CZ20002361A3 - Triazine derivatives - Google Patents

Abstract

The present invention relates to a triazine compound of formula I, useful in the treatment of diseases and disorders of the central nervous system, as well as pharmaceutically acceptable derivatives thereof, pharmaceutical compositions containing them, their use in the treatment of these diseases and methods of their production.

Description

The present invention relates to a triazine compound useful in the treatment of diseases and disorders of the central nervous system (CNS) and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions containing them, their use in the treatment of these diseases and methods of their manufacture.

State of the art

EP-A-0021121 and EP-A-0247892 describe 3,5-diaminotriazines, for example 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (lamotrigine), which are effective in the treatment of CNS disorders and are particularly useful in the treatment of epilepsy.

The present invention relates to a 5-aminotriazine derivative which is a sodium channel blocker. This compound has surprisingly potent anticonvulsant effects, with increased potency compared to lamotrigine and increased selectivity in terms of CNS side effects and inhibition of the enzyme dihydrofolate reductase. The compound is therefore useful in the treatment of central nervous system diseases such as epilepsy.

The essence of the invention

The present invention therefore provides a compound of formula (I)

0) i.e. 5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine and its pharmaceutically acceptable derivatives.

The term pharmaceutically acceptable derivative is intended to mean any pharmaceutically acceptable salt or solvate of the compounds of formula (I), or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the compound of formula (I) or an active metabolite or moiety thereof (e.g., a prodrug). References to compounds of formula (I) will therefore hereinafter include both the compound of formula (I) and pharmaceutically acceptable derivatives thereof.

Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, for example hydrochlorides, hydrobromides and sulphates.

Suitable precursors are well known in the art and include N-acyl derivatives, for example on any of the four nitrogen atoms of the compounds of formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as RO- _CH2 -nitrogen or ROC(O)-nitrogen.

The compounds of formula (I) are particularly useful as anticonvulsants. They are therefore useful in the treatment of epilepsy. They can be used to improve the condition of a patient, typically a human, suffering from epilepsy. They can be used to alleviate the symptoms of epilepsy in a patient. Epilepsy is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalized seizures,

generalized seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures and atonic seizures.

Compounds of formula (I) are further useful in the treatment of bipolar disorder, also known as manic depression. Bipolar disorder type I or II can be treated. Compounds of formula (I) can therefore be used to improve the condition of a patient suffering from bipolar disorder. They can be used to alleviate the symptoms of bipolar disorder in a host. Compounds of formula (I) can also be used in the treatment of unipolar depression.

The compounds of formula (I) are useful as analgesics. Therefore, they can be used in the treatment or prevention of pain. They can be used to improve the condition of a patient, typically a human, suffering from pain. They can also be used to alleviate pain in a patient. The compounds of formula (I) can be used as analgesics for the treatment of acute pain such as musculoskeletal pain, post-operative pain and post-surgical pain, chronic pain such as chronic pain of inflammatory origin (for example rheumatoid arthritis and osteoarthritis), neuropathic pain (for example post-herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compounds of 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, including non-ulcer dyspepsia, in the treatment of chest pain of non-cardiac origin and in particular in the treatment of irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterized by abdominal pain and altered bowel behavior without any evidence of organic disease. The compounds of formula (I) can therefore be used to alleviate the pain associated with irritable bowel syndrome. The condition of a patient suffering from irritable bowel syndrome can therefore be improved.

• ·

Compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, muscular sclerosis, macular degeneration and glaucoma. Compounds of formula (I) may also be used as neuroprotective agents and in the treatment of nerve degeneration following stroke, cardiac arrest, pulmonary bypass, brain injury, spinal cord injury and the like.

Compounds of formula (I) are further useful in the treatment of tinnitus.

The compounds of formula (I) are further useful in preventing or reducing dependence or preventing or reducing tolerance or rebound tolerance to an addictive substance. Examples of addictive substances are opiates (e.g. morphine), central nervous system depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.

The present invention therefore further provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in human and veterinary medicine.

The present invention further provides the use of a compound of formula (I) in the manufacture of a pharmaceutical composition for the treatment of disorders such as those described above.

The present invention further includes a method of treating a patient suffering from or susceptible to a disease as substantially as hereinbefore described, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I).

The term "treatment" as used herein includes both the treatment of already developed disorders and their prevention.

The precise amount of compounds of formula (f) administered to a host, particularly a human, will be at the discretion of the attending physician. However, the dosage employed

will depend on a number of factors including the age and sex of the patient, the specific condition being treated and its severity, and the route of administration.

The compound of formula (I) can be administered in a dose of from 0.1 to 10 mg/kg body weight per day and in particular 0.3 to 3 mg/kg body weight per day, calculated as the free base. The dosage range for an adult human 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 formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. In another embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be in a form for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

Although it is possible to administer the compounds of formula (I) as pure chemicals, it is preferred to administer them in the form of a pharmaceutical composition. The pharmaceutical compositions of the present invention comprise the compounds of formula (I) together with one or more pharmaceutically acceptable carriers or diluents and optionally other therapeutic ingredients. The carrier or carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and must not have deleterious effects on the recipient.

Formulations include forms suitable for oral, parenteral (including subcutaneous, e.g., as an injection or depot tablet, intradermal, intrathecal, intramuscular, e.g., depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration, although the most suitable route may depend, for example, on the condition and disorder of the patient. These formulations may conveniently be presented in unit dosage form and may be

9 9 ·

9 9 · • 9 99 9 9999

999 999 99 99 9· 99 prepared by any method known in the art of pharmacy. All such methods include the step of bringing into association a compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof ("active ingredient") with a carrier which is one or more accessory ingredients. Formulations are generally prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired form.

Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets or tablets (e.g. chewable tablets, particularly 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 non-aqueous liquid; or as a liquid emulsion of the oil-in-water or water-in-oil type. The active ingredient may also be present as a bolus, elixir or paste.

Tablets may be manufactured by compression or wet molding, optionally with one or more other accessory ingredients. Compressed tablets may be manufactured by compressing the active ingredient in free-flowing form such as powder or granules, optionally in admixture with a binder, glidant, inert diluent, surface-active or dispersing agent. Wet-molded tablets may be manufactured by compressing a powder mixture moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient from the tablet.

Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents and solvents which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be in unit dose or multidose containers, for example in sealed ampoules and vials, and may be kept in a lyophilized state requiring only the addition of a sterile liquid carrier, for example water for injection, immediately before use. Injectable solutions and suspensions for preparation before use may be prepared from sterile powders, granules and tablets of the type described above.

Formulations for rectal administration may be in the form of suppositories with conventional carriers such as cocoa butter, solid fat or polyethylene glycol.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges containing the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and lozenges containing the active ingredient in a base such as gelatin and glycerol or sucrose and acacia.

The compounds of the invention may also be formulated as depot preparations. These long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. For example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., sparingly soluble salts.

In addition to the above ingredients, the formulations may contain other agents conventional in the art, taking into account the type of formulation in question, for example, forms suitable for oral administration may contain flavoring agents.

Preferred unit dosage forms are those containing an effective daily dose as hereinbefore set forth, or a suitable proportion thereof, of the active ingredient. Typically, this may range from 5 mg to 1000 mg, such as from • fc fcfc • · · · ♦ ♦ · · • fc · · • fc fcfcfc · • fc fcfc • · · • · fc • fcfcfc • · · fcfc · · mg to 1000 mg, more preferably 35 mg to 800 mg and most preferably 10 to 200 mg or 20 to 200 mg, calculated as the free base.

Compounds of formula (I) may be used in combination with other therapeutic agents, for example other anticonvulsants. When compounds of formula (I) are used in combination with other therapeutic agents, these compounds may be administered by any suitable route either sequentially or simultaneously. Accordingly, in a further embodiment, the invention provides a combination comprising compound (I) or a pharmaceutically acceptable derivative thereof together with another therapeutic agent.

The above combinations may conveniently be formulated for use as a pharmaceutical composition and further embodiments of the invention will therefore comprise pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient. The individual components of these combinations may be administered either sequentially or concurrently in separate or combined pharmaceutical compositions.

When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent effective against the same disease, the dosage of each compound may differ from that when used alone. Suitable dosages will be apparent to those skilled in the art.

The present invention further provides a process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof.

Compounds of formula (I) may be prepared by the methods set forth below, which constitute further embodiments of the invention.

According to general process (A), it is possible to prepare a compound of formula (I) under suitable reaction conditions from a compound of formula (II)

SMe • · « · 9 9 9 9

9 999 9 9 · · ·

9 9 9 9 9 9 (Π) for example by reduction, preferably using a reducing metal such as Raney nickel and a hydrogen source such as hydrazine monohydrate, in a suitable solvent such as ethanol, preferably at an elevated temperature, for example between 70 and 75 °C.

According to another process (B), which constitutes a further embodiment of the invention, the compound of formula (I) may be prepared under suitable reaction conditions by reacting a compound of formula (III)

S(O) _n Me (III) where n can be 1 or 2, 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 ether, preferably tetrahydrofuran and an alcohol, preferably t-butanol, and at room temperature.

The compound of formula (III) may be prepared under suitable reaction conditions by reacting a compound of formula (II) with an oxidizing agent such as a peracid, for example potassium peroxymonosulfate or m-chloroperbenzoic acid, and at a reduced temperature, for example <5°C, which process forms a further embodiment of the invention.

• 4 ·« 44 *4 • · · · 4 · · · «4 4 4·4 4 4 4 · 4 4

4 · 4 4 4 4

The compound of formula (II) may conveniently be prepared by reacting 2,3,5-trichlorobenzoyl cyanide with an S-methylthiosemicarbazide salt, preferably the hydroiodide, in the presence of a dilute mineral acid, preferably dilute sulfuric acid, which process forms a further embodiment of the invention.

The compound of formula (II) may alternatively be prepared under suitable reaction conditions by photolysis of a solution of the compound of formula (IV) with radiation in the wavelength range of 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, which process constitutes a further embodiment of the invention.

2,3,5-Trichlorobenzoyl cyanide and S-methylthiosemicarbazide can be prepared by methods conventional in the art and thus represent further embodiments of the invention.

The compound of formula (IV) can be prepared under suitable reaction conditions by reacting the compound of formula (V)

(IN)

99 99 • · 9 9 9 9 9 9 9 • • · · • ··· 9 9 9 • 9 • • · • · 9 9 • 9 ··· »·* ·· 99 99 ··

with a dehydrating agent, preferably diphosphoryl chloride, this method representing a further embodiment of the invention.

The compound of formula (V) may conveniently be prepared by reacting a compound of formula (VI)

COCONH ₂ (VI) with an S-methylthiosemicarbazide salt, preferably the hydroiodide, in a suitable solvent, for example ethanol, and at an elevated temperature, for example 50°C, which process represents a further embodiment of the invention.

The compound of formula (VI) can be prepared under suitable reaction conditions by reacting 2,3,5-trichlorobenzoyl cyanide with a strong aqueous acid, preferably concentrated hydrochloric acid, which process constitutes a further embodiment of the invention.

Precursors of compounds of formula (I) can be prepared by conventional methods.

The following examples are provided to illustrate the invention but should not be construed as limiting it.

• · · · ti titi ti • · · · · • ti

Examples of embodiments of the invention

Intermediate 1

2,3,5-Trichlorobenzoic acid

2,3,5-Trichlorobenzaldehyde (197.40 g, 0.94 mol, Lancaster) was dissolved in t-butanol (785 ml), stirred and heated under nitrogen at 50 °C. 2M aqueous sodium hydroxide (940 ml) was heated to 50 °C and added to the aldehyde solution. Hydrogen peroxide (27.50% aqueous solution, 699 g, 5.65 mol) was added via a metering pump over 45 min, maintaining the temperature between 57 - 60 °C. The reaction mixture was then stirred and heated under nitrogen for a further hour, cooled and evaporated in vacuo. The resulting slurry was filtered and the filtrate was washed with toluene (2 x 300 ml) and then acidified (pH 1) with 5M hydrochloric acid with thorough stirring. The resulting thick white precipitate was filtered, washed with water (3 x 300 ml) and dried in vacuo at 50°C. Yield 180 g (85%). Melting point 155-158°C (foam).

Intermediate 2

2,3,5-Trichlorobenzoyl chloride

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 under reflux in anhydrous toluene (350 mL) at 120 °C for 3 h. 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 brown viscous oil.

Alternatively, preparation can be done as follows:

2,3,5-Trichlorobenzoic acid (75 g, 333 mmol, 1 eq.) was added to toluene (225 mL) and the slurry was heated under reflux.

0000 00 • 0 0000 000· 0 0 00 0 00000 00 0 0 0 0000

000 000 00 00 00 00 condenser for 2 h with a Dean-Stark apparatus attached. The acid dissolved upon heating. The solution was cooled with thorough stirring and pyridine (0.2 ml, cat. ~0.5 mol. %) and thionyl chloride (26.7 ml, 365 mmol, 1.1 equiv.) were added via addition funnel over 1 h while maintaining the internal temperature between 70 - 80 °C. After the addition was complete, the mixture was heated under reflux for 2 h. The solution was cooled, the volatiles were removed in vacuo and then azeotroped with toluene (2 x 50 ml) to give a clear yellow oil as product.

Intermediate 3

2,3,5-Trichlorobenzoyl cyanide

Copper (I) cyanide (63.88 g, 0.71 mol), potassium iodide (108.20 g, 0.65 mol) were refluxed in anhydrous xylene (590 ml) at 150 °C for 24 h using a Dean-Stark apparatus. A solution of 2,3,5-trichlorobenzoyl chloride in anhydrous xylene (150 ml) was added and the resulting suspension was refluxed under nitrogen at 150 °C for 3 days. The suspension was filtered and the filtrate was evaporated in vacuo, δ (CDCl ₃ ): 7.80 (s, 1H), 8.0 (s, 1H).

Alternatively, preparation can be carried out as follows:

Potassium iodide (66.25 g, 400 mmol, 1.2 equiv.) (sieved to obtain a particle size <1 mm) and copper cyanide (36 g, 400 mmol, 1.2 equiv.) in xylene (400 mL) were heated under reflux for 3 h with a Dean-Stark apparatus attached. The mixture was cooled and 2,3,5-trichlorobenzoyl chloride in xylene (100 mL) was added. The mixture was heated under reflux with a Dean-Stark apparatus attached. The mixture gradually changed color from red to orange over 30 min and a light brown solution was obtained overnight.

··· · • 9 9 9 9 9 9 *

9 9 9 9 9 9 9

9 · · · · · · · · · · • · · · · · · · · 9 9 9 9 9 9

The mixture was heated at reflux for 40 h, then cooled and the inorganics were filtered off. The xylene was removed in vacuo at 55 °C, azeotroped with toluene (2 x 50 ml), then petroleum ether b.p. 60-80 °C (260 ml) was added via a Buchi inlet to give a brown solution. A brown precipitate formed on cooling. The solution was stirred at room temperature overnight, the solid was filtered off and washed with petroleum ether b.p. 60-80 °C (100 ml). The solids were sucked dry under nitrogen to give a first crop of yellow solid, 2,3,5-trichlorobenzoylnitrile (45.5 g, 58.1%).

The filtrate was concentrated, left to stand for 24 hours, and then a second crop (6.5 g, 8.7%) was obtained, and finally a third crop (5.3 g, 6.8%).

Total yield (57.6 g, 73.8%). NMR (d6-DMSO) dppm: 8.03 (d, 1H), 8.34 (d, 1H)

Intermediate 4

S-methylthiosemicarbazide hydroiodide

Thiosemicarbazide (448 g, 0.50 mol, Aldrich) and iodomethane (300 mL, 5 mol) were heated under reflux in 95% ethanol (2000 mL) for 5 h and then cooled to room temperature. The desired product was filtered off, washed with ether (3 x 100 mL) and dried in vacuo. Yield 647 g. Melting point 138-140 °C.

Intermediate 5

3-Thiomethyl-5-amino-6-[2,3,5-trichlorophenone-1,2,4-triazine [formula (II)1

Method A

S-Methylthiosemicarbazide hydroiodide (38.59 g, 0.17 mol) was suspended in dilute sulfuric acid (95.83 mL concentrated sulfuric acid/95.83 mL water) and the mixture was stirred for 1 h at *

• · · · · · * • · · 4 4 4 ·· ·· · • · · · · · · · · • · · 4 · · 44 room temperature. A solution of 2,3,5-trichlorobenzoyl cyanide (18 g, 0.077 mol) in acetonitrile (90 ml) was added slowly and the resulting mixture was stirred at room temperature for 11 days. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 250 ml). The ethyl acetate layer was washed with water (2 x 300 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 under reflux at 130 °C for 4 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was partitioned between 2N aqueous sodium hydroxide solution (100 ml) and ethyl acetate (300 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography using cyclohexane to a 1 : 3 cyclohexane:ether mixture as eluent. Yield 1.90 g (8%). Melting point 138 - 140 °C.

Method B

2-[S-Methylthiosemicarbazono]-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 W tungsten lamp was immersed in the mixture and the reaction was allowed to proceed under these conditions for 48 h. The reaction mixture was cooled to room temperature, the lamp was turned off and the solution was evaporated in vacuo to give a dark oil which crystallized on standing. 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. Yield 770 mg (77.0%). NMR (d ₆ -DMSO) δ 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 electrospray (M+1) ⁺ = 321/323 • · · · · · · ·

Intermediate 6

3-Methylsulfoxy-5-amino-6-F 2,3,5-trichlorophenyl-1,2,4-triazine [formula (III)j

3-Thiomethyl-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine (6 g, 18.7 mmol, 1 equiv) was suspended in dichloromethane (650 mL) and the mixture was cooled to 5 °C. m-Chloroperbenzoic acid (5.66 g, 18.7 mmol, 57% expected, ~1 equiv) was added in one portion and the mixture was stirred at <10 °C for 20 min under nitrogen to give a clear yellow solution. TLC analysis (1:1 cyclohexane:ethyl acetate) showed no more starting material present. The reaction was quenched by adding sodium sulfite (10 g) and water (200 mL) to the well-stirred solution. The layers were separated and the organic layer was washed with 10% aqueous sodium sulfite (100 mL). Merck peroxide test strips showed a negative result. The organic layer was washed with saturated sodium bicarbonate (200 mL), then washed with brine (200 mL) and 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. Yield 5.82 g (92.2%).

NMR( _CDCl3 ) δ ppm: 3.05 (s, 3H), 7.39 (d, 1H), 7.69 (d, 1H). LC/MS Positive electrospray (M+1) ⁺ = 337/339.

Intermediate 7

2-Oxo-2-[2,3,5-trichlorophenyl]-acetamide [formula (VI)]

2,3,5-Trichlorobenzoyl cyanide (10.0 g, 46 mmol) was added to concentrated hydrochloric acid (140 mL) and stirred at room temperature for 48 h. The suspension was diluted with water (100 mL) and filtered. The light brown solid was washed with water and then air dried for 1 h. The crude product was then dissolved in ethyl acetate (400 mL), washed with saturated aqueous sodium bicarbonate (2 x 300 mL) and then brine (300 mL) and then dried over magnesium sulfate, filtered and evaporated to give a beige solid.

This solid was triturated in hexane/toluene (200 mL), filtered and dried under vacuum to give an off-white solid, 2-oxo-2-[2,3,5-trichlorophenyl]-acetamide. Yield 7.02 g (65.3%). NMR (d ₆ DMSO) δ ppm: 7.77 (d, 1H), 8.09 (d, 1H), 8.13 (br s, 1H), 8.48 (br s, 1H). LC/MS, Negative Electrospray (M - 1)' = 250/252.

Intermediate 8

2-[S-Methylthiosemicarbazono1-2-f2,3,5-trichlorophenone-acetamide fformula

ÍYH

2-Oxo-2-[2,3,5-trichlorophenyl]acetamide (5.00 g, 19.8 mmol) and S-methylthiosemicarbazide hydroiodide (9.20 g, 39.5 mmol) were suspended in ethanol (100 mL) and heated at 50 °C under nitrogen overnight. Thin layer chromatography showed that starting material was still present, so additional S-methylthiosemicarbazide hydroiodide (4.00 g, 172 mmol) was added and stirring continued at 50 °C for 2 h. 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 brine (300 mL), dried over magnesium sulfate, filtered, and evaporated in vacuo to give a tan gum. This gum was purified by column chromatography using 1:1 ethyl acetate:hexane as eluent. The product, predominantly the E isomer, was obtained as a pale yellow solid, yield 4.25 g (63.2%). NMR ( _d6 -DMSO) δ ppm: 2.14 (s, 3H), 7.28 (d, 1H), 7.31 (br s, 1H), 7.84 (d, 1H), 8.28 (br s, 1H). LC/MS, Positive electrospray (M+1) ⁺ = 339/341.

9 · • · 9 4 4 · 4«·· · 9 · ······ · · 4

4 4 9 4 9 4 4 ·

4·· ·44 44 «4 49 49

Intermediate 9

2-1S-Methylthiosemicarbazono1-2-12,3,5-trichlorophenone-acetonitrile Formula

2-[S-Methylthiosemicarbazide]-2-[2,3,5-trichlorophenyl]-acetamide (2 g, 5.89 mmol) was added portionwise to a solution of diphosphoryl chloride (2.97 g, 1.63 mL, 11.8 mmol) in 1,4-dioxane (16 mL) and the mixture was stirred under nitrogen for 6 h. The dark solution was evaporated in vacuo to give a dark yellow oil. This oil was dissolved in ethyl acetate (50 mL), washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), then dried over magnesium sulfate, filtered and evaporated in vacuo to give a dark yellow oil. The crude product was purified by column chromatography using 3:1 hexane:ethyl acetate as eluent. The product 2-[S-methylthiosemicarbazono]-2-[2,3,5-trichlorophenyl)-acetonitrile was obtained as a yellow oil, which crystallized on standing to a yellow solid. Yield 1.16 g (61.2%). NMR (d6-DMSO) δ ppm: 2.20 (s, 1H), 3.38 (br s, 3H), 7.68 (br s, 1H), 7.95 (d, 1H), 8.12 (br s, 1H). LC/MS, Positive electrospray (M+1) ⁺ =321/323.

Example

5-Amino-6-12,3,5-trichlorophenyl1-1,2,4-triazine

Method 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, 5.44 x ^10-3 mol) in absolute ethanol (30 ml) and the mixture was stirred at 70 °C. Hydrazine monohydrate (3.50 ml, 3.54 g, 0.11 mol) was added dropwise to the suspension over 30 min.

• · • · ·· · · · * · #· · • · · · · · ·«·« • · · · ······ · · · • · · · · · · · . I9 _f f......

The resulting mixture was stirred at 70-75 °C for 2 h, filtered, washed with hot absolute ethanol (3 x 20 ml) and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography using a 15:25 cyclohexane:ether mixture as eluent and then by preparative HPLC on a Supelcosil ABZ column and 50% acetonitrile/water and 0.1% formic acid as eluent. Yield 0.134 g (9%). Melting point 220-222 °C, R _t = 13.691 min, NMR(d ₆ -DMSO) δ ppm: 6.90 (broad, s, 1H), 7.60 (d, 1H), 7.70 (broad, s, 1H), 8.0 (d, 1H), 8.70 (s, 1H). LC/MS (EI) M ⁺ = 275/277.

Method B

3-Methylsulfoxy-5-amino-6-[2,3,5-trichlorophenyl)-1,2,4-triazine (5.82 g, 17.2 mmol, 1 equiv.) was dissolved in a 1:1 mixture of THF:t-butanol (1800 mL). Sodium borohydride (915 g, 24.08 mmol, ~1.4 equiv.) was added in one portion and the resulting mixture was stirred at room temperature under nitrogen for 2 h. All solvent was removed in vacuo to give a yellow solid which was then azeotroped with tetrahydrofurane (200 mL). 10% aqueous citric acid (500 mL) was added slowly while maintaining 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 brine, dried over anhydrous magnesium sulfate, filtered, and all volatiles were removed in vacuo to give a yellow solid. The product was purified using column chromatography eluting with 20% ethyl acetate in hexane, increasing to 60% ethyl acetate in hexane. The product fractions were combined and evaporated in vacuo to give a yellow solid, 3-thiomethyl-5-amino-6-[2,3,5-trichlorophenyl]-1,2,4-triazine. Yield 1.5 g (31.7%).

• · φ • φ φ « φ φ φ φ φ · φ « φ φφφ • · φ · φ « · φφ φ φ φ φ φ φφφ φφφ φφ φφ φφ φφ

NMR( _d6 -DMSO) δ ppm: 7.67 (d, 1H), 8.02 (d, 1H), 8.75 (s, 1H), 7.0-7.2 (br s, 1H), 7.7-8.0 (br s, 1H). LC/MS Positive electrospray (M+1) ⁺ = 275/277.

Pharmaceutical examples

Sterile formulation

Example A mg/ml

Compounds of the invention 0.1 mg

Sodium Chloride USP 9.0 mg

Water for Injection USP to make up to 1 ml

The components are dissolved in a portion of water for injection and the solution is made up to the total volume to provide a concentration of 0.1 mg/ml of the compounds of the invention. If a salt of the compounds is used, the amount of compounds is increased to provide a concentration of 0.1 mg/ml of the free base. The solution may be packaged for injectable use, for example by filling and sealing into ampoules, vials or syringes. These may be aseptically filled and/or terminally sterilized, for example by autoclaving at 121°C.

Other sterile formulations can be prepared similarly to obtain other concentrations of the compounds.

Example B

Compounds of the invention

Mannitol

Water for injections to make up to mg/ml 0.5 mg 50.0 mg ml «· ·· *· ··

9 9 9 9 9 9 ·

9 9 9 9 9 9 9

9 9999· 99 9

The components are dissolved in a portion of water for injections. The mixture is made up to the final volume and mixed until homogeneous. The preparation is filtered through a sterilizing filter and filled into glass vials. The vials are lyophilized and sealed. Reconstitution is carried out with a suitable solvent before use.

Formulation for oral administration

Tablets may be prepared by conventional methods such as direct compression or wet granulation. The tablets may be coated with a suitable film-forming material such as Opadry using standard methods. Alternatively, the tablets may be sugar-coated.

Example C

Directly compressed tablets mg/tablet

Compounds of the invention 5.0 mg

Magnesium stearate 4.0 mg

Microcrystalline cellulose (Avicel PH102) up to 400.0 mg

The compounds of the invention are passed through a 30 mesh (595 µm) screen and mixed with Avicel and magnesium stearate. The resulting mixture is compressed into tablets using a suitable tablet press equipped with a punch of 11.0 mm diameter, so that an amount of 5 mg of the compounds of the invention per tablet is obtained. Tablets with other active ingredient contents can be prepared in a similar manner, for example, containing 25 or 100 mg of the compound of the invention per tablet.

· • · · · · ··· • · · ····«· · « • ·

Example D

Wet granulated tablets mg/tablet

Compounds of the invention 5.0 mg

Pregelatinized starch 28.0 mg

Sodium starch glycolate 16.0 mg

Magnesium stearate 4.0 mg

Lactose up to 400.0 mg

The compounds of the invention, lactose, pregelatinized starch and sodium starch glycolate are dry mixed and then granulated using a suitable volume of purified water. The granules obtained are dried and mixed with magnesium stearate. The dried granules are compressed on a suitable tablet press equipped with a 11.0 mm punch to obtain a tablet containing 5 mg of the compounds of the invention.

Tablets with other contents, such as 25 and 100 mg/tablet, have also been prepared.

Example E

Hard gelatin capsule mg/capsule

Compounds of the invention 5.0 mg

Microcrystalline cellulose (Avicel PH102) up to 700.0 mg

The compounds of the invention are passed through a 30 mesh (595 µm) screen and then mixed with microcrystalline cellulose to obtain a homogeneous mixture. The mixture can then be filled into size 0EL hard gelatin capsules to obtain capsules containing 5.0 mg of the compounds of the invention per capsule.

φ φ φ • · · • φ φ φ ♦

· φφ φφ' ·· φφ φ φ • φ φ φ • 9 9 ·

Φ · Φ Φ • 9 9 * • Φ ΦΦ

Capsules with other contents of the compounds of the invention, such as 25 or 100 mg/capsule, can be prepared 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 up to 200.0 mg

Polyethylene glycol and propylene glycol are mixed together, if necessary under heat. The mixture is stirred until homogeneous. The compounds of the invention are added and the mixture is stirred again until homogeneous. The mixture is then filled into a suitable gelatin mass to obtain soft gelatin capsules containing 200 mg of the composition to obtain a content of 10.0 mg of the compounds of the invention per capsule.

In a similar manner, it is possible to prepare capsules with different active ingredient contents, for example 5 and 25 mg/capsule of the compounds according to the invention.

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 up to 5.0 ml *·· · «0 0 0 · 0 ·

040« 0 00 «

0* 0 9 9 9 9 9 99 9

9 9 9 9 9 9

00 00 0« 99

Sodium benzoate is dissolved in a portion of purified water and sorbitol solution is added. Compounds of the invention, flavoring and glycerol are added and the mixture is stirred until homogeneous. The resulting mixture is made up to the desired volume with purified water.

Other formulations

Example H

Suppository mg/suppository

Compounds of the invention 10.0 mg

Solid fat Witepsol W32 up to 2000.0 mg

The Witepsol W32 material is melted at a temperature of approximately 36°C. To a portion thereof, the compounds of the invention are added and the mixture is stirred. The remaining melted Witepsol W32 is added and the mixture is stirred until homogeneous. The molds are filled with 2000 mg of the formulation to obtain a content of 10.0 mg of the compounds of the invention per suppository.

Example I

Transdermal device

Compounds of the invention 5.0 mg

Liquid silicone 90.9 mg

Colloidal silicon dioxide 5.0 mg

The liquid silicone and active ingredient are mixed and colloidal silicon dioxide is added. The material is then dosed into a polymer laminate consisting of a polyester release liner, a skin contact adhesive composed of silicone or acrylic polymers, a drug permeation control membrane made of polyolefin (made from, for example, polyethylene or polyvinyl acetate) or polyurethane, and an impermeable cover membrane made of multilayer polyester, where the laminate is then heat sealed.

Biological data

Inhibitory effect on voltage-gated sodium channels

Whole-cell voltage-clamp techniques were used to evaluate the efficacy of the compound of formula (I) on recombinant human brain type IIA Na ⁺ channel expressed in Chinese hamster ovary cells. Compound of formula (I) inhibits these channels in a voltage- and application-dependent manner with an estimated K value of 11 μΜ for steady-state inactivation, which is approximately 70 times greater than the efficacy in the resting state (IC50 = 785 μΜ).

The increased selectivity for channel state and greater use-dependent inhibition compared to lamotrigine (approximately 30x) provides a mechanism by which the compound of formula (I) selectively blocks transmission caused by high-frequency firing of action potentials (seizure activity). This supports the finding that the compound of formula (I) is a more potent anticonvulsant than lamotrigine and has a higher therapeutic index.

Antispasmodic efficacy

The compound of formula (I) has been shown to have antiepileptic effects in two rodent models of generalized epilepsy, the rat maximal electroshock test (MES), which is an animal model reflecting human generalized tonic-clonic seizures, and the mouse pentylenetetrazole infusion test, which mimics human absence seizures and petit mal myoclonic seizures.

For example, male Han Wistar rats (weight 150-200 g) were orally administered a suspension of the test compound in 0.25%

• ··· «9

9· • · 9 9 · * · · 9 *

9 9 ·

9 9 9 methylcellulose 2 hours before the test. Immediately before testing, visual observation for the presence of ataxia is made. A current of 200 mA is applied for 200 ms using ear electrodes and the presence or absence of hindlimb extension is recorded. The compound of formula (I) had an ED ₅ value of 1.7 mg/kg compared to 6.1 mg/kg for lamotrigine with a therapeutic index (ratio of ED ₅₀ for ataxia to ED ₅₀ for the MES test) of 23.7 compared to 3.3 for lamotrigine.

The compound of formula (I) had an ED50 of 3.8 mg/kg in the mouse pentylenetetrazole infusion test when dosed 1 hour after PTZ, compared to an _{ED50 of} 8.4 mg/kg for lamotrigine.

Analgesic effects

The compound of formula (I) has also been shown to have analgesic effects in pain models. Three hours after intraplantar administration of carrageenan (100 μΙ 2%) to rats, there is a reduction in inflamed paw loading and an increase in paw volume associated with acute hyperalgesia and inflammation. Compound of formula (I) administered orally 30 min before carrageenan provides a dose-dependent inhibition of carrageenan-induced loading with an ED50 of 7.5 mg/kg compared to 23.5 mg/kg for lamotrigine. Compound of formula (I) also had significant anti-inflammatory effects in this model at a dose of 30 mg/kg (50% reduction in paw volume).

Efficacy against MPTP-induced neurotoxicity

The MPTP mouse model is generally used as a model of Parkinson's disease.

Male C57BL/6 mice received four intraperitoneal injections of MPTP.HCI (15 mg free base per kg; Research Biochemicals) in saline at 2-hour intervals. Control mice received saline alone. The test compound was administered as four subcutaneous injections in olive oil at 2-hour intervals, 30 min before each MPTP injection.

Seven days after MPTP injection, mice were sacrificed and the corpus striatum was removed, which was immediately frozen and stored at -80°C until analysis. On the day of analysis, tissue samples were sonicated in 10 volumes (w/v) of 0.1 M perchloric acid containing 1.9 mM sodium bisulfite and 1.6 mg/ml DBA-HBr. After centrifugation (2800 g, 10 min at room temperature) and filtration (pore size 0.5 pm, Millipore), the supernatant was transferred to a vial and placed in an autosampler (M231XL, Gilson). Dopamine content was measured by HPLC. Compound of formula (I) provided 75% protection against dopamine depletion at a dose of 3 mg/kg (x 4) and 98% protection at a dose of 10 mg/kg (x 4).

Claims (6)

Triazine derivatives of formula (I) Cl h ₂ n Cl Whose N 1 N (1) and pharmaceutically acceptable derivatives thereof. A compound according to claim 1 for use in medicine. A pharmaceutical composition comprising a triazine derivative according to claim 1 together with a pharmaceutically acceptable carrier. Use of a triazine derivative according to claim 1 in the manufacture of a pharmaceutical composition for use in the treatment of epilepsy, bipolar disorder or manic depression, pain, functional bowel disorders, neurodegenerative diseases, neuroprotection, neurodegeneration, ear murmurs or dependence or tolerance on addiction inducing agents. 5. A method of treating a patient suffering from or susceptible to epilepsy, bipolar disorder or manic depression, pain, functional • 9 · 9 9 9 9 9 999 9 9 9 99 99 9 9 9 9 9 · • · 99 bowel disorders, neurodegenerative diseases, neuroprotection, neurodegeneration, tinnitus or dependence or tolerance to addiction-inducing substances. A process for the preparation of a triazine derivative of formula (I) according to claim 1, characterized in that the compound of formula (II) is reduced.