MXPA01001983A - Pyrazine compounds - Google Patents

Abstract

A compound of formula (I) wherein R1 is phenyl substituted by one or more halogen atoms;R2 is -NH2;R3 is -NH2 or hydrogen;R4 is -CXNRaRb, -CXNH-(CH2)y-NRaRb;wherein X is=O or=S;y is an integer zero, 1 or 2;Ra and Rb, which may be the same or different, are selected from hydrogen and C1-4 alkyl or together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms, which heterocycle can be further substituted with one or more C1-4 alkyl groups;and pharmaceutically acceptable derivatives thereof.

Description

PIRAZINE COMPOUNDS The present invention relates to a class of pyrazine compounds which are used in the treatment of diseases and disorders of the Central Nervous System (CNS) and their acceptable pharmaceutical derivatives, to pharmaceutical compositions containing these, to their uses in the treatment of These disorders and methods of preparation.

Numerous phenylpyrazine derivatives are known in the prior art. For example, Synthesis (1987), (10), 914-915, describes phenylpyrazine derivatives which include, among other things, 3- (4-chlorophenyl) -pyrazinamine. However, no pharmaceutical utility is described in this prior art document.

The present invention relates to pyrazine derivatives which are sodium cause blockers. The compounds are surprisingly potent anti-convulsants which have an increased potency with respect to lamotrigine and an increased selectivity in terms of side effects of the SNC Ref. No.: 127412 and the inhibition of the dihydrofolate reductase enzyme.

Therefore, the compounds are useful in the treatment of CNS diseases such as epilepsy.

Accordingly, the present invention provides a compound of the formula (I) (i) wherein R1 is phenyl substituted by one or more halogen atoms; R is -NH 2, R is -NH2 or Hydrogen; Rq e s -CXNRaRb, -CXNH - (CH2)? -NRaRi where X is = 0 or = S; and is a zero, 1 or 2 integer; Ra and Rb, which may be the same or different, are selected from hydrogen and C alquilo_alkyl, or together with the nitrogen atom to which they are attached, form a saturated heterocycle with 5- or 6- members containing one or two nitrogen heteroatoms, these heterocycles may further be substituted with one or more C? - alkyl groups; and pharmaceutically acceptable derivatives thereof By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of this ester of the compounds of the formula (I), or any other compound that upon administration to the recipient is capable of providing (directly or indirectly) a compound of the formula (I) or an active metabolite or the residue thereof (eg, pro-drug).

It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of the formula (I) and the physiologically acceptable salts thereof.

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

Suitable pro-drugs are well known in the art and include N-acyl derivatives, for example in any of the nitrogens in the compounds of the formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as R-0-CH2 ~ nitrogen or ROC (O) -nitrogen.

As used herein, the term "halogen atom" includes fluorine, chlorine, bromine or iodine.

The term C? _4 alkyl as used herein includes straight and branched chain alkyl groups containing 1 to 4 carbon atoms, and in particular includes methyl and isopropyl.

The term heterocycle saturated with 5- or 6- membered containing one or two nitrogen heteroatoms as used herein, include heterocycles with 5- or 6-members containing at least one nitrogen heteroatom, and preferably two nitrogen heteroatoms, this one The heterocycle can also be substituted with one or more C? _4 alkyl groups. A particularly suitable heterocycle is a pyrrolidine or piperazine ring.

R1 is appropriately selected from phenyl substituted by one or more halogen atoms. Particularly, R 1 represents phenyl substituted by more than 1 halogen atom, such as di- or tri-halogenated phenyl. Preferably, all the halogen atoms are identical. Preferably the halogen substituents in R1 are chloro. R1 is suitably selected from 2, 3, 5-trichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl. Preferably, R1 is 2,3,5-trichlorophenyl.

R is preferably -NH2 When R4 is the group -CXNRaRb or -CXNH- (CH2) and -NRaRb where Ra and Rb, together with the nitrogen atom to which they are attached, forms a 5- or 6-membered saturated heterocycle containing one or two heteroatoms of nitrogen, this 5- or 6-membered saturated heterocycle is conveniently a pyrrolidine or piperazine ring.

X is preferably = O.

The integer and is preferably 2.

When R4 is the group -CXNH- (CH2) and -NRaRb, Ra and R are preferably C? - alkyl. Preferred values for -CXNH- (CH2)? -NRaRb include for example -CONH- (CH2) 2-N (CH3) 2.

R4 is preferably the group -CXNRaRb. Preferably X is = 0 and, other preferred, are compounds where Ra and Rb are selected from hydrogen and C? _4 alkyl. Preferably R4 is -C0NH2, -C0NH (CH3), -CONH (CH2CH3), CONH [CH (CH3) 2] or -CON (CH3) 2. A particularly preferred R 4 is -CONH 2.

It is understood that the present invention encompasses all isomers of the compounds of the formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, mixtures thereof (e.g., racemic mixtures).

Preferred compounds of the present invention include - . 5-Ca rboxamido-2, 6-diamino-3- (2,3,5-trichlorophenyl) pyrazine 2,6-diamino-5-N-methylcarboxamido-3- (2, 3, 5-trichlorophenyl) pyrazine 2,6-diamino-5-N-ethylcarboxamido-3- (2, 3, 5-trichlorophenyl) pyrazine 2,6-diamino-5-N-isopropylcarboxamido-3- (2,3,5-trichlorophenyl) pyrazine 2, 6-diamino-5-N, N-dimet-1-ylcarboxamido-3- (2, 3, 5-trichlorophenyl) pyrazine 2, 6-diamino-5-thiocarboxamido-3- (2, 3, 5-trichlorophenyl) pyrazine and pharmaceutically acceptable derivatives thereof A particularly preferred compound according to the invention is: 5-carboxamido-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine and pharmaceutically acceptable derivatives thereof.

It is understood that the present invention covers all combinations of particular and preferred groups as described hereinbefore.

The compounds of the formula (I) are particularly useful as anticonvulsants. Therefore, they are useful in the treatment of epilepsy. These can be used to improve the condition of a host, typically a human who is suffering from epilepsy. These can be used to alleviate the symptoms of epilepsy in a host. The "epilepsy" tries to include the following partially simple attacks, complex partial attacks, secondary attacks, generalized attacks that include absence of attacks, monoclonal attacks, clonic attacks, tonic attacks, tonic-clonic attacks and atonic attacks.

The compounds of the formula (I) are additionally useful in the treatment of bipolar disorder, alternatively known as manic depression. Bipolar disorders of type I or II can be treated. The compounds of the formula I can thus be used to improve the condition of a human patient suffering from bipolar disorders, These can be used to alleviate 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 also useful as analgesics. Therefore, they are useful in the treatment or prevention of pain. These may be useful for improving the condition of a host, typically a human suffering from pain. These can be used to relieve pain in a host. Thus, the compounds of the formula (I) can be used as an analgesic that pre-discharges its content to treat acute pain such as musculoskeletal pain, postoperative pain and chronic inflammatory pain (for example, rheumatoid arthritis and osteoarthritis), neuropathic pain (for example, example, posterpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and 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 the formula (I) are also useful in the treatment of functional bowel disorders including non-ulcer dyspepsia, non-cardiac chest pain and in particular irritable bowel syndrome in the joint. Irritable bowel syndrome is a gastrointestinal disorder characterized by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compounds of formula (I) can thus be used to alleviate the pain associated with irritable bowel syndrome. The condition of a human patient suffering from irritable bowel syndrome can thus be improved.

The compounds of formula (I) can thus be useful in the treatment of neurodegenerative diseases, such as Alzheimer's disease, ALS, neuromotor disease, Parkinson's disease, macular degeneration and glaucoma. The compounds of the formula (I) can also be used in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary shunt, traumatic brain damage, spinal cord damage or the like.

The compounds of the formula (I) are also useful in the treatment of ear hum.

Furthermore, the compounds of the formula (I) are also useful for preventing or reducing dependence on, or preventing or reducing tolerance or inverse tolerance to, a dependency-inducing agent. Examples of dependence-inducing agents include opioids (e.g., morphine), CNS sedatives (e.g., ethanol), psychostimulants (e.g., cocaine), and nicotine.

According to another aspect of the invention, a compound of the formula (I) or a pharmaceutically acceptable derivative thereof is provided for use in human or veterinary medicine.

According to another aspect of the invention, there is provided the use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for use in the treatment of a disorder substantially as described hereinabove.

According to another aspect of the invention, a method is provided for the treatment of a human or animal subject suffering from, or susceptible to, a disorder substantially as described hereinabove, this method comprises administering to the subject a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof.

It is understood that reference to treatment as used herein includes the treatment of established symptoms and prophylactic treatment, unless otherwise stated explicitly.

The compound of the formula (I) and its salts can be administered orally in a dose from 0.1 to 10 mg / kg body weight per day and more particularly 0.3 to 3 mg / kg body weight per day, calculated as free base . The dose range for a human adult is generally from 8 to 1000 mg / day, such as from 35 to 800 mg / day, preferably from 20 to 200 mg / day, calculated as free base.

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 to be treated and its severity, and the route of administration.

The "compounds of the formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions." Thus, in another aspect of the invention, a pharmaceutical composition comprising a compound of the formula (I) or a derivative is provided. pharmaceutically acceptable thereof adapted for use in human or veterinary medicine These compositions may conveniently be presented for use in conventional manner in admixture with one or more substances acting as a physiologically acceptable carrier or excipients.

Since it is possible for the compounds of the formula (I) or a pharmaceutically acceptable derivative thereof to be administered as the unprocessed chemical, it is preferable to present this as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of the formula (I) or a pharmaceutically acceptable derivative thereof together with one or more acceptable substances which act as a carrier or diluents thereof and optionally other therapeutic ingredients. The substance (s) must be "acceptable" in the sense that they are compatible with other ingredients of the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (including subcutaneous, for example, injection or by intradermal, intracellular, intramuscular, intramuscular, deposition and intravenous deposition) rectal and topical tablets (including dermal, buccal and under the tongue) although the most appropriate route may depend, for example, on the condition and disorder of the recipient. The formulations can conveniently be presented in unit dose form and can be prepared by any methods well known in the art of pharmacy. All methods include the step of formulating in association with the compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof ("active ingredient") with the substance which acts as the carrier which constitutes one or more complementary ingredients. In general, the formulations are prepared by formulating uniformly and intimately in association of the active ingredient with liquid substances that act as a vehicle or finely divided solid substances that act as a carrier or both and, if necessary, form the product in the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, circular sheets of paste enclosing medicament or tablets (for example, chewable tablets in particular for pediatric administration) each containing a predetermined amount of the ingredient active as a powder or granules; as a solution or a 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 may also be presented as a medicinal material similar to a pill, a pasty mass mixed with a sweet substance or paste.

A tablet can be made by compression or molding, optionally with one or more complementary ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in an easily flowing form such as a powder or granules, optionally mixed with a mixing agent, lubricant, inert diluent, lubricating the surface, dispersing or active agent of the surface. The molded tablets can also be made by molding in a suitable machine a mixture of the humidified powder compound with an inert liquid diluent. The tablets may optionally be coated or labeled and may be formulated so as to provide a slow and controlled release of the active ingredient therein.

Formulations for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain buffering antioxidants, agents that inhibit bacterial growth and solutes which leave the formulation isotonic in the blood of the intended recipient; and sterile aqueous or non-aqueous suspensions which may include suspension forming agents and thickening agents. The formulations can be prepared in unit doses or multi-dose containers, eg sealed vials and vials and can be stored in a dry and frozen condition (lyophilized) which require only the addition of a sterile liquid substance that acts as a vehicle, for example, water for injection immediately before use. Solutions and suspensions of extemporaneous injection can be prepared with sterile powders, granules and tablets of the type previously described.

Formulations for rectal administration can be presented as a suppository with substances that act as a carrier such as cocoa fat, solid fat or polyethylene glycol.

Formulations for topical administration in the mouth, for example buccally or under the tongue, include tablets comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and lozenges comprising the active ingredient in such a base. like gelatin and glycerin or sucrose and acacia.

The compounds of the invention can also be formulated as non-active preparations that are stored at specific sites. These long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in a suitable oil) or ion exchange resins, or as frugally soluble derivatives, for example, as a frugally soluble salt.

In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having consideration of the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The compounds of formula (I) can be used with other therapeutic agents, for example other anticonvulsants. When the compounds of the formula (I) or pharmaceutically acceptable derivatives thereof are used in combination with other therapeutic agents, the compounds may be administered sequentially or simultaneously by any route. The invention thus provides, in another aspect, a combination comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof with another therapeutic agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus the pharmaceutical formulations comprise a combination as defined above together with a substance which acts as a carrier or excipient comprises another aspect of the invention. The individual compounds of these combinations can be administered sequentially or simultaneously in pharmaceutical formulations separately in combination.

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 when the compound is used alone. The appropriate doses will be readily appreciated by persons skilled in the art.

Formulations with preferred unit doses are those containing an effective daily dose, as mentioned above, or an appropriate fraction thereof, of the active ingredient. Conveniently these 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 20 to 200 mg, calculated as free base.

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

The compounds of the formula (I) and the pharmaceutically acceptable derivatives thereof can be prepared by any method known in the art by the preparation of compounds of analogous structure.

Suitable methods for the preparation of the compounds of the formula (I) and pharmaceutically acceptable derivatives thereof are described below and these form another aspect of the invention. In the formula that follows R1 to R4 are as defined in formula (I) above unless otherwise stated.

According to the first process (A), the compounds of the formula (I) can be prepared by interconversion, using other compounds of the formula (I) as precursors.

Thus the compounds of the formula (I) wherein X is S can be prepared from the corresponding compound of the formula (I) wherein X is 0, by treatment with an agent for the synthesis of the thio group, preferably the reagent La essons. Conveniently, the reaction is carried out in the presence of a solvent or solvents, such as a halogenated hydrocarbon (for example, dichloromethane) and / or toluene and an elevated temperature, for example 100 ° C.

According to another process (B), the compounds of the formula (I), wherein R 4 is -CONH 2, can be prepared from a compound of the formula (II) by hydrolysis under suitable reaction conditions and according to conventional procedures, for example using sulfuric acid.

According to another process (C), the compounds of formula (I) wherein X is O can be prepared under suitable reaction conditions by reaction of a compound of the formula (III) (III) or a protected derivative thereof, wherein Hal (D) represents a halogen atom, suitably bromo, with a palladium catalyst, preferably palladium (II) acetate, a ferrocene, preferably bis (diphenylphosphino) ferrocene and an amine , in the presence of carbon monoxide. The reaction is carried out in a solvent, such as dimethylformamide and at elevated temperature, for example between 65 ° C and 125 ° C.

The compounds of the formula (II) can be prepared by reacting the compounds of the formula (III) or a protected derivative thereof, wherein Hal (D) represents a halogen atom, suitably bromo, with an agent for the synthesis of the cyanide group preferably with a mixture of sodium cyanide and copper cyanide (I). The reaction is carried out in a solvent, such as dimethylformamide and at an elevated temperature, for example 130 ° C.

The compounds of the formula (III) can be prepared by reacting the compounds of the formula (IV) (IV) or a derivative of this protected with a suitable halogenating agent, for example N-bromosuccinamide. The reaction is conveniently carried out in a suitable solvent, such as dimethyl sulfoxide and at a lower room temperature, for example 15 ° C.

The compounds of the formula (IV), wherein R 2 represents NH 2 can be prepared by the formation of a cyclic compound and oxidation of a compound of the formula (V) (V) or a salt thereof according to conventional procedures, for example by neutralizing a salt of a compound of the formula (V), for example, with lithium hydroxide in a suitable solvent such as alcohol, for example, methanol , occurs under spontaneous oxidation conditions to give a compound of formula (IV).

The compounds of the formula (V) can be prepared by reacting the compounds of the formula (VI) R 1 C (O) H with compounds of the formula (VII) H-1J - CH- NH or a salt thereof, in the presence of a source of cyanide, for example potassium cyanide. The compounds of the formula (VI), wherein R 1 is trihalo-substituted phenyl, for example 2, 3, 5-trichlorobenzaldehyde, are known and can be prepared according to the methods described in the patent O95 / 07877. The compounds wherein R1 represent alternating values are also known or can be prepared according to known methods for the preparation of known compounds.

The compounds of the formula (VII), for example aminoacetamidine, can be prepared according to the known procedures, for example, those described in Chem. Berichte, 89, 1185 (1956).

The compounds of the formula (IV) can also be prepared from compounds of the formula (VIII) or a protected derivative thereof where Hal (B) represents a halogen atom, suitably chloro. For example, Hal (B) can be converted to -NRbRc by reaction with an appropriate amine in a solvent, such as ethanol and at elevated temperature, for example 180 ° C.

A compound of formula (VIII) can be suitably prepared from a compound of formula (IX) (IX) or a derivative protected therefrom by reaction with a compound of formula (X) R 1 B (OH) 2 in the presence of a palladium catalyst preferably tetracis (triphenylphosphine) palladium (0). Examples of the compounds of formula (X) R 1 B (OH) 2 include 2, 3, 5-trichlorobenzeneboronic acid, 2,3-dichlorobenzeneboronic acid and 2,5-dichlorobenzeneboronic acid. Suitably, the Hal (A) in the above formula (IX) is more reactive than Hal (B), and appropriately Hal (A) is selected from bromine and iodine, while Hal (B) is cleverly chlorine. The compounds of the formula (X) are commercially available or can suitably be prepared from commercially available benzene analogs, for example, 1-bromo-2,3-dichlorobenzene or 2-bromo-, 6-dichloroaniline as described herein. hereinafter in more detail in the accompanying examples.

A compound of formula (IX) can suitably be prepared by another halogenation of a compound of formula (XI) (XI) or a derivative protected from this, for example, by reaction with a halogenating agent, such as N-bromosuccinimide, with stirring below room temperature, for example between -5 ° C and 0 ° C for several hours.

A compound of formula (XI) can be prepared from a dihalogenated compound of formula (XII) (XII) by reaction with R2H, where Hal (B) and Hal (C) can be the same or different halogen substituents. Appropriately both Hal (B) and Hal (C) are chlorine. The compounds of formula (XII) are commercially available. The reaction was carried out at elevated temperature, for example 150 ° C.

Certain intermediates described above are novel compounds, and it is understood that all novel intermediates herein form another aspect of the present invention.

Conveniently, the compounds of the invention are isolated following the work in free base form. The pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared using conventional means.

The solvates (for example, hydrates) of a compound of the invention can be formed during the working procedure of one of the steps of the aforementioned process.

The following examples should not be construed as constituting a limitation these are provided to illustrate the invention.

Intermediary 1 2, 3, 5-trichlorobromobenzene Sodium nitrate (3.88 g, 0.056 mol) was added in portions to concentrated sulfuric acid (28.16 ml) by stirring below 10 ° C. A solution of 2-bromo-4,6-dichloroaniline (12g, 0.05 moles, Lancaster) in glacial acetic acid (126 ml) was added maintaining the temperature below 10 ° C. The mixture was stirred below 10 ° C for 1 hour and then slowly added to a stirred solution of copper chloride (10 μg, 0.10 mol) in concentrated hydrochloric acid (101.05 ml) at room temperature. The mixture was then stirred at room temperature for 17 hrs. The product was filtered, washed with water (3 X 50 ml), dissolved in chloroform (150 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give the desired product. Yield lOg (77%), p.f. 55-57 ° C.

Intermediary 2 2, 3, 5-trichlorobenzanboronic Acid A solution of 2,3,5-t riclorobromobenzene (8.60 g, 0.033 mol) in dry ether was added dropwise (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mol) were added to a suspension of magnesium which changed (2.80 g, 0.12 mol) in dry ether (21.50 ml) at room temperature.

The mixture was refluxed for 0.50 hr and cooled to room temperature. The mixture was then added dropwise under nitrogen to a solution of trimethyl borate (5.16 ml, 5.16 g, 0.05 mol) in dry ether (8.60 ml) keeping the temperature below -60 ° C. This was ed to room temperature overnight, then cooled in a bath with ice and treated with 2M hydrochloric acid (10 ml). The ether layer was separated, washed with water (2X20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was triturated with petroleum ether at 40-60 ° C, filtered and dried in vacuo. Yield 4.57g (61%), m.p. 257-260 ° C.

Intermediary 3 2-chloro-6-amino-pyrazine A suspension of 2,6-dichloropyrazine (100g, 0.67 moles, Lancaster) in 0.880 ammonia (500ml) was stirred and heated to 150 ° C in a glass-lined autoclave at 20atm for 16 hrs. The cold mixture was filtered, washed well with water (200 ml) and dried. The product was crystallized again from the chloroform. 4 1. 9 8 g (4 8%), p. f. 150 - 1 52 ° C.

Intermediate 4 2-chloro-3-bromo-6-aminopyrazine and 2-amino-3-bromo-6-chloropyrazine A solution of 2-chloro-6-aminopyrazine (20 g, 0.15 mol) in chloroform (1940 ml) was stirred at -5 ° C to 0 ° C. N-bromosuccinimide (27.58 g, 0.15 mol) was added in portions maintaining the temperature between -5 and 0 ° C. The mixture was warmed to room temperature and stirred for 3.50 hrs. The mixture was then washed with saturated aqueous sodium bicarbonate (1X300 ml), then with water (1X500 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by "separation chromatography" using chloroform as eluent. The yield of 2-chloro-3-bromo-6-aminopyrazine 13.89g (43%), m.p. 146-147 ° C. Yield of 2-amino-3-bromo-6-chloropyrazine 4.90g (15%), p. f .124 -125 ° C.

Intermediate 5 2-amino-6-chloro-3- (2, 3, 5-trichlorophenyl) pyrazine A solution of 2,3,5-trichlorobenzanboronic acid (1.62g, 7.18X10-3 moles) in absolute ethanol (2.05 ml) was added slowly to a mixture of 2-amino-3-bromo-6-chloropyrazine (lg, 5.1 X10"3 moles and tetracis (triphenylphosphine) palladium (0) (0.334g, 2.89X10" 4 moles) in benzene (10.20 ml) / 2M aqueous sodium carbonate (5.50 ml) The mixture was refluxed for 17 hrs. The cold reaction mixture was evaporated in vacuo and then extracted with chloroform (50 ml) The chloroform layer was washed with water (2X30 ml), dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was triturated with petroleum ether at 40-60 ° C, filtered and dried in vacuo Yield 0.205g (14%), mp 211-214 ° C.

Intermediate 6 hydrobromide 2-. { [cyano- (2, 3, 5-trichlorophenyl) -methyl] -amino} -acetamidine Aminoacetamidine dibromhydrate (162.1 g, 0.774 mol) was added in portions to a solution of 2,3,5-trichlorobenzaldehyde (200.Og, 0.851 mol) in Intermediate 8 5 -bromo-2,6-diamino-3- (2 , 3, 5-trichlorophenyl) pyrazine N-bromosuccinimide (0.194g, 1.09X10"3 moles) was added in 20 minutes to a mixture of 2,6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine (0.3g, 1.04X10" 3 moles) in dimethylsulfoxide (10 ml) and water (0.25 ml) below 15 ° C. The resulting reaction mixture was stirred at 15 ° C for 1 hour, emptied onto ice water (150 ml) and extracted with ethyl acetate (2X75 ml). The extract was then washed with 2 M sodium carbonate solution (50 ml) and water (100 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by "separation chromatography" using 5-13% ethyl acetate in cyclohexane as the eluent. Yield 0.183g (48%), p. f. 222-224 ° C.

Intermediate 9 5-cyano-2, 6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine A mixture of 97% sodium cyanide (0.064g, 1.306X10"3 moles) and 90% copper cyanide (1) (0.135g, 1.306X10" 3 moles)) was stirred and heated to 130 ° C. Dry dimethylformamide (5 ml). To the resulting solution was added 5-bromo-2,6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine (0.35g, 0.95X10"3 moles) in small portions, and the solution was maintained at 140- 150 ° C for 16 hrs The reaction mixture was cooled and evaporated in vacuo, the residue was extracted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over Anhydrous magnesium sulfate was filtered and the filtrate was evaporated in vacuo The residue was purified by "separation chromatography" using 5-17% ethyl acetate in cyclohexane as eluent Yield 0.152g (51%), mp 277-279 ° C.

Example 1 5-carboxamido-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine -Cyano-2,6-diamino-3- (2, 3, 5-t-riclorophenyl) pyrazine (O.lg, 3.18X10"4 mol) was dissolved in 75% sulfuric acid (8 ml) and heated to 90 ° C for 20 min The reaction was then cooled to 0 ° C and basified (in the form of drops) with 2M sodium hydroxide solution.

The yellow suspension was extracted with ethyl acetate (100 ml), washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by "separation chromatography" using 9-27% ethyl acetate in cyclohexane as eluent. Yield 0.079g (75%), m.p. 245-247 ° C. Ana l. Cale. For CnH8N5Cl30: C, 39.73; H, 2.42; N, 21.06. Found: C, 39.88; H, 2.13; N, 20.53.

Example 2 2, '6-diamino-5-N-methylcarboxamido-3- (2,3,5-trichlorophenyl) pyrazine - . 5-Bromo-2, 6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine (0.5g, 1.36X10-3 moles), palladium (II) acetate (1.0xl0 ~ 2g, 4.45X10"5 moles, 3 mol%), and bis (diphenylphosphino) ferrocene (2.3Xl0" 2g, 4.15X10"5 mol, 3 mol) were all added to dimethylformamide (5 ml). Gas of carbon monoxide and methylamine gas were continuously bubbled through the solution while heating at 70 ° C, for 6 hours. The mixture was cooled, poured into water (50 ml), extracted with ethyl acetate (3X30 ml). The organics were combined and washed with 10% aqueous citric acid solution (2X20 ml), brine (20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Purification was by "separation chromatography" using 50% cyclohexane / ethyl acetate as eluent. Yield 0.078g (16.6%), Ana l. Cale. for C2H10N5Cl3O: C, 41.56; H, 2.89; N, 20.20. Found: C, 41.42; H, 2.64; N, 19.87 R.M.N. (CDCl 3) dppm: 2.91 + 2.92 (3H, 2xs), 7.34 (1H, d), 7.49 (1H, broad s), 7.57 (lH, d).

Example 3 2, -diamino-5-N-ethylcarboxamido-3- (2, 3, 5-trichlorophenyl) pyrazine -Bromo-2, 6-diamino-3- (2,3,5-trichlorofel) pyrazine (0.5g, 1.36X10"3 moles), palladium (II) acetate (3.0X10 ~ 2g, 1.36X10-4 moles , 10 mol%), bis (diphenylphosphino) ferrocene (7.5X10"2g, 1.36X10" 4 mol, 10 mol%) and 2M ethylamine in tetrahydrofuran (9ml, 1.8X10-2, 13 eq) were all added to dimethylformamide (50%). ml) Carbon monoxide gas was bubbled through the mixture for 10 minutes then heated at 100 ° C for 4 hours, the mixture was cooled, the volatiles were removed in vacuo, and the brown oil was divided between the water and diethyl ether The aqueous layer was extracted again with diethyl ether (x2) The organics were changed, filtered through a harbolite pad J2, washed with 10% aqueous citric acid solution, brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo.The purification was by "separation chromatography" using cyclohexane / ethyl acetate 1: 1 as elution. yente. Performance 0.048g, (9.8%), R.M.N. (CDCl 3) dppm: 1.22 (3H, t), 3.41 (2H, m), 4.60 (2H, broad s), 7.35 (lH, d), 7.42 (1H, broad s), 7.57 (1H, d). LC / MS The M + = 360/362.

Example 4 2, 6-diamino-5-N-isopropylcarboxamido-3- (2, 3, 5-trichlorophenyl) pyrazine -Bromo-2, 6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine (0.5g, 1.36 XlO "3 mol), palladium (II) acetate (3.0xl0" 2g, 1.36 XlO "4 moles) , 10 mol%), ferrous bis (diphenylphosphino) (7.5X10"2g, 1.36X10" 4 mol, 10 mol%), and isopropylamine (5 ml, 5.9X10"2, 43eq) were all added to dimethylformamide (50 ml) inside an autoclave. Carbon monoxide gas was bubbled through the mixture for 10 minutes, the autoclave was then sealed and heated at 120 ° C for 4 hours. The mixture was cooled, more palladium (II) acetate (3.0X10"2g, 1.36X10" 4 moles, 10 mol%), ferrous bis (diphenylphosphino) (7.5X10"2g, 1.36X10" moles, 10 mol%) was added. ), and isopropylamine (4ml, 4.7X10"2, 34.5eq) and more carbon monoxide gas was bubbled through the mixture for another 10 minutes.The autoclave was then sealed and heated to 120 ° C., for another 4 hours. The mixture was then cooled, the volatiles were removed in vacuo, and the brown oil was partitioned between water and diethyl ether. The aqueous layer was extracted again with diethyl ether (x2). The organics were combined, filtered through a harbolite pad J2, washed with 10% aqueous citric acid solution, brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Purification was by "separation chromatography" using cyclohexane / ethyl acetate 1: 1 as eluent. Yield 0.098g (19.3%), R.M.N. (CDCl 3) dppm: 1.23 (6H, d), 4.16 (1H, m), 4.59 (2H, broad s), 7.24 (1H, broad s), 7.34 (1H, d), 7.57 (1H, d). LC / MS The M + = 374/376.

Example 5 2, 6-diamino-5-N, N-dimethyl-ylcarboxamido-3- (2,3,5-trichlorophenyl) pyrazine.

-Bromo-2, 6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine (0.5g, 1.36X10"3 moles), palladium (II) acetate (2.3X10"2g1 1.02X10 - moles, 7.6% mol) and bis (diphenylphosphino) ferrous (4.6X10 ~ 2g, 8.30X1 O "5 moles, 6.1% mol) were all added to dimethylformamide (50 ml). Carbon monoxide gas was bubbled through this mixture for 10 minutes and then bubbled continuously methylamine gas through this solution while heating at 70 ° C, for 4.5 hours The mixture was cooled, more palladium (II) acetate was added (2.3X10"2g, 1.02X10" 4 moles, 7.6% moles), and ferrous bis (diphenylphosphino) (4.6X10"2g, 8.30X10" 5 moles, 6.1% mol) was added and more carbon monoxide was bubbled through of the mixture for 10 more minutes. The methylamine gas was bubbled continuously through the solution while being heated at 70 ° C, for an additional 3 hours. The mixture was cooled, more palladium (II) acetate was added (2.3X10"2g, 1.02X10" 4 moles, 7.6% moles), and ferrous bis (diphenylphosphino) (4.6XlO "2g, 8.30X10" 5 moles) was added. , 6.1% moles) and more carbon monoxide was bubbled through the mixture for 10 more minutes. Methylamine gas was continuously bubbled through the solution while heating at 70 ° C, for another 2.5 hours. The mixture was then cooled, the volatiles were removed in vacuo, and the brown oil was partitioned between water and ethyl acetate. The aqueous layer was extracted again with ethyl acetate (x2). The organics were combined, washed with 10% aqueous aq. Citric acid solution. brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The purification was by "separation chromatography" using cyclohexane / ethyl acetate 2: 1-1: 1 as the eluent. Yield 0.061g (12.5%), R. M. N. (CDC13) dppm: 3.07 +3.24 (2X3H, 2xs), 4.45 (2H, broad s), 6.06 (2H, broad s), 7.30 (1H, d), 7.54 (1H, d). LC / MS The M + = 360/362. Example 6 2, 6-diamino-5-thiocarboxyamido-3- (2,3,5-trichlophenyl) pyrazine -carboxamido-2,6-diamino-3- (2, 3, 5-trichlorophenyl) pyrazine, (0.05 g, 1.50X10"4 mol) was dissolved in toluene (20 ml) and dichloromethane (5 ml). to the Lawessons reagent (O.Oßlg, 1.50X10"4 moles) and the reaction was stirred at 100 ° C under nitrogen for 16 hours. Then another three equivalents of the Lawessons reagent (0.183g) were added and the reaction was stirred for another six hours. The reaction mixture was cooled and evaporated in vacuo. The residue was purified by "separation chromatography" using 5-22% ethyl acetate in cyclohexane as eluent. Yield 0.009g (17%).

Spec. Mass: (electrorrociado) 350 (MH +) Retention Time 3.23 minutes Mícromasa Platform Series 2 Grad. 5 min (2mmABZ) Instrument: Red Flow Rate: 0.8ml / min Eluents: A-0.1% V / V Acid Formic + lOmmol of Ammonium Acetate B-95% of MeCN + 0.05% V / V of Formic Acid Column: 5cm X 2. lmm DI ABZ + PLUS Vol. Inyecf 5 ul Temp. : TR Time% A% B 0.00 100 0 3.50 0.0 100 5.00 0.0 100 5.50 100 Pharmaceutical Examples Sterile Formulations Example A mg / ml Compound of the Invention 0.1 mg Sodium Chloride USP 9.0 mg Water for USP Injection for 1 ml The compounds were dissolved in a portion of water for injection and the solution was prepared to a final volume to provide 0.1 mg / ml of the compound of the invention. Where a salt of the compound was used the amount of the compound was increased to provide 0.1 mg / ml of free base. The solution can be packaged for injection, for example when filling and sealing in ampoules, vials or syringes. These can be filled aseptically and / or sterilized at the end, for example, in an autoclave at 121 ° C.

Other 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 Injection cant / p 1.0 ml The compounds are dissolved in a portion of water for injections. The final volume is prepared and mixed homogeneously. The formulation is filtered through a sterile filter and filled with glass jars with it. It is lyophilized and the bottles are sealed. It is reconstituted with an appropriate solvent before use.

Formulations for oral administration Tablets can be prepared by standard methods such as direct compression or wet granulation. The tablets may be coated with a coating material to form the coating, such as an Opadry, using standard techniques. Alternatively, the tablets may be coated with sugar.

Example C Tablets by Direct Comprehension mg / tablet Compounds of the Invention 5.0 mg Magnesium stearate 4.0 mg Microcrystalline cellulose (Avicel PH102) Qty. for 400 mg The compound of the invention was passed through a 30 mesh screen and mixed with the Avicel and the Magnesium Stearate. The resulting mixture was compressed into tablets using a press fitted for a suitable tablet with 11.0 mm diameter punches in order to provide 5 mg of the Compound of Invention per tablet. Tablets of other capacities, which contain for example 25 or 100 mg / tablet of the compound of. the invention can be prepared in a similar manner.

Example D Tablet by Wet Granulation mg / tablet Compound of the Invention 5.0 mg Pregelatinous Starch 28.0 mg Sodium Glycolate Starch 16.0 mg Magnesium Stearate 4.0 mg Lactose cant. suf. 400.0 mg The compound of the invention, Lactose, Pregelatinous Starch and Sodium Glicolate Starch were mixed dry and then granulated using an adequate volume of purified water. The resulting granules were dried and then mixed with Magnesium Stearate. The dried granules were compressed using a press fitted for a suitable tablet with 11.0 mm diameter punches in order to provide 5 mg of the Compound of Invention per tablet.

Tablets of other capacities such as 25 and 100 mg / tablet can be prepared.

Example E Hard Gelatin Capsule mg / capsule Compound of the Invention 5.0 mg Microcrystalline Cellulose [Avicel PH102) cant. sufic 700.0 mg The compound of the invention was passed through a 30 mesh screen and then mixed with Microcrystalline Cellulose to provide a homogenous mixture. The mixture can then be filled into hard gelatin capsules of OEL size to provide capsules containing 5.0 mg / capsule of the Compound of the Invention.

Alternate capacities such as 25 and 100 mg / capsule of the Compound of the Invention can be similarly prepared.

Example F Soft Gelatin Capsule Mg / capsule Compound of the Invention 10.0 mg Polyethylene glycol 90.0 mg Propylene glycol Cant. Suf. 200.0 mg Polyethylene glycol and propylene glycol were mixed together using heat if necessary. It was stirred until homogenized. The Compound of the Invention was added and mixed until homogeneous. It was filled into a suitable gelatin dough to give soft gelatine capsules containing 200 mg of the formulation, to provide 10.0 mg / capsule of the Compound of the Invention.

Alternate capacities can be prepared similarly, for example, such as 5 and 25 mg / capsule of the Compound of the Invention.

Example G Syrup Compound 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 qty. suf 5.0 ml The Sodium Benzoate was dissolved in a portion of the purified water and the Sorbitol Solution was added. The Compound of the invention, flavor and glycerol were added and mixed until homogeneous. The resulting mixture was prepared with the volume of purified water.

Other Formulations Example H Suppositories mg / suppository Compound of the Invention 10 .0 mg Hard Fat itepsol W32 c.s 2000.0 mg The Witepsol W32 was melted at approximately 36 ° C. To a portion thereof, the Compound of the Invention was added and mixed. The remaining Witepsol W32 was added and mixed until homogenized. It was filled in molds with 2000 mg of the formulation to provide 10.0 mg / suppository of the Compound of the Invention.

Example I Transdermal Compound of the Invention 5.0 mg Silicone Fluid 90.9 mg Colloidal Silicone Dioxide 5.0 mg The silicone fluid and the active are mixed together and the colloidal silicon dioxide is added. The material is then metered into a polymer laminate subsequently sealed with heat comprising of the following: a polyester release liner, the adhesive that is in contact with the skin composed of silicone or acrylic polymers, a control membrane which is a polyolefin (for example polyethylene or polyvinyl acetate) or polyurethane, and a waterproof backing membrane of a multilamellar polyester.

Biological Data Anticonvulsive Activity A compound of the formula (I) has been shown to have anti-epileptic activity in a generalized epilepsy model in a rodent, the maximum electro-shock test (MES) in the rat is an animal model reflecting the generalized tonic-clonic seizures in humans. For example, male Wis Wistar rats (150-200 grams) were dosed with a suspension of the test compound in 0.25% methylcellulose 2 hours before 1-test. A visual observation was made just before the test for the presence of ataxia. A current of 200mA, lasting 300 millisec, was applied using atrial electrodes, and the presence or absence of the posterior part of the extremity was noted. A compound of the formula (I) exhibited an ED50 of 1.4 mg / kg compared to 6.1 mg / kg of lamotrigine with therapeutic index (ratio of ataxia ED50 and MES ED50) of 21.6 compared to 3.3 for lamotrigine.

No apparent adverse or toxic effect was observed during the previous in vi ve test due to the administration of the compounds of the invention.

It is noted that in relation to this date, the best method known by 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, property is claimed as contained in the following:

Claims (6)

1. A compound of formula (I (0 characterized in that, R1 is phenyl substituted by one or more halogen atoms; R is -NH 2 r R is -NH2 or hydrogen; R4 is -CXNRaRb, -CXNH- (CH2) and -NRaRb; where X is O or = S; is a zero integer, 1 Ra and R, which may be the same or different, are selected from hydrogen and C? -4 alkyl, or together with the nitrogen atom to which they are attached, form a saturated heterocycle with 5- or 6-members containing one or two nitrogen heteroatoms, these heterocycles can further be substituted with one or more C? -4 -4 alkyl groups; and pharmaceutically acceptable derivatives thereof.

2. A compound according to claim 1, characterized in that R is 2, 3, 5-trichlorophenyl

3. A compound according to claim 1 or claim 2, characterized in that R3 is -NH2.

4. A compound according to any of claims 1 to 3, characterized in that R 4 is -CONH 2.

5. The compound according to any of claims 1 to 4, characterized in that it is 2,6-diamino-5-carboxamido-3- (2,3,3-trichlorophenyl) pyrazine.

6. A compound according to any of claims 1 to 5, for use in human and veterinary medicine. The use of a compound according to any of claims 1 to 5, in the manufacture of a medicament for use in the treatment of epilepsy, bipolar disorder or manic depression, unipolar depression, pain, disorders in the function of the intestine, disorders neurogenerative, neuroprotection, neurodegeneration, ear tinnitus or inverse tolerance to, a dependency-inducing agent. A method for treating a human or animal subject suffering from, or susceptible to, epilepsy, bipolar disorder or manic depression, unipolar depression, pain, impaired bowel function, neurogenerative disorders, neuroprotection, neurodegeneration, tinnitus, hearing, or prevention or reduction of dependence to, or preventing or reducing tolerance or inverse tolerance to, a dependency-inducing agent, this method is characterized in that it comprises administering to the subject a therapeutically effective amount of a compound according to any claims 1 to 5. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 5, in admixture with one or more substances that act as a physiologically acceptable carrier or excipients. A process for preparing a compound of formula (I) and pharmaceutically acceptable derivatives thereof according to any one of claims 1 to 5, characterized in that it comprises: (A) the interconversion of a compound of formula (I) to another compound of formula (I) ); or (B) reacting a compound of formula (II) where R4 is -CONH2 with an agent for carrying out the hydrolysis; or (C) reacting a compound of formula (III) RJ (III) or a protected derivative thereof, wherein R 4 is C 1-4 alkyl, with palladium II acetate, bis (diphenylphosphino) ferrocene and an amine; or (D) reacting a compound of formula (III) (II!) or a protected derivative thereof, with sodium cyanide and copper cyanide (I); and optionally converting the compounds of formula (I) prepared by any of processes (A) to (D) into pharmaceutically acceptable derivatives thereof. PIRAZINE COMPOUNDS SUMMARY OF THE INVENTION A compound of formula (I) (l) where R? is phenyl substituted by one or more halogen atoms; R * is -NH2; R is -NH2 or hydrogen; Rq is -CXNRaRD, -CXNH- (CHZ) and -NRaRD; of X is = 0 or = S; and is a zero integer, 1 2; Ra and R, which may be the same or different, are selected from hydrogen and C? -4 alkyl, or together with the nitrogen atom to which they are fixed, form a saturated heterocycle with 5- or 6-members containing one or two nitrogen heteroatoms, these heterocycles may also be substituted with one or more C? - alkyl groups; and pharmaceutically acceptable derivatives thereof