intermediate Compound 1 2, 3, 5-trichlorobenzoic acid 2, 3, 5-trichlorobenzaldehyde (197.40 g, 0.94 moles, Lancaster) was dissolved in t-butanol (785 ml), stirred and heated under nitrogen at 50 ° C. The 2M aqueous sodium hydroxide (940 ml) was heated to 50 ° C and added to the aldehyde solution. Hydrogen peroxide (27.50% aqueous, 699 g, 5.65 moles) was added using a dosing pump for 45 minutes, maintaining the temperature at 57-60 ° C.

Then the reaction mixture was stirred and heated under nitrogen for an additional hour, cooled and evaporated in vacuo. The slurry, residual slurry was filtered and the filtrate was washed with toluene (2 x 300 ml) and then acidified (pH 1) with 5M hydrochloric acid while stirring vigorously. The precipitated, white, thick, resulting product was filtered, washed with water (3 x 300 ml) and dried in vacuo at 50 ° C. Yield 180 g (85%). P.f. 155-158 ° C (foam).

Intermediate 2 Chloride 2, 3, 5-trichlorobenzoyl The 2,3,5-trichlorobenzoic acid (75 g, 0.33 mol, Example 1) and thionyl chloride (197.47 ml, 271.32 g, 2.28 mol) were heated to reflux in anhydrous toluene (350 ml) at 120 ° C for 3 hours. hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was azeotroped with anhydrous toluene (3 x 100 ml) to give a viscous brown oil. An alternative preparation can be carried out as follows: The 2,3,5-trichlorobenzoic acid (75 g, 333 mmol, 1 equivalent) was added to toluene (225 ml) and the slurry was heated to reflux for 2 hours with a dean-stark apparatus attached or annexed. The acid dissolved in the solution during heating. The solution was cooled with good agitation, and pyridine (0.2 ml, cat.-0.5% in mol) and thionyl chloride (26.7 ml, 365 mmol, 1.1 equivalents) were added by means of a dropping funnel over a period of 1 hour. hour, maintaining an internal temperature of between 70-80 ° C. Once the addition was complete, the mixture was refluxed for 2 hours. The solution was cooled, the volatiles were removed in vacuo, and then converted to an azeotrope with toluene (2 x 50 ml) to give a faint yellow oil as the product.

Intermediate Compound 3 2, 3, 5-trichlorobenzoyl cyanide Copper (I) cyanide (63.88 g, 0.71 moles), potassium iodide (108.20 g, 0.65 moles) were heated to reflux in anhydrous xylene (590 ml) at 150 ° C for 24 hours using a Dean's apparatus. Stark A solution of 2, 3, 5-trichlorobenzoyl chloride in anhydrous xylene (150 ml) was added and the resulting suspension was heated to reflux under nitrogen at 150 ° C for 3 days. The suspension was filtered and the filtrate was evaporated in vacuo, d (CDC13): 7.80 (s, 1H), 8.0 (S, 1H). An alternative preparation can be carried out as follows: Potassium iodide (66.25 g, 400 mmol, 1.2 equivalents) (sieved to a particle size <1 mm) and copper cyanide (1) (36 g, 400 mmoles, 1.2 equivalents), in xylene (400 ml), for 3 hours with a dean-stark device attached or attached. The mixture was cooled and 2, 3, 5-trichlorobenzoyl chloride in xylene (100 ml) was added. The mixture was heated to reflux with a fixed or attached dean-stark apparatus. The mixture became gradually reddish / orange for 30 minutes, and a light brown solution was obtained during the night. The mixture was refluxed for 40 hours, then cooled and the organic substances were removed by filtration. The xylene was separated in vacuo at 55 ° C, converted to an azeotrope with toluene (2 x 50 ml), then 60-80 petroleum ether (260 ml) was added by means of a die-shaped entry, for Give a brown solution. During cooling, a precipitated brown product was formed. The solution was stirred at room temperature overnight, the solid was removed by filtration, and washed with petroleum ether 60-80 (100 ml). The solid was sucked dry under a blanket of nitrogen to give a first crop of a yellow solid, 2,3,5-trichlorobenzoyl nitrile (45.5 g, 58.1%). The filtrate was concentrated, allowed to stand for 24 hours, and then a second crop (6.8 g, 8.7%) was collected, followed by a third crop (5.3 g, 6.8%). Total yield (57.6 g, 73.8%). R.N.N. (DMSO-d6) d ppm: 8.03 (d, 1H), 8.34 (d, 1H).

Intermediate Compound 4 S-methylthiosemicarbazide hydroiodide Thiosemicarbazide (448 g, 0.50 moles, Aldrich) and iodomethane (300 ml, 5 moles) were heated to reflux in 95% ethanol (2000 ml) for 5 hours and then cooled to room temperature. The desired product was filtered, washed with ether (3 x 100 ml) and dried in vacuo. Production 647 g. P.f. 138-140 ° C.

Intermediate 5-Thiomethyl-5-amino-6- [2, 3, 5-trichlorophenyl] -1,4,4-triazine [Formula (II)] Route A S-methylthiosemicarbazide hydroiodide (38.59 g, 0.17 mmol) was suspended in dilute sulfuric acid (95.83 ml of concentrated sulfuric acid / 95.83 ml of water) and stirred at room temperature for one hour. A solution of 2,3,5-trichlorobenzoyl cyanide (18 g, 0.077 moles) in acetonitrile (90 ml) was added slowly and the resulting mixture was stirred at room temperature for eleven days. The reaction mixture was diluted with water and extracted with ethyl acetate (3x250 ml). The ethyl acetate layer was washed with water (2x300 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was dissolved in propan-1-ol (500 ml) and heated to reflux at 130 ° C for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was partitioned between 2N aqueous sodium hydroxide (100 ml) and ethyl acetate (300 ml). The ethyl acetate layer was washed with water (2x100 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate in vacuo evaporated. The residue was purified by "flash chromatography" using cyclohexane to 1: 3 cyclohexane: ether as the eluent. Production 1.90 g (8%). P.f. 138-140 ° C.

Lane B: 2- [S-methylthiosemicarbazone] -2- [2, 3, 5-trichlorophenyl] -acetonitrile (1.00 g, 3.11 mmol) was stirred in propan-1-ol (40 ml) and heated to reflux under nitrogen . A 300-watt tungsten lamp was made to shine over the mixture and the reaction was left under these conditions for forty-eight hours. The reaction was cooled to room temperature, then the lamp was turned off and the solution evaporated in va cuo to leave a dark oil which crystallized during rest. The solid was triturated with methanol, filtered and dried to give the product, 3-thiomethyl-5-amino-6- [2, 3, 5-trichlorophenyl] -1,2,4-triazine. Production 770 mg (77.0%). R.M.N. (DMSO-d6) d ppm: 2.50 (s, 3H), 7.15 (broad s, 1H), 7.63 (d, 1H), 7.90 (broad s, 1H), 8.00 (d, 1H). LC / MS, positive electrorrocio (M + l) + = 321/323.

Intermediate Compound 3-Methylsulfoxy-5-amino-6- [2, 3, 5-trichlorophenyl] -1, 2,4-triazine [Formula (III)] The 3-thiomethyl-5-amino-6- [2,3,5-trichlorophenyl] -1,2,4-triazine (6 g, 18.7 mmol, 1 equivalent) was suspended in dichloromethane (650 ml), and cooled to 5 ° C. The m-chloroperbenzoic acid (5.66 g, 18.7 mmol, supposedly 57%, ~ 1 equivalent) was added in one portion and stirred at < 10 ° C for 20 minutes, under nitrogen, resulting in a light yellow solution. Analysis by CCD (cyclohexane: ethyl acetate 1: 1) showed no remaining starting material. The reaction was quenched by the addition of sodium sulfite (10 g) and water (200 ml) to the vigorously stirred solution. The layers were separated and the organic layer was washed with a 10% aqueous sodium sulfite solution (100 ml). It was found that the Merck peroxide test strips were negative. The organic layer was washed with saturated sodium hydrogen carbonate (200 ml), then washed with a brine solution (200 ml), and then dried over anhydrous magnesium sulfate. The organic solution was filtered and the solvent was removed in vacuo to give a yellow solid, 3-methylsulfoxy-5-amino-6- [2,3,5-trichlorophenyl] -1,2,4-triazine. Production 5.82 g (92.2 %) • R.M.N. (CDC13) d ppm: 3.05 (s, 3H), 7.39 (d, 1H), 7.69 (d, 1H), LC / MS, positive electrorrocity (M + 1) + = 33T / 339.

Intermediate 7-OXO-2- [2,3,5-trichlorophenyl] -acetamide [Formula (VI)] The 2, 3, 5-trichlorobenzoyl cyanide (10.0 g, 46 mmoles) was added to the concentrated hydrochloric acid (140 ml) and stirred at room temperature for forty-eight hours. The suspension was diluted with water (100 ml) and then filtered. The light brown solid was washed with water, then dried with air for one hour. The crude product was then dissolved in ethyl acetate (400 ml), washed with a saturated aqueous sodium carbonate solution (2x300 ml), followed by brine (300 ml) and then dried over magnesium sulfate, filtered and evaporated to leave a beige solid. This solid was triturated in hexane / toluene (200 ml), filtered and dried in vacuo to give an off-white solid, 2-oxo-2- [2, 3, 5-trichlorophenyl] -acetamide. Yield 7.02 g (65.3%). R.M.N. (DMS0-d6) d ppm: 7.77 (d, 1H), 8.09 (d, 1H), 8.13 (broad s, 1H), 8.48 (broad s, 1H). LC / MS, Negative electro-negative (M-l) "= 250/252.

Intermediate 8 2- [S-methylthiosemicarbozone] -2- [2, 3, 5-trichlorophenyl] -acetamide [Formula (V)] The 2-OXO-2- [2, 3, 5-trichlorophenyl] -acetamide (5.00 g, 19.8 mmol) and the S-methylthiosemicarbazide hydroiodide (9.20 g, 39.5 mmol) were suspended in ethanol (100 ml) and heated at 50 ° C, under nitrogen, overnight. When thin layer chromatography showed that the starting material was still present, an additional amount of S-methylthiosemicarbazide hydroiodide (4.00 g, 17.2 mmol) was added and stirring was continued at 50 ° C for 2 hours. The reaction mixture was evaporated in vacuo to give a brown oil. This oil was dissolved in ethyl acetate (400 ml), washed with water (300 ml), then with brine (300 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to give a gum. yellow-coffee color. This gum was purified by column chromatography using ethylhexane acetate 1: 1 as the eluent. The product, predominantly the E-isomer, was obtained as a light yellow solid, yield 4.25 g (63.2%). R.M.N. (DMSO-d6) d ppm 2.14 (s, 3H), 7.28 (d, 1H), 7.31 (broad s, 1H), 7.84 (d, 1H), 8.28 (broad s, 1H). LC / MS, positive electro-positive (M + l) + = 339/341.

Intermediate 9 2- [S-Methylthiosemicarbazone] -2- [2, 3, 5-trichlorophenyl] -acetonitrile [Formula (IV)] The 2- [S-methylthiosemicarbazide] -2- [2, 3, 5-trichlorophenyl] -acetamide (2 g, 5.89 mmol) was added in portions to a solution of diphosphoryl chloride 2.97 g, 1.63 ml, 11.8 mmol) in 1,4-dioxane (16 ml) and stirred under nitrogen for six hours. The dark solution was evaporated in vacuo to leave a dark yellow oil. The oil was dissolved in ethyl acetate (50 ml), washed with water (50 ml), with saturated aqueous sodium hydrogen carbonate (50 ml), with brine (50 ml), then dried over magnesium sulfate, it was filtered and evaporated in vacuo to give a dark yellow oil. The crude product was purified by column chromatography using hexane: ethyl acetate 3: 1 as the eluent. The product, 2- [S-methylthiosemicarbazone] -2- [2, 3, 5-trichlorophenyl] -aceto-nitrile was obtained as a yellow oil which crystallized to a yellow solid during rest. Production 1.16 g (61.2%). R.M.N. (DMSO-d6) d ppm: 2.20 (s, 1H), 3.38 (broad s, 3H), 7.68 (broad s, 1H), 7.95 (d, 1H), 8.12 (broad s, 1H). LC / MS, positive electrorrocio (M + l) + = 321/323.

Example 5-Amino-6- [2, 3, 5-trichlorophenyl] -1, 2,4-triazine Procedure A Raney nickel (3.50 g, suspension in water, Fluka) was suspended in a solution of 3-thiomethyl-5-amino-6- (2,3,5-trichlorophenyl) -1,2,4-triazine (1.75 g). g, 5.44xl0 ~ 3 moles) in pure ethanol (30 ml) and stirred at 70 ° C. The hydrazine monohydrate (3.50 ml, 3.54 g, 0.11 mol) was added dropwise to the suspension for 30 minutes. The resulting mixture was stirred at 70-75 ° C for 2 hours, filtered, washed with pure, hot ethanol (3x20 ml) and the filtrate was evaporated in vacuo. The residue was purified by "flash chromatography" using cyclohexane: ether 15:25 to ether as the eluent and then by preparative CLAP using a Supercosil ABZ column and 50% acetonitrile / water and 0.1% formic acid as the eluent Yield 0.134 g (9%). P.f. 220-222 ° C, Rt = 13,691 minutes, R.M.N. (DMSO-de) d ppm: 6.90 (broad, s, 1H), 7.60 (d, 1H), 7.70 (broad, s, 1H), 8.0 (d, 1H), 8.70 (s, t 1H), LC / MS (El) M + = 275/277.

Procedure B The 3-methylsulfoxy-5-amino-6- [2,3,5-trichlorophenyl] -1,2,4-triazine (5.82 g, 17.2 mmol, 1 equivalent) was dissolved in a 1: 1 mixture of THF : t-butanol (1800 ml). Sodium borohydride (915 g, 24.08 mmol, ~ 1.4 equivalents) was added in one portion and the resulting mixture was stirred at room temperature, under nitrogen, for 2 hours. All the solvent was removed in vacuo to give a yellow solid which was then converted to an azeotrope with tetrahydrofuran (200 ml). 10% aqueous citric acid (500 ml) was slowly added, keeping the temperature below 20 ° C, followed by ethyl acetate (500 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (500 ml). The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and any volatiles removed in vacuo to give a yellow solid.

The product was purified using column chromatography, using 20% ethyl acetate in hexane as the eluent, increasing to 60% ethyl acetate in hexane. The fractions containing the product were combined and evaporated in vacuo, yielding a yellow solid, 3-thiomethyl-5-amino-6- [2,3,5-trichlorophenyl] -1,2,4-triazine. Production 1.5 g (31.7%). R.M.N. (DMSO-de) d ppm: 7.67 (d, 1H), 8.02 (d, 1H), 8.75 (s, 1H), 7.0-7.2 (broad s, 1H), 7.7-8.0 (broad s, 1H). LC / MS Positive electro-positive (M + 1) + = 275/277.

Examples of Pharmacy Sterile Formulations Example A mg / ml Compounds of the Invention 0.1 mg Sodium Chloride USP 9.0 mg Water for Injection USP cs. for 1 ml The components are dissolved in a portion of the water for injection and the solution is prepared to a final volume to provide 0.1 mg / ml of the Compounds of the Invention. Where a salt of the compounds is used, the amount of the compounds is increased to provide 0.1 mg / ml of the free base. The solution can be packaged for injection, for example by filling and sealing in ampoules, vials or syringes. These can be filled aseptically and / or periodically sterilized for example, by treatment in an autoclave at 121 ° C. Additional, sterile formulations can be prepared in a similar manner to obtain alternative concentrations of the compounds.

Example B mg / ml Compounds of the Invention 0.5 mg Mannitol 50.0 mg Water for Injections cs. for 1.0 ml Dissolve the components in a portion of the Water for Injection Prepare the final volume and mix until homogeneous. Filter the formulation through a sterilizing filter and fill in glass bottles. Freeze and seal the bottles. Reconstitute with an appropriate solvent before use.

Formulations for Oral Administration Tablets can be prepared by normal methods such as direct compression or wet-phase granulation. The tablets can be film coated with suitable film-forming materials, such as an Opadry, using standard techniques. Alternatively, the tablets may be coated with sugar.

Example C Direct Compression Tablet mg / Tablets Compounds of the Invention 5.0 mg Magnesium Stearate 4.0 mg Microcrystalline Cellulose (Avicel PH102) cs. for 400.0 mg The compounds of the invention are passed through a 30 mesh screen and combined with Avicel and Magnesium Stearate. The resulting mixture is compressed into tablets using a suitable tableting press, equipped with 11.0 mm diameter punches to provide 5 mg of the Compounds of the Invention per tablet. Tablets of other concentrations, containing for example 25 or 100 mg / tablet of the Compounds of the Invention, can be prepared in a similar manner.

Example D Granulation Tablet in the Wet Phase mg / Tablet Compounds of the Invention 5.0 mg Pre-gelled starch 28.0 mg Sodium Glycolate Sodium 16.0 mg Magnesium Stearate 4.0 mg Lactose cs. 400.0 mg The compounds of the invention, lactose, pre-gelled starch and sodium starch glycolate were mixed dry and then granulated using an adequate volume of purified water. The resulting granules were dried and then combined with Magnesium Stearate. The dried granules were compressed using a suitable tableting press, equipped with punches of 11.0 mm in diameter, to provide 5 mg of the Compounds of the Invention per tablet.

Tablets of other concentrations such as tablets of 25 and 100 mg / tablet were prepared.

Example E Hard Gelatin Capsule mg / Capsule Compounds of the Invention 5.0 mg Microcrystalline Cellulose (Avicel PH102) cs. 700.0 mg The compounds of the invention are passed through a 30 mesh screen and then combined with the Microcrystalline Cellulose to provide a homogeneous mixture. The mixture can then be filled into covers or shells of 0EL hard gelatin capsules to provide capsules containing 5.0 mg / capsule of the Compounds of the Invention. Alternative concentrations such as 25 or 100 mg / capsule of the Compounds of the invention can also be made in a similar manner.

Example F Soft Gelatin Capsule mg / Capsule Compounds of the Invention 10.0 mg Polyethylene glycol 90.0 mg Propylene glycol cs. 200.0 mg "Mix together the polyethylene glycol and propylene glycol using the necessary heat, stir until homogeneous, add the compounds of the invention and mix until homogeneous, fill in an appropriate gelatin mixture to give soft gelatine capsules containing 200 mg of the formulation, to provide 10.0 mg / capsule of the Compounds of the Invention Capsules of alternative concentrations, eg, 5 and 25 mg / capsule of the Compounds of the Invention, can be prepared in a similar manner.

Example G Syrup Compounds of the Invention 5.0 mg Sorbitol Solution 1500.0 mg Glycerol 1000.0 mg Sodium Benzoate 5.0 mg Flavor 12.5 mg Purified Water qs. for 5.0 ml Sodium Benzoate is dissolved in a portion of the purified water and the Sorbitol Solution is added. The Compounds of the Invention, the Flavor and the Glycerol are added and mixed until homogeneity. The resulting mixture is made up to the volume with the purified water.

Other Formulations Example H Suppository mg / suppository Compounds of the Invention 10.0 mg Witepsol W32, solid fat cs. 2000.0 mg Melt the Witepsol W32 at approximately 36 ° C. To a portion of this add the Compounds of the Invention and mix. Incorporate the Witepsol W32 cast, remaining and mix until homogeneous. Fill a mold with 2000 mg of the formulation to provide 10.0 mg / suppository of the Compounds of the Invention.

Example 1 Transdermal Compounds of the invention 5.0 mg Silicone Fluid 90.9 mg Colloidal Silicon Dioxide 5.0 mg Mix the silicone fluid and activate together and add the colloidal silicon dioxide. The material is then dosed into a subsequent heat-sealed polymer laminate, comprised of the following: polyester release coating, skin contact adhesive, silicone compound or acrylic polymers, a control membrane which is a polyolefin ( example polyethylene or polyvinyl acetate) or polyurethane, and a waterproof backing membrane of a polyester multilaminate.

Biological Data Activity against sodium channels with voltage gates Cell or whole cell voltage fixation techniques were employed to evaluate the activity of a compound of the formula (I) on the recombinant human type IIA Na + channel expressed in Chinese hamster ovary cells. A compound of the formula (I) inhibits these channels in a manner dependent on use and voltage with an estimated Ki value of 11 μM for the permanent state of inactivation, approximately 70 times greater than the power in the resting state (IC50 = 785 μM). The increased state selectivity and the largest usage dependent inhibition compared to lamotrigine (approximately 30 times), provides a mechanism through which a compound of formula (I) selectively blocks transmission during high frequency activation of potentials. of action (for example the activity of the accesses). This supports the discovery that a compound of formula (I) is a stronger anticonvulsant than lamotrigine and with a larger therapeutic index.

Anticonvulsive activity It has been shown that a compound of the formula (I) has an antiepileptic activity in two rodent models of generalized epilepsy, the maximum electric shock test in rats (MES) which is an animal model that reflects the generalized clonic-tonic accesses in and the infusion test of pentylenetetrazol in mice, predictive of the accesses of absence in humans and the epilepsy of petit mal, myoclonic. For example, male Wis Wistar rats (150-200 grams) were dosed orally with a suspension of the test compound in 0.25% methylcellulose, 2 hours before the test. A visual observation is made just before the test to detect the presence of ataxia. Using atrial electrodes, a current of 200mA is applied, duration of 200 milliseconds, and the presence or absence of the extension of the meta limbus is observed. A compound of formula (I) exhibited an ED5Q of 1.7 mg / kg compared to 6.1 mg / kg for lamotrigine with a therapeutic index (ratio of ED50 of ataxia and ED50 of MES) of 23.7 compared to 3.3 for Lamotrigine A compound of the formula (I) exhibited an ED50 of 3.8 mg / kg in the pentylenetetrazole infusion test in mice (time to the second spasmodic contraction) when dosed 1 hour after PTZ, compared to an ED50 of 8.4 mg / kg for lamotrigine.

Analgesic activity It has also been shown that a compound of the formula (I) has an analgesic activity in pain models. Three hours after the administration of intraplantar carrageenan (100 μl of 2%) in the rat, there is a reduction in the weight carried in the inflamed leg and an increase in the volume of the leg consistent with acute hyperalgesia and inflammation. A compound of the formula (I), administered orally 30 minutes before the carrageenan, produced a dose-related inhibition of the carrageenan-induced reduction in the supported weight, with an ED50 of 7.5 mg / kg compared to 23.5 mg / kg for lamotrigine. A compound of the formula (I) also showed an anti-inflammatory activity, significant in this model at 30 mg / kg (50% reduction in paw volume).

Activity against MPTP-induced neurotoxicity The MPTP model of mice is generally used as a model of Parkinson's disease. Male C57BL / 6 mice received four intraperitoneal injections of MPTP. HCl (15 mg of free base per kg, Research Biochemicals) in a saline solution at 2 hour intervals. Control mice received only saline. The test compound was administered as four subcutaneous injections in olive oil at intervals of 2 hours, 30 minutes before each MPTP injection. Seven days after the MPTP injection, the mice were sacrificed and the striated tissue was removed by dissection, frozen immediately, and stored at -80 ° C until analysis. On the day of tissue evaluation, samples were subjected to sound action in 10 volumes (weight / volume) of 0.1 M perchloric acid containing 1.9 mM sodium hydrosulfite and 1.6 mg / ml DBA-HBr. After centrifugation (2800 g, 10 minutes at room temperature) and filtration (0.5 μm pore size, Millipore), the supernatant was transferred to a vial and placed in an automatic sampler (M231XL, Gilson). The dopamine content was measured by high performance liquid chromatography. A compound of the formula (I) produced 75% protection against depletion of dopamine when dosed at 3 mg / kg (x 4) and 98% protection when dosed at 10 mg / kg (x 4).

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 claims is claimed as property.

Claims (8)

1. A compound of the formula (I) (0 and pharmaceutically acceptable derivatives thereof
2. 2. A compound according to claim 1, characterized in that it is for use in therapy.
3. 3. A pharmaceutical composition characterized in that it comprises a compound according to claim 1, together with a pharmaceutically acceptable carrier.
4. 4. The use of a compound according to claim 1 in the manufacture of a medicament for use in the treatment of epilepsy, bipolar disorder or manic depression, pain, functional bowel disorders, neurodegenerative diseases, neuroprotection, neurodegeneration, tinnitus or dependent on , or that has tolerance to, an agent inducing dependency.
5. 5. A method characterized in that it is for the treatment of a patient suffering from, or who is susceptible to, epilepsy, bipolar disorder or manic depression, pain, functional bowel disorders, neurodegenerative diseases, neuroprotection, neurodegeneration, tinnitus or dependent on, or has tolerance to, an agent inducing dependence.
6. 6. A process for the preparation of a compound of the formula (I) according to claim 1, characterized by the reduction of a compound of the formula (II) (»)
7. 7. A process for preparing a compound of the formula (I) according to claim 1, characterized by the reduction of a compound of the formula (III) (" where n can be one or two.
8. 8. A process for the preparation of a compound of the formula (I) according to claim 1, characterized in that a compound of the formula (III) is prepared by oxidation of a compound of the formula (II) («) A compound of the formula (II) (") and pharmaceutically acceptable derivatives thereof 10. A compound of the formula (III! (III) characterized in that n can be one or two, and pharmaceutically acceptable derivatives thereof.